July/August 2012 Vol4, No 2

July/AuguSt 2012

www.infertilityrepronewS.Com

Vol 4, no 2

The OncOlOgy Issue

ONS ANNUAL CONGRESS

OVARIAN CANCER new Agents prove potent Against Her2-positive Breast Screening for ovarian Cancer Cancer

Researchers seek to resolve outstanding issues regarding testing

By Caroline Helwick

By D. “Jeff” Nordquist, RN, MS, CS, FNP, Nurse Practitioner Karin Goodman, RN, CNP, Adult Nurse Practitioner Mayo Clinic, Rochester, Minnesota

O

varian cancer is said to “whisper,” because the symptoms are seldom obvious. The most frequent symptoms seen in women diagnosed with ovarian cancer are abdominal bloating, pelvic or abdominal pain, difficulty eating/feeling full fast, or urinary symptoms. These are often passed off as nothing other than symptoms of getting older, gaining weight, or related to menopause. However, this whispering disease is the most lethal of all the breast and gynecologic cancers and accounts for more deaths than any other cancer of the female reproductive system.1

The American Cancer Society estimates that about 22,280 women will be diagnosed with ovarian cancer in 2012, and 15,500 women will die of ovarian cancer.1 Approximately 75% of women will survive 1 year after diagnosis and treatment. The 5-year survival rate is 46%, an increase of less than 10% since 1974, when the survival rate was 37%.

Those diagnosed at an early stage (stage I) have a 5-year survival rate of 94%; however, only about 15% of all ovarian cancers are diagnosed at this early stage.

One in 71 women will have a diagnosis of ovarian cancer in her lifetime, Continued on page 7

BLADDER CANCER Images representing a HER2 gene amplified specimen to the left and a nonamplified specimen to the right.

T

rastuzumab changed the course of HER2-positive breast cancer, and future anti-HER2 therapies may have an even greater impact, said Kristine Abueg, RN, MSN, OCN,

clinical research nurse at Kaiser Permanente in Roseville, California, who discussed “What’s New in HER2?” at the 37th Annual Congress of the Oncology Nursing Society.

Continued on page 6

Cultivating personalized medicine Clinical Acumen in the management of Breast Cancer An interview with Edith Perez, MD

I

f any cancer can be said to have launched personalized medicine into orbit and establish it as the standard for all cancer therapy to aspire toward, it

is breast cancer. The discovery of the estrogen receptor (ER) and HER2 biomarkers has astonished healthcare professionals and the public alike and raised Continued on page 12

The Publicationof of The Official Offical Publication

We thank Watson Pharmaceuticals, Inc., for their gold level support. ©2012 Novellus Healthcare Communications, LLC

Screening for Bladder Cancer

By Gary Shelton, MSN, NP, ANP-BC, AOCNP NYU Cancer Institute, New York, New York

A

lthough the increased incidence of bladder cancer (BC) has softened in recent years, proposed to be due in part to smoking cessation strategies, BC remains a significant healthcare problem with high recurrence rates.1,2 Currently, there is inadequate evidence that screening for BC in the asymptomatic population promotes improved overall morbidity or mortality.3 Despite this current state of the science, there is great interest in bettering the gold standard for early diagnosis – cystoscopy, cytology, and imaging – as these are expensive, uncomfortable, and not suggested for low-risk individuals or for those without hematuria.4

Background BC is projected to be the fourth most common cancer diagnosed in American men in 2012, with an expected incidence of over 55,000 cases; for women, the incidence is estimated to be just under 18,000 new cases. More than 10,000 men are expected to die of the disease in 2012, with an estimated 4000 women succumbing as well. BC occurs 4 times more commonly in men than in women and in twice as many white men as African American men.5 Efforts should be made to promote smoking cessation, as smoking is the most well-established risk factor for BC. Other risk factors include workrelated exposures to dyes, rubber, and Continued on page 9

INS IDE MAle FeRTIlITy . . . . . . . . . . . . . . . .

11

Age and semen characteristics affect the achievement of pregnancy in in vitro fertilization treatments with donated oocytes

IVF In sAMe-seX cOuPles . . .

11

The challenges of IVF are unique for same-sex couples and range from legal and contractual hurdles to treatment coordination

Crinone® 4% Crinone® 8% (progesterone gel) For vaginal use only.

Rx only

BRIEF SUMMARY For full prescribing information, see package insert.

INDICATIONS AND USAGE Assisted Reproductive Technology Crinone 8% is indicated for progesterone supplementation or replacement as part of an Assisted Reproductive Technology (“ART”) treatment for infertile women with progesterone deficiency.

Secondary Amenorrhea Crinone 4% is indicated for the treatment of secondary amenorrhea. Crinone 8% is indicated for use in women who have failed to respond to treatment with Crinone 4%.

CONTRAINDICATIONS Crinone should not be used in individuals with any of the following conditions: known sensitivity to Crinone (progesterone or any of the other ingredients); undiagnosed vaginal bleeding; liver dysfunction or disease; known or suspected malignancy of the breast or genital organs; missed abortion; active thrombophlebitis or thromboembolic disorders, or a history of hormone-associated thrombophlebitis or thromboembolic disorders.

WARNINGS The physician should be alert to the earliest manifestations of thrombotic disorders (thrombophlebitis, cerebrovascular disorders, pulmonary embolism, and retinal thrombosis).

Should any of these occur or be suspected, the drug should be discontinued immediately.

Progesterone and progestins have been used to prevent miscarriage in women with a history of recurrent spontaneous pregnancy losses. No adequate evidence is available to show that they are effective for this purpose.

PRECAUTIONS General 1. The pretreatment physical examination should include special reference to breast and pelvic organs, as well as Papanicolaou smear.

2. In cases of breakthrough bleeding, as in all cases of irregular vaginal bleeding, nonfunctional causes should be considered. In cases of undiagnosed vaginal bleeding, adequate diagnostic measures should be undertaken.

3. Because progestogens may cause some degree of fluid retention, conditions which might be influenced by this factor (e.g., epilepsy, migraine, asthma, cardiac or renal dysfunction) require careful observation.

4. The pathologist should be advised of progesterone therapy when relevant specimens are submitted.

5. Patients who have a history of psychic depression should be carefully observed and the drug discontinued if the depression recurs to a serious degree.

6. A decrease in glucose tolerance has been observed in a small percentage of patients on estrogen-progestin combination drugs. The mechanism of this decrease is not known. For this reason, diabetic patients should be carefully observed while receiving progestin therapy.

Information for Patients The product should not be used concurrently with other local intravaginal therapy. If other local intravaginal therapy is to be used concurrently, there should be at least a 6-hour period before or after Crinone administration. Small, white globules may appear as a vaginal discharge possibly due to gel accumulation, even several days after usage.

Drug Interactions No drug interactions have been assessed with Crinone.

Carcinogenesis, Mutagenesis, Impairment of Fertility Nonclinical toxicity studies to determine the potential of Crinone to cause carcinogenicity or mutagenicity have not been performed. The effect of Crinone on fertility has not been evaluated in animals.

Pregnancy Crinone 8% has been used to support embryo implantation and maintain pregnancies through its use as part of ART treatment regimens in two clinical studies (studies COL1620-007US and COL1620-F01). In the first study (COL1620-007US), 54 Crinonetreated women had donor oocyte transfer procedures, and clinical pregnancies occurred in 26 women (48%). The outcomes of these 26 pregnancies were as follows: one woman had an elective termination of pregnancy at 19 weeks due to congenital malformations (omphalocele) associated with a chromosomal abnormality; one woman pregnant with triplets had an elective termination of her pregnancy; seven women had spontaneous abortions; and 17 women delivered 25 apparently normal newborns.

In the second study (COL1620-F01), Crinone 8% was used in the luteal phase support of women undergoing in vitro fertilization (“IVF”) procedures. In this multi-center, openlabel study, 139 women received Crinone 8% once daily beginning within 24 hours of embryo transfer and continuing through Day 30 post-transfer.

Clinical pregnancies assessed at Day 90 post-transfer were seen in 36 (26%) of women.

Thirty-two women (23%) delivered newborns and four women (3%) had spontaneous abortions. Of the 47 newborns delivered, one had a teratoma associated with a cleft palate; one had respiratory distress syndrome; 44 were apparently normal and one was lost to follow-up.

Geriatric Use The safety and effectiveness in geriatric patients (over age 65) have not been established.

Pediatric Use Safety and effectiveness in pediatric patients have not been established.

Nursing Mothers Detectable amounts of progestins have been identified in the milk of mothers receiving them. The effect of this on the nursing infant has not been determined.

ADVERSE REACTIONS Assisted Reproductive Technology In a study of 61 women with ovarian failure undergoing a donor oocyte transfer procedure receiving Crinone 8% twice daily, treatment-emergent adverse events occurring in 5% or more of the women were: bloating (7%), cramps not otherwise specified (15%), pain (8%), dizziness (5%), headache (13%), nausea (7%), breast pain (13%), moniliasis genital (5%), vaginal discharge (7%), pruritus genital (5%).

In a second clinical study of 139 women using Crinone 8% once daily for luteal phase support while undergoing an IVF procedure, treatment-emergent adverse events reported in 5% or greater of the women were: abdominal pain (12%), perineal pain female (17%), headache (17%), constipation (27%), diarrhea (8%), nausea (22%), vomiting (5%), arthralgia (8%), depression (11%), libido decreased (10%), nervousness (16%), somnolence (27%), breast enlargement (40%), dyspareunia (6%), nocturia (13%).

Secondary Amenorrhea In three studies, 127 women with secondary amenorrhea received estrogen replacement therapy and Crinone 4% or 8% every other day for six doses. Treatment-emergent adverse events during estrogen and Crinone treatment that occurred in 5% or more of women treated with Crinone 4% or Crinone 8% respectively were: abdominal pain (5%, 9%), appetite increased (5%, 8%), bloating (13%, 12%), cramps not otherwise specified (19%, 26%), fatigue (21%, 22%), headache (19%, 15%), nausea (8%, 6%), back pain (8%, 3%), myalgia (8%, 0%), depression (19%, 15%), emotional lability (23%, 22%), sleep disorder (18%, 18%), vaginal discharge (11%, 3%), upper respiratory tract infection (5%, 8%), and pruritus genital (2%, 6%).

Additional adverse events reported in women at a frequency of less than 5% in Crinone ART and secondary amenorrhea studies and not listed above include: autonomic nervous system–mouth dry, sweating increased; body as a whole–abnormal crying, allergic reaction, allergy, appetite decreased, asthenia, edema, face edema, fever, hot flushes, influenza-like symptoms, water retention, xerophthalmia; cardiovascular, general–syncope; central and peripheral nervous system–migraine, tremor; gastro-intestinal–dyspepsia, eructation, flatulence, gastritis, toothache; metabolic and nutritional–thirst; musculo-skeletal system– cramps legs, leg pain, skeletal pain; neoplasm–benign cyst; platelet, bleeding & clotting– purpura; psychiatric–aggressive reactions, forgetfulness, insomnia; red blood cell– anemia; reproductive, female–dysmenorrhea, premenstrual tension, vaginal dryness; resistance mechanism–infection, pharyngitis, sinusitis, urinary tract infection; respiratory system–asthma, dyspnea, hyperventilation, rhinitis; skin and appendages–acne, pruritus, rash, seborrhea, skin discoloration, skin disorder, urticaria; urinary system–cystitis, dysuria, micturition frequency; vision disorders–conjunctivitis.

OVERDOSAGE There have been no reports of overdosage with Crinone. In the case of overdosage, however, discontinue Crinone, treat the patient symptomatically, and institute supportive measures.

As with all prescription drugs, this medicine should be kept out of the reach of children.

DOSAGE AND ADMINISTRATION Assisted Reproductive Technology Crinone 8% is administered vaginally at a dose of 90 mg once daily in women who require progesterone supplementation. Crinone 8% is administered vaginally at a dose of 90 mg twice daily in women with partial or complete ovarian failure who require progesterone replacement. If pregnancy occurs, treatment may be continued until placental autonomy is achieved, up to 10-12 weeks.

Secondary Amenorrhea Crinone 4% is administered vaginally every other day up to a total of six doses. For women who fail to respond, a trial of Crinone 8% every other day up to a total of six doses may be instituted.

It is important to note that a dosage increase from the 4% gel can only be accomplished by using the 8% gel. Increasing the volume of gel administered does not increase the amount of progesterone absorbed.

HOW SUPPLIED Crinone is available in the following strengths: 4% gel (45 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.

NDC 52544-283-24 - 6 Single-use prefilled applicators.

8% gel (90 mg) in a single use, one piece, disposable, white polyethylene vaginal applicator with a twist-off top. Each applicator contains 1.45 g of gel and delivers 1.125 g of gel.

NDC 52544-284-12 - 15 Single-use prefilled applicators.

Each applicator is wrapped and sealed in a foil overwrap.

Store at 20-25°C (68-77°F). [See USP controlled room temperature.]

Rx only

Address medical inquiries to: WATSON Medical Communications P.O. Box 1953 Morristown, NJ 07962-1953 800-272-5525 Distributed by: Watson Pharma, Inc., Morristown, NJ 07962 USA Manufactured by: Fleet Laboratories Ltd., Watford, Herts WD18 7JJ UK Revised: July 2010

Editorial Board Richard P. Dickey, MD, PhD Director, Reproductive Medicine Fertility Institute of New Orleans, LA

Juergen Liebermann, PhD, HCLD IVF Laboratory Director River North Fertility Centers of Illinois, Chicago

Patricia Rucinsky, RN, BSN Clinical Nurse Manager IRMS at Saint Barnabas, NJ

Gina Paoletti-Falcone, RN, BSN Clinical Services Manager Freedom Fertility Pharmacy Byfield, MA

Mary M. Macgregor, RNC IVF Nurse Coordinator Fertility Institute of New Orleans, LA

Elizabeth A. Shrader, MSN, APN-C IVF Nurse Coordinator DVIF&G Marlton, NJ

Margaret-Rose Agostino, DNP, MSW, RN-BC, IBCLC Assistant Professor Department of Nursing Delaware State University

Donielle Farrington, RNC Clinical Nursing Manager Brunswick Hills OB/GYN, NJ

Jill Marchetti, RN Director, Egg Donor Program IVF New Jersey

Christopher S. Sipe, MD OB/GYN & Reproductive Endocrinology Fertility Centers of Illinois, Chicago

Barbara Alice, RN, APN-C, MSN Nursing Manager, IVF Coordinator South Jersey Fertility Center

Sandra Fernandez, RPh, PharmD Pharmacist Mandell’s Clinical Pharmacy, NJ

Donna Makris, RN, BSN, IBCLC Parent Education Coordinator OB/GYN, St. Peter’s Medical Center, NJ

Dale C. Smith, RN, MPH, MSN NFP Nursing Supervisor DHEC Region 6 Conway, SC

Monica R. Benson, BSN, RNC Nurse Manager Third Party Reproduction, RMA New Jersey

Jennifer Iannaccone, RNC Nursing Manager, IVF Coordinator IVF New Jersey

Norah S. Nutter, MSN, WHNP-BC, IBCLC Women’s Health Nurse Practitioner Magnolia OB/GYN Myrtle Beach, SC

Harvey J. Stern, MD, PhD Director, Reproductive Genetics Genetics & IVF Institute Fairfax, VA

Melissa B. Brisman, Esq Owner Reproductive Possibilities, LLC Surrogate Fund Management, LLC Montvale, NJ

Carolyn E. Keating, BSN, RNC, NP Piedmont Reproductive and Endocrinology Group Greenville, SC

Kutluk Oktay, MD, FACOG Director, Division of Reproductive Medicine & Infertility, Department of Obstetrics & Gynecology, New York Medical College; Director, Institute for Fertility Preservation, NY

Kriston Ward, RN, MS, NP-C Strong Fertility Center University of Rochester Medical Center, Rochester, NY

Kit Devine, MSN, ARNP Advanced Nurse Practitioner Fertility & Endocrine Associates, Kentucky

Cheryl Kilