Personalized Medicine in Oncology December 2014 by The Oncology Nurse

Unifying Oncologists & Pathologists

A Peer-Reviewed Journal December 2014 • Volume 3 • Number 8

PM O

BIOMARKERS • TARGETED THERAPIES • DIAGNOSTICS

Personalized Medicine in Oncology TM

INTERVIEW WITH THE INNOVATORS Providing Therapeutic Guidance for Breast Cancer Patients in the Molecular Era With the Breast Cancer IndexSM Assay: An Interview With Stephen C. Malamud, MD, and Susan K. Boolbol, MD, of Mount Sinai Beth Israel Hospital.........................................Page 429

PSYCHOSOCIAL ONCOLOGY Putting the “Person” in Personalized Cancer Medicine: A Systematic Review of Psychological Aspects of Targeted Therapy........................ Page 438

WORLD CUTANEOUS MALIGNANCIES CONGRESS Highlights From the Third Annual WCMC......Page 450

PMO LIVE Highlights From the Third Annual PMO Live: A Global Biomarkers Consortium Initiative.....Page 462

THE LAST WORD Personalized Medicine’s Progress................ Page 476

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

The official publication of

GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS MALIGNANCIES CONGRESS

WORLD CUTANEOUS

In partnership with

™

ISTODAX® (romidepsin) for injection is indicated for treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. This indication is based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated.

ISTODAX FOR THE 2ND-LINE TREATMENT OF PTCL

Important Safety Information WARNINGS AND PRECAUTIONS • Myelosuppression: ISTODAX® (romidepsin) can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia; monitor blood counts regularly during treatment with ISTODAX; interrupt and/or modify the dose as necessary • Infections: Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses, have been reported during and within 30 days after treatment with ISTODAX in clinical trials. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow. Reactivation of Epstein Barr viral infection led to liver failure. Consider monitoring for reactivation and antiviral prophylaxis in patients with evidence of prior hepatitis B infection. Ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation in one case • Electrocardiographic (ECG) changes: ECG changes have been observed with ISTODAX. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within the normal range before administration of ISTODAX • Tumor lysis syndrome: TLS (Tumor lysis syndrome) has been reported during treatment with ISTODAX. Patients with advanced stage disease and/or high tumor burden are at greater risk and should be closely monitored and managed as appropriate • Embryo-fetal toxicity: ISTODAX may cause fetal harm when administered to a pregnant woman. Advise women of potential hazard to the fetus and to avoid pregnancy while receiving ISTODAX

ADVERSE REACTIONS Peripheral T-Cell Lymphoma The most common Grade 3/4 adverse reactions (>5%) regardless of causality in Study 3 (N=131) were thrombocytopenia (24%), neutropenia (20%), anemia (11%), asthenia/fatigue (8%), and leukopenia (6%), and in Study 4 (N=47) were neutropenia (47%), leukopenia (45%), thrombocytopenia (36%), anemia (28%), asthenia/ fatigue (19%), pyrexia (17%), vomiting (9%), and nausea (6%).

www.istodax.com

ISTODAX demonstrated efficacy in PTCL after at least one prior therapy1 Efficacy and safety evaluated in the largest prospective single-arm PTCL study (Study 3, N=131) in a pretreated, histologically diverse PTCL population. All patients received prior systemic therapy for PTCL. Patients could be treated until disease progression at their discretion and that of the investigator. 60% (12/20) of complete responses were known to exceed

26% ORR

11.6 Months

(34/130)

(CR + CRu + PR) [95% CI: 18.8, 34.6a]

15% CR/CRu

(20/130)

Primary End Point

(CR + CRu) [95% CI: 9.7, 22.8a] 0

Months

• Follow-up on the remaining 8 patients was

56 days

(1.8 months, n=34)

median time to objective disease response2

discontinued prior to 8.5 months

a95% confidence interval. Response rates above are rounded to the nearest whole number.

CR=complete response; CRu=complete response unconfirmed; ORR=overall disease response rate.

Infections were the most common type of serious adverse event reported in Study 3 (N=131) and Study 4 (N=47). In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatmentrelated infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. The most common adverse reactions regardless of causality in Study 3 (N=131) were nausea (59%), asthenia/ fatigue (55%), thrombocytopenia (41%), vomiting (39%), diarrhea (36%), and pyrexia (35%), and in Study 4 (N=47) were asthenia/fatigue (77%), nausea (75%), thrombocytopenia (72%), neutropenia (66%), anemia (62%), leukopenia (55%), pyrexia (47%), anorexia (45%), vomiting (40%), constipation (40%), and diarrhea (36%).

DRUG INTERACTIONS • Monitor more frequently prothrombin time and International Normalized Ratio in patients concurrently administered ISTODAX and warfarin or coumarin derivatives • Romidepsin is metabolized by CYP3A4 —Monitor patients for toxicity related to increased romidepsin exposure and follow dose modifications for toxicity when ISTODAX is initially co-administered with strong CYP3A4 inhibitors —Avoid co-administration of ISTODAX (romidepsin) with rifampin and other potent inducers of CYP3A4 • Exercise caution with concomitant use of ISTODAX and P-glycoprotein (P-gp, ABCB1) inhibitors

USE IN SPECIFIC POPULATIONS • Pregnancy Category D: If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus • Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother • Patients with moderate and severe hepatic impairment and/or patients with end-stage renal disease should be treated with caution Please see Brief Summary of Full Prescribing Information, including WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS, on the following pages. References: 1. ISTODAX [package insert]. Summit, NJ: Celgene Corp; 2014. 2. Data on file, Celgene Corporation, Summit, NJ.

10-MG SINGLE-USE VIAL

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NK/T-cell lymphoma. In one case, ganciclovir prophylaxis failed to prevent Epstein Barr viral reactivation. 5.3 Electrocardiographic Changes Several treatment-emergent morphological changes in ECGs (including T-wave and ST-segment changes) have been reported in clinical studies. The clinical significance of these changes is unknown [see Adverse Reactions (6)]. In patients with congenital long QT syndrome, patients with a history of significant cardiovascular disease, and patients taking anti-arrhythmic medicines or medicinal products that lead to significant QT prolongation, consider cardiovascular monitoring of ECGs at baseline and periodically during treatment. Confirm that potassium and magnesium levels are within normal range before administration of ISTODAX [see Adverse Reactions (6)]. 5.4 Tumor Lysis Syndrome Tumor lysis syndrome (TLS) has been reported to occur in 1% of patients with tumor stage CTCL and 2% of patients with Stage III/IV PTCL. Patients with advanced stage disease and/or high tumor burden may be at greater risk, should be closely monitored, and managed as appropriate. 5.5 Use in Pregnancy There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose of 14 mg/m2/week. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following adverse reactions are described in more detail in other sections of the prescribing information. • Myelosuppression [see Warnings and Precautions (5.1)] • Infection [see Warnings and Precautions (5.2)] • Electrocardiographic Changes [see Warnings and Precautions (5.3)] • Tumor Lysis Syndrome [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Peripheral T-Cell Lymphoma The safety of ISTODAX was evaluated in 178 patients with PTCL in a sponsor-conducted pivotal study (Study 3) and a secondary NCI-sponsored study (Study 4) in which patients received a starting dose of 14 mg/m2. The mean duration of treatment and number of cycles were 5.6 months and 6 cycles in Study 3 and 9.6 months and 8 cycles in Study 4. Common Adverse Reactions Table 2 summarizes the most frequent adverse reactions (≥ 10%) regardless of causality, using the NCI-CTCAE, Version 3.0. The AE data are presented separately for Study 3 and Study 4. Laboratory abnormalities commonly reported (≥ 10%) as adverse reactions are included in Table 2. Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Any adverse reactions 128 (97) 88 (67) 47 (100) 40 (85) Gastrointestinal disorders Nausea 77 (59) 3 (2) 35 (75) 3 (6) Vomiting 51 (39) 6 (5) 19 (40) 4 (9) Diarrhea 47 (36) 3 (2) 17 (36) 1 (2) Constipation 39 (30) 1 (<1) 19 (40) 1 (2) Abdominal pain 18 (14) 3 (2) 6 (13) 1 (2) Stomatitis 14 (11) 0 3 (6) 0 General disorders and administration site conditions Asthenia/Fatigue 72 (55) 11 (8) 36 (77) 9 (19) Pyrexia 46 (35) 8 (6) 22 (47) 8 (17) Chills 14 (11) 1 (<1) 8 (17) 0 Edema peripheral 13 (10) 1 (<1) 3 (6) 0 Blood and lymphatic system disorders Thrombocytopenia 53 (41) 32 (24) 34 (72) 17 (36) Neutropenia 39 (30) 26 (20) 31 (66) 22 (47) Anemia 33 (25) 14 (11) 29 (62) 13 (28) Leukopenia 16 (12) 8 (6) 26 (55) 21 (45) (continued)

Cosmos Communications

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ISTODAX® (romidepsin) for injection For intravenous infusion only The following is a Brief Summary only; see full Prescribing Information for complete product information. 1 INDICATIONS AND USAGE ISTODAX is indicated for: • Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy. These indications are based on response rate. Clinical benefit such as improvement in overall survival has not been demonstrated. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The recommended dose of romidepsin is 14 mg/m2 administered intravenously over a 4-hour period on days 1, 8, and 15 of a 28-day cycle. Cycles should be repeated every 28 days provided that the patient continues to benefit from and tolerates the drug. 2.2 Dose Modification Nonhematologic toxicities except alopecia • Grade 2 or 3 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then therapy may be restarted at 14 mg/m2. If Grade 3 toxicity recurs, treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline and the dose should be permanently reduced to 10 mg/m2. • Grade 4 toxicity: Treatment with romidepsin should be delayed until toxicity returns to ≤ Grade 1 or baseline, then the dose should be permanently reduced to 10 mg/m2. • Romidepsin should be discontinued if Grade 3 or 4 toxicities recur after dose reduction. Hematologic toxicities • Grade 3 or 4 neutropenia or thrombocytopenia: Treatment with romidepsin should be delayed until the specific cytopenia returns to ANC ≥1.5×109/L and platelet count ≥75×109/L or baseline, then therapy may be restarted at 14 mg/m2. • Grade 4 febrile (≥38.5°C) neutropenia or thrombocytopenia that requires platelet transfusion: Treatment with romidepsin should be delayed until the specific cytopenia returns to ≤ Grade 1 or baseline, and then the dose should be permanently reduced to 10 mg/m2. 2.3 Instructions for Preparation and Intravenous Administration ISTODAX is a cytotoxic drug. Use appropriate handling procedures. ISTODAX must be reconstituted with the supplied diluent and further diluted with 0.9% Sodium Chloride Injection, USP before intravenous infusion. • Each 10 mg single-use vial of ISTODAX (romidepsin) must be reconstituted with 2 mL of the supplied diluent. With a suitable syringe, aseptically withdraw 2 mL from the supplied diluent vial, and slowly inject it into the ISTODAX (romidepsin) for injection vial. Swirl the contents of the vial until there are no visible particles in the resulting solution. The reconstituted solution will contain ISTODAX 5 mg/mL. The reconstituted ISTODAX solution is chemically stable for up to 8 hours at room temperature. • Extract the appropriate amount of ISTODAX from the vials to deliver the desired dose, using proper aseptic technique. Before intravenous infusion, further dilute ISTODAX in 500 mL 0.9% Sodium Chloride Injection, USP. • Infuse over 4 hours. The diluted solution is compatible with polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), polyethylene (PE) infusion bags as well as glass bottles, and is chemically stable for up to 24 hours when stored at room temperature. However, it should be administered as soon after dilution as possible. Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Myelosuppression Treatment with ISTODAX can cause thrombocytopenia, leukopenia (neutropenia and lymphopenia), and anemia. Monitor blood counts regularly during treatment with ISTODAX, and modify the dose as necessary [see Dosage and Administration (2.2) and Adverse Reactions (6)]. 5.2 Infections Fatal and serious infections, including pneumonia, sepsis, and viral reactivation, including Epstein Barr and hepatitis B viruses have been reported in clinical trials with ISTODAX. These can occur during treatment and within 30 days after treatment. The risk of life threatening infections may be greater in patients with a history of prior treatment with monoclonal antibodies directed against lymphocyte antigens and in patients with disease involvement of the bone marrow [see Adverse Reactions (6)]. Reactivation of hepatitis B virus infection has occurred in 1% of PTCL patients in clinical trials in Western populations [see Adverse Reactions (6)]. In patients with evidence of prior hepatitis B infection, consider monitoring for reactivation, and consider antiviral prophylaxis. Reactivation of Epstein Barr viral infection leading to liver failure has occurred in a trial of patients with relapsed or refractory extranodal

T:7”

Table 2. Adverse Reactions Occurring in ≥10% of Patients with PTCL in Study 3 and Corresponding Incidence in Study 4 (N=178) Study 3 Study 4 (N=131) (N=47) Adverse Reactions n (%) All grades Grade 3 or 4 All grades Grade 3 or 4 Metabolism and nutrition disorders Anorexia 37 (28) 2 (2) 21 (45) 1 (2) Hypokalemia 14 (11) 3 (2) 8 (17) 1 (2) Nervous system disorders Dysgeusia 27 (21) 0 13 (28) 0 Headache 19 (15) 0 16 (34) 1 (2) Respiratory, thoracic and mediastinal disorders Cough 23 (18) 0 10 (21) 0 Dyspnea 17 (13) 3 (2) 10 (21) 2 (4) Investigations Weight decreased 14 (11) 0 7 (15) 0 Cardiac disorders Tachycardia 13 (10) 0 0 0

Manufactured for: Celgene Corporation Summit, NJ 07901 Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 or Baxter Oncology GmbH Halle/Westfalen, Germany ISTODAX® is a registered trademark of Celgene Corporation © 2010-2014 Celgene Corporation. All Rights Reserved. Pat.www.celgene.com/therapies IST_PTCL_BSv006 10/2014

Cosmos Communications

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Serious Adverse Reactions Infections were the most common type of SAE reported. In Study 3, 26 patients (20%) experienced a serious infection, including 6 patients (5%) with serious treatment-related infections. In Study 4, 11 patients (23%) experienced a serious infection, including 8 patients (17%) with serious treatment-related infections. Serious adverse reactions reported in ≥ 2% of patients in Study 3 were pyrexia (8%), pneumonia, sepsis, vomiting (5%), cellulitis, deep vein thrombosis, (4%), febrile neutropenia, abdominal pain (3%), chest pain, neutropenia, pulmonary embolism, dyspnea, and dehydration (2%). In Study 4, serious adverse reactions in ≥ 2 patients were pyrexia (17%), aspartate aminotransferase increased, hypotension (13%), anemia, thrombocytopenia, alanine aminotransferase increased (11%), infection, dehydration, dyspnea (9%), lymphopenia, neutropenia, hyperbilirubinemia, hypocalcemia, hypoxia (6%), febrile neutropenia, leukopenia, ventricular arrhythmia, vomiting, hypersensitivity, catheter related infection, hyperuricemia, hypoalbuminemia, syncope, pneumonitis, packed red blood cell transfusion, and platelet transfusion (4%). Reactivation of hepatitis B virus infection has occurred in 1% of patients with PTCL patients in clinical trials in Western population enrolled in Study 3 and Study 4 [see Warnings and Precautions (5.2)]. Deaths due to all causes within 30 days of the last dose of ISTODAX occurred in 7% of patients in Study 3 and 17% of patients in Study 4. In Study 3, there were 5 deaths unrelated to disease progression that were due to infections, including multi-organ failure/sepsis, pneumonia, septic shock, candida sepsis, and sepsis/cardiogenic shock. In Study 4, there were 3 deaths unrelated to disease progression that were due to sepsis, aspartate aminotransferase elevation in the setting of Epstein Barr virus reactivation, and death of unknown cause. Discontinuations Discontinuation due to an adverse event occurred in 19% of patients in Study 3 and in 28% of patients in Study 4. In Study 3, thrombocytopenia and pneumonia were the only events leading to treatment discontinuation in at least 2% of patients. In Study 4, events leading to treatment discontinuation in ≥ 2 patients were thrombocytopenia (11%), anemia, infection, and alanine aminotransferase increased (4%). 6.2 Postmarketing Experience No additional safety signals have been observed from postmarketing experience. 7 DRUG INTERACTIONS 7.1 Warfarin or Coumarin Derivatives Prolongation of PT and elevation of INR were observed in a patient receiving ISTODAX concomitantly with warfarin. Although the interaction potential between ISTODAX and warfarin has not been formally studied, monitor PT and INR more frequently in patients concurrently receiving ISTODAX and warfarin. 7.2 Drugs That Inhibit Cytochrome P450 3A4 Enzymes Romidepsin is metabolized by CYP3A4. Strong CYP3A4 inhibitors increase concentrations of romidepsin. In a pharmacokinetic drug interaction trial the strong CYP3A4 inhibitor ketoconazole increased romidepsin (AUC0-∞) by approximately 25%. Monitor for toxicity related to increased romidepsin exposure and follow the dose modifications for toxicity [see Dosage and Administration (2.2)] when romidepsin is initially co-administered with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). 7.3 Drugs That Induce Cytochrome P450 3A4 Enzymes Avoid co-administration of ISTODAX with rifampin. In a pharmacokinetic drug interaction trial with co-administered rifampin (a strong CYP3A4 inducer), romidepsin exposure was increased by approximately 80% and 60% for AUC0-∞ and Cmax, respectively. Typically, co-administration of CYP3A4 inducers decrease concentrations of

drugs metabolized by CYP3A4. The increase in exposure seen after co-administration with rifampin is likely due to rifampin’s inhibition of an undetermined hepatic uptake process that is predominantly responsible for the disposition of ISTODAX. It is unknown if other potent CYP3A4 inducers (e.g., dexamethasone, carbamazepine, phenytoin, rifabutin, rifapentine, phenobarbital, St. John’s Wort) would alter the exposure of ISTODAX. Therefore, the use of other potent CYP3A4 inducers should be avoided when possible. 7.4 Drugs That Inhibit Drug Transport Systems Romidepsin is a substrate of the efflux transporter P-glycoprotein (P-gp, ABCB1). If ISTODAX is administered with drugs that inhibit P-gp, increased concentrations of romidepsin are likely, and caution should be exercised. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.5)]. There are no adequate and well-controlled studies of ISTODAX in pregnant women. However, based on its mechanism of action and findings in animals, ISTODAX may cause fetal harm when administered to a pregnant woman. In an animal reproductive study, romidepsin was embryocidal and resulted in adverse effects on the developing fetus at exposures below those in patients at the recommended dose. If this drug is used during pregnancy, or if the patient becomes pregnant while taking ISTODAX, the patient should be apprised of the potential hazard to the fetus. Romidepsin was administered intravenously to rats during the period of organogenesis at doses of 0.1, 0.2, or 0.5 mg/kg/day. Substantial resorption or post-implantation loss was observed at the high-dose of 0.5 mg/kg/day, a maternally toxic dose. Adverse embryo-fetal effects were noted at romidepsin doses of ≥0.1 mg/kg/day, with systemic exposures (AUC) ≥0.2% of the human exposure at the recommended dose of 14 mg/m2/week. Drug-related fetal effects consisted of folded retina, rotated limbs, and incomplete sternal ossification. 8.3 Nursing Mothers It is not known whether romidepsin is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from ISTODAX, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness of ISTODAX in pediatric patients has not been established. 8.5 Geriatric Use Of the approximately 300 patients with CTCL or PTCL in trials, about 25% were >65 years old. No overall differences in safety or effectiveness were observed between these subjects and younger subjects; however, greater sensitivity of some older individuals cannot be ruled out. 8.6 Hepatic Impairment No dedicated hepatic impairment study for ISTODAX has been conducted. Mild hepatic impairment does not alter pharmacokinetics of romidepsin based on a population pharmacokinetic analysis. Patients with moderate and severe hepatic impairment should be treated with caution. 8.7 Renal Impairment No dedicated renal impairment study for ISTODAX has been conducted. Based upon the population pharmacokinetic analysis, renal impairment is not expected to significantly influence drug exposure. The effect of end-stage renal disease on romidepsin pharmacokinetics has not been studied. Thus, patients with end-stage renal disease should be treated with caution. 10 OVERDOSAGE No specific information is available on the treatment of overdosage of ISTODAX. Toxicities in a single-dose study in rats or dogs, at intravenous romidepsin doses up to 2.2 fold the recommended human dose based on the body surface area, included irregular respiration, irregular heartbeat, staggering gait, tremor, and tonic convulsions. In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., clinical monitoring and supportive therapy, if required. There is no known antidote for ISTODAX and it is not known if ISTODAX is dialyzable.

DECEMBER 2014

VOLUME 3, NUMBER 8

TABLE OF CONTENTS INTERVIEW WITH THE INNOVATORS

429 Providing Therapeutic Guidance for Breast Cancer Patients in the Molecular Era With the Breast Cancer IndexSM Assay: An Interview With Stephen C. Malamud, MD, and Susan K. Boolbol, MD, of Mount Sinai Beth Israel Hospital

PMO speaks with Drs Malamud and Boolbol about their collaboration as medical and surgical oncologists and the utility of the Breast Cancer Index in the treatment decision-making process for patients. PSYCHOSOCIAL ONCOLOGY

438

Putting the “Person” in Personalized Cancer Medicine: A Systematic Review of Psychological Aspects of Targeted Therapy

Daniel C. McFarland, DO; Jada G. Hamilton, PhD, MPH; Rosanne Fox, MD; Jimmie Holland, MD The authors discuss psychological considerations that arise for patients in the advent of “personalized medicine.” WORLD CUTANEOUS MALIGNANCIES CONGRESS

450

Highlights From the Third Annual WCMC

PMO proudly presents highlights of presentations from key opinion leaders at the Third Annual WCMC, the congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies.

451 Melanoma 453 BCC 454 CTLC 456 MCC OUR MISSION Personalized Medicine in Oncology provides the bridge between academic research and practicing clinicians by demonstrating the immediate implications of precision medicine – including advancements in molecular sequencing, targeted therapies, and new diagnostic modalities – to the management of patients with cancer, offering oncologists, oncology nurses, payers, researchers, drug developers, policymakers, and all oncology stakeholders the relevant practical information they need to improve cancer outcomes. This journal translates the new understanding of the biology of cancer into the day-to-day management of the individual patient with cancer, using a patient’s unique genetic makeup to select the best available therapy. OUR VISION Our vision is to transform the current medical model into a new model of personalized care, where decisions and practices are tailored for the individual – beginning with an incremental integration of personalized techniques into the conventional practice paradigm currently in place.

422

Personalized Medicine in Oncology

www.PersonalizedMedOnc.com

PUBLISHING STAFF Senior Vice President/Sales & Marketing Philip Pawelko ppawelko@the-lynx-group.com Group Director, Sales & Marketing John W. Hennessy jhennessy2@the-lynx-group.com Vice President/Group Publisher Russell Hennessy rhennessy@the-lynx-group.com Manager, Client Services Travis Sullivan tsullivan@the-lynx-group.com Editorial Directors Kristin Siyahian ksiyahian@the-lynx-group.com Anne Cooper acooper@the-lynx-group.com Strategic Editor Robert E. Henry Senior Copyeditor BJ Hansen Copyeditor Rosemary Hansen Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Jr Digital Media Specialist Charles Easton IV Web Content Manager Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Alyson Bruni Jini Gopalaswamy Project Manager Deanna Martinez Project Coordinator Mike Kodada IT Manager Kashif Javaid Administrative Services Team Leader Rachael Baranoski Office Coordinator Robert Sorensen Green Hill Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-656-7935 • fax: 732-656-7938

December 2014

Vol 3, No 8

The Oncotype DX® assay reveals the unique biology of a tumor, presenting a more complete and individualized picture of the patient’s cancer. It is essential information that can fundamentally change decisions about treatment. With over 440,000 patients tested worldwide,

the Oncotype DX portfolio—assays for breast, colon, and prostate—is a world leader in applying genomic science to cancer treatment planning. For more information on using the Oncotype DX assay with appropriate patients, visit OncotypeDX.com/portfolio.

breast | colon | prostate

DECEMBER 2014

VOLUME 3, NUMBER 8

M ay 3-6, 2015

(Continued)

PMO LIVE

462

Highlights From the Third Annual PMO Live: A Global Biomarkers Consortium Initiative

As the official publication of the Global Biomarkers Consortium, PMO provides highlights of presentations from the Third Annual PMO Live Conference focused on the value and clinical impact of biomarker research in oncology.

AnnuAl ConferenCe

466 CRC Lung Cancer

467

Breast Cancer

RSARY VE NI

466

468 CML THE LAST WORD

476 Personalized Medicine’s Progress Edward Abrahams, PhD

Having recently marked the 10th anniversary of the Personalized Medicine Coalition (PMC) at the 10th Annual Personalized Medicine Conference at Harvard Medical School, Dr Abrahams provides a review of the progress in personalized medicine and reflects on the continuing challenges facing the field.

Omni Shoreham Hotel Washington, DC

ANNUAL INDEX

480 2014 Annual Index 482 2014 Author Index Personalized Medicine in Oncology is included in the following indexing and database services: Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO research databases

Personalized Medicine in Oncology, ISSN 2166-0166 (print); ISSN applied for (online) is published 8 times a year by Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2014 by Green Hill Healthcare Communications, LLC. All rights reserved. Personalized Medicine in Oncology logo is a trademark of Green Hill Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Personalized Medicine in Oncology (PMO), 1249 South River Road, Suite 202A, Cranbury, NJ 08512. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $50.00; institutions, $90.00; single issues, $5.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. The ideas and opinions expressed in PMO do not necessarily reflect those of the editorial board, the editorial director, or the publishers. Publication of an advertisement or other product mention in PMO should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the editorial board nor the publishers assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the editorial director.

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Personalized Medicine in Oncology

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www.avbcconline.org/ conference

December 2014

Vol 3, No 8

VALCHLOR® (mechlorethamine) gel is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides–type cutaneous T-cell lymphoma (MF-CTCL) in patients who have received prior skin-directed therapy WHEN IT’S TIME TO MANAGE THE CHALLENGES OF STAGE IA AND IB MF-CTCL

VALCHLOR IS ON IT The first and only FDA-approved topical formulation of mechlorethamine (commonly known as nitrogen mustard) • Proven efficacy in a 12-month study 1 • Once-daily gel (special handling and disposal procedures should be followed)

• Dependable formulation manufactured with consistent quality and potency • Comprehensive resources provided by VALCHLOR Support ™

For more information, including how to prescribe, visit www.valchlor.com or call 1-855-4-VALCHLOR (1-855-482-5245).

DOSING AND APPLICATION VALCHLOR is for topical dermatologic use only. Apply a thin film of gel once daily to affected areas of the skin. VALCHLOR is a cytotoxic drug and special handling and disposal procedures should be followed during use. Caregivers must wear disposable nitrile gloves when applying VALCHLOR. Patients and caregivers must wash hands thoroughly after handling or applying VALCHLOR.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine.

WARNINGS AND PRECAUTIONS • Mucosal or eye injury: Exposure of mucous membranes to mechlorethamine such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe. Exposure of the eyes causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Should eye exposure or mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation • Secondary exposure: Avoid direct skin contact with VALCHLOR in individuals other than the patients due to risk of dermatitis, mucosal injury, and secondary cancers

• Dermatitis: Dermatitis may be moderately severe or severe. Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. Stop treatment with VALCHLOR or reduce dose frequency • Non-melanoma skin cancer: Monitor patients during and after treatment with VALCHLOR • Embryo-fetal toxicity: Women should avoid becoming pregnant while using VALCHLOR due to the potential hazard to the fetus. For nursing mothers, discontinue use of VALCHLOR or nursing • Flammable gel: VALCHLOR is an alcohol-based gel. Avoid fire, flame, and smoking until the gel has dried

ADVERSE REACTIONS The most common adverse reactions (≥5%) were dermatitis (56%), pruritus (20%), bacterial skin infection (11%), skin ulceration or blistering (6%), and skin hyperpigmentation (5%). These reactions may be moderately severe or severe. Elderly patients aged 65 and older may be more susceptible. Depending on severity, treatment reduction, suspension, or discontinuation may be required. To report SUSPECTED ADVERSE REACTIONS, contact Actelion Pharmaceuticals US, Inc., at 1-855-4-VALCHLOR (1-855-482-5245) or FDA at 1-800-FDA-1088 or visit www.fda.gov/medwatch.

Please see Brief Summary of Prescribing Information on adjacent page. REFERENCE: 1. VALCHLOR [package insert]. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2013.

A great idea finally gels

VALCHLOR® (mechlorethamine) gel, 0.016% For Topical Dermatological Use Only BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION This brief summary does not include all the information needed to use VALCHLOR safely and effectively. See Full Prescribing Information for VALCHLOR. • INDICATIONS AND USAGE VALCHLOR is an alkylating drug indicated for the topical treatment of Stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in patients who have received prior skin-directed therapy. • CONTRAINDICATIONS The use of VALCHLOR is contraindicated in patients with known severe hypersensitivity to mechlorethamine. Hypersensitivity reactions, including anaphylaxis, have occurred with topical formulations of mechlorethamine. • WARNINGS AND PRECAUTIONS >> Mucosal or Eye Injury Exposure of the eyes to mechlorethamine causes pain, burns, inflammation, photophobia, and blurred vision. Blindness and severe irreversible anterior eye injury may occur. Advise patients that if eye exposure occurs, (1) immediately irrigate for at least 15 minutes with copious amounts of water, normal saline, or a balanced salt ophthalmic irrigating solution and (2) obtain immediate medical care (including ophthalmologic consultation). Exposure of mucous membranes such as the oral mucosa or nasal mucosa causes pain, redness, and ulceration, which may be severe. Should mucosal contact occur, immediately irrigate for at least 15 minutes with copious amounts of water, followed by immediate medical consultation. >> Secondary Exposure to VALCHLOR Avoid direct skin contact with VALCHLOR in individuals other than the patient. Risks of secondary exposure include dermatitis, mucosal injury, and secondary cancers. Follow recommended application instructions to prevent secondary exposure. >> Dermatitis The most common adverse reaction was dermatitis, which occurred in 56% of the patients. Dermatitis was moderately severe or severe in 23% of patients. Monitor patients for redness, swelling, inflammation, itchiness, blisters, ulceration, and secondary skin infections. The face, genitalia, anus, and intertriginous skin are at increased risk of dermatitis. Follow dose modification instructions for dermatitis. >> Non-Melanoma Skin Cancer Four percent (4%, 11/255) of patients developed a non-melanoma skin cancer during the clinical trial or during one year of post-treatment follow-up: 2% (3/128) of patients receiving VALCHLOR and 6% (8/127) of patients receiving the mechlorethamine ointment comparator. Some of these non-melanoma skin cancers occurred in patients who had received prior therapies known to cause non-melanoma skin cancer. Monitor patients for non-melanoma skin cancers during and after treatment with VALCHLOR. Non-melanoma skin cancer may occur on any area of the skin, including untreated areas. >> Embryo-fetal Toxicity Based on its mechanism of action, case reports in humans, and findings in animals, VALCHLOR can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations in pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic and embryo-lethal after a single subcutaneous administration to animals. Advise women to avoid becoming pregnant while using VALCHLOR. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. >> Flammable Gel Alcohol-based products, including VALCHLOR, are flammable. Follow recommended application instructions. • ADVERSE REACTIONS In a randomized, observer-blinded, controlled trial, VALCHLOR 0.016% (equivalent to 0.02% mechlorethamine HCl) was compared to an Aquaphor ®-based mechlorethamine HCl 0.02% ointment (Comparator). The maximum duration of treatment was 12 months. Sixty-three percent (63%) of patients in the VALCHLOR arm and 67% in the comparator arm completed 12 months of treatment. The body system associated with the most frequent adverse reactions was skin and subcutaneous tissue disorders. The most common adverse reactions (occurring in at least 5% of the patients) are shown in Table 1.

Table 1. Most Commonly Reported (≥5%) Cutaneous Adverse Reactions Comparator VALCHLOR N=127 N=128 % of patients % of patients Any ModeratelyAny ModeratelyGrade Severe or Severe Grade Severe or Severe Dermatitis 56 23 58 17 Pruritus 20 4 16 2 Bacterial skin infection 11 2 9 2 Skin ulceration or blistering 6 3 5 2 Skin hyperpigmentation 5 0 7 0 In the clinical trial, moderately-severe to severe skin-related adverse events were managed with treatment reduction, suspension, or discontinuation. Discontinuations due to adverse reactions occurred in 22% of patients treated with VALCHLOR and 18% of patients treated with the comparator. Sixty-seven percent (67%) of the discontinuations for adverse reactions occurred within the first 90 days of treatment. Temporary treatment suspension occurred in 34% of patients treated with VALCHLOR and 20% of patients treated with the comparator. Reductions in dosing frequency occurred in 23% of patients treated with VALCHLOR and 12% of patients treated with the comparator. Reductions in hemoglobin, neutrophil count, or platelet count occurred in 13% of patients treated with VALCHLOR and 17% treated with Comparator. • DRUG INTERACTIONS No drug interaction studies have been performed with VALCHLOR. Systemic exposure has not been observed with topical administration of VALCHLOR; therefore, systemic drug interactions are not likely. • USE IN SPECIFIC POPULATIONS >> Pregnancy Pregnancy Category D Risk Summary Mechlorethamine can cause fetal harm when administered to a pregnant woman. There are case reports of children born with malformations to pregnant women systemically administered mechlorethamine. Mechlorethamine was teratogenic in animals after a single subcutaneous administration. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. Animal Data Mechlorethamine caused fetal malformations in the rat and ferret when given as single subcutaneous injections of 1 mg/kg. Other findings in animals included embryolethality and growth retardation when administered as a single subcutaneous injection. >> Nursing Mothers It is not known if mechlorethamine is excreted in human milk. Due to the potential for topical or systemic exposure to VALCHLOR through exposure to the mother’s skin, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. >> Pediatric Use Safety and effectiveness in pediatric patients have not been established. >> Geriatric Use A total of 79 patients age 65 and older (31% of the clinical trial population) were treated with either VALCHLOR or the comparator in the clinical trial. Forty-four percent (44%) of patients age 65 or older treated with VALCHLOR achieved a Composite Assessment of Index Lesion Severity (CAILS) response compared to 66% of patients below the age of 65. Seventy percent (70%) of patients age 65 and older experienced cutaneous adverse reactions and 38% discontinued treatment due to adverse reactions, compared to 58% and 14% in patients below the age of 65, respectively. Similar differences in discontinuation rates between age subgroups were observed in the comparator group. Manufactured for: Actelion Pharmaceuticals US, Inc. South San Francisco, CA 94080, USA © 2014 Actelion Pharmaceuticals US, Inc. All rights reserved.

VAL-00170 0814

EDITORIAL BOARD

EDITORS IN CHIEF Sanjiv S. Agarwala, MD St. Luke’s Hospital Bethlehem, Pennsylvania

Nikhil C. Munshi, MD Dana-Farber Cancer Institute Boston, Massachusetts

Prostate Cancer Oliver Sartor, MD Tulane University New Orleans, Louisiana

Al B. Benson III, MD, FACP, FASCO Northwestern University Chicago, Illinois

EDITORIAL BOARD Gregory D. Ayers, MS Vanderbilt University School of Medicine Nashville, Tennessee

SECTION EDITORS Biomarkers Pranil K. Chandra, DO PathGroup Brentwood, Tennessee

Lyudmila Bazhenova, MD University of California, San Diego San Diego, California

Darren Sigal, MD Scripps Clinic Medical Group San Diego, California Breast Cancer Edith Perez, MD Mayo Clinic Jacksonville, Florida Hematologic Malignancies Gautam Borthakur, MD The University of Texas MD Anderson Cancer Center Houston, Texas Pathology David L. Rimm, MD, PhD Yale Pathology Tissue Services Yale University School of Medicine New Haven, Connecticut Drug Development Igor Puzanov, MD Vanderbilt University Vanderbilt-Ingram Cancer Center Nashville, Tennessee Lung Cancer Vincent A. Miller, MD Foundation Medicine Cambridge, Massachusetts Predictive Modeling Michael Kattan, PhD Case Western Reserve University Cleveland, Ohio Gastrointestinal Cancer Eunice Kwak, MD Massachusetts General Hospital Cancer Center Harvard Medical School Boston, Massachusetts Melanoma Doug Schwartzentruber, MD Indiana University Simon Cancer Center Indianapolis, Indiana

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Steven O’Day, MD John Wayne Cancer Institute Santa Monica, California Rafael Rosell, MD, PhD Catalan Institute of Oncology Barcelona, Spain Steven T. Rosen, MD, FACP Northwestern University Chicago, Illinois

Leif Bergsagel, MD Mayo Clinic Scottsdale, Arizona

Hope S. Rugo, MD University of California, San Francisco San Francisco, California

Mark S. Boguski, MD, PhD Harvard Medical School Boston, Massachusetts Gilberto Castro, MD Instituto do Câncer do Estado de São Paulo São Paulo, Brazil Madeleine Duvic, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Lee Schwartzberg, MD The West Clinic Memphis, Tennessee John Shaughnessy, PhD University of Arkansas for Medical Sciences Little Rock, Arkansas Lillie D. Shockney, RN, BS, MAS Johns Hopkins University Baltimore, Maryland

Beth Faiman, PhD(c), MSN, APRN-BC, AOCN Cleveland Clinic Taussig Cancer Center Cleveland, Ohio

Lawrence N. Shulman, MD Dana-Farber Cancer Institute Boston, Massachusetts Jamie Shutter, MD South Beach Medical Consultants, LLC Miami Beach, Florida

Steven D. Gore, MD The Johns Hopkins University School of Medicine Baltimore, Maryland

David Spigel, MD Sarah Cannon Research Institute Nashville, Tennessee

Gregory Kalemkerian, MD University of Michigan Ann Arbor, Michigan

Moshe Talpaz, MD University of Michigan Medical Center Ann Arbor, Michigan

Howard L. Kaufman, MD Rush University Chicago, Illinois

Sheila D. Walcoff, JD Goldbug Strategies, LLC Rockville, Maryland

Katie Kelley, MD UCSF School of Medicine San Francisco, California

Anas Younes, MD The University of Texas MD Anderson Cancer Center Houston, Texas

Minetta Liu, MD Mayo Clinic Cancer Center Rochester, Minnesota Kim Margolin, MD University of Washington Fred Hutchinson Cancer Research Center Seattle, Washington Gene Morse, PharmD University at Buffalo Buffalo, New York

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LETTER TO OUR READERS

Reflections on 2014 – Enthusiasm for 2015 Dear Colleague,

W Sanjiv S. Agarwala, MD

Al B. Benson III, MD, FACP, FASCO

hat an incredible year for the oncology community. We have witnessed great strides in our ability to fight cancer, most notably with immunotherapeutics. As a result, we have glimpsed a possible future of cancer care that will cater to the individual patient, making personalized medicine a reality, and ultimately improve the lives of our patients. In addition to the advances in immunotherapy, we have presented important, timely information on targeted therapies, diagnostics, and biomarker identification. What is the most effective way to present this information? That depends on the reader. To better meet the individual needs of our readership, Personalized Medicine in Oncology (PMO) extends its reach beyond the print journal alone. We are pleased to offer additional resources to disseminate information to our valued readership, including: • Immunotherapy in Oncology The publishers of PMO proudly present this timely journal focusing on the significant role of immunotherapies in the treatment of many cancers. • World Cutaneous Malignancies Congress (WCMC) As one of the official meetings of PMO, this dynamic congress offers an expert international faculty and is dedicated to fostering the exchange of clinically relevant information in the field of cutaneous malignancies. • PMO Live: A Global Biomarkers Consortium Initiative The only global meeting dedicated to advancing the understanding of the value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will achieve a thorough understanding of the relevance of biomarkers in effectively personalizing cancer care in the clinical setting. • Continuing Medical Education (CME) To meet the continuing educational needs of our reading community, you’ll find CME opportunities in many of our issues and on our website. • PersonalizedMedOnc.com We designed our website to be a valuable resource complete with information from all our offerings.

Thank you for your loyal readership throughout 2014. We look forward to serving you in the coming year by bringing you the latest advances in personalized care in the hope of enhancing your ability to care for patients. Any suggestions as to how we can better serve you are welcome and should be addressed to our editorial director at ksiyahian@the-lynx-group.com. Our very best to you this holiday season and in the new year. Sincerely,

Sanjiv S. Agarwala, MD Coeditor in Chief Personalized Medicine in Oncology

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Al B. Benson III, MD, FACP, FASCO Coeditor in Chief Personalized Medicine in Oncology

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Providing Therapeutic Guidance for Breast Cancer Patients in the Molecular Era With the Breast Cancer IndexSM Assay: An Interview With Stephen C. Malamud, MD, and Susan K. Boolbol, MD, of Mount Sinai Beth Israel Hospital

ith the advent of gene expression profiling, we have gained the ability to objectively advise patients with breast cancer, among other cancers, on their risk of recurrence and potential benefit of therapies through the administration of assays designed to provide predictive and prognostic data. This is welcome news for a patient who has successfully endured treatment for cancer and remains fearful of the risk of relapse. Also welcome news for patients with estrogen receptorâ&#x20AC;&#x201C;positive (ER+) breast cancer, recently presented data suggest a survival benefit for some patients by extending endocrine therapy to 10 years, rather than stopping at 5 years. But the question remains, which subset of ER+ patients stands to benefit? Physicians have a variety of choices on the assays to apply to their patients. There are many genetic expression profiling and expanded immunohistochemistry (IHC) tests to guide the adjuvant therapy of women with breast cancer, including Breast Cancer Index (BCI), MammaPrint, Oncotype DX, and Prosigna. In this installment of Interview With the Innovators, we focus on BCI â&#x20AC;&#x201C; the only validated test available to physicians and patients that provides guidance on the benefit of extend-

ing endocrine therapy for an additional 5 years. BCI is a biomarker test that assesses distinct biological pathways for breast cancer. It predicts both early recurrence (0-5 years) and late distant recurrence (5-10 years) as well as the likelihood of benefit from extended Stephen C. endocrine therapy. About two-thirds Malamud, MD of breast cancer patients are ER+, and the risk of late distant recurrence is a concern, with more than 50% of recurrences occurring after 5 years. The publishers of PMO had the unique opportunity to discuss the utility of BCI with Dr Stephen Malamud and Dr Susan Boolbol of Mount Sinai Beth Israel Hospital Susan K. about their collaboration as a mediBoolbol, MD cal and surgical oncology team to employ a test such as BCI in the treatment decision-making process for patients. What follows are highlights from their thoughtful exchange. To view the video of their discussion, please visit www.personalizedmedonc.com.

PMO Thank you for talking with us today about guiding the adjuvant therapy of women with breast cancer using the Breast Cancer Index (BCI). To begin, can you describe the circumstance in which you would use this test? Dr Malamud At the time of diagnosis, a woman with breast cancer will come to the office to make that critical decision on how to move forward with their

adjuvant therapy. There are many parameters we will use to ascertain risk and determine what the best treatment might be. First and foremost is the clinical presentation in the stage of the cancer. Second comes a variety of these biomarkers that we now use to help differentiate who needs chemotherapy, hormone therapy, or combinations of those therapies and predictions in terms of outcome of treatment and the benefits of those same therapies. The markers we have considered to date include the estrogen or progesterone receptor by IHC, but more importantly, as we enter the era of personalized medicine, we look at the genomic analysis of the tumor to

Dr Malamud is Associate Professor of Medicine, Hematology and Medical Oncology at Mount Sinai Hospital in New York, New York. Dr Boolbol is Chief of Breast Surgery, Appel-Venet Comprehensive Breast Service at Mount Sinai Beth Israel Hospital in New York, New York.

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Figure 1 Predictive and Prognostic Indications

BCI Predictive

Predicts Likelihood of Beneﬁt From Endocrine Therapy   (5-10 yrs)

BCI Prognostic

Assesses Individual Risk of Late Recurrence   (5-10 yrs)

decide what needs to happen in the first 5 years. If they are hormone positive, do they need chemotherapy in addition to their hormone therapy? Secondly, what should we do when those patients have survived without a recurrence for their first 5 years and we need to decide how to move forward? We now have genomic analysis for both of those scenarios. The most critical new question is what to do at that fifth year when we have been relatively stuck with information that tells us that only a small percentage of women will benefit from an additional time on anti-estrogen therapy beyond the fifth year. The Breast Cancer Index (BCI), a newly developed second-generation genomic assay, will tell us who is likely to benefit with the additional therapy (Figure 1). Other women, who have a low likelihood of benefit, may be absolved from continuing therapy. We can look at BCI to determine not only the risk of recurrence but the likelihood of benefit from additional therapy. We determine the risk of recurrence over those next 5 years, defined as low or high risk, and use that information as a segue to the discussion of the potential additional benefit of therapy. Based on data from the MA.17 study, those patients who have anything other than a low BCI predictive are more likely to benefit from an additional 5 years of therapy. Dr Boolbol This field has changed enormously over the past 20 years. We wouldn’t think of treating a patient now without information from the initial biopsy, IHC of estrogen and progesterone, and Her2 status. And now we need genomic information when we’re discussing the potential benefit of chemotherapy. We now have assays to help guide us in treatment decisions. We have several clinical trials showing that 10 years of endocrine treatment is better than 5 years. That benefit for the overall population of women with breast cancer is relatively small, single digits. But, with BCI, we now have an assay to give us more information, to personalize the treatment for individual patients. We

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can tell a patient, we’ve run this assay on you and you are not likely to derive much benefit from an additional 5 years or, you will likely derive benefit. It’s a paradigm shift of great benefit to patients. PMO Can you discuss the importance of the multidisciplinary treatment team and the value of gene expression profile tests to the team? Dr Boolbol A critical part of taking care of women with breast cancer is the team approach. A surgeon cannot take care of a breast cancer patient alone, a medical oncologist cannot do it alone, and a radiation oncologist cannot do it alone. It really is a working, functioning team that needs to take care of the individual patient. In doing that, part of the surgeon’s job as potentially the first interaction with the patient is educating the patient on how their team functions and all the treatment options, from surgery to systemic therapy. Considering these new genomic tests and patients’ involvement with the multidisciplinary team, it’s important that the patient understands that there are tests that the treatment team uses for early and late treatment. The patient should anticipate interaction with all of the team members, and that will make a difference to their overall care. In fact, studies have shown that patients treated at high-volume centers, meaning centers that take care of a lot of breast patients, treat patients in a multidisciplinary fashion, and the patients have better outcomes.

Only a small percentage of women will benefit from an additional time on anti-estrogen therapy beyond the fifth year. Dr Malamud Dr Boolbol and I are very fortunate in that when patients come in for their first visit after they’ve had a diagnosis established, we have the opportunity to see patients together or within several days of each other. Patients really pick up on that, and they understand that there is a multidisciplinary collaborative effort to maintain their health and continue their care for years. I’m not going to take care of you only for these couple of months and then I’m gone and will turn you over to this person. It is a team that continues for at least 5 years and usually more. That kind of interaction is appreciated, and having us both in the same room sometimes at the same time where you’re talking about the surgical aspects and the postoperative care and introducing the concept of genomic testing, prognostic testing, hormonal therapy, chemotherapy, etcetera. The treat-

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ments segue into my role quite nicely, and then if at the end of the day they still have some questions, the fact that we can assure them that the following day their case is going to be presented at an even larger, multidisciplinary session again affords some relief because now they’re going to have 20-odd heads discussing their case, hopefully getting a check mark of approval to what we’ve already discussed. Dr Boolbol As I tell patients, breast cancer is too big for them to handle alone. They need support. And it’s the same thing for those of us caring for them. As a multidisciplinary team we support each other in order to take care of the individual patient. It’s important for patients to know how the team interacts and functions. For example, since I am the first one seeing the patient postoperatively and seeing their pathology first, I’m the one who orders any genomic test that will aid in the decision of chemotherapy. As the patient moves through treatment and follows up with me and with Dr Malamud, then we start discussing other tests that will aid in the decision of long-term treatment, specifically endocrine treatment such as BCI. PMO BCI touts the unique ability to predict risk of both early and late recurrence, as well as likelihood of benefit from extended endocrine therapy in early ER+ breast cancer. In your experience, are these performance characteristics unique for BCI compared with the other assays? Dr Malamud Yes, BCI testing has become an important adjunct in our care of patients, especially as we make decisions about therapy beyond 5 years. Normally it’s been the paradigm in the adjuvant treatment of breast cancer that the endocrine treatment continue for 5 years, and we’ve been hard-pressed to find data to support going past the 5-year mark. Recently, however, several trials, including the ATLAS, MA.17, and others, have shown that there is an advantage for some women to go on with extended adjuvant treatment beyond the fifth year. The BCI test can help us decide which of those women are actually likely to see benefit from an additional 5 years. If one looks at those trials that were done years ago and now beyond the 10-year mark, the absolute benefit for most of the women if one looks at the mean is only about 5% or 6%, which means that most women do not benefit from being on 5 years of additional therapy. Our goal is to try and isolate those patients who are going to benefit from treatment and not give extended 5 or 10 more years of hormonal therapy to those women who are not likely to realize benefit. So BCI is a test that separates those patients who are more likely to benefit from those who are unlikely to benefit. It offers a genomic profile of the tumor using a

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genomic panel completely distinct from the one that they may have had 5 years earlier and looks at the likelihood of benefit from continuing that treatment. We are able to explain to the patient that this test is designed to help tell us whether or not there’s more therapy that’s likely to work for them in preventing this disease from coming back. It will help tell us whether or not you need to be treated beyond that fifth year or if we can just stop and be comfortable with that idea. The idea of being able to stop potentially problematic hormonal therapy that they’ve endured for the 5 years prior is an amazing relief for these women who do not have to continue therapy. And for the women who are likely to benefit from continuing therapy, knowing that there is something that’s going to help them if they are at high risk is again almost of the same benefit.

So BCI is a test that separates those patients who are more likely to benefit from those who are unlikely to benefit. It offers a genomic profile of the tumor using a genomic panel completely distinct from the one that they may have had 5 years earlier and looks at the likelihood of benefit from continuing that treatment. Dr Boolbol If you compare how we treated patients 10 years ago to now, it’s vastly different. That was really just a cookie-cutter mold. You have breast cancer, it’s this size, it’s this stage, this is what you get. We still have a long way to go, but we really have moved so far past that, and it’s because of these genomic tests. If the patient is not likely deriving any benefit and this treatment is not helping them, why would we put them at risk for any side effect? I only want to give a patient treatment if they will benefit. The studies show that there is a small benefit for longer than 5 years of treatment, up to 10 years of endocrine treatment. When we exclude the low-benefit patients and treat the patients who stand to benefit, we’re making strides in treating their disease. When we look at chemotherapy, we see the same thing. When we look at the overall benefit of chemotherapy, it was only about 4% for the individual patient. But when you remove the low-risk patients and you just treat the high-risk patients with chemotherapy, you’re now seeing benefits of over 25%. That’s what we’re doing now in the extended endocrine phase of their treatment. If we eliminate the low-risk patients who really are

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not likely to derive any benefit, and we’re only treating the high-risk patients who are likely to benefit, that’s where we’re going to see an enormous difference in outcome. Dr Malamud To take data from 10,000 people and point to the 3% or 5% that may benefit and guess that you might be in that 5% is now an unnecessary gamble. That’s 5 years of treatment with the side effects of anti-estrogen therapy for a potential 5% difference in outcome. It is a big deal for a 40-year-old to continue another 5 years of tamoxifen or for a 60-year-old to continue another 5 years of an aromatase inhibitor (AI). There can be consequences of the treatments that may be in excess of that 5% to 6% difference in the long-term survivorship, or disease-free survivorship. Dr Boolbol It’s no longer one size fits all – we’re really treating the individual patient. Ten years ago I could tell a patient with a tumor measuring greater than 1 centimeter they were getting chemotherapy. We’ve moved into the era of genomic testing that looks at the individual cancer to determine if the patient will benefit from chemotherapy. Now my discussion with a patient includes educating

them on a test to help with the decision for chemotherapy, and at 4½ to 5 years we’ll be implementing another test to help us with the decision of continuing endocrine or anti-estrogen treatment for another 5 years. Dr Malamud BCI testing has now become a critical part of our decision making in that 4-, 4½-year mark and provides another opportunity to educate the patients. It behooves us as physicians to stay educated because breast cancer patients come in with that information. I relish that discussion because this is something that’s going to help us decide who gets treated. PMO Please describe the prognostic and predictive characteristics of this assay. Dr Malamud The Breast Cancer Index has 2 unique qualities. The first is that it is prognostic in terms of the recurrence of breast cancer in those second 5 years of disease-free state, and secondly, it will give us a prediction in terms of the value of the additional hormonal therapy for the additional 5 years. Those data are actually the only validated data for any test in demonstrating likelihood of benefit for some patients in treating beyond 5 years (Figure 2). Those data actually come from a very large multi-

Figure 2 BCI Validation Studies

MA.17 RCT

Stockholm RCT

Multiinstitutional

TransATAC RCT

Predictive

Prognostic

J Natl Cancer Inst, 2013

Clinical Cancer Research, 2013

Lancet Oncology,   2013

Validation in Prospective RCT Cohort

Validation in   Multi-institutional Cohort of Consecutive Cases

Validation in Prospective RCT Cohort & Head to Head with Oncotype Dx

249 Patients

317 Patients

358 Patients

665 Patients

Post-menopausal

Pre- and Postmenopausal

Post-menopausal

ER+ LN- and LN+

ER+ LN-

Extended AI

Adjuvant TAM

Adjuvant TAM or AI

Validation in Prospective RCT Cohort

Case-control design to enrich for recurrences

Over 1,500 patients across 4 study cohorts

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center trial, a randomized trial done from the NCIC in Canada called the MA.17, which looked at continued adjuvant therapy, continuing an AI after the first 5 years of tamoxifen. When that patient population was analyzed, there was a demonstrable benefit for those patients who received the additional AI therapy 2 years or more. In fact, at the 2-year mark, when the code was broken, it already was such a dramatic difference that the patients were unblinded and offered cross-over, which has been a criticism of that protocol.

BCI occupies a pivotal role now in our decision making when a woman receiving hormone adjuvant therapy reaches the fourth to fifth year of their treatment. But when one looks at that protocol and looks at the outcome, again the results were relatively small for the overall population. When that tumor population was looked at and classified by BCI analysis, it was quite clear there were 2 groups – those that were benefiting and those that were not. Those that were benefiting had a 15% or more, perhaps even 16% difference in terms of likelihood of benefit, or likelihood of recurrence versus the group that was statistically not getting any benefit at all. PMO How has BCI changed the discussions you have had with your patients? Dr Malamud Using those data and the discussion with the patient regarding risk and benefits, we’re able to separate out those patients who are more likely to be getting an increased benefit from that additional time on drug. Without that, we were obliged to offer at least the discussion regarding continued adjuvant therapy, and patients would look at those data relatively quizzically and wonder whether or not they were going to be in that small subgroup of patients who are actually benefiting and whether or not converting from a tamoxifen to an AI was worth that little incremental gain and the toxicities associated with the AIs. The Breast Cancer Index has made that discussion not only objective but more acceptable at the patient’s level. Dr Boolbol You hit on some key points, especially that this now gives us objective evidence. BCI allows us to have this objective discussion with our patients and move away from that one size fits all to where we have a validated test to show us that you are not likely to benefit or that you are likely to benefit. And we know that 50% or more of patients are of low benefit for ex-

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tended treatment, and that makes a big difference to those patients. Dr Malamud To be able to point to the other bar graph and say look, you’re going to be one of the women who’s more likely to benefit from additional therapy; you’ve already done the first 5 years, let’s go the full-court press. We have the evidence that you’re in the potential group that’s going to benefit from treatment, let’s move forward. That kind of objective information will oftentimes convince the patient to get off the fence and to move forward. That’s incredibly important for us now at that fifth year where we’re sort of stuck in terms of weighing the benefits without data. The Breast Cancer Index has provided the data that allow for an objective discussion. Dr Boolbol We know with endocrine treatment compliance is an issue with most of our patients. Patients have heard for years that you take 5 years of endocrine treatment and you’re done. But then we’re asking for another 5 years because we have studies to show that an additional 5 years may be of benefit, many patients think “I’m not doing this another 5 years. I’ve endured side effects from this for 5 years.” But if we tell a patient, listen, we’ve done the BCI test for you, and we know you are likely to benefit from this, they may be much more likely to be compliant with the next 5 years of treatment.

It’s a paradigm shift in how we’re treating patients with breast cancer. Dr Malamud If one has that information and it’s there in black and white, and anyone tells them that this test was devised just for this purpose and there is a strong likelihood that you’re in this category that will benefit from treatment, it turns an hour-long discussion as to risks and benefits into something much more manageable and focused such that the patient who thought, “Gee whiz, I’m all finished,” now can at least be given some objective data that there is value for more. PMO Extending endocrine therapy past 5 years is a notion recently studied in the ATLAS and MA.17 trials. Can you please discuss this development, the role BCI plays in making the decision of whether to continue therapy, and the impact on patients? Dr Malamud BCI occupies a pivotal role now in our decision making when a woman receiving hormone adjuvant therapy reaches the fourth to fifth year of their treatment. That has been the paradigm and the therapy for women with hormone-positive breast cancer such that they remain on anti-estrogen therapy for 5 years.

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Figure 3 Treatment Implications

BCI Result

Treatment Implications

Low likelihood of benefit May allow you to confidently stop endocrine therapy Low risk of recurrence after year 5 – and avoid unwanted side effects High likelihood of benefit May allow you to strongly recommend extending   High risk of recurrence and adhering to endocrine therapy We’ve been struggling to find that population of women who will benefit from extended adjuvant, meaning continuing that anti-estrogen therapy onto the fifth and now into the tenth year. Several clinical trials showed definitively that there is improvement in a population of women to be treated beyond that fifth year. Both the ATLAS and MA.17 trials demonstrate an improvement somewhere between 3% and 6% for the overall population. However, the woman sitting in front of you at that fourth to fifth year is not really interested in the general population of 5000 or more women. They really want to know what the likelihood is that they’re going to benefit, and pointing out that there is a 3% to 6% difference is not helpful to me because it also means that they’re also at risk for all the complications of treatment that take place beyond the fifth year; whether that’s a continued menopausal symptomatology of tamoxifen or the potential risk of osteoporosis, and other complications of the aromatase inhibitors.

Medicare has recently provided coverage for patients receiving testing with the Breast Cancer Index. It’s also worth noting that BCI can be used to revisit a previously made treatment decision. For example, if you have a 42-year-old patient, 7 years postdiagnosis, who opted to discontinue tamoxifen 2 years ago at the 5-year point, you can obtain the BCI test to provide reassurance of that treatment decision. If the test result for this patient shows a high likelihood of benefit from an additional 5 years of therapy, the patient can be offered to restart endocrine treatment. The reverse is also true; you may have a patient who decided to continue anti-estrogen treatment for an additional 5 years, but obtaining the BCI test at the seventh year yielded a result of low likelihood of benefit. For this patient, I may recommend discontinuation of therapy at this point.

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Dr Boolbol I think that the Breast Cancer Index and really the ATLAS trial and the MA.17 trial are pivotal changes or paradigm shifts in how we’re taking care of patients. Prior to the release of these studies I would tell a patient that they were on endocrine treatment for 5 years. Again, this goes on during their initial consult as part of their overall treatment plan. Now I tell them that they’ll be on it for 5 to 10 years depending on the results of this test. I do not know whether they will benefit from extended therapy or not. I have trials to say yes, the population at large benefits, but sitting in front of that patient, they’re really not interested in the population at large. They’re interested in what will benefit them, and I now can sit there and say we have a test, BCI or Breast Cancer Index, that we’ll be doing around 4½ years to tell us and give us that information of whether you are likely to benefit from extended therapy. If there is a low likelihood of benefit, I may recommend that you don’t need it. No one wants to be taking a medication with potential side effects for little to no benefit. If there is benefit, you will want to take it, and that’s really what we’ve gotten down to. It’s a paradigm shift in how we’re treating patients with breast cancer (Figure 3). Dr Malamud We always think that it’s relatively easy to convince somebody to take their medication that’s going to be potentially lifesaving for the first 5 years. Compliance in the first 5 years is critical. Convincing someone who’s already endured some considerable discomfort for those first 5 years to consider going on for another 5 years can be difficult. It’s nice, in fact, it’s critical to have this information that justifies the continuation of therapy. PMO Can you share your thoughts on how BCI affects patients in terms of their notions of survivorship or the psychological impact of stopping versus continuing treatment? Dr Malamud The Breast Cancer Index is an important tool to help at the decision point at that 4½- to

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5-year mark. Clearly, it’s important for the patient to know whether additional therapy will be beneficial for them over the next 5 years. But probably, almost of equal importance, is the reliance on Breast Cancer Index in helping us decide to stop after 5 years. A breast cancer patient, when she hits that 4½-year mark, is looking toward that goal line as the time that they can finally stop treatment. They need to go on with their life off of medication, be assured their disease is under control and likely to stay under control for the next 5 to 10 years. In the past, we were reluctant to do that without testing that could help us, especially after the recent trials of the ATLAS or MA.17 and the extended adjuvant trial to tell us more might be better. But more is only better in a few patients. Being able to tell a patient with more confidence that I think it is safe to stop, that I think it’s safe to go on with your life without additional medication, that it’s safer to perhaps not have any of these side effects that are destined or at least likely to happen over these next 5 years is very important. I often tell the patient they’re a survivor from the minute they meet me. But that 5-year mark has become a goalpost for many women with breast cancer and, frankly, for many people with all sorts of cancer, that 5-year mark has been their unofficial guidepost, and now being able to actually tell them in an objective way that after the fifth year, I think it’s safe to stop. You don’t need to go on. Breast cancer is a scary disease for many women, and stopping therapy is every bit as difficult as continuing treatment and being able to show them with reliance that their likelihood of recurrence is small and their likelihood of benefit is equally small gives us the ammunition to support that decision. Dr Boolbol It’s interesting how patients fall into 1 of 2 camps, and as a surgeon, at the 4-, 4½-year mark this discussion really is ramping up where you have the patient who cannot wait to get off their endocrine treatment and they’re marking it on their calendar. And then you have the other camp of patients that this is really their crutch, and they feel like taking this pill every day is really helping them – it’s saving their life. We really do now have objective data with BCI to help them through this period at the 5-year mark – we now can say this will continue to help you or this is not likely to give you any additional benefit. And it helps both camps of patients, because for the women who really feel as though this pill is making an enormous difference and they never want to stop it, we now have a test in BCI to say we’ve run this test and we know that the likelihood of benefit is small for you. At that point the risk/benefit ratio switches. There may be more risks than benefits. That helps them.

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For the other patients where the benefits outweigh the risks, that helps them. So really, every step along the way we as physicians are weighing the risk/benefit profile along with the patients to help determine the best, most ideal treatment for them. Dr Malamud The best survivorship with the best quality of life. That’s what we’re trying to do. PMO How does the use of this test (BCI) impact patient confidence in their treatment plan and ensure adherence to medication? How difficult is it to explain gene expression profiling and BCI to patients and how this technology will impact their care? Dr Boolbol It comes down to risk/benefit. If we have a test result telling us that there’s low likelihood of benefit to continued treatment, the patients, knowing that this is a validated test, are going to go along with that. And the reverse is true. If we have a test telling us that they will derive benefit from continued treatment, although they may not be thrilled about continuing endocrine treatment for another 5 years, they will willingly go along with it and are more likely to be compliant.

Now we have genomic testing that looks at the production and expression of genes associated with risk of recurrence and value of endocrine therapy in years 5-10. Dr Malamud For the 5 years prior we’ve talked about survivorship and getting through the treatment. We tell our patients to win the battle, fight the battle today to survive the next couple of years so when the next test or next treatment becomes available, you’re there to participate. Had we not been in clinical trials, had we not stored your tumor, had we not survived these 5 years, we wouldn’t be having this discussion, so here we are, here’s the information, and it is individualized. Dr Boolbol We have to remember it’s validated, predictive data, and that’s critically important. I talk to patients about short term and long term and we want to get through the short term so that we have the long term, and that’s really what it comes down to. PMO How can payers be educated on the value of these technologies to ensure patient access and cost reimbursement? Dr Malamud Medicare has recently provided coverage for patients receiving testing with the Breast Cancer Index. This is clearly appropriate in my mind, and I would certainly support that it extends onto the other private insurers because, frankly, anyone receiving hormonal therapy, whether they’re Medicare eligible or

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not, should have the opportunity for this sort of test to be applied to them when they hit the appropriate time frame. Medicare is often the first to adopt new technologies and new treatments, but they’re also a signpost for the third-party coverage to look with a critical eye at the test and appropriately adopt them into their treatment plans as well. Clearly, if one looks at the advantages to them, the Breast Cancer Index score that would indicate a patient should come off of therapy is advantageous not only to the patient in terms of their side effects and risks, but also advantageous to the insurer to avoid having not only to pay for the course of the drugs over the next 5 years but also to potentially deal with risks and complications over those 5 years to come. Dr Boolbol I think that insurance coverage really goes back to personalized medicine and now we have coverage for BCI from Medicare, it really seems as though every insurance company out there should follow suit. Just as we want to individually take care of our patients, insurance companies should want the same. There is no medication without potential side effects, and limiting access to a test such as BCI that’s out there and available to tell us whether or not a patient will benefit from therapy or withhold coverage really does not make any sense and it is not in the patient’s best interest. PMO What are the next steps in comprehensive personalized medicine for patients with breast cancer? Dr Malamud As we move forward in the treatment of women with breast cancer, we will continue to see increasing use of a personalized approach. We’ve seen personalization of treatment, first in the development of the estrogen and progesterone receptor for those women who would benefit from hormone therapy. After that came Her2 testing to figure out who required anti-Her2 therapy. Now we have genomic testing that looks at the production and expression of genes associated with risk of recurrence and value of endocrine

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therapy in years 5-10. And now with the Breast Cancer Index, helping us to decide what to do when they hit that fifth-year mark. There are a variety of other genomic tests out there to determine the interactions or potential resistance mechanisms for chemotherapy, resistance mechanisms in Her2, mTOR inhibition, PI3 kinase. There are companies where you can send tumors for complete geno mic analysis to find actionable mutations with the hope that if there’s a mutation for which we have an appropriate drug, we can use that drug to target that mutation. Dr Boolbol The way in which we treat patients 10 years from now will be completely different from what we’re doing today. Systemic issues, local treatment of breast cancer, how we do surgery, when we do surgery, what options we’re offering the patients, all these will be very different 10 years down the road. I think that we’re going to be taking a minimally invasive approach to surgery such as cryoablation as opposed to excising the patient’s cancer in the operating room. We’re making advances in all of the arenas of how we treat breast cancer. Radiation, for instance, there will be fewer patients who receive radiation. We’re also moving into the era of determining who will benefit from radiation rather than just treating every patient who has undergone breast conservation with radiation. In every discipline of our multidisciplinary team, we’re making advances in the treatment of breast cancer, all taking a personalized approach. If you look at genetic testing, we’ve made incredible advances; so many advances that we don’t have answers to everything that we know right now. That’s one of the things that clinical trials will help us with. PMO Thank you both very much for your time today, and our best to you and your continued success in your treatment of patients with breast cancer. u

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2014-2015

SCIENTIFIC CONFERENCES Presenting the most significant research on cancer etiology, prevention, diagnosis, and treatment

Translation of the Cancer Genome Co-Chairpersons: William C. Hahn, Lynda Chin, and William R. Sellers February 7-9, 2015 • San Francisco, CA Computational and Systems Biology of Cancer Co-Chairpersons: Andrea Califano, Brenda Andrews, and Peter Jackson February 8-11, 2015 • San Francisco, CA AACR-Society of Nuclear Medicine and Molecular Imaging Joint Conference: Molecular Imaging in Cancer Biology and Therapy Co-Chairpersons: Carolyn J. Anderson, Christopher H. Contag, and David Piwnica-Worms February 11-14, 2015 • San Diego, CA Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers Co-Chairpersons: Rakesh K. Jain, Peter Carmeliet, Helen Chen, Harold F. Dvorak, and Napoleone Ferrara March 5-8, 2015 • Orlando, FL AACR Annual Meeting 2015 Program Committee Chairperson: Lewis C. Cantley April 18-22, 2015 • Philadelphia, PA Advances in Brain Cancer Research Co-Chairpersons: Eric C. Holland, Franziska Michor, Martine F. Roussel, and Michael D. Taylor May 27-30, 2015 • Washington, DC Metabolism and Cancer Co-Chairpersons: Ralph J. DeBerardinis, David M. Sabatini, and Almut Schulze June 7-10, 2015 • Bellevue, WA Methods in Cancer Biostatistics Workshop: Clinical Trial Designs for Targeted Agents Director: Steven Piantadosi June 7-13, 2015 • Lake Tahoe, CA AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy Co-Chairpersons: Charles L. Sawyers, Elaine R. Mardis, and Arul M. Chinnaiyan June 13-16, 2015 • Salt Lake City, UT

www.AACR.org/Calendar

EACR-AACR-SIC Special Conference on Anticancer Drug Action and Drug Resistance: From Cancer Biology to the Clinic Co-Chairpersons: Richard M. Marais, Pasi Jänne, and Riccardo Dolcetti, June 20-23, 2015 • Florence, Italy Chromatin and Epigenetics in Cancer Co-Chairpersons: Sharon Y. R. Dent, Peter A. Jones, and Charles W. M. Roberts September 24-27, 2015 • Atlanta, GA CRI-CIMT-EATI-AACR The Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival 2015 September 27-30, 2015 • New York, NY Advances in Breast Cancer Research Co-Chairpersons: Matthew J. Ellis, Charles M. Perou, and Jane E. Visvader October 17-20, 2015 • Bellevue, WA Advances in Ovarian Cancer Co-Chairpersons: Kathleen R. Cho, Douglas A. Levine, and Benjamin G. Neel October 17-20, 2015 • Orlando, FL Fourth AACR International Conference on Frontiers in Basic Cancer Research Chairperson: M. Celeste Simon; Co-Chairpersons: James P. Allison, John E. Dick, Nathanael S. Gray, and Victor E. Velculescu October 23-26, 2015 • Philadelphia, PA Basic Science of Sarcomas Co-Chairpersons: Robert G. Maki, Jonathan A. Fletcher, Lee J. Helman, Angelo Paolo Dei Tos, and Brian Van Tine November 3-4, 2015 • Salt Lake City, UT New Horizons in Cancer Research Co-Chairpersons: Lewis C. Cantley and Carlos L. Arteaga November 2015 • Shanghai, China AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Scientific Committee Co-Chairpersons: Levi A. Garraway, Lee J. Helman, and Jean-Charles Soria November 5-9, 2015 • Boston, MA

PSYCHOSOCIAL ONCOLOGY

Putting the “Person” in Personalized Cancer Medicine: A Systematic Review of Psychological Aspects of Targeted Therapy Daniel C. McFarland, DO, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai Jada G. Hamilton, PhD, MPH, Memorial Sloan Kettering Cancer Center Rosanne Fox, MD, Hudson Valley Psychiatric Associates Jimmie Holland, MD, Memorial Sloan Kettering Cancer Center

“Cancer therapy has become an extremely technical undertaking involving the strenuous efforts of highly specialized professionals, each taking responsibility for a share of the patient’s problem, sometimes working at a rather impersonal distance from the patient as an individual.” —Lewis Thomas, MD, 1989 Foreword to Handbook of Psychooncology1

Daniel C. McFarland, DO

argeted therapies in the new era of molecular medicine are currently used in most oncologic settings with increasing success. They have hit the prime time and are the star agents for many oncologic diseases. Yet, they add an additional layer of complexity to cancer care. They represent a paradigmatic shift in treatment based on specific gene expression or mutational analysis. This deepening understanding of biology has led to overall survival and Jimmie Holland, MD symptom-based improvements. However, biological “personalization” is often translated into the general term “personalized medicine,” which has traditionally been used broadly to mean patient-centered care, the biopsychosocial model that conceptualizes illness within the context of a patient’s

Jada G. Hamilton, PhD, MPH

Dr McFarland is a clinical fellow in the Division of Hematology/ Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai in New York, New York. Dr Hamilton is Assistant Attending Psychologist in the Department of Psychiatry & Behavioral Sciences at Memorial Sloan Kettering Cancer Center in New York, New York. Dr Fox is a psychiatrist at Hudson Valley Psychiatric Associates in Kingston, New York. Dr Holland is the Wayne E. Chapman Chair in Psychiatric Oncology, Department of Psychiatry & Behavioral Sciences at Memorial Sloan Kettering Cancer Center in New York, New York.

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total life situation. This perspective emphasizes the importance of interactions between biological, psychological, and social factors in the context of disease and treatment. Ironically, very little is known about these issues in molecular-based medicine.

How Do Patients Understand Treatments That Are Based on the DNA of Their Tumor? What Are the Psychological Considerations That Arise for Patients? The patient experience with targeted therapies is not well documented in the literature. This contrasts with the burst of psychological studies and remarkable number of citations that became available after the advent of genetic testing for heritable tumors, such as BRCA1/2 in breast and ovarian cancer in healthy patients (for reviews, see references 2 and 3). The experience more closely parallels that of patients receiving traditional chemotherapy treatment. Similarities exist between informed consent for chemotherapy, clinical trials, and targeted therapies. As such, clinical experience suggests that patients are less concerned about the molecular basis of treatment and more concerned about efficacy and side effects. Patients’ expectations for the success of targeted therapies appear to be similar to the experience with chemotherapy in that their hope for efficacy far exceeds the actual survival data.4,5 In this transitional era from cytotoxic to targeted therapy, it is incumbent upon the oncology community to examine psychological and social implications of

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targeted therapy in order to provide an approach to patient-centered care with an eye toward improving quality. However, research at the intersection of oncology and mental health comprises a total of only 0.26% of all oncology publications and 0.51% of all mental health publications over the past 10 years.6 Treatment decisions need to be guided by scientific and technological advances, but also by aspects of the patient’s personal experience. A qualitative study of patients with metastatic lung, breast, and colorectal cancer found that patients did not understand somatic genetic testing and were not aware of or harbored misunderstandings about the term “personalized medicine.”7 If we want to advocate for “patient-centered care” in oncology, we must do more than simply call it “personalized.”8 In order to provide a foundation for future work at this intersection, this paper reviews the current literature on psychological and social issues associated with targeted therapies and their impact on clinical care and research.

Materials and Methods Databases Included in the Search Literature searches were conducted utilizing PubMed on April 6 and April 24, 2014, and Web of Science (WOS) on April 26, 2014. Search Strategy This review was performed in 2 parts and tracked publications back to 1995. Step 1 utilized a free-text key term search, and step 2 combined the key search terms (see below) with specific targeted therapy drugs as defined by the National Cancer Institute (NCI). For step 1, free-text terms were entered in both PubMed and WOS to search for citations containing the following: “cancer personalized medicine AND psychological,” “novel cancer therapy AND psychological,” “cancer targeted therapy AND psychological,” and “cancer targeted therapy AND psychosocial.” For step 2, a search was conducted in PubMed only using the terms “psychological” and “quality of life” in combination with each targeted cancer therapy as designated by the NCI (total 39 drugs) as listed on www.cancer.gov/ cancertopics/factsheet/Therapy/targeted on April 24, 2014. This review adhered to the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis report. Study Inclusion and Exclusion Criteria The inclusion criteria in step 1 were more broadly inclusive and accepted relevant review papers as well as prospective or retrospective studies that were either qualitative or quantitative. In step 2 (ie, review of specific targeted agents), the inclusion criteria were re-

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KEY POINTS Psychosocial research has not kept pace with rapid scientific advances in targeted therapies ➤ There is little research evidence available to help oncologists educate patients on the psychosocial implications of their therapies ➤ Psychological concerns of patients receiving targeted therapies mainly relate to outcomes and side effects ➤ Patients tend to accept experimental treatments because they hope for a better outcome, fear the disease without treatment, and trust the doctor’s recommendation for treatment ➤ Psychological aspects of targeted therapies are beginning to receive attention, yet much work remains to be done to assure that truly patientcentered care remains the goal in the era of targeted therapies ➤

stricted to studies that reported prospectively obtained quantitative data (ie, no review papers) in which quality of life (QOL) was either the primary or secondary aim and QOL scales specifically included psychological content. All included articles were peer reviewed, involved human research, were written in English, and involved psychological or QOL content. Exclusion criteria included review articles (for step 2 only), editorials, and preclinical studies.

If we want to advocate for “patientcentered care” in oncology, we must do more than simply call it “personalized.” Screening and Data Abstraction Article titles and abstracts were reviewed for psychological content. Articles were included if they related to targeted therapy (based on molecular/cellular targets used in cancer treatment) and addressed a psychological issue. Steps 1 and 2 of the literature search were conducted by DCM. Inclusion of “relevant” articles was decided by DCM according to the topic relevance, article quality, and data analysis methodology. Inclusion of relevant articles was reviewed by JGH, and disagreements settled by author discussion. Results Step 1 identified 711 relevant citations using PubMed and WOS (Figure 1), of which only 10 were

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Table 1 Step 1 Systematic Review Results (Relevant Citations) Selected Studies or Highly Relevant Reviews

Study Design

Cancer Type

Content/Theme

Gray et al. 2012

Prospective/ qualitative

Lung, CRC, breast (n=69)

Patient attitudes about 1) Greater than 50% didn’t know personalized medicine or misunderstood the term; and genetic testing 2) Reluctance to undergo full genome sequencing (62%)

Thorne et al.10 2013

Prospective/ qualitative

Metastatic malignancies (n=15)

Communication challenges in era of novel therapeutics

1) Changing “landscape” of communication

Cornetta et al.9 2013

Review

Variable

Incongruence of term “personalized”

1) Threat to spiritual/ psychological aspect of care

Shun et al.11 2012

Prospective/ quantitative

HCC receiving TACE treatments (n=89)

Psychological distress and QOL (SDS, HADS, SF-12)

1) Fatigue most distressful; 2) QOL improved monthly after discharge

Capuron et al.12 2004

Prospective/ quantitative

RCC or malignant melanoma (n=32)

Role of subclinical mood symptoms in predicting clinical depression with cytokine therapy

1) Depressive symptoms predicted by baseline emotional symptoms, sleep disturbance, and low social support

Rouanne et al.14 2013

Prospective/ quantitative

Advanced or metastatic cancer refractory to classic lines of chemotherapy on phase 1 trials (n=63)

Effect of phase 1 targeted agents on HRQOL, depression, and sexual function

1) Preserved emotional and physical domains, whereas sexual activity declined in both sexes

Peppercorn et al.15 2011

Position paper – None ASCO special article

Communication and decision making for patients with advanced cancer

1) Goals for individualized care, barriers, and possible strategies

Garcia et al.16 2007

Review/position None paper

Implementation of 1) Outline of PROMIS methods PROs for clinical trials for developing PRO measures

Viele.17 2007

Review

Patients receiving oral chemotherapy

Challenges to managing oral chemotherapy

1) Role of healthcare practitioners in educating patients about side effects and assessing adherence

Von Gool et al.13 2003

Review

Patients receiving inter feron alpha (melanoma, CML, RCC, MM)

Neuropsychiatric effects of interferon alpha

1) An evaluation of evidence of psychiatric depressive effects of interferon alpha

Results/Conclusions

Results from systematic review (step 1) using search terms “cancer personalized medicine AND psychological,” “novel cancer therapy AND psychological,” “cancer targeted therapy AND psychological,” and “cancer targeted therapy AND psychosocial” in both PubMed and Web of Science. ASCO indicates American Society of Clinical Oncology; CML, chronic myelogenous leukemia; CRC, colorectal cancer; HADS, Hospital Anxiety and Depression Scale; HCC, hepatocellular carcinoma; HRQOL, health-related quality of life; MM, multiple myeloma; PRO, patient-reported outcome; PROMIS, Patient-Reported Outcome Measurement Information System; QOL, quality of life; RCC, renal cell carcinoma; SDS, Symptom Distress Scale; SF-12, Short Form-12; TACE, transarterial chemoembolization.

found to be relevant (Table 1). Three studies evaluated patients’ perception of personalized medicine7,9,10; 4 studies reported symptoms related to targeted therapy11-14; 2 position papers called for greater patient-centered care15,16; and 1 paper reviewed oral chemotherapy

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management.17 Specifically, the 2 position papers called for improved communication in advanced cancer15 and enhanced use of patient-reported outcomes (PROs) in clinical care.16 Among the themes reported were the lack of patient understanding and awareness of the

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Figure 1 Consort Diagram for Step 1 of Systematic Review

Potentially relevant studies were searched via PubMed using the following:

Potentially relevant studies were searched via Web of Science using the following:

1. “cancer personalized medicine AND psychological” (n=49)

1. “cancer personalized medicine AND psychological” (n=35)

2. “novel cancer therapy AND psychological” (n=77)

2. “novel cancer therapy AND psychological” (n=45)

3. “cancer targeted therapy AND psychological” (n=162)

3. “cancer targeted therapy AND psychological” (n=140)

4. “cancer targeted therapy AND psychosocial” (n=105)

4. “cancer targeted therapy AND psychosocial” (n=98)

Number of records screened: 711

Papers excluded for the following (n=701): 1. Not relevant/repeated papers (n=481) 2. Nonrelevant review papers (n=177) 3. Not English (n=25) 4. Case reports (n=10) 5. Editorials (n=8)

Papers with relevant content for review inclusion (n=10): 1. Prospective quantitative data (n=4) 2. Prospective qualitative data (n=2) 3. Highly relevant review article (n=3) 4. Position paper (n=1)

term “personalized medicine”7; patient questions related to the term “personalized”9; and doctor-patient communication challenges regarding novel therapeutics in presentations of molecularly based therapy.10 Additional citations addressed side effects associated with targeted therapies such as psychological distress,11 depression,12,13 and sexual dysfunction.14 One study reviewed the management of oral chemotherapy and its challenges.17 Step 2 identified 75 citations related to “psychological” and 2262 citations related to “quality of life.” The vast majority of studies addressed QOL and showed either a benefit in QOL from the therapy or that QOL was noninferior to other treatments. Fifteen papers were

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deemed relevant to this review (Table 2). More publications were identified for drugs that have been FDA approved for a longer period of time (Figure 2). Publications related to QOL or psychological considerations generally lagged behind FDA approval by 5 to 8 years. The psychological themes from the 75 citations in step 2 studies are presented in Table 2. Eleven of 15 selected papers dealt specifically with a symptom (eg, depression,18 fatigue,19-23 rash,24 cognitive function25), or adherence26-28 to a regimen of targeted therapy (eg, imatinib, sunitinib, cetuximab). One paper evaluated targeted therapy use at the end of life.29 Most of the QOL trials only evaluated tolerability and did not explore other experiential or psychological issues. Of the

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P a g e | 14

Figure 2. Number of Step 2 Total Citations (blue) and Selected Relevant Citations (red)

Targeted Agent (FDA approval year) Targeted Agent (FDA Approval Year)

Figure 2 Number of Step 2 Total Citations and Selected Relevant Citations Ziv-aflibercept(2012) (2012) Ziv-‐aflibercept Carfilzomib(2012) (2012) Carfilzomib Cabozantinib (2012) Cabozan.ib (2012) Regorafenib(2012) (2012) Regorafenib Bosutinib(2012) (2012) Bosu.nib Brentuximab(2011) (2011) Brentuximab Crizotinib(2011) (2011) Crizo.nib Ipilimumab(2011) (2011) Ipilimumab Vemurafenib(2011) (2011) Vemurafenib Vandetanib 2(2011) Vande.nab 011) Pazopanib(2009) (2009) Pazopanib Pralatrexate(2009) (2009) Pralatrexate Romidepsin(2009) (2009) Romidepsin Ofatumumab(2009) (2009) Ofatumumab Everolimus(2009) (2009) Everolimus Ontak®(2008) (2008) Ontak® Bexarotene(2007) (2007) Bexarotene Alemtuzumab(2007) (2007) Alemtuzumab Lapatinib(2007) (2007) Lapa.nib Temsirolimus(2007) (2007) Temsirolimus Nilotinib(2007) (2007) Nilo.nib Rituximab(2006) (2006) Rituximab Panitumumab(2006) (2006) Panitumumab Vorinostat(2006) (2006) Vorinostat Bortezomib(2006) (2006) Bortezomib Sunitinib(2006) (2006) Suni.nib Trastuzumab(2006) (2006) Trastuzumab Dasatinib(2006) (2006) Dasa.nib Gefitinib(2005) (2005) Gefi.nib Sorafenib(2005) (2005) Sorafenib Cetuximab(2004) (2004) Cetuximab Erlotinib(2004) (2004) Erlo.nib Bevacizumab(2004) (2004) Bevacizumab Bexxar®(2003) (2003) Bexxar® Zevalin®(2002) (2002) Zevalin® Imatinib(2001) (2001) Ima.nib Alitretinoin(1999) (1999) Alitre.noin Tretinoin(1995) (1995) Tre.noin

Selected Selected relevant Cita.ons citations Total Total citations Cita.ons

100

150

200

250

300

350

Number Numberof ofPublica9ons Publications

Citations are listed by each targeted agent as denoted by the National Cancer Institute (www.cancer.gov/cancertopics/factsheet/ Citations are listed by performing each targeted agent search as denoted by terms the National Cancer Institute Therapy/targeted) after a PubMed with the “psychological” and “quality of life” for each agent (step 2). Targeted agent FDA approval year is listed in parentheses. Total numbers of citations drug is highlighted with blue columns, (www.cancer.gov/cancertopics/factsheet/Therapy/targeted) after performing a per PubMed search with the terms and relevant included citations are highlighted in the red columns. “Psychological” and “Quality of Life” for each agent (step 2). Targeted agent FDA approval year is listed in parentheses. Total numbers of citations per drug is highlighted with blue columns, and relevant included citations are highlighted in 26

QOL trials that used an instrument with psychological the red column. measures and were included in the study, all showed favorable tolerability except for a small decrement of QOL with bevacizumab in ovarian cancer.30,31 Six of the 15 studies evaluated imatinib in the setting of chronic myeloid leukemia (CML) with an emphasis on adherence.22,23,26-28,32 Common reasons for stopping

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imatinib were negative medication experiences, polypharmacy in patients on many medications,32 and low social support or lack of satisfaction with medication information.27 Patient-level differences were noted in intentional versus nonintentional nonadherence: younger age, lower socioeconomic status, and poorer understanding of treatment rationale.28 Symptom bur-

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den of imatinib in CML was fatigue, depression, and reduced QOL while on treatment.18,23 Healthcare professionals often underestimated the severity of such patient-reported symptoms.21

Discussion This review of extant literature revealed a paucity of studies that explored psychological or social aspects of targeted therapies, perhaps with the exception of tyrosine kinase inhibitors and fatigue. However, several points become clear from those studies reported in this review. First, the term “personalized medicine” is poorly understood by patients. They do not relate molecular medicine to personalization, which is also consistent with the experience of the authors. “Precision medicine” or targeted therapy may be preferable terms. This also reduces the confusion with the widespread use of terms like “patient-centered care” to denote attention to the whole patient, from biology through psychological and social issues. Second, although few studies examined this issue, the review did not find evidence that cancer patients have concerns about genetic testing of their tumor to inform targeted treatment. This is in sharp contrast to the careful preparation of healthy individuals undergoing genetic testing for hereditary cancer syndromes where genetic counselors are often involved.2,3 In fact, patients readily expressed that they did not understand the described “pathways” but that side effects and treatment outcome were much more important in giving consent.7,12 This suggests that patients’ motivations and concerns regarding targeted therapeutics appear to be similar to those observed in patients receiving cytotoxic chemotherapy. For example, in a CALGB study, patients were asked why they agreed to receive chemotherapy for a wide range of cancers.33 Patients were clear that they feared the outcome of the cancer if they did nothing. They hoped for a favorable benefit and they trusted the oncologist. This triad of fear, hope, and trust appears highly relevant to patients receiving new therapies today. Extended description of the complex molecular drivers and biologic mechanisms may not be essential or indeed desired except by those patients who request detailed explanations in order to make an informed treatment choice. It must be noted, however, that as genomic sequencing of tumors increases, the potential for patients to learn meaningful, incidental germline risk information also increases. Genetic incidentalomas will become more prevalent and demand further attention into their ethical, clinical, and psychological implications.34 Similar to the advent of chemotherapy a few decades ago, the oncologic community and the public at large

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are both excited by the new hope that novel therapies bring. News from national cancer meetings is widely reported with great enthusiasm, and there is an exuberant sense that a new era of cancer care has arrived.35,36 For newly diagnosed patients, the wait for a molecular analysis is anxiety-provoking and is colored by “Will I qualify? Do I have the right gene?” Having the gene is viewed as winning the lottery, and not having it is often perceived with sadness, as if it were a personal failure. Both the oncologist and the patient share the optimism of a new treatment. However, for the patient with advanced disease, it is necessary to present the targeted therapeutic treatment with hope, but also tempering it with reality. Data are clear that patients’ expectations of outcome in receiving phase 1 clinical trial therapy far exceed the reality.37 This issue in communication can be most difficult in the advanced cancer setting after multiple lines of ther-

Similar to the advent of chemotherapy a few decades ago, the oncologic community and the public at large are both excited by the new hope that novel therapies bring. apy have been used. A new drug is a symbol of hope that is powerful; however, it may serve as a deterrent from dealing with the realities of disease burden. Even so, moving on to the next agent may actually symbolize defeat in the mind of the patient. Caring and commitment inspire hope and trust for the patient who understands, “I am cared for.” These responses help to mitigate targeted therapy overuse at the end of life. Physicians and care teams play an enormous role in the lives of patients who are coming to terms with mortality. This constancy and concern is therapeutic in itself. This review found that all targeted therapies had reports of their impact on QOL (functioning in healthrelated domains). Overall, targeted therapies are well tolerated, with fatigue and rash being the most commonly reported symptoms. Depression, anxiety, and cognitive dysfunction are reported with specific therapies and will need to be explored further. Adherence to oral therapies, late-emerging side effects, and psychological ramifications will become increasingly important as oral targeted agents depend on patient administration and are generally utilized for longer periods. The oncologist has an obligation to arrive at a decision that is truly shared with a patient who understands the treatment plan, goals, and side effects and that considers the patient’s personal values and preferences. To that end,

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Table 2 Step 2 Systematic Review Results (Relevant Citations) Selected Studies

Targeted Agent/ Cancer Type

Trial Design

Content/Theme

Results/Conclusions

Hirji et al. 2013

First- and secondgeneration TKIs/ CML

Prospective/ quantitative (n=303)

Negative medication experiences are associated with decreased HRQOL and treatment adherence

1) 30% reported difficulties with treatment, highest with nilotinib (62%) associated with treatment nonadherence

Philips et al.18 2013

TKIs/CML

Prospective/ quantitative (n=124)

TKI associated with symptom burden, including depression measured with CES-D

1) Compared with control, TKI therapy was associated with fatigue, fatigue interference, depression, symptoms burden, and worse physical QOL

Iurlo et al.32 2014

TKIs/geriatric CML (>65 years old)

Cross-sectional (n=16)

Fewer comorbidities and polypharmacy predicted for complete cytogenetic response to TKI

1) Small cohort

Efficace et al.27 2012

Imatinib/CML

Multicenter, crosssectional, secondary analysis (n=413 CML patients)

Evaluate patient-reported personal factors associated with adherence behavior

1) 53% optimal adherence behavior; 2) Greater adherence was associated with higher level of social support, satisfaction with information received, and lower concomitant drug burden

Efficace et al.28 2014

Imatinib/CML

Multicenter crosssectional, secondary analysis (n=175)

Outline HRQOL, symptoms, SES, and clinical characteristics in patients reporting intentional or unintentional reasons for nonadherence to imatinib

1) Among nonadherents, 27% reported intentional (eg, due to side effects), while 73% reported unintentional nonadherence (eg, reasons other than avoiding side effects)

Efficace et al.23 2013

Imatinib/CML

Multicenter crosssectional, primary analysis (n=422)

Investigate factors associated with long-term HRQOL outcomes of CML patients receiving imatinib

1) Fatigue was the only variable showing an independent and consistent association across all physical and mental HRQOL outcomes

Efficace et al.21 2012

Imatinib/CML

Multicenter, crosssectional, mixedmethods data obtained (n=236)

Compare HRQOL aspects valued by patients versus healthcare professionals

1) Patients and HCP agreed on most important HRQOL: fatigue, muscle cramps, swelling, worries, uncertainty about health condition in the future, and the importance of social support in coping with disease; 2) Patients placed greater emphasis on symptoms such as dry mouth, trouble concentrating, drowsiness, and skin problems

Efficace et al.22 2011

Imatinib/CML

Cross-sectional, case-control, quantitative (n=472)

Investigate differences in HRQOL in control versus CML patients on imatinib

1) Largest HRQOL found in younger patients 18-39 years of age; 2) Younger and female patients reported the most limitations; fatigue was most commonly reported

Romito et al.24 2010

Cetuximab/mCRC

Cross-sectional, quantitative (n=80)

Investigate the psychological sequelae of EGFR inhibitorâ&#x20AC;&#x201C;induced skin rash

1) 53% of patients did not avoid going out; 2) Although QOL was correlated with rash, psychological distress and social avoidance were not; 3) Possible explanations include that rash is considered part of complex of suffering or that patients are encouraged to continue because skin rash is indicative of response to treatment

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Table 2 Step 2 Systematic Review Results (Relevant Citations) continued Selected Studies

Targeted Agent/ Cancer Type

Hui et al. 2013

Trial Design

Content/Theme

Results/Conclusions

Variable

Cross-sectional, quantitative (n=816)

Determine the frequency and predictors of targeted therapy use in the last days of life

1) Median interval between last treatment and death was 47 days for targeted agents and 57 days for chemotherapeutic agents; 2) Targeted agents were used as frequently as chemotherapy at end of life, particularly among younger patients and those with hematologic malignancies

Mulder et al.25 2014

Sorafenib or sunitinib/mRCC, GIST

Case cohort, crosssectional (n=80)

Investigate the objective and subjective cognitive function of patients during treatment with VEGFR TKIs

1) Both patient groups performed significantly worse on cognitive domains Learning & Memory and Executive Functions compared with healthy controls; 2) Longer duration of treatment on VEGFR TKI was associated with a worse score on Working Memory tasks

Goebell et al.19 2014

RCC

Cross-sectional, quantitative analysis of patients and physicians surveys (n=98)

Assess fatigue in patients with advanced RCC by comparing the evaluation of the physician to the one provided by their respective patients

1) Fatigue was more severe when reported by the patient; 2) The severity of fatigue increased with progressing treatment lines; 3) QOL was lower with greater fatigue; 4) Emotional, functional, and physical well-being were all affected by fatigue; 5) Social well-being was least affected by fatigue

Cella et al.20 2014

Sunitinib/mRCC

Phase 3, longitudinal quantitative analysis (n=750)

Characterizing fatigue associated with sunitinib and its impact on HRQOL in mRCC

1) Patient-reported fatigue with sunitinib was worst during cycle 1; 2) Less fatigue was reported during subsequent cycles, with no statistically significant worsening; 3) CTCAE may not fully capture the patient treatment experience

Stark et al.30 2013

Bevacizumab/ advanced ovarian cancer

Phase 3 data (n=764)

Aims to describe the HRQOL outcomes from ICON7 phase 3 randomized trial

1) Bevacizumab continuation treatment seems to be associated with a small but clinically significant decrement in QOL

Monk et al.31 2013

Bevacizumab/ advanced ovarian cancer

Phase 3 trial (n=1693) Analysis of QOL in a randomized phase 3 trial concluding that addition of concurrent and maintenance bevacizumab to carboplatin and paclitaxel prolongs PFS

1) The small QOL difference observed during chemotherapy did not persist during maintenance bevacizumab

Results of the systematic review (step 2) of studies that contain specific psychological content with regard to each National Cancer Institute–designated targeted agent using PubMed search terms “psychological” or “Quality of Life” AND each targeted agent. CES-D indicates Centers for Epidemiologic Studies Depression Scale; CML, chronic myelogenous leukemia; CTCAE, Common Terminology Criteria for Adverse Events; EGFR, epidermal growth factor receptor; GIST, gastrointestinal stromal tumor; HCP, healthcare professional; HRQOL, health-related quality of life; ICON7, International Collaboration on Ovarian Neoplasms 7; mRCC, metastatic renal cell carcinoma; PFS, progression-free survival; QOL, quality of life; RCC, renal cell carcinoma; SES, socioeconomic status; TKI, tyrosine kinase inhibitor; VEGFR, vascular endothelial growth factor receptor.

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shared decision making should consider the financial burden of treatment as well.38 In terms of future research, clinical trials of targeted therapies increasingly utilize PROs, which far more adequately capture subjective symptoms and increase patient satisfaction and sense of participation.39 Symptoms are often underestimated by oncologists’ reported observations.39 The FDA definition of a PRO is “any report of the status of a patient’s health condition that comes directly from the patient without interpretation of the patient’s response by a clinician or anyone else.”39 In clinical care, collecting and providing PRO results to oncologists have been shown to have positive effects on patient-physician communication.40 These discussions were raised primarily by patients or their relatives; however, this suggests that the proper utilization and interpretation of PRO data need to be explored further. PROs could be used to further understanding and knowledge of the informed consent process for targeted therapies. Compared with the rich literature on in-

Existing research suggests that fatigue and rash are the most commonly observed symptoms so far with targeted therapies and that QOL remains tolerable. formed consent for chemotherapy and clinical trials, there is currently very little information regarding the optimization of informed consent in the era of precision medicine. This trend in utilizing PROs should continue as new therapies emerge and side effects can be identified and anticipated. Limitations of this review include the likelihood that limited search terms may not have captured all potentially relevant topics, and that only English language studies were reviewed. An additional limitation is that the review did not include studies of the financial burden of expensive targeted drugs, although such burden may add to psychological stress. For instance, “financial toxicity” was reported in 42% of an insured cohort of 254 patients who had been prescribed a targeted treatment. They described applying for copayment assistance (75%), reducing spending on food (46%), taking less than prescribed (20%), and partially filling (19%) and avoiding filling prescriptions altogether (24%).38 Leaders in the oncology community have recently engaged in the economic aspects of rising drug costs for patients.41 In summary, this review confirms that psychosocial research has not kept pace with rapid scientific advanc-

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es in targeted therapies. Although patients may receive detailed information about the more complex basis upon which their treatment is determined, there is currently little research evidence available to help oncologists educate their patients on the broader psychosocial implications of their therapies. The new psychological concerns expressed by patients receiving targeted therapies appear to be most similar to those concerns observed in patients receiving cytotoxic chemotherapy and relate to questions about side effects and outcomes. Patients need adequate biological and molecular information about the treatment proposed, but on the whole, information on the clinical outcome and side effects is far more important to them. Existing research suggests that fatigue and rash are the most commonly observed symptoms so far with targeted therapies and that QOL remains tolerable. Specific subjective symptoms, particularly psychological, will need further study with each new agent. In general, patients accept experimental treatments because they hope for a better outcome, fear the disease without treatment, and trust the doctor’s recommendation for treatment. Research into the patient experience with targeted therapy should inform shared decision making and clinical care in this era of genome-driven treatment. Psychological aspects of targeted therapies are beginning to receive attention, yet much work remains to be done to assure that truly patient-centered care remains the goal in the era of targeted therapies. u

References

1. Holland JC, Rowland JH, eds. Handbook of Psychooncology: Psychological Care of the Patient with Cancer. Volume 236. New York, NY: Oxford University Press; 1989. 2. Hamilton JG, Lobel M, Moyer A. Emotional distress following genetic testing for hereditary breast and ovarian cancer: a meta-analytic review. Health Psychol. 2009;28:510-518. 3. Heshka JT, Palleschi C, Howley H, et al. A systematic review of perceived risks, psychological and behavioral impacts of genetic testing. Genet Med. 2008;10:19-32. 4. Temel JS, Greer JA, Muzikansky A, et al. Early palliative care for patients with metastatic non-small-cell lung cancer. N Engl J Med. 2010;363:733-742. 5. Zafar SY, Peppercorn JM, Schrag D, et al. The financial toxicity of cancer treatment: a pilot study assessing out-of-pocket expenses and the insured cancer patient’s experience. Oncologist. 2013;18:381-390. 6. Purushotham A, Bains S, Lewison G, et al. Cancer and mental health – a clinical and research unmet need. Ann Oncol. 2013;24:2274-2278. 7. Gray SW, Hicks-Courant K, Lathan CS, et al. Attitudes of patients with cancer about personalized medicine and somatic genetic testing. J Oncol Pract. 2012;8:329-335. 8. Oliver A, Greenberg CC. Measuring outcomes in oncology treatment: the importance of patient-centered outcomes. Surg Clin North Am. 2009;89:17-25. 9. Cornetta K, Brown CG. Balancing personalized medicine and personalized care. Acad Med. 2013;88:309-313. 10. Thorne SE, Oliffe JL, Oglov V, et al. Communication challenges for chronic metastatic cancer in an era of novel therapeutics. Qual Health Res. 2013;23:863-875. 11. Shun SC, Chen CH, Sheu JC, et al. Quality of life and its associated factors in patients with hepatocellular carcinoma receiving one course of transarterial chemoembolization treatment: a longitudinal study. Oncologist. 2012;17:732-739. 12. Capuron L, Ravaud A, Miller AH, et al. Baseline mood and psychosocial characteristics of patients developing depressive symptoms during interleukin-2 and/or interferon-alpha cancer therapy. Brain Behav Immun. 2004;18:205-213. 13. Van Gool AR, Kruit WH, Engels FK, et al. Neuropsychiatric side effects of interferon-alfa therapy. Pharm World Sci. 2003;25:11-20. 14. Rouanne M, Massard C, Hollebecque A, et al. Evaluation of sexuality, healthrelated quality-of-life and depression in advanced cancer patients: a prospective study in a phase 1 clinical trial unit of predominantly targeted anticancer drugs. Eur J

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Cancer. 2013;49:431-438. 15. Peppercorn JM, Smith TJ, Helft PR, et al. American Society of Clinical Oncology statement: toward individualized care for patients with advanced cancer. J Clin Oncol. 2011;29:755-760. 16. Garcia SF, Cella D, Clauser SB, et al. Standardizing patient-reported outcomes assessment in cancer clinical trials: a patient-reported outcomes measurement information system initiative. J Clin Oncol. 2007;25:5106-5112. 17. Viele CS. Managing oral chemotherapy: the healthcare practitioner’s role. Am J Health Syst Pharm. 2007;64:S25-S32. 18. Philips KM, Pinilla-Ibarz J, Sotomayor E, et al. Quality of life outcomes in patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors: a controlled comparison. Support Care Cancer. 2013;21:1097-1103. 19. Goebell PJ, Münch A, Müller L, et al. A cross-sectional investigation of fatigue in advanced renal cell carcinoma treatment: results from the FAMOUS study. Urol Oncol. 2014;32:362-370. 20. Cella D, Davis MP, Négrier S, et al. Characterizing fatigue associated with sunitinib and its impact on health-related quality of life in patients with metastatic renal cell carcinoma. Cancer. 2014;120:1871-1880. 21. Efficace F, Breccia M, Saussele S, et al. Which health-related quality of life aspects are important to patients with chronic myeloid leukemia receiving targeted therapies and to health care professionals? GIMEMA and EORTC Quality of Life Group. Ann Hematol. 2012;91:1371-1381. 22. Efficace F, Baccarani M, Breccia M, et al. Health-related quality of life in chronic myeloid leukemia patients receiving long-term therapy with imatinib compared with the general population. Blood. 2011;118:4554-4560. 23. Efficace F, Baccarani M, Breccia M, et al. Chronic fatigue is the most important factor limiting health-related quality of life of chronic myeloid leukemia patients treated with imatinib. Leukemia. 2013;27:1511-1519. 24. Romito F, Giuliani F, Cormio C, et al. Psychological effects of cetuximab-induced cutaneous rash in advanced colorectal cancer patients. Support Care Cancer. 2010;18:329-334. 25. Mulder SF, Bertens D, Desar IM, et al. Impairment of cognitive functioning during sunitinib or sorafenib treatment in cancer patients: a cross sectional study. BMC Cancer. 2014;14:219. 26. Hirji I, Gupta S, Goren A, et al. Chronic myeloid leukemia (CML): association of treatment satisfaction, negative medication experience and treatment restrictions with health outcomes, from the patient’s perspective. Health Qual Life Outcomes. 2013;11:167. 27. Efficace F, Baccarani M, Rosti G, et al. Investigating factors associated with adherence behaviour in patients with chronic myeloid leukemia: an observational pa-

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tient-centered outcome study. Br J Cancer. 2012;107:904-909. 28. Efficace F, Rosti G, Cottone F, et al. Profiling chronic myeloid leukemia patients reporting intentional and unintentional non-adherence to lifelong therapy with tyrosine kinase inhibitors. Leuk Res. 2014;38:294-298. 29. Hui D, Karuturi MS, Tanco KC, et al. Targeted agent use in cancer patients at the end of life. J Pain Symptom Manage. 2013;46:1-8. 30. Stark D, Nankivell M, Pujade-Lauraine E, et al. Standard chemotherapy with or without bevacizumab in advanced ovarian cancer: quality-of-life outcomes from the International Collaboration on Ovarian Neoplasms (ICON7) phase 3 randomised trial. Lancet Oncol. 2013;14:236-243. 31. Monk BJ, Huang HQ, Burger RA, et al. Patient reported outcomes of a randomized placebo-controlled trial of bevacizumab in the front-line treatment of ovarian cancer: a Gynecologic Oncology Group Study. Gynecol Oncol. 2013;128:573-578. 32. Iurlo A, Ubertis A, Artuso S, et al. Comorbidities and polypharmacy impact on complete cytogenetic response in chronic myeloid leukemia elderly patients. Eur J Intern Med. 2014;25:63-66. 33. Penman DT, Holland JC, Bahna GF, et al. Informed consent for investigational chemotherapy: patients’ and physicians’ perceptions. J Clin Oncol. 1984;2:849-855. 34. Bombard Y, Robson M, Offit K. Revealing the incidentalome when targeting the tumor genome. JAMA. 2013;310:795-796. 35. The New York Times. Targeted cancer. http://topics.nytimes.com/top/news/ health/series/target_cancer/index.html. Accessed September 26, 2014. 36. The Washington Post. New therapies raise hope for a breakthrough in tackling cancer. www.washingtonpost.com/national/health-science/new-therapies-raisehope-for-a-breakthrough-in-tackling-cancer/2014/02/14/b4f8e4fc-8dad-11e3-95dd36ff657a4dae_story.html. Accessed September 26, 2014. 37. Jenkins VA, Anderson JL, Fallowfield LJ. Communication and informed consent in phase 1 trials: a review of the literature from January 2005 to July 2009. Support Care Cancer. 2010;18:1115-1121. 38. Zafar SY, Peppercorn JM, Schrag D, et al. The financial toxicity of cancer treatment: a pilot study assessing out-of-pocket expenses and the insured cancer patient’s experience. Oncologist. 2013;18:381-390. 39. Basch E, Abernethy AP, Mullins CD, et al. Recommendations for incorporating patient-reported outcomes into clinical comparative effectiveness research in adult oncology. J Clin Oncol. 2012;30:4249-4255. 40. Takeuchi EE, Keding A, Awad N, et al. Impact of patient-reported outcomes in oncology: a longitudinal analysis of patient-physician communication. J Clin Oncol. 2011;29:2910-2917. 41. Kantarjian HM, Fojo T, Mathisen M, et al. Cancer drugs in the United States: Justum Pretium – the just price. J Clin Oncol. 2013;31:3600-3604.

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REFERENCES: 1. Santarpia L, Lippman SM, El-Naggar AK. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:103-119. 2. Wang AX, Qi XY. Targeting RAS/RAF/MEK/ERK signaling in metastatic melanoma. IUBMB Life. 2013;65:748-758.

WCMC

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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World Cutaneous Malignancies Congress

WORLD CUTANEOUS MALIGNANCIES CONGRESS ™

The Third Annual World Cutaneous Malignancies Congress (WCMC) took place in San Francisco, California, on October 29-31, 2014. The WCMC is a 2-day meeting dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies. Following are highlights of presentations from the meeting.

Panel Considers Role of Conventional Treatment in Cutaneous Malignancies in Era of Targeted Therapy Is there still a role for conventional therapies for cutaneous malignancies in the era of targeted agents? This was the question put before a panel of oncologic experts convened at the conference. Paul Nghiem, In Merkel cell carcinoma (MCC), conMD, PhD ventional treatment for local and regional disease is effective, said Paul Nghiem, MD, PhD, professor of medicine, dermatology, and pathology, University of Washington, Seattle. “Without too much morbidity, we can render almost 100% of our patients free of detectable disease,” he said. In contrast, treatment of MCC in the adjuvant setting is open to debate. “We have patients with nodal disease who have a 70% Sanjiv S. chance of dying of this cancer in a few years, Agarwala, MD yet they have no evidence of disease clinically,” said Nghiem. “This is the perfect setting to ask that adjuvant question.” In Europe, ipilimumab is being tried in this setting, he noted. Conventional therapy for metastatic disease is a huge area of need, he said, as the response to chemotherapy in this setting is not durable. “You’re suppressing the immune system and making those cancer cells really angry. When they come back, they’re really hard to deal with,” he said. In basal cell carcinoma (BCC), “we can be satisfied to say that targeted therapy is the only way to go for advanced disease. There’s not much argument there,” said Sanjiv S. Agarwala, MD, chief of oncology and hematology, St. Luke’s Cancer Center, Bethlehem, PA. Vismodegib is an oral agent approved for the treatment of adult patients with BCC that has metastasized or recurred after surgery, in addition to patients whose tumors are deemed untreatable with surgery or radiation. Patients who desire the oral drug in lieu of conventional surgery or radiation therapy represent a dilemma for healthcare systems, said Axel Hauschild, MD, head

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of the Skin Cancer Center at the University of Kiel, Germany. “Ethically, does the community need to pay for those patients not willing to be operated on, although the oral drug is indicated after surgery?” he asked. No targeted therapy exists for the Axel Hauschild, management of cutaneous T-cell MD lymphoma (CTCL), with the exception of alemtuzumab for Sézary syndrome. The therapeutic window for alemtuzumab in Sézary syndrome is relatively narrow because of its immunosuppressive side effects, said Pierluigi Porcu, MD, associate professor of internal medicine, Division of Hematology, The Ohio State University, Columbus. Pierluigi Porcu, “Otherwise, CTCL essentially is a MD chronic disease for which patients stay on therapy for a greater part of their lives. The additional component is that there is a tendency to overlay different therapies as we go along,” said Porcu. Every patient who starts treatment of early-stage CTCL will receive a series of therapies that include a variety of topical agents and eventually phototherapy when the level of skin involvement becomes significant despite the topicals. The key question, said Porcu, is when to add systemic therapy in CTCL. “In the past, the question was moot because the systemic therapies we had were relatively ineffective and certainly toxic,” he said. The discussion became more relevant with the introduction of bexarotene and, more recently, histone deacetylase (HDAC) inhibitors. After phototherapy, “do you still go with bexarotene as your first agent or do you start using the new HDAC inhibitors?” he asked. The mechanisms of action of retinoids in CTCL must be better understood to make this decision, he believes. “Moving down the road as far as disease severity, we

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don’t have a good way of debulking patients with advanced CTCL and taking them potentially to reduced-intensity stem cell therapy transplantation,” said Porcu. The role of conventional treatments in metastatic melanoma seems to be dependent on the health system. In Germany, where ipilimumab is not reimbursed as first-line therapy, many patients with melanoma are treated with dacarbazine, said Hauschild. “If ipilimumab were available as first-line therapy, I would favor ipilimumab over dacarbazine,” he said. “There are some patients with clear contraindications, such as diverticulitis and other underlying autoimmune diseases, that preclude treatment with anti–CTLA-4 antibodies.” “In France, it’s even worse because ipilimumab is not reimbursed for the BRAF-mutant patient,” said Caroline Robert, MD, PhD, head of dermatology, Institut Gustave Roussy, Paris. “If I had the choice, I would favor giving ipilimumab first line most of the time in BRAF wildtype and sometimes in BRAF muCaroline Robert, MD, PhD tant patients as well.” In the future, clinicians may have the choice of an anti–PD-1 antibody, ipilimumab, or the combination of the 2 as first-line therapy. The choice then would depend on the magnitude of the benefit with the combination, Robert and Hauschild agreed. A survival rate of 80% to 90% with no grade V adverse events would tip the scale toward combination treatment, said Robert. If combination therapy vastly improves overall survival, the toxicity would be little consideration given that treatment duration would be short, said Hauschild. “Maybe some people need just 2, 3, or 4 infusions and the job is done,” he said.

Knowledge of Biology of Malignant Melanoma Is Informing Treatment An understanding of the molecular biology and genetics of melanoma is now integrated into the management of patients with this disease. Knowledge of the oncogenic driver mutations has allowed the developAntoni Ribas, ment of targeted therapies, said AnMD, PhD toni Ribas, MD, PhD, director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center at the University of California Los Angeles. Genomic studies have identified several targetable oncogenes in melanoma, in particular the protein ki-

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nase BRAF. The BRAF V600E mutation is the most common point mutation in melanoma. WORLD Resistance occurs because inCUTANEOUS two-thirds to threefourths of cases, the tumor finds aMALIGNANCIES way to reactivate the CONGRESS MAPK pathway by increasing oncogenic signaling, either by amplifying BRAF or through alternate splicing that reactivates the kinase, or by allowing the copresence of a mutation of RAS and BRAF. Genomic studies have also allowed uncovering of the major mechanisms of acquired resistance to BRAF inhibitors. Mutually exclusive mechanisms of resistance to single-agent BRAF inhibitors such as secondary RAS mutations, BRAF alternative splicing, BRAF amplification, or PTEN deletions have been described, said Ribas. “This mutual exclusivity is not in 1 patient; it’s in 1 lesion or another,” he said. “The melanoma finds ways to progress, and one lesion may progress differently from another one.” In this way, a branched evolution underlies acquired BRAF inhibitor resistance, and the tumors are finding different ways to escape. ™

The clinical data are progressing more rapidly than the ability to understand the rationale behind successful approaches to target resistance. “This tells us that we shouldn’t be chasing resistance; we should be anticipating resistance,” he said. The clinical data are progressing more rapidly than the ability to understand the rationale behind successful approaches to target resistance, such as up-front treatment with BRAF inhibition combined with MEK inhibition as a superior strategy to BRAF inhibition alone. Combination therapy is proving to improve initial responses and provide more durable responses and better overall survival. An unanticipated benefit to double oncogenic pathway inhibition (BRAF and MEK) is the reduction in toxicities from paradoxical MAPK activation by blocking BRAF alone, in which blockade of BRAF within a dimer with CRAF results in increased MAPK signaling through the paradoxical transactivation of CRAF. This paradigm described above can be used to treat RAS-driven melanoma, which preferentially signals through MAPK, he said. No RAS inhibitors have been developed so far, but blockade at the cell proliferation step – CDK 4/6 – has been shown in a phase 1b/2 trial to induce early tumor shrinkage when administered with a MEK inhibitor in NRAS-mutant melanoma, although duration of response has been short.

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Genetics are also becoming important in the under-

standing of immunotherapy in melanoma. Patients WORLD with melanoma who have vast mutational heterogeneCUTANEOUS MALIGNANCIES ity may actually be easier to treat, Ribas explained, beCONGRESS cause their immune systems may be better able to dif™

ferentiate the cancer cell from the normal cell, but the immune system is being blocked by PD-1. The anti tumor activity of PD-1/PD-L1–blocking antibodies is likely to be related to immunogenic epitopes derived from genomic mutations.

Patients who progress on these therapies are candidates for pembrolizumab, recently approved for the treatment of advanced melanoma in patients who have previously received a BRAF inhibitor. Treatment Algorithm in the United States: Current and Future Ribas followed with a discussion of current approaches to therapy in malignant melanoma in the United States. The treatment algorithm for advanced melanoma hinges on BRAF mutation; in BRAF-positive patients, options include anti–CTLA-4 therapy with ipi limumab or the combination of a BRAF and MEK inhibitor. High-dose interleukin (IL)-2 is also approved for this indication and is associated with a durable response in a subset of patients, but “it’s hard to advocate for high-dose IL-2 when you talk to a patient because it has not been tested in a randomized trial, it’s inpatient therapy, and it’s more toxic, at least in the short term,” he said. Patients who progress on these therapies are candidates for pembrolizumab, recently approved for the treatment of advanced melanoma in patients who have previously received a BRAF inhibitor. In BRAF-negative patients, the thinking is the same but without the option of a BRAF inhibitor. “My first option is to offer ipilimumab and discuss the pros and cons,” he said. “This is not how we’re going to be treating melanoma in 1 or 2 years, I would assume,” he said. “In 1 or 2 years, we’re going to be diagnosing melanoma based on the interaction between the cancer cell and the immune system.” The future approach will involve detecting a T cell that recognizes the cancer and leads to the production of interferon, one of the signaling molecules used by the immune system to attract other cells that can attack the target after specific recognition of antigen. The same signal leads to the expression of brakes that limit the immune response, and interferons lead to

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the expression of PD-L1. “If there’s PD-L1 and no T cells, it doesn’t matter if we block PD-1 or PD-L1. The effector cells are the immune system cells,” said Ribas. The initial decision will depend on predictive factors for response to PD-1/PD-L1 blockade. If factors (T cells) are present, single-agent PD-1 or PD-L1 will be initiated. If features likely for response are present and the response is mixed or progression of disease occurs eventually, delayed combination therapy may be tried. If predictive factors are not present, combination therapy may be tried up front.

The Perspective From Europe Hauschild explained systemic treatment approaches for advanced metastatic melanoma in Europe. The reimbursement mechanism is different across Europe, where treatment is price sensitive and the availability of new drugs may be limited. Recent approvals for melanoma in Europe include ipilimumab (reimbursed primarily for second-line treatment), and the BRAF inhibitors vemurafenib and da brafenib (single-agent approval). IL-2 has never made it to the market in Europe for the treatment of melanoma. “In France, ipilimumab is approved but only reimbursed for patients not carrying a BRAF mutation,” he said. “There is zero scientific evidence for this. The BRAF-mutated patients should be referred for targeted therapy since they have no opportunity for ipilimumab. This is in the interest of money; the questions in Europe are circulating around reimbursement of these drugs.” The European Medicines Agency seeks phase 3 trials that must demonstrate at least an advantage in progression-free survival, “but they are more likely to accept an overall survival improvement, and it must be clinically meaningful,” he said. ESMO developed a guideline for screening, early detection, treatment of the various stages of melanoma, and follow-up, but it is only 2 pages and therefore weak, believes Hauschild. German Guideline The new German guideline is based on a Cochrane review of the existing literature, involves 32 disciplines from the German Cancer Society in a complex consensus process, and is updated annually. The current German guideline recommends evaluating BRAF mutations from stage IIIB+ melanoma. “This means that we are not waiting for stage IV disease, because stage IIIB and IIIC have a bad prognosis, and very many of them will progress to stage IV,” he said. If the patient is BRAF-negative, it is recommended that the pathologist test for NRAS mutation. Only 1% of melanomas in Europe carry cKIT mutations, so it can be neglected.

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In “triple-negative” melanoma (negative for BRAF/ NRAS/cKIT), the first choice is referral to a clinical trial. Other options are single-agent chemotherapy or polychemotherapy. If the tumor load is low and the disease is progressing slowly, first choice is referral to a clinical trial, with single-agent chemotherapy (dacarbazine) or ipilimumab as options. With progressive disease at this point, ipilimumab is an option, as is monochemotherapy. For patients carrying a BRAF mutation and a high tumor load and rapidly progressive disease, “there is no doubt that they should be referred to BRAF inhibition,” either in combination with a MEK inhibitor or as a single-agent BRAF inhibitor, he said. The time to response is important in the decision, as anti–CTLA-4 antibody treatment requires time to work, whereas targeted therapies work quickly. In general, a high tumor burden, symptomatic disease, and a high level of lactate dehydrogenase favors combination treatment “because treatment outcomes, in terms of response rate induction, are very good, and also the time to best response is very fast,” said Hauschild.

Molecular Understanding of BCC Leads to Effective Targeted Therapy Hedgehog pathway activation is instrumental for initiation and maintenance of BCC. The understanding of the molecular basis of BCC has led to the advent of HedgeJames hog pathway–targeting agents that Macdonald, MD are changing the approach to the treatment of BCC, said presenters at the conference. The majority of BCCs develop through altered activation of the Hedgehog signaling pathway. Its origins were described by James Macdonald, MD, dermatologist at Central Utah Clinic in Provo. The Hedgehog pathway was originally described in embryonic devel- Karl D. Lewis, MD opment and controls proliferation, differentiation, and apoptosis. This pathway was first linked to cancer when a mutation in the transmembrane receptor protein PTCH was found to cause Gorlin syndrome. In the resting state, PTCH acts to suppress the seventransmembrane protein Smoothened (Smo), preventing further downstream signal transduction. Stoichiometric binding of the Hedgehog ligand to PTCH releases inhibition of Smo, which serves to activate transcription

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factors (Gli1, Gli2), cell proliferation genes (cyclin D, cyclin E, Myc), and regulators of angiogenesis. “The WORLD balance of PTCH (inhibition) and Smo (activation) CUTANEOUS MALIGNANCIES therefore manages the essential regulatory downstream CONGRESS Hedgehog signal transduction pathway,” said Macdonald. “Loss-of-function mutations of PTCH or gain-offunction mutations of Smo tip this balance toward constitutive activation, a key event in potential neoplastic transformation.” BCC demonstrates heterogeneous molecular progression, resulting in various subtypes of the disease: • Molecularly, metatypical BCC shares the most features with squamous metaplasia. For example, compared with other subtypes of BCC, metatypical forms express high levels of immune-response genes such as ß-catenin and CXCR4 • Infiltrative forms of BCC are often embedded in a sclerotic stroma, in keeping with the molecular finding of high levels of profibrotic cytokines (ie, transforming growth factor-beta) and fibroblastic markers (ie, alpha-SMA) • Micronodular forms highly express altered p53 protein • Superficial BCC is the least molecularly complex, with the fewest aberrations on gene expression profile • Fibroepithelioma of Pinkus type has minimal chromosomal aberrations compared with BCC Overexpression of p53 is observed in aggressive BCC subtypes. Mutations of p53 occur in as many as half of BCCs, with most of these mutations being UV signature mutations. A particularly aggressive subtype of BCC has both Smo mutation and p53 mutation. In the different BCC subtypes, driver mutations are similar and occur predominantly through the Hedgehog signaling pathway. With the ubiquitous expression of the Hedgehog pathway in BCC, therapy targeting this pathway is logical, said Karl D. Lewis, MD, associate director, Melanoma Research Clinics, University of Colorado Denver. “Hedgehog inhibitors have demonstrated high activity as well as durability in advanced BCC,” he said. “They have a predictable toxicity profile, and that toxicity profile does make it difficult for patients to maintain on these drugs long-term.” The first agent that acts on the Hedgehog pathway to be approved for the treatment of advanced BCC is vismodegib. Erivance BCC was a pivotal phase 2 study that included patients with metastatic BCC measurable by imaging and locally advanced BCC (N Engl J Med. 2012;366:2171-2179). Patients with metastatic BCC or patients with locally advanced BCC who had inoperable disease or for whom surgery was inappropriate were

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treated with vismodegib 150 mg/day until disease pro-

gression, intolerable toxicity, or withdrawal from study WORLD for other reasons. Responses in the metastatic cohort CUTANEOUS MALIGNANCIES were measured by imaging using RECIST criteria, and CONGRESS in the locally advanced cohort using a novel composite ™

end point that included measurable diameter and ulceration of visible tumor as well as RECIST measures of the deeper tumor component when present. The objective response rate (ORR) in the 33 patients with metastatic BCC was 30% as measured by independent review (P=.001) and 46% by the investigators. Another 64% of patients had stable disease, and progression as best response was observed in only 3% of patients.

Alternate targets in the Hedgehog pathway, perhaps Gli, and targets outside of this pathway are still needed for patients who lack a complete response on Hedgehog inhibitors or who have disease progression. In the 63 patients with locally advanced BCC, the ORR was 43% as measured by independent review (P<.001) and 60% by the investigators, with complete response in 13 patients (21%). Another 38.1% of patients had stable disease, with progression in 12.7% of patients. “Of relevance, the response rate observed by investigators in this study is identical to that observed by investigators in the phase 1 study,” said Lewis. “Clinical response to vismodegib observed in responders frequently occurred in a matter of weeks.” A second agent that blocks Hedgehog activity is the selective Smo inhibitor sonidegib. Updated results from the BOLT study of sonidegib in patients with metastatic or locally advanced BCC were presented at the 2014 ESMO. The randomized phase 2 study was conducted in 230 patients with locally advanced (n=194) or metastatic (n=36) BCC who were randomized in a 1:2 fashion to 200 or 800 mg/day of sonidegib. “It met its primary end point of objective response rate of >30% after a median follow-up of 13.9 months,” said Lewis. The updated results presented at ESMO were from a median follow-up of 20 months, at which time the ORR in the 200-mg/day cohort in patients with locally advanced BCC improved from 47% (primary analysis) to 58% (12 months), and from 35% (primary analysis) to 44% (12 months) in the 800-mg/day cohort. In the group with metastatic BCC, the ORR dropped from 15% (primary analysis) to 8% (12 months) in the 200-mg/day cohort because a patient initially deemed to

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have a partial response was subsequently deemed to have stable disease, and was maintained at 17% in the patients assigned to 800 mg/day. The disease control rates were high, at about 90%, in both dosage groups. The main adverse events were predictable – muscle spasms, alopecia, dysgeusia, nausea, fatigue, and weight loss. About 30% of patients had elevations in creatine kinase. The dose of sonidegib likely to go forward is 200 mg/day based on the better benefit-risk profile, said Lewis. “It’s my understanding that they’re trying for first-line approval,” he said. “Which one you’ll use up front is unknown at this point in time.” He said that both vismodegib and sonidegib probably impact the natural history of locally advanced BCC, although this remains to be proved. Alternate targets in the Hedgehog pathway, perhaps Gli, and targets outside of this pathway are still needed for patients who lack a complete response on Hedgehog inhibitors or who have disease progression.

Treatment Algorithms for CTCL Reflect Involvement of Different T-Cell Subsets Overexpression of IL-15 has a causal role in the pathogenesis of CTCL, which displays response to inhibitors of HDAC. The anti-CD52 antibody alemtuzumab effectively treats leukemic CTCL without compromising the immune response to infection. These were themes discussed during the congress. IL-15 Overexpression Induces CTCL CTCL describes a group of heterogeneous diseases derived from skin-homing T cells. Malignant T cells of the CD4 phenotype target and persist in the skin but also accumulate in the lymph nodes and peripheral blood with disease progression. IL-15 is a potent stimulant and growth factor for CTCL cells. Analysis of malignant CD4+ T cells demonstrates overexpression of IL-15 in patients with CTCL, said Anjali Mishra, PhD, assistant professor at The Ohio State University Comprehensive Cancer Center, Columbus. In patients with CTCL, the Anjali Mishra, increase in IL-15 transcript is directPhD ly proportional to disease severity. “IL-15 transgenic mice progress to a severe stage of CTCL, as characterized by extensive patch/plaque skin lesions, progressive alopecia, and severe pruritus within 6 weeks of birth,” said Mishra. Adult IL-15 transgenic mice develop extensive involvement with cutaneous lymphoma causing fatality. Antibodies staining of CTCL mice reveal expression of

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CD3+CD62L–CD44hiCCR4+CLA+. Further, lymphoma cells from IL-15 transgenic mouse skin engrafted and mimicked the primary disease in immunodeficient mice upon adoptive transfer.

Epigenetic Events in CTCL CD4+ T cells from CTCL patients show high expression of HDAC1, HDAC2, and HDAC6 transcripts. Using specific HDAC inhibition to target HDAC1/2 and/or HDAC6 in IL-15 transgenic mice was able to prevent clinical disease, said Mishra, whereas IL-15 transgenic mice receiving placebo progressively developed lesions during the course of treatment. The data suggest that “inhibiting HDAC1, HDAC2, and/or HDAC6 pathways inhibits the development of CTCL in IL-15 transgenic mice,” she said. A novel pan-HDAC inhibitor can reverse severe dermatologic disease in the CTCL model. Histopathologic analysis of IL-15 transgenic mice treated with a pan-HDAC inhibitor (AR42) showed clearance of CD3+ and CD4+ atypical lymphocytic infiltrate compared with mice that received placebo. Treatment Options in CTCL The 2 most common subtypes of CTCL are mycosis fungoides and Sézary syndrome. A staging system implies a uniform transition from mycosis fungoides to Sézary syndrome, but this staging system does not accurately portray the natural history of disease. In addition, criteria used to define blood and lymph node involvement vary according to the study. “The exact risk of stage progression is not very well known,” said Porcu. “The risk could be as low as 10% to 15% or as high as 25% to 40%.” Treatment of CTCL is dependent upon the stage at diagnosis. The 2 categories of treatment are skin-directed and systemic therapies. The effect of treatment on stage progression and survival in CTCL is not known. Approved systemic agents for the treatment of CTCL are romidepsin, an HDAC inhibitor; denileukin diftitox, a fusion protein; bexarotene, a retinoid; and vorinostat, another HDAC inhibitor. Some agents have been approved with restrictive indications. For example, denileukin diftitox is approved specifically for a subset of patients with tumors that express CD25, and bexarotene and vorinostat are approved specifically for the skin manifestation of CTCL. Of the HDAC inhibitors, vorinostat is approved for the treatment of cutaneous manifestations in patients with CTCL who have progressive, persistent, or recurrent disease on or following 2 systemic therapies, and romidepsin is approved for the treatment of CTCL in

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patients who have received at least 1 prior systemic therapy. WORLD The response rates for these agents are approximately CUTANEOUS MALIGNANCIES 30%, and the durations of response range from 4 to 6+ months (a high of 15 months in CONGRESS the pivotal trial of romidepsin). Response to romidepsin is observed across all stages of disease. “The overall management of CTCL across the stages is complex,” said Porcu. “It requires a coordination of care between medical, oncology, and dermatology. There is no unified standard of care. The closest thing to standard of care is HDAC inhibitors in Sézary syndrome.” ™

Approved systemic agents for the treatment of CTCL are romidepsin, an HDAC inhibitor; denileukin diftitox, a fusion protein; bexarotene, a retinoid; and vorinostat, another HDAC inhibitor. Immunology of Malignant T Cells Diverse populations of T cells are found in human skin and blood, and all of them can undergo malignant transformation. Human skin is populated by a combination of resident memory T cells and recirculating memory T cells. Resident memory T cells don’t recirculate; they make copious amounts of inflammatory cytokines, are highly protective locally, and accumulate in barrier tissues. “Resident memory T cells persist, protect, and they stay put,” said Rachael A. Clark, MD, PhD. Central memory T cells, by virtue of their expression of Rachael A. Clark, MD, PhD L-selectin and CCR7, can gain access to the lymph nodes. Central memory T cells recirculate between the blood and the lymph nodes. Previously thought to be different stages of the disease, recent evidence shows that mycosis fungoides and Sézary syndrome represent lymphomas derived from these different T-cell subsets. Leukemic CTCL is a malignancy of central memory T cells, whereas mycosis fungoides is a malignancy of skin resident effector memory T cells. “If you know that the malignant T cell that is responsible for the disease is skin resident and nonrecirculating, then local therapies can be a possible cure,” said Clark, associate professor, Department of Dermatology,

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Harvard Medical School, Boston, MA. In fact, very low-

dose radiation therapy reduces malignant T-cell clones WORLD by 90% and maintains benign T-cell populations in paCUTANEOUS MALIGNANCIES tients with mycosis fungoides. CONGRESS The story is different in leukemic CTCL because ™

memory T cells recirculate. Alemtuzumab is a humanized anti-CD52 antibody that rapidly depletes all T and B cells from blood. At low doses, alemtuzumab induces partial response in 100% or complete response in 50% of patients with refractory leukemic CTCL. “To put this in perspective, vorinostat and the other systemic therapies are only partially effective in 30% of patients,” she said.

PI3K pathway inhibitors are being studied, as well as a number of new monoclonal antibodies and antibody-drug conjugates, such as pertuzumab and mogamulizumab, an anti-CCR4 antibody. “We biopsied the skin of patients on alemtuzumab and found that healthy, benign T cells were present in the skin after alemtuzumab, but the malignant clone was missing after alemtuzumab, as was the population of normal central memory cells,” she said. “It turns out that alemtuzumab depletes in only 1 specific way: by antibody-dependent cellular cytotoxicity.” T-cell depletion with alemtuzumab requires the presence of neutrophils, a cell type frequent in blood but rare in normal skin. The findings suggest that central memory T cells were depleted because they recirculate between the blood and the skin, whereas skin resident T cells were spared because they are sessile and don’t recirculate. In addition, despite the absence of T cells in the blood, there was a marked lack of infections in alem tuzumab-treated leukemic CTCL patients, “which suggests that skin resident T cells can protect the skin from pathogens even in the absence of T-cell recruitment from the circulation,” she said. Critical lessons about the human immune system were learned from this research. “The population of cells that don’t recirculate can provide a lot of immune protection, even in the complete absence of circulating B and T cells,” she said. Also, there are some central memory T cells that recirculate, as in the case of Sézary syndrome, which are the malignant cell type.

CTCL Therapies on the Horizon Desirable features of systemic therapy in CTCL are response rates ≥30%, favorable toxicity, an impact on symptoms (itching), an improvement in time to progression or time to next therapy, a favorable schedule of

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administration, competitive cost, avoidance of the need for IV catheters, preservation or restoration of immune competence, activity across all anatomic components, and few drug-drug interactions. There are several promising new therapeutic approaches in the management of CTCLs, said Porcu. The JAK/STAT signaling pathway has been found to harbor somatic mutations in human CTCL, opening the possibility of JAK/STAT inhibition as a targeted therapy. IL-2–inducible T-cell kinase is crucial for T-lymphocyte development and in the pathophysiology of T-cell malignancies; it is another promising target being explored in drug development. PI3K pathway inhibitors are being studied, as well as a number of new monoclonal antibodies and antibody-drug conjugates, such as pertuzumab and mogamulizumab, an anti-CCR4 antibody. An antibody-drug conjugate against CD3 with diphtheria toxin conjugate is in clinical phase. Immune checkpoint inhibitors such as anti–PD-1 antibody are also being developed for the treatment of leukemic variants of CTCL.

Merkel Cell Carcinoma Update Merkel cell polyomavirus (MCPyV) is a newly discovered human virus that causes MCC. MCPyV may function as an immune target in MCC, said Isaac Brownell, MD, PhD, at the meeting. The polyomavirus family expressIsaac Brownell, es T (tumor) antigens. Expression of MD, PhD T antigens “is like taking the brakes out of the cell cycle and driving a proliferative state, which is conducive to forming a tumor,” said Brownell, in describing the role of MCPyV in the pathogenesis of MCC. MCPyV is common; by adulthood, almost everybody has circulating antibodies in the blood, indicating infection by this virus at some time in their lives. To cause MCC, MCPyV must be integrated into the host genome. In addition, a mutation must occur in the large T antigen, which removes its helicase activity, making virus replication difficult. MCPyV also interacts with the immune system, most likely at 2 different stages. “It’s possible that as people age, they lose their protective immunity to polyoma virus, and this may allow an expansion of this virus, making it more likely for these 2 integration and mutation events to occur,” said Brownell, head, Cutaneous Development and Carcinogenesis Section, Dermatology Branch, Center for Cancer Research at the National Cancer Institute. While the immune system may clear the subsequent

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transformed cells, denying tumor expansion, in a person with a healthy immune system, the tumor will expand in a person with a defective immune system. At present, no gold standard to detect MCPyV exists, and no CLIA test is certified. Polymerase chain reaction (PCR) is most often used in the research setting, but there’s no gold standard PCR test, he said. Depending on the PCR approach, MCPyV is detected in 50% to 100% of tumors. A number of antibodies can detect viral proteins, particularly T antigens, but only the CM2B4 is commercially available. “It has a lower sensitivity than PCR; we know that there are virus-positive tumors that don’t stain for CM2B4,” he said. On serology, people with MCC have a higher level of antibodies against viral peptides circulating in their blood. However, people with MCPyV-negative tumors can have high serology titers, and the reason is not clear. The clinical significance of MCPyV detection in a Merkel cell tumor is also uncertain. Among a cohort of MCC patients from Finland, those with virus-positive tumors had a better prognosis than those with virus-negative tumors. “It may be that a tumor that expresses a non-self viral protein is a better target for the immune system to hone in on to clear that tumor,” said Brownell. However, studies examining survival have produced conflicting results, with some finding improved survival in patients with MCPyV-positive tumors, while others have found no difference in outcomes between patients with MCPyV-positive and -negative tumors. Few studies have examined serological tests to determine prognosis in MCC or risk for the disease. A validated serology test, available as a send-out test through the University of Washington in Seattle, demonstrated that detection of MCPyV small T-antigen antibodies reflects tumor load in some patients, offering a means to detect recurrence after treatment.

Potential for Immunotherapy MCPyV may be an immune target in MCC, said Brownell. “About half of MCC patients will have circulating T cells that will react to the MCPyV, and about one-third of those patients will have circulating T cells that are reactive to the T-antigen expressed by the virus,” he said. “This could be leveraged to use T cells to treat these patients.” A phase 1/2 trial of MCPyV-reactive autologous T-cell therapy for metastatic MCC is being conducted at the Fred Hutchinson Cancer Research Center in Seattle, WA. Patients are being treated with adoptive CD8+ MCPyV-reactive T cells after major histocompatibility complex class I up-regulation with radiation therapy or intralesional interferon.

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Updated MCC Guideline Most patients with MCC are WORLD diagnosed in an early stage where most CUTANEOUS MALIGNANCIES advances in treatment have been CONGRESS made in recent years, said Christopher Bichakjian, MD, who provided the most recent update to the National Comprehensive Cancer Network (NCCN) guideline on MCC. Christopher Bichakjian, MD The first addition is a footnote stating that “imaging may be useful to identify and quantify regional and distant metastases.” Antibodies to MCPyV-specific oncoproteins have been discovered in 40.5% of MCC cases. Among MCC patients with serum antibody, titers fell or remained stable in 226 of 231 samples from patients who remained disease-free, for a specificity of 97.8%. In 14 of 18 patients who progressed within 30 days from blood draw, oncoprotein antibody titer increased at least 20% (sensitivity 77.8%); in 4, increasing titers preceded clinical recognition. ™

A clear conceptual separation in the treatment algorithm was established between the management of the primary site and the regional nodal basin in relation to surgery and radiation therapy. “It is a very interesting development that may provide us with a prognostic tool that may either supplement or replace certain imaging studies that we’re doing now in a routine for patients with MCC,” said Bichakjian, director, Multidisciplinary Merkel Cell Carcinoma Program, University of Michigan, Ann Arbor. The NCCN advised changes in the treatment of both primary and adjuvant therapy for node-negative patients, which represent most patients with MCC. A clear conceptual separation in the treatment algorithm was established between the management of the primary site and the regional nodal basin in relation to surgery and radiation therapy. The second minor change was to encourage observation of the nodal basin in patients with a negative sentinel lymph node biopsy. Sentinel lymph node status is the most prognostic predictor of recurrence-free and overall survival, and the results should be trusted, said Bichakjian. “The point is that if you’re doing a sentinel lymph node biopsy, if your result is negative, you should trust that result,” he said. “If you don’t trust that result, you probably shouldn’t be doing it in the first place.”

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The third update was to discourage morbid resection

for extensive disease in favor of adjunct radiation theraWORLD py. If a clear surgical margin around an infiltrative tumor CUTANEOUS MALIGNANCIES is difficult to achieve, this would be an indication for CONGRESS adjunct radiation. “We’re not saying not to do surgery,” ™

he said. “These patients should have surgery, if nothing else, to debulk this tumor.” The fourth update of importance is the recommendation to consider observation of the primary tumor bed in low-risk patients following surgery. He shared data from his institution on a cohort of 113 patients with primary MCC who did not have radiation to the primary tumor. The size of the primary tumor was 1 cm in 57%, 1 to 2 cm in 36%, and 2 cm in 7%. Few patients had nodal disease, and angiolymphatic invasion was absent in three-fourths. With a mean follow-up of 31 months, recurrence of MCC was 21%, but only 1 patient (0.9%) had a local recurrence. One patient had a concurrent local and in-transit recurrence, and 1 other patient had a concurrent satellite and regional recurrence. “There were 3 people who could have possibly benefited from adjunct radiation therapy to the primary site,” he said. Seventeen of the 24 (71%) patients who had a recurrence had stage 3 disease at the time of presentation. The remaining 7 had regional or distant recurrence without local recurrence.

The goal of chemoprevention of melanoma would be to prevent an initial cancer in high-risk individuals, to prevent cancers in those with premalignant conditions, and to prevent secondary primary cancer. “We are not trying to say that primary MCC should not be radiated at the primary site,” said Bichakjian. “But at least that there is a well-defined and probably fairly sizeable group of people who could probably be treated curatively with surgery at the primary site, without the morbidity and cost associated with several weeks of adjunct radiation therapy.” For patients with clinical M1 disease, the updated NCCN guideline urges enrollment in a clinical trial, if available. A Principles of Excision page reiterates that surgical margins should be balanced with the morbidity of surgery. “The first goal is to obtain histologically negative margins, when clinically feasible,” he said.

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Efforts in Prevention and Early Detection of Skin Cancers Are Bearing Fruit Prevention and early detection of melanoma, recurrent MCC, and other skin cancers were the focus of a session. Susan M. Swetter, MD, spoke Susan M. Swetter, about the potential for chemopreMD vention of primary melanoma. Clinically atypical nevi (CAN) may manifest markers of progression or predictive response markers and might therefore be appropriate for evaluation of early-phase candidate chemoprevention agents. The reported frequency of CAN among patients with a history of melanoma ranges from 34% to 59%. The goal of chemoprevention of melanoma would be to prevent an initial cancer in high-risk individuals, to prevent cancers in those with premalignant conditions, and to prevent secondary primary cancer, said Swetter, codirector, Pigmented Lesion & Melanoma Program, Stanford University Medical Center and Cancer Institute, Stanford, CA. “Early detection is critical to reducing mortality,” she said. Fifty-eight percent of all melanoma deaths are in white men ≥50 years of age. This group is less likely to have a regular healthcare provider, receive routine preventive care, and participate in cancer prevention programs. Further, data from registries show that women have a consistent 30% advantage in overall survival, disease-specific survival, and time to lymph node metastases and distant metastases compared with men. For these reasons, there is a rationale for targeting older men for prevention. In the Cancer Prevention Institute of California/Stanford collaboration, males accounted for 40% of the melanoma cases overall but comprised 64% of melanoma-specific deaths. Health behaviors and practices play a large role in prevention. Thinner tumors are related to physician detection versus self-detection, higher education, and non-nodular subtypes of melanoma. Biologic sex differences in melanoma have been proposed, including differences in vitamin D metabolism, immune homeostasis and regulation, methylation, and ultraviolet radiation–induced gene mutations and exposure patterns, “but the bottom line is we really don’t know,” said Swetter. MCC Serologic Assay Serology may allow early detection of MCC, when a tumor may be more amenable to immune therapy, said Nghiem in describing a new serologic assay for early detection of recurrent MCC.

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Committed to Immuno-Oncology Research Dedicated to furthering research in Melanoma Immuno-Oncology research is increasing our understanding of the immune system’s role in fighting cancer, as well as how cancer cells evade recognition and attack.1 Over the past few years, research has significantly deepened our understanding of the body’s immune response to cancer and the role of immunotherapy, particularly in melanoma.2 At Bristol-Myers Squibb, our research has focused on how melanoma cells can escape multiple immune mechanisms to evade the body’s natural response to cancer cells.1 Through our ongoing clinical development programs, we continue to investigate ways to help restore the body’s natural ability to fight melanoma.1,3

Visit us at ImmunoOncology.com References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4)12:252-264. 2. Maio M. Melanoma as a model tumour for immuno-oncology. Ann Oncol. 2012;23(suppl 8):viii10-viii14. 3. Kim R, Emi M, Tanabe K. Cancer immunoediting from immune surveillance to immune escape. Immunology. 2007;121(1):1-14.

ONCUS14UB02104-01-01

10/14

Leading the way

WCMC

WORLD CUTANEOUS MALIGNANCIES CONGRESS

™

Half of MCCs will recur, and most will be fatal, em-

phasizing the need for early detection of recurrence. WORLD “The Merkel polyomavirus [MCPyV] drives most CUTANEOUS MALIGNANCIES MCCs,” said Nghiem. CONGRESS Humoral immunity is a powerful biomarker. The T ™

antigen of MCPyV, present in 80% of MCC tumors, is critical for most MCC tumors to grow. Antibodies that recognize this oncoprotein are present in about 50% of newly diagnosed MCCs. These antibodies are present in <1% of controls without MCC, even though about half of all people have the Merkel virus oncoprotein on normal skin at any time.

A complex logic was required to determine how to interpret the results. A 75-step assay that takes 1.5 days is demanding, and the proteins used in the preps must be highly reproducible. The level of antibodies to MCPyV decreases rapidly after treatment, and by 1 year after successful treatment are reduced by about 90%. With recurrence, antibody levels rise rapidly among the patients who had antibodies to MCPyV at the time of their first cancer. Nghiem’s laboratory has developed a clinical MCPyV antibody assay, available since January 2014. “We are detecting our body’s response to a cancer-associated protein; that is, the antibody to it,” he said. The process has been long and challenging. His team has collected 1342 samples from 104 controls and 519 MCC patients from around the world that had to be correlated with clinical status on the day the blood was drawn. A complex logic was required to determine how to interpret the results. A 75-step assay that takes 1.5 days is demanding, and the proteins used in the preps must be highly reproducible. “The observed titer vs the predicted titer has a beautiful relationship, and similarly, stability over greater than 1 year,” he said. Of the 104 control subjects, 98% were seronegative for oncoprotein, compared with 47% of 219 MCC patients. Those who are likely to make antibodies have classic CK20+ MCC, are immunocom-

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petent, and are younger (≤65 years). The hazard ratio for MCC-specific survival is 0.46 for those who are oncoprotein antibody-positive versus antibody-negative. “We tend to scan more often in the oncoprotein antibody-negative people and a lot less often in those who are antibody positive,” he said. Oncoprotein antibodies have been shown to predict MCC recurrence. The test also has the potential to be useful to predict recurrence in the next 6 months: a decreasing titer at the time of a second blood draw was associated with a low chance of recurrence, and an increasing titer was a significant predictor of recurrence.

SCREEN Trial Skin cancer screening in Germany has proved to be valuable in increasing detection, said Hauschild. He described a systematic skin cancer screening program in northern Germany called SCREEN (Skin Cancer Research to Provide Evidence for Effectiveness of Screening in Northern Germany). All residents of Schleswig-Holstein with statutory health insurance were eligible for whole body examination (from July 2003 to June 2004) by a physician who had undergone an 8-hour training course. The screening model used a 2-step program. Subjects first visited a general practitioner; if a suspicious lesion was found, the patient was referred to a dermatologist, who conducted a second whole body examination and a biopsy if necessary, followed by excision of a cancerous lesion. Alternatively, subjects could go directly to a dermatologist, bypassing the general practitioner. Most insurance companies offered skin cancer screening for volunteers ≥20 years of age, and some even earlier, said Hauschild. During the 1-year pilot trial, 3100 skin cancers were detected. The impact on incidence was clear, with a rising incidence of cancer during screening, and a decreased incidence thereafter. Mortality rates declined over time and were 52% lower over the following 10 years in Schleswig-Holstein, but not in other neighboring regions. The program shows that early detection is feasible and that the observed reduction in mortality is most likely caused by screening. The current skin cancer incidence in Germany has increased by 30% since 2003. u

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PMO LIVE

PMO Live: A Global Biomarkers Consortium Initiative The Third Annual PMO Live Conference, a Global Biomarkers Consortium Initiative, took place in San Francisco, California, on October 31 – November 1, 2014. PMO Live is the only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Following are highlights of presentations from the meeting.

New Diagnostic Approach Identifies Actionable Genetic Alterations in Tumors Missed by Traditional Tests The utility of traditional tests to identify actionable genetic alterations in tumors is suboptimal, whereas comprehensive genetic profiling can identify clinically meaningful alterations in 85% of cancer patients, said Juliann Chmielecki, PhD. As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies. Molecularly targeted therapy is evolving, but the number of clinically relevant cancer genes across solid tumors is high. In 2012, Stephens et al found at least 1 clinically relevant genomic alteration in 59% of colo rectal cancer (CRC) and non–small cell lung cancer (NSCLC) tissue specimens, and revealed 2 gene fusions: C2orf44-ALK in a CRC and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas found RET fusions in 2%.

As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies. The pace of targeted therapy discovery is rapid, such that by 2014, RET fusion–positive NSCLC was found to respond to a RET inhibitor (cabozantinib). Multiple different diagnostic tests for the myriad of relevant genetic alterations in cancers may exhaust precious biopsy material, said Chmielecki, senior scientist of cancer genomics at Foundation Medicine. The low tumor purity in many clinical tumor specimens is a diagnostic challenge that requires diagnostic tests with high accuracy. (Purity is the relative proportion of extracted DNA originating from tumor cells.) In a study of clinically relevant somatic mutations in NSCLC specimens, the fraction of mutations with an allele frequency under the limit of detection by capillary

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Sanger sequencing was 55%. “Next-generation sequencing–based tests miss most of the actionable alterations within a given patient,” she said. Given the challenges of small biopsies, multiple classes of genetic alterations, and tumor samples that may have small tumor content, “we developed a test that has all 4 classes of alterations with very high sensitivity and positive predictive value,” she said. The cancer genomic profiling test is based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions, copy number alterations, and selected fusions across 314 cancer-related genes from fixed formalin paraffin-embedded specimens. Experience in more than 13,000 patients who had genomic profiling of their tumors shows 97% with an alteration reported and 85% of samples with at least 1 clinically relevant alteration. Clinical relevance was defined as an alteration for which an FDA-approved targeted therapy in the tumor type or in another tumor type existed, or an open clinical trial of therapy relating to the alteration found in the gene. “When we look at the 314 cancer-related genes, we’re not finding a huge number of alterations per patient,” she said. “A higher number is usually cancers that are associated with carcinogens, such as lung cancer and melanoma.” The mean number of alterations per sample was 4.5 (range, 0-57), and the mean number of clinically relevant alterations per sample was 2.0 (range, 0-28). Solid tumor types represented in the more than 13,000 clinical specimens included lung (19%), breast (14%), colon (9%), brain (5%), ovary (5%), pancreas (4%), soft tissue (4%), and other (32%; mainly rare tumors). The investigators found a huge number of low-frequency alterations that could be linked to targeted therapies “that may be clinically relevant, even though they’re not occurring in hot spots of high-frequency genes,” she said. A novel KIF5B-RET fusion was identified and later discovered to be in 1% to 2% of NSCLCs; KIF5B-RET transformed cells are sensitive to RET inhibitors, suggesting that RET kinase inhibitors should be tested in prospective trials in patients with NSCLC with RET fusions.

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Multiple patients with KIF5B-RET fusion are known to have responded to a RET inhibitor, she indicated. HER2/ERBB2 alterations were observed across 27 tumor types. “This phenomenon may extend well beyond the gastric and breast cancer fields and into areas that haven’t been looked at,” said Chmielecki. “There are clinical case reports showing sensitivity of HER2 amplification outside of breast and gastric cancer as well as some of these newer mutations being discovered.” Nearly half of all HER2/ERBB2 alterations are missed by current tests, she noted. Epidermal growth factor receptor (EGFR) alterations were identified in 151 cases (6.8% of total cases) across 13 different tumor types, including breast cancer. An EGFR mutation is not usually tested for in a person with breast cancer. By site of organ, EGFR alterations occurred in glial, lung, brain, head and neck, bladder, kidney, uteral, breast, bone, colorectal, esophageal, skin, and stomach tumors. Fusions were identified in 13 kinases across multiple tumor types. Of the 248 kinase fusions identified, many with novel 5ʹ′partners were identified (2.2% of total cases).

Payers Debate Economics and Molecular Biomarkers in Personalized Medicine The rising costs of biomolecular testing and targeted drugs have prompted many to ask whether the United States can afford personalized medicine in oncology. At the conference, medical directors from 2 health plans tackled this question from the payer perspective. Ken Schaecher, MD, medical director at SelectHealth, answered “it depends” to the key question. He noted that healthcare costs in the US now stand at 17.2% of the gross domestic product. The US can afford personalized medicine “until we decide not to,” he said, pointing out that some targeted medicines cost upward of $100,000 per year because the US has no threshold to pay for these medicines. Most payers have defined sets of rules, he said, but the problem in the US is the large number of payers, each with its own set of rules. Sometimes, even within a plan, one set of rules may be applied, but different benefits structures mean that one patient can get a therapy that another cannot. Gary Johnson, MD, MS, MBA, regional medical director at Humana, said that paying for treatments and tests is always possible, but the real question is, “should we pay?” As stewards of the premium dollar, insurers can cover anything they want to, but they’ll have to raise premiums to do so. The targeted approach to care allowed by personalized medicine creates the opportunity for greater costeffectiveness, as in KRAS testing to select patients for

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targeted therapy in CRC. Being able to select the right treatment for the right patient improves health outcomes, said Johnson. “It [personalized medicine] shows us where treatments will be effective, and just as important, where treatments will not be effective, so we can avoid toxicities and morbidities from treatments that in essence cause harm,” he said. “All of this is the goal of managed care and of clinical care.” By reducing unnecessary risks of treatments not likely to work in a given patient, personalized medicine can reduce liability, said Johnson. A well-defined treatment pathway linked with a diagnostic marker provides legal cover for denial of a treatment.

Paying for treatments and tests is always possible, but the real question is, “should we pay?” As stewards of the premium dollar, insurers can cover anything they want to, but they’ll have to raise premiums to do so. “We can identify disease at an earlier state, and as a general rule, the earlier we treat various cancers the more effective it is clinically, and as important, the more cost-effective it is,” he said. “BRCA testing, which has been around for decades, and Oncotype DX for breast cancer are additional examples of why the answer to this question, can we afford personalized medicine?, is a resounding yes.” The higher price tags of targeted therapies reduce the cost-effectiveness of personalized medicine, said Schaecher. “We’ve found that typically with more targeted therapies, the price tag goes up, and there’s only so much money in the bank,” he reasoned. “A great example is crizotinib. It has a $96,000 price because it only works in 4% of the non–small cell lung cancer population that has the mutation. That price tag is much above most of the other therapies used in NSCLC.” Biomarker costs are increasing as well, he said, with some tests exceeding $3000. The misapplication of information in directing therapy is another potential con to personalized medicine in oncology. Sometimes, tests with low sensitivity or specificity are being used to determine clinical utility. And in some instances, providers select the same treatment they would have otherwise without the biomarker test. There is also a risk that information from testing may be applied when evidence is not present, said Schaech-

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er. “It’s arguable that there is adequate evidence for whole genome sequencing in oncology, but for most payers, they don’t believe that the evidence is there yet,” he said. “Using biomarkers in a one-off circumstance can help 1 patient, but unfortunately, as payers, we have to make broad payer-based decisions and not individual decisions. When there’s a lack of evidence, we have to be consistent in our decisions. If I make an exception for one patient, that can bind us to make an exception for every patient going forward.” Pharmacogenetic testing to identify drug metabolism may also add cost without utility. It’s unproven that knowing that a patient may be a rapid metabolizer of an antidepressant medication is going to alter the therapy. That can occur in the oncology arena also, said Schaecher.

It’s unproven that knowing that a patient may be a rapid metabolizer of an antidepressant medication is going to alter the therapy. A lack of process standardization across laboratories argues against wholesale use of biomarker tests. “As much as we would like all of the tests to be FDA approved, sometimes FDA approval can mean different things,” he said. “Many [tests] are home brewed, done in university labs, and when you don’t have that standardization, it’s harder for us to want to approve having a test covered.” Finally, a patient may still insist on a therapy anyway with a negative biomarker test. “Provide payers with evidence that it’s useful and that it would be no more costly or preferably less costly than the current approach to management, and you win the day,” said Schaecher. “It’s that easy.”

CoMMpass Study Will Drive Myeloma Into Precision Medicine Territory A landmark clinical trial is underway in multiple myeloma, sponsored by the Multiple Myeloma Personalized Medicine initiative (MMPM) of the Multiple Myeloma Research Foundation (MMRF). The trial aims to elucidate the molecular variations that underpin the development and progression of myeloma and to create an unprecedented data set to facilitate clinical trials and support the personalized care of patients. The CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile) trial was described by Jeffrey Wolf, MD, director of the myeloma program at the University of California

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San Francisco Helen Diller Family Comprehensive Cancer Center. “The CoMMpass longitudinal study is a core element of the MMPM program to identify patient segments based on their molecular profiles,” Wolf said. He noted that MMRF can already be credited with first identifying a number of unusual mutations in this disease. The CoMMpass Study will enroll at least 1000 newly diagnosed, symptomatic myeloma patients from at least 90 community and academic cancer centers. These patients will be tracked from diagnosis through treatment over 10 years by means of sequential tissue sampling, mutational analysis, and clinical exam. The goal is to determine how their molecular profiles may affect treatment response and disease progression. Clinical and genomic data will be obtained every 6 months and incorporated into the MMRF Researcher Gateway. The gateway will allow researchers outside of the CoMMpass Study to access the data acquired in the trial. Centralized molecular tests will include flow cytometry for determining BRAF mutation status, RNA sequencing expression analysis, whole exome DNA sequencing, whole genome chromosome analysis, and cytospin slides for fluorescence in situ hybridization. There will be a biorepository of peripheral blood mononuclear cells, plasma, and tumor tissue. The study is on track to meet its goals. The current status of projects is shown in the Table. “The CoMMpass Study is already generating high-quality data and achieving critical milestones,” Wolf observed. By interrogating the molecular profile of tumors and determining whether certain profiles respond best to certain drugs, the CoMMpass Study will help change the paradigm of drug development and treatment

Table CoMMpass Study Update, September 2014 2014 Goals

• Enroll 850-900 patients by year end: 1000 patients expected by Q2 2015 • Complete interim data analysis #6 • Complete draft interim data analysis #7

Current • 1144 patients screened with bone marrow Status samples collected (9/15/14) • 706 patients enrolled • 90 sites active • 4 industry members: Millennium, Onyx, Bristol-Myers Squibb, Janssen Interim Analysis

• Interim data analysis #6 completed • 626 patients with usable samples, clinical data • 363 patients with full genomic profiling results • Interim data analysis #7 under development

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NOW covered by Medicare For more information call 1-877-886-6739 or visit www.biotheranostics.com Prediction. Personalized. References: 1.Sgroi DC, et al. J Natl Cancer Inst. 2013;105:1036-1042. 2.Sgroi DC, et al. Lancet Oncol. 2013;14:1067-1076. 3.Zhang Y, et al. Clin Cancer Res. 2013;19:4196-4205. BCI INDICATIONS FOR USE AND LIMITATIONS BCI provides a quantitative assessment of the likelihood of distant recurrence in patients diagnosed with ER+ node-negative breast cancer, and prediction of likelihood of beneÿ t from extended (>5 year) endocrine therapy in patients who are recurrence-free after an initial 5 years of adjuvant endocrine therapy. Treatment decisions require correlation with all other clinical ÿ ndings. This test was developed and its performance characteristics determined by bioTheranostics, Inc. and has not been cleared or approved by the FDA. BREAST CANCER INDEX is a registered service mark of bioTheranostics, Inc.

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PMO LIVE

from one of “blockbusters” to one of “orphans,” Wolf predicted. Today, clinical trials aim to test for safety in phase 1, test for activity in phase 2, and compare new treatments to standard treatments in phase 3, he noted. Tomorrow’s will be biomarker-driven Bayesian trials and will essentially be “trials” of individual patients. Results from such trials, he said, will propel the field of multiple myeloma beyond “personalized” medicine and into the “next big leap of precision medicine.”

Progress Is Steady in Search of Molecular Biomarkers for Early Detection of Several Types of Cancer Of the nearly 5000 molecular biomarkers for early detection, diagnosis, and prognosis of cancer, very few receive regulatory approval. At the conference, a panel informed attendSudhir Srivastava, PhD, MPH ees about the progress made in the development of early detection biomarkers for cancer. Sudhir Srivastava, PhD, MPH, spoke about developing and validating biomarkers through the Early Detection Research Network (EDRN). The organizational structure of EDRN is modeled after the drug discovery pipeline and cooperative groups. Funding is provided for individual and collaborative research under coordination and oversight by the National Cancer Institute (NCI). Key elements include biomarker developmental laboratories, reference laboratories for analytic validation, and centers for subsequent clinical validation. “The goal is to accelerate development of useful biomarkers, but also, importantly, to discard poor markers early on, thus avoiding wasted efforts due to false leads and irreproducible early results,” said Srivastava, chief, Division of Cancer Prevention at NCI. A steering committee of the investigators provides internal governance, and an EDRN consulting team provides independent scientific guidance and review. Key objectives of EDRN are to establish an investigator-initiated infrastructure that will foster interaction among stakeholders; standardize biomarker validation criteria; and, ultimately bring biomarkers to clinical use. EDRN has 4 major collaborative disease-oriented groups: prostate, lung, colon, and breast and related cancers. Five FDA-approved and 11 CLIA-approved biomarker tests have been developed from the structure and process. He provided an example of markers that were tested and compared with fecal occult blood testing and fecal immunochemical test (FIT), and the decision rules, including performance bars, used during the validation

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process. Of 21 markers tested, 2 markers met the criteria for further evaluation: galectin-3 ligand and methylated vimentin. “Both have far better operating characteristics than CEA [carcinoembryonic antigen], which appears in the middle of the pack,” said Srivastava.

Early Detection of Colorectal Cancer The rationale for a stool DNA test to detect CRC, and the pivotal study to secure its approval, were discussed by Barry Berger, MD. The biologic rationale for using stool DNA for a screening test is that Barry Berger, MD colonocytes are continuously shed into the fecal stream, degenerate, and release aberrant DNA biomarkers, he said. Further, colorectal neoplasia-associated biomarkers have been well characterized and are available for analysis. “Exfoliation of cellular material is scarce in normal colon lining and abundant in advanced adenoma and colorectal cancer,” said Berger, chief medical officer, Exact Sciences Corporation, Madison, WI. A multitargeted stool DNA test that consists of quantitative molecular assays for KRAS mutations, aberrant NDRG4 and BMP3 methylation, and ß-actin, plus a hemoglobin immunoassay was developed and validated. From quantitative measurements of each marker, a validated, prespecified logistic regression algorithm was derived, with a value of 183 or more indicating a positive test result. In 9989 asymptomatic individuals at average risk for CRC, the study sought to determine sensitivity and specificity of the multitargeted stool DNA test for CRC and advanced adenoma and to compare the sensitivity and specificity with FIT. The sensitivity for cancer (92.3% vs 73.8%; P=.0018) and advanced adenoma (42.4% vs 23.8%; P<.0001) was superior to that of FIT, although specificity was lower with DNA testing, said Berger. The stool DNA test was superior in detecting stage I to III CRCs and high-grade dysplasia compared with FIT. Centers for Medicare & Medicaid Services coverage of the stool DNA test was approved on October 9, 2014. Airway Biomarkers for Lung Cancer Bronchial airway gene expression can serve as an early diagnostic biomarker for lung cancer, said Avrum Spira, MD, MSc. Nasal gene expression may serve as a less invasive surrogate for the bronchial airway. In smokers, epithelial cell gene expression is altered throughout the respiratory tract, but the epithelial cell genomic response to smoking is variable. A validation

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study of airway epithelial gene expression in 350 smokers undergoing bronchoscopy for suspected lung cancer had a sensitivity of 88% for lesions <3 cm and 86% for earlystage lung cancer. Patients with lung cancer have deregulation of 7 different pathways in bronchial epithelial cells, said Avrum Spira, MD, MSc Spira, from the Division of Computational Biomedicine at Boston University. Gene expression profiling reveals increased activation of PI3K in the airway of smokers with dysplasia, and chemoprevention has been shown to alter airway gene expression in such patients. The field of injury with smoking extends to the nasal epithelium for both diagnosis and screening, he said. Examination of RNA obtained from nasal mucosal brushing has discovered that nasal gene expression reflects the bronchial airway gene expression response to smoking. Genes associated with cancer in the nasal epithelium are similarly up- and down-regulated in the bronchial epithelium, he said. MicroRNA regulates part of the gene expression response to smoking. Using small RNA sequencing, a novel microRNA – miR-4423 – was found to be associated with lung cancer and might be useful for early detection. miR-4423 is expressed almost exclusively in the respiratory tract and localizes to airway epithelium, said Spira, and is down-regulated in lung cancer and in the proximal airway of smokers with lung cancer. Overexpression of miR-4423 has been shown to inhibit tumor cell growth in a subset of cancer cell lines and in a xenograft model.

Early Detection Biomarkers for Breast Cancer Multiple protein and autoantibody biomarkers have been identified for early detection of breast cancer, said Karen Anderson, MD, PhD. Antibodies are a measure of the immune response to cancer. An advantage to antibodies in cancer detection is their long half-life and minimal hourly or daily fluctuation. They are stable in a serum sample, said Anderson, associate professor, Biodesign Institute at Arizona State University, Tempe. Her group probed novel high-density custom protein microarrays expressing nearly 5000 candidate tumor antigens with sera from patients with early-stage breast cancer. From these microarrays, a 28-autoantibody panel for breast cancer detection was identified that had a sensitivity of 80.8% and a specificity of 61.6%, primarily for estrogen receptor–positive cancers. Triple-negative breast cancer is an especially aggres-

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sive form of breast cancer that is often not detected with screening mammography. “The goal for screening is a blood-based test that will lead to further imaging,” she said. Plasma biomarkers are currently undergoing a validation study by NCI/EDRN in an effort to find a composite biomarker panel with 98% specificity and 60% sensitivity for early detection of triple-negative breast cancer.

Cancer Research and Treatment in the Era of Molecular Biomarkers Incorporates New Sequencing Technologies, Clinical Trial Designs Transformative changes in cancer therapy will require new models for clinical research and practice. Retrofitting current knowledge into Razelle Kurzrock, MD traditional paradigms is suboptimal and will slow the progress in discovering effective targeted agents, said Razelle Kurzrock, MD, director, Center of Personalized Therapy and Clinical Trials, University of California, San Diego, Moores Cancer Center. Common cancers are difficult to treat because each may be >100 different diseases, especially in the metastatic setting. Metastatic tumors are complicated, she said, and it’s unlikely that monotherapy will produce prolonged responses or complete remission. “While it is often claimed that we need new drugs to treat cancer, a more fundamental problem may be the way we classify cancer,” she said. Although excellent anticancer drugs may exist, they often work poorly because patients with the wrong cancers are being treated with them. In unselected populations, the survival gain with targeted agents is minimal – an average gain of 2 months. These agents work only in those patients with a sensitizing aberration. More rational patient selection will identify those patients with the best chance to respond, and it is already occurring. The Profile Related Evidence to Determining Individualized Cancer Therapy (PREDICT) Program in Advanced Cancer Patients uses a histologyindependent targeted approach in which multiple molecular aberrations are assessed and used to match patients with targeted agents. Patients with 1 genetic mutation discovered had a 27% complete/partial response rate when a matched therapy was available, compared with only 5% in patients with a cancer that did not have a matching therapy (P<.0001). “Molecular aberrations do not segregate well by organ of origin,” said Kurzrock. For example, in PREDICT, a PIK3CA mutation was evident in 10% of advanced cancers originating in var-

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ious organs, including 29% of endometrial cancers, 24% of breast cancers, and 13% of lung cancers. Even when initiated in a phase 1 clinical trials program, personalized medicine improves clinical outcomes. At MD Anderson Cancer Center, failure-free survival improved with phase 1 matched therapy but not unmatched compared with prior conventional therapy (Tsimberidou AM, et al. Clin Cancer Res. 2012;18: 6373-6383). Using next-generation sequencing of 75 cancer patients, no 2 patients had the same molecular portfolio, “which speaks to the need to customize therapy for each patient,” she said. “This is going to get even more complicated because so far we’ve only done targeted next-generation sequencing in the genomics, not having touched on transcriptomics, proteomics, or epige netic changes.”

In PREDICT, a PIK3CA mutation was evident in 10% of advanced cancers originating in various organs, including 29% of endometrial cancers, 24% of breast cancers, and 13% of lung cancers. Three-dimensional in silico modeling is being used to predict response to treatment and is showing that patients with the same genetic abnormality may behave differently depending on where the precise mutation is located. For example, patients with insertion exon 20 mutations are classically resistant to EGFR inhibitors, but 2 patients with NSCLC with insertion exon 20 mutations have responded to cetuximab, which was predicted by in silico modeling “because that mutation brings the dimerization domains closer together.”

Transformation in Chronic Myelogenous Leukemia The revolution in improved outcomes (>90% response rates, median survival of 20+ years) in chronic myelogenous leukemia (CML) may be a model for solid tumors, Kurzrock said. This revolution has been driven by a known target (Bcr-Abl), development of a targeted agent (imatinib), and a move to treat newly diagnosed patients. When in blast crisis, however, the response rate in CML is <10%, and the median survival is only about 12 months, much like outcomes with solid-tumor metastatic disease. Strategies to transform outcomes in solid tumors may lie in treating newly diagnosed disease and using combination treatments for advanced disease. Supercomputers are being used to identify convergence path-

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ways in patients with several genetic alterations to reduce the number of drug combinations that may be necessary. Liquid biopsies (sequencing DNA taken from the bloodstream) are also being tried, and “may obviate the problem that each metastasis may be a little different,” she said.

Looking Downstream The complexity of the molecular pathways and tumor hypermutability and heterogeneity are prompting the search for effective molecular targeting sites downstream from the activated pathways, said Caroline Robert, MD, PhD. Caroline Robert, The cap-dependent translation MD, PhD initiation complex appears to be one such promising target, said Robert, head of dermatology, Institut Gustave Roussy, Paris. When BRAF is inhibited with dabrafenib, the signaling pathway is blocked, resulting in an arrest of cell proliferation and induction of apoptosis. Duration of response to BRAF inhibition is limited, however, due to secondary resistance. Initiating therapy with a BRAF inhibitor and a MEK inhibitor can improve the response compared with a BRAF inhibitor alone, as demonstrated in the phase 3 COMBO-v trial, which demonstrated a 31% reduction in the hazard for survival in patients treated with dabrafenib and trametinib versus vemurafenib monotherapy (Robert C, et al. ESMO 2014. Abstract LBA4). Treatment with the combination was associated with a 44% reduction in the hazard for progression or death. Most frequently, mechanisms that result in resistance to dabrafenib involve a reactivation of the MAP kinase pathway. A persistence in the formation of the eIF4F complex, a cap-dependent translation initiation complex, is associated with resistance to anti-BRAF therapy. The eIF4E cap-binding protein is part of the eIF4F preinitiation complex. Reducing the level of this translation initiation factor suppresses malignancy. The formation of the eIF4F complex is associated with multiple mechanisms of resistance to vemurafenib and anti-MEK inhibitors. Inhibiting the eIF4F complex synergizes with inhibiting BRAF to inhibit cell proliferation and tumor growth and may therefore represent a rational therapeutic target in cancers with initial sensitivity to a BRAF inhibitor. Validating Molecular Biomarker Testing As sequencing technologies evolve rapidly, ensuring the validity of next-generation sequencing techniques is paramount for clinical decision making, said Mark

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Sausen, PhD, director of research and development at PGDx, a provider of advanced cancer genome analysis and testing services in Baltimore, MD. A characteristic acquisition of somatic mutations occurs throughout tumorigenesis. Even within different histologic subtypes of any given tumor type, genetic differences can be observed. Many mutations occur very early in tumor development, necessitating evaluation of the genetic landscape of a patient’s tumor both when initially diagnosed as well as throughout the progression of the disease, said Sausen. Mutations can come in the form of sequence mutations as well as copy number changes and translocations. Next-generation sequencing allows evaluation of all types of somatic mutations within a single platform. Technical process elements of quality management to ensure analytic validity have been developed by the Next-generation Sequencing: Standardization of Clinical Testing workgroup (Gargis AS, et al. Nat Biotechnol. 2012;30:1033-1036). The validation component to next-generation sequencing–based approaches involves several steps: • Assay validation – documentation of the assay performance metrics and bioinformatics pipeline • Quality control – evaluation of metrics over time, ensuring consistency with values provided during validation testing • Proficiency testing – independent evaluation of performance metrics • Reference materials – samples used for the evaluation of performance metrics, ideally using disease-associated variants Performance characteristics include accuracy, precision, analytical sensitivity, analytical specificity, reportable range, and the reference range. An assay developed by PGDx, called Cancer Select-R, is an assay for detection of sequence mutations, copy number changes, rearrangements, and microsatellite instability in 120 genes. “Information contained within the targeted gene panel reports includes the genetic mutations identified, the clinically actionable alterations, and the performance metrics and limitations of the next-generation sequencing assay employed,” said Sausen.

Examining Circulating Tumor DNA Liquid biopsy approaches are becoming appealing as a noninvasive way to evaluate a patient’s genotype for sensitizing agents for specific targeted therapies as well as the detection of resistance mutations and the potential for relapse, said Sausen. Circulating tumor DNA was recently found to be detectable across tumor types with rearrangements and sequence mutations (Bette-

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gowda C, et al. Sci Transl Med. 2014;6:224ra24). “In the majority of patients, we were able to detect quantifiable amounts of circulating tumor DNA,” he said. “In some tumor types we could detect it in nearly all patients, and in other tumor types, particularly the brain tumor types, we could only identify circulating tumor DNA in a small subset of patients. Both within and across tumor types, there was a lot of variability in the actual levels of circulating tumor DNA.” Circulating tumor DNA could be found in early- and late-stage disease in most patients, and, as expected, the fraction of patients with detectable circulating tumor DNA increases as the cancer stage increases.

Cancer Select-R is an assay for detection of sequence mutations, copy number changes, rearrangements, and microsatellite instability in 120 genes. Tsunami of Clinical Trial Designs Coming There is a “tsunami” of innovative clinical trial designs testing the effect of matching genomic abnormal ities to molecularly targeted therapies, said John J. Wright, MD, PhD. This tsunami has emerged from the convergence of transformative technology “with the abject failure of our standardized randomized controlled approach using unselected ‘all-comer’ populations,” he said. The new direction in clinical trial design is converging on platform-based trials, discarding the all-comer trials for a randomized screening-based approach with broad panels of genomic predictors as a definitive new way into thinking how to best integrate the development of targeted drug and biomarker combinations, said Wright, of the Investigational Drug Branch, NCI, National Institutes of Health, Bethesda, MD. “These trials may extend the screening technology beyond the pretreatment information by incorporating a repeat biopsy at the time of progression on treatment,” he said. He described the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST), a near-term National Clinical Trials Network– based phase 3 master protocol in adjuvant lung cancer. The protocol will screen up to 8000 patients with earlystage, completely resectable or resected, nonsquamous NSCLC. In the screening component trial, which is the only point of entry for all enrollments, eligible patients will have tumor tissue screened for EGFR mutations and

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ALK rearrangements in a central CLIA-certified labo ratory. Those positive for EGFR mutations or ALK re arrangements will be stratified into 1 of 2 randomized treatment marker–specified clinical trials in which the use of erlotinib and crizotinib will be evaluated. Patients negative for these mutations will be followed for 5 years. All patients will undergo biopsy at disease progression to assess for actionable mutations. Patients will also contribute tissue and blood for genomic research by the NCI,. “ALCHEMIST is designed to accommodate evolving clinical science and research opportunities,” said Wright. “Evaluation of other targeted therapies could be added to the research effort in the future as new and promising therapies emerge.”

When a biopsy is performed of CRC tissue from a patient who has acquired resistance to cetuximab, only a fraction of the cells in the biopsy carry KRAS mutations, which suggests a nongenetic mechanism of acquired resistance may also be in play. Acquired Resistance to Targeted Therapy in Colorectal Cancer Is Similar to Primary Resistance KRAS mutations are often drivers of acquired resistance to EGFR inhibitors in the treatment of CRC, which is the main limitation of such therapy, said Alberto Bardelli, PhD. Cetuximab and panitumumab as monotherapy are effective in 15% to 20% of patients with metastatic CRC. The molecular mechanisms underlying primary resistance to anti-EGFR therapy in CRC are oncogenic activation of EGFR downstream effectors such as KRAS, BRAF, PIK3CA, and PTEN. More recently, ERBB2 amplification and MET amplification were also determined to play a role in the lack of response in this setting. “Discovery has been associated with a lack of response rather than predictive value,” said Bardelli, associate professor, Candiolo Cancer Center, University of Torino, Candiolo, Italy. “Nobody has determined what makes these patients sensitive to cetuximab and panitumumab.” After the initial response to cetuximab or panitum umab, secondary resistance invariably develops. “It’s rare that somebody has a complete response with antiEGFR therapy,” he said. “It’s fair to say that patients will relapse.”

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Drivers of Secondary Resistance The basis for secondary resistance had been poorly understood. Almost all colorectal tumors will develop with an APC/beta catenin mutation. Expression of mutant KRAS, NRAS, or BRAF mutation follows in about 50% of cases. Alternatively, colorectal tumors will evolve with a receptor tyrosine kinase alteration instead of a BRAF mutation. This alteration occurs in 20% to 30%. The third possibility in CRC progression, in which the transition to late stage is driven by an autocrine loop, is much less frequent. This last category of colorectal tumors grows despite being sensitive to EGFR inhibitors. There is no genetic biomarker to identify this third category, said Bardelli. “Not all biomarkers will be genetically driven, and in these tumors I don’t think genetics explains why they don’t respond,” he said. In order to understand resistance mechanisms, Bardelli and colleagues went back to the laboratory to use CRC cell lines, and also developed “xenopatients,” which are patient-derived, drug-resistant CRCs grafted and grown in mice. They currently have about 170 CRC cell lines, 12 of which were derived directly from xenopatients. A cetuximab trial in CRC cell lines showed that 15% to 20% of cells are sensitive to cetuximab, and the ones that are not sensitive have biomarkers of resistance. “Most of the cells that respond will have a KRAS or NRAS or BRAF mutation, but in some instances we can’t explain what’s happening,” he said. The cells that were cetuximab-sensitive were transformed through cetuximab or panitumumab treatment into cells that became resistant. “In doing so, we studied acquired resistance to EGFR blockade in CRC,” said Bardelli. “The first cell line we studied was a cell line that was highly sensitive to cetuximab, had an amplification of EGFR, and when we turned it into a resistant cell line, it lost amplification of EGFR and acquired a KRAS amplification.” Therefore, a predominant mechanism of acquired resistance to anti-EGFR therapy is the acquisition and emergence of KRAS mutation. “We continue to identify alleles that drive resistance,” he said. “Other pathways are involved. We recently discovered a patient that had a K57N as an acquired mechanism of resistance to EGFR therapy.” A second mechanism of acquired resistance involves mutation of the primary target. “The 2 mechanisms are incredibly similar,” Bardelli said. “I would argue that primary and acquired resistance to EGFR are driven by the same molecular entities. Essentially, when you start treating your patients and you apply selective pressure, you simply select for alleles that will drive secondary resistance. The same alleles that

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drive primary resistance also drive acquired resistance. The difference is the time it took for the clones that contain these mutations to emerge and develop.” When a biopsy is performed of CRC tissue from a patient who has acquired resistance to cetuximab, only a fraction of the cells in the biopsy carry KRAS mutations, which suggests a nongenetic mechanism of acquired resistance may also be in play.

Payers have a difficult role because they work with tightly controlled budgets. They must be convinced of the value of medicines and new technology, especially in the context of current treatment options. When supernatant taken from cetuximab-resistant cells is reinserted into cells sensitive to cetuximab and panitumumab, both sensitive and resistant cells grow, which suggests that the resistance is not genetic. In this case, cetuximab-resistant cells create a permissive environment for sensitive cells. A paracrine cross talk driven by the resistant subpopulation provides protection of surrounding sensitive cells. “Only a fraction of the cells will acquire mutations, and the other cells will survive based on networks of ligands,” said Bardelli.

Liquid Biopsies: Genetic Markers in the Blood Sampling tumor tissue has several limitations, including difficulty in obtaining the tissue and selection bias resulting from tumor heterogeneity. Biomarkers found in the blood are not novel, but the technology to measure circulating tumor DNA has evolved. Advances in the sensitivity and accuracy of DNA analysis have permitted genotyping of circulating cell-free DNA for somatic genomic alterations found in tumors. APC mutations in the blood are the “perfect specific biomarker,” he said, because they’re present early in CRC tumors, and there is little tumor heterogeneity with liquid biopsy. “We are looking at the blood only, so we can’t say from which metastasis there is the evolution of the mutation,” said Bardelli. “But certainly we can say that the patient is having major progression associated with multiple KRAS mutations. These mutations are not stable. Some will extinguish themselves and be taken over by other mutations.” Liquid biopsies will gain in importance in the future, Bardelli predicted. Clinical applications include monitoring response to therapy and detection of resistance mutations.

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Personalized Medicine in Oncology Brings Challenges to Regulatory Agencies in Their Appraisal Process While personalized medicine is evolving to become an integral part of modern medicine, regulators are grappling with the assignment of value to new technologies, said Andrew Stainthorpe, PhD, who spoke on the regulatory aspects of personalized medicine in oncology. Stainthorpe was speaking from the perspective of associate director of the National Institute for Health and Care Excellence (NICE), which is an independent organization established in the United Kingdom to provide guidance for decisions on which drugs and treatments are made available. Appraisals of new health technologies are based primarily on evaluations of efficacy and cost-effectiveness under various circumstances. “Does the current regulatory landscape work well for manufacturers and researchers?” he asked. “And does it work well for patients, clinicians, payers, and health technology assessment [HTA] committees? In some respects it doesn’t, and that’s why perhaps you’re seeing from NICE...a number of negative decisions about the cost-effectiveness of diagnostic tests and for new technologies and the cost-effectiveness of those.” Healthcare expenditures are outpacing the growth of the gross domestic product in most countries at a pace that is not sustainable. Key parts of regulatory agencies and HTA committees are the process by which decisions are made with budget constraints in mind. Payers have a difficult role because they work with tightly controlled budgets, said Stainthorpe. They must be convinced of the value of medicines and new technology, especially in the context of current treatment options. Cancer is not a uniform disease, as there are several molecular subsets of most cancers. In addition, some drugs are now effective for the treatment of several rare cancers, such as imatinib for CML with a Bcr-Abl translocation and gastrointestinal stromal tumors with KIT mutations, or trastuzumab for HER2-overexpressing breast cancer and gastric cancer. The research is leading to a plethora of different cancers, and questions arise regarding the best way to treat them “and which technologies work best to treat patients who may have more than 1 tumor type expressing a range of different mutations,” he said. NICE typically considers a range of factors in making its guidance. It assesses the evidence put before them by manufacturers of technology. Whereas a threshold of £20,000 per quality-adjusted life year has been accepted as cost-effective, NICE may allow higher prices for innovative technologies, he said. It is in the process of establishing a formal transparent process that lays out

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the appraisal parameters that enter into its decisions, “so the manufacturers bringing such technology to market will know what evidence to collect and what actually makes a difference in the technology appraisal,” said Stainthorpe. “There are technology appraisals for which a manufacturer might bring a companion diagnostic into the process,” he said. “And there’s a diagnostic appraisal program with appraisal of a new diagnostic without it being linked to a drug. Those are the 2 programs where NICE operates where a biomarker is featured.” Often, NICE will give a qualified “yes” to a new technology, usually when in a post hoc review of the data it determines that a subset of the population benefits more than the overall population from the technology. “It may be that there’s a genetic aspect to it,” he said.

“There are still situations in which there’s a good match between a companion diagnostic and its indication, but it’s not cost-effective, and NICE has said that it can’t recommend that treatment.” The patient perspective is also considered in decisions. Evidence must show benefit of a treatment on quality of life and not only on the disease. With personalized medicine, regulators face the challenge not only of small sample size (in some instances, N=1) but also of patients with a number of different genotypes. How that fits into decisions about therapies to make available and the cost of such medicines is uncertain. “It’s an exciting time, but I think we need more research and more input in a way that’s digestible for the regulators and the HTA community,” he said. u

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THE LAST WORD

Personalized Medicine’s Progress Edward Abrahams, PhD President Personalized Medicine Coalition

n November 12, 2014, the Personalized Medicine Coalition (PMC) celebrated its 10th anniversary at the 10th Annual Personalized Medicine Conference at the Harvard Medical School. The occasion gave us a chance to review the progress of personalized medicine and to reflect on the continuing challenges facing Edward the field. Abrahams, PhD Personalized medicine has in fact changed the face of healthcare during these past 10 years. Progress has been steady, if incremental. Although we have come far, we still have a long way to go before we can declare victory, which could be defined as no longer treating the disease but rather treating the patient, according to what works best for that individual.

Personalized medicine has in fact changed the face of healthcare during these past 10 years. Progress has been steady, if incremental. The PMC was launched at the end of 2004 by some 20 institutions across healthcare that believed – then and now – that we needed a friendlier environment in the important space between the science and the patient so that we can in fact replace one-size-fits-all trial-and-error medicine, which – then and now – still defines the way most healthcare is practiced. A little historical context. 2004 is remembered best by the launch of something a group of Harvard undergraduates called “The Facebook.” But closer to home in the world of personalized medicine, where things don’t move quite so fast as they do in social media, but maybe with equal significance for the future of humanity, the final map of the human genome had just been published. Also in 2004, with enormous significance for the future of the pharmaceutical industry as well as personalized medicine, Merck withdrew Vioxx from the market because it could not predict which patients taking the painkiller were at risk of severe cardiovascular side effects.

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While personalized medicine cannot point to the equivalent of Facebook’s impact on society, it can cite significant advancements during the past decade. Let me reference 10 facts. First, the coalition I referred to earlier has about 225 members, a number I like to think of as a “surrogate end point” that reflects interest in and commitment to personalized medicine. Second, the number of prominent examples of available personalized medicine drugs, treatments, and diagnostic products have increased, by our count, from 13 in 2006 to 113 in 2014. Third, with as yet unknown significance for the future of diagnostics, the cost of sequencing a single human genome has declined from about $100 million in 2004 to around $1000 ten years later. Fourth, beginning in 2004, new diagnostic companies began producing stand-alone, sophisticated prognostic tests to help guide important medical decisions, thereby saving patients and the health system unnecessary expense and side effects. Fifth, while it took 26 years before the discovery of the EGFR mutation led to the development of Erbitux in 2003, it only took 4 years until the discovery of the ALK mutation led to the development of Xalkori in 2011, pointing to a new era of drug development in which it may be said, and has been said, that without a test there can be no drug. Sixth, whereas in the early 1990s, only 5% of the FDA’s new drug approvals were for targeted therapeutics, 20 years later that number is now a quarter of the new approvals. And last year, it was 45%, including “break-through” drugs to treat selected cancers in segmented populations. Today, 137 FDA-approved drugs have pharmaco genomic information in their labeling, and 155 pharmacogenomic biomarkers are included on FDAapproved drug labels. It is also estimated that marketed therapeutics with an associated companion diagnostic generate over $19 billion annually. Seventh, led by the passage of the Genetic Information Nondiscrimination Act, which removed an important roadblock on the path to personalized medicine by assuaging public anxiety that genetic information might be used to deny health insurance or employment opportunities, public policies have been put in place to encourage the growth of personalized medicine. They include the FDA’s guidance on volun-

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THE LAST WORD

tary pharmacogenomics data submission and the development of pharmacogenomics-based clinical dosing guidelines; FDA’s guidance on codeveloped diagnostic-therapeutic products; FDA’s encouragement of adaptive clinical trial designs that incorporate genetics and take trials to patients for the first time; revised Current Procedural Terminology coding and marketbased pricing beginning in 2017 to encourage diagnostic development; the launch of the voluntary National Institutes of Health genetic testing registry; and the development and implementation of FDA/Centers for Medicare & Medicaid Services parallel review for molecular diagnostic tests.

PMC found in a poll released earlier this year that 68% of the public had never heard of personalized medicine. And most of the 32% that said that they had heard of it got it wrong. We have overcome many challenges in the past 10 years and have made much progress, but suffice it to say, we have far to go. Let me suggest 3 final points, or facts, if you will, that remain challenges for the field. Eighth, the uncertain future and continuing contention regarding the regulation of laboratory-developed tests prevents the personalized medicine commu-

nity from working together and deters investment because the rules of the road remain unclear. Ninth, while we know wise policy would encourage coverage and payment for products based on their value, payers and manufacturers do not agree on the levels of evidence we need to make those decisions. In this new environment, in which it is understood that healthcare costs must be contained, it is incumbent on all to show that personalized medicine can not only improve outcomes but also save the healthcare system money by providing the right treatment to the right patient at the right time, as the mantra of personalized medicine puts it. And finally, we have only scratched the surface of educating healthcare providers about the power of personalized medicine, never mind patients. A 2010 American Medical Association/Medco survey of physicians found, for example, that while 98% believed that genetics play an important role in affecting treatment response, only a quarter had any formal training in pharmacogenomics. And only 10% felt that they had sufficient knowledge to incorporate it into their practices. Regarding patients, PMC found in a poll released earlier this year that 68% of the public had never heard of personalized medicine. And most of the 32% that said that they had heard of it got it wrong. So, in short, with regard to education and advocacy, we have work cut out for us if we want to build on the progress we have made in the past 10 years. u

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SAVE THE DATE JULY 22-25, 2015 THE WESTIN SEATTLE • SEATTLE, WASHINGTON

The Global Biomarkers Consortium (GBC) and World Cutaneous Malignancies Congress (WCMC) will be holding their fourth annual joint meeting focused on personalized and precision medicine in oncology (PMO) on July 22-25, 2015, in Seattle, Washington. July 22-24 A Focus on the Application of Molecular Biomarkers in Clinical Practice Across Multiple Tumor Types

SCHEDULE OF EVENTS (subject to change)

July 24-25 Spotlight on Cutaneous Malignancies, Including Melanoma, Cutaneous T-Cell Lymphoma, and Basal Cell Carcinoma

CONFERENCE CO-CHAIRS

Sanjiv S. Agarwala, MD

Professor of Medicine Temple University School of Medicine Chief, Medical Oncology & Hematology St. Luke’s Cancer Center Bethlehem, PA

Jorge E. Cortes, MD

Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

Hope S. Rugo, MD

Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Hope Comprehensive S. Rugo, M.D. Cancer Center San of Francisco, Professor MedicineCA Director, Breast Oncology and Clinical Trials Education University of California San Francisco Helen Diller Famil Cancer Center San Francisco, CA

www.pmo-live.com

PMOLive2015_112114

Hope S. Rugo, MD, is a Professor of Medicine in the Divis

ANNUAL INDEX 2014

The Biomarker KIT Genetic Mutation in a Melanoma Patient. Chandra PK...........................................................2:82 JAK2 V617F in a Patient With AML. Chandra PK, Gottwals J............................................................3:136 Molecular Diversity of CLL. Chandra PK, Gottwals J............................................................4:202 RAS and Colon Cancer: What You’re Missing. Ali SL, Sigal DS..................................................5:264

Breast Cancer Faculty Perspectives: Latest Treatment Advances for Individualized Care of Breast Cancer. Carey LA, Shockney LD, Kaddis AA..................................7:382 Editorial New Technology Diffusion Essential to Personalized Medicine. Henry RE.............................................1:66 The Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady Paradigm Shift. Piper K.......................................................2:121 The Affordable Care Act and Cancer Patients – Winners and Losers in an Unsteady Paradigm Shift: Part 2. Piper K...........................................3:181 PMO and the PMC – A Collaboration to Advance Precision Medicine. Introducing Dr Edward Abrahams, President of PMC, as the Author of The Last Word. Siyahian K...................................4:238 The Case for Personalized Medicine: Defining the Field and Envisioning the Future of Healthcare. Abrahams E.........................................................5:299 The Personalized Medicine Coalition and Turning the Tide Against Cancer Through Sustained Medical Innovation. Abrahams E......................................6:350 Personalized Medicine’s Progress. Abrahams E.....8:476

Global Biomarkers Consortium Clinical Approaches to Targeted Technologies: Highlights From the Second Annual Conference of the Global Biomarkers Consortium. Coleman R, Cortes JE...............................................................1:32 Hematologic Malignancies Considerations in Multiple Myeloma. Ask the Experts:

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Beyond Complete Responses. Wolf J, Marsala A, Young R.................................................................1:24 Molecular Profiling in Acute Myeloid Leukemia....2:86 Faculty Perspectives. Advances in the Treatment of Hematologic Malignancies. Richardson P, Gregory SA, Mesa RA, O’Brien SM..................................2:92 Highlights From the 6th International Symposium on Acute Promyelocytic Leukemia. Raedler LA.....6:324

Immunotherapy Anti–PD-1/PD-L1 Therapy: New Immunotherapy Options for Patients With a Variety of Cancers. Bae S, Chmielowski B........................................3:144 Blocking Immune Checkpoints in Metastatic Melanoma. Puzanov I...........................................5:275 FDA Approves Pembrolizumab for Advanced Melanoma..............................................................6:320

Interview With the Innovators Partners HealthCare Center for Personalized Genetic Medicine: Utilizing Genetics and Genomics to Improve Care of Patients. An Interview With Scott T. Weiss, MD, MS, and Heidi L. Rehm, PhD.....1:18 Empowering the Practice of Personalized Medicine: The Evolving Role of Pathology in Cancer Diagnostics. An Interview With Pranil K. Chandra, DO.........................................................................2:88 A Breakthrough Treatment for ALL and CLL: The New Biologic Agent, CTL019. An Interview With David L. Porter, MD, of the University of Pennsylvania.......................................................3:138 Perspectives on the Landscape of Personalized Medicine. An Interview With Gail E. Herman, MD, PhD; Barbara L. McAneny, MD; and Charles L. Sawyers, MD.......................................................3:154 Implementing Global Healthcare: Partners In Health and the Rwandan Cancer Center Initiative. An Interview With Lawrence N. Shulman, MD, of Dana-Farber Cancer Institute.............................4:206 Personalizing Medicine and Value: An Interview With Faculty at the Fourth Annual Conference of the Association for Value-Based Cancer Care.....................................................................5:254

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ANNUAL INDEX 2014

Tissue Phenomics: Closing the Gap Between Genomic Information and Patient Outcomes. An Interview With Thomas P. Heydler, CEO of Definiens.........................................................6:314 Persistence and the Expedition to Mine the Immune System for Cancer Cures: An Interview With Dr James Allison of MD Anderson Cancer Center.....................................................7:366 Providing Therapeutic Guidance for Breast Cancer Patients in the Molecular Era With the Breast Cancer IndexSM Assay: An Interview With Stephen C. Malamud, MD, and Susan K. Boolbol, MD, of Mount Sinai Beth Israel Hospital.......................8:429

Lung Cancer Navigating the Molecular Testing Landscape in Lung Cancer. Experts discuss how they use mutational testing...............................................6:334 Pediatric Oncology A Win for Pediatric Cancer Research: The Gabriella Miller Kids First Research Act and Smashing Walnuts Foundation...........................................3:160

Psychosocial Oncology Putting the “Person” in Personalized Cancer Medicine: A Systematic Review of Psychological Aspects of Targeted Therapy. McFarland DC, Hamilton JG, Fox R, Holland J..........................8:438 Reimbursement ASCO Proposes New Model for Reimbursement by Medicare for Cancer Care...................................2:106 Transforming Cancer Research Progress Report: Implementation of ASCO’s Blueprint for Transforming Clinical and Translational Cancer Research....................................................................1:14 Value-Based Cancer Care Need for Innovative Strategies for Quality Care Will Continue to Grow.................................................1:44 Promise of Personalized Care Hinges on Reimbursement Reform.......................................3:162 Personalizing Value-Based Medicine. Elfiky A.....4:220 Value-Based Insurance – Not Such an Easy Sell..5:298

PMO Live: A Global Biomarkers Consortium Initiative Abstracts From the Third Annual PMO Live: A Global Biomarkers Consortium Initiative..........7:406

Determining the Value of Cancer Therapies: A Paradigm Shift Focused on Quality, Outcomes, and Cost. Wong W....................................................6:348

Highlights From the Third Annual PMO Live: A Global Biomarkers Consortium Initiative..........8:462

World Cutaneous Malignancies Congress Abstracts From the Third Annual WCMC..........7:394

Prostate Cancer Androgen Suppression in Castration-Resistant Prostate Cancer...................................................4:212

Highlights From the Third Annual WCMC........8:450

Predictors of Hormone Responsiveness in Prostate Cancer. Danchaivijitr P, George S.....................7:376

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481

AUTHOR INDEX 2014

Abrahams E....................................... 5:299, 6:350, 8:476 Ali SL............................................................................5:264 Bae S............................................................................ 3:144 Carey LA.................................................................... 7:382 Chandra PK......................................... 2:82, 3:136, 4:202 Chmielowski B.........................................................3:144 Coleman R.................................................................... 1:32 Cortes JE.....................................................................1:32 Danchaivijitr P.........................................................7:376 Elfiky A.....................................................................4:220 Fox R.........................................................................8:438 George S.......................................................................7:376 Gottwals J.........................................................3:136, 4:202 Gregory SA.................................................................2:92 Hamilton JG.............................................................8:438 Henry RE....................................................................1:66

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Personalized Medicine in Oncology

Holland J........................................................................8:438 Kaddis AA................................................................7:382 Marsala A....................................................................... 1:24 McFarland DC..........................................................8:438 Mesa RA.....................................................................2:92 Oâ&#x20AC;&#x2122;Brien SM.................................................................... 2:92 Piper K.......................................................... 2:121, 3:181 Puzanov I......................................................................5:275 Raedler LA................................................................... 6:324 Richardson P.................................................................. 2:92 Shockney LD............................................................7:382 Sigal DS....................................................................5:264 Siyahian K................................................................4:238 Wolf J..........................................................................1:24 Wong W...................................................................6:348 Young R......................................................................1:24

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December 2014

Vol 3, No 8

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ersonalized edicine in Oncology

BIOMARKERS • IMMUNOTHERAPY • TARGETED THERAPIES • DIAGNOSTICS

Providing Critical Insights for Clinical Application Customized Drugs/Biologics Pharmacogenomics Diagnostics & Assays Gene Sequencing Targeted Therapies Immunotherapy Biomarkers Prevention Pathology

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The ofﬁcial publication of

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GLOBAL BIOMARKERS CONSORTIUM Clinical Approaches to Targeted Technologies ™

WORLD CUTANEOUS

WORLD CUTANEOUS MALIGNANCIES CONGRESS

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Cancer cell

Amgen is researching ways to help T cells target cancer.

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Oncolytic Immunotherapy is an innovative area of research that uses a modified virus designed to induce tumor cell lysis and expose tumor-derived antigens.

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Activated dendritic cells can teach T cells to help find and fight cancer cells with a matching antigen profile.1

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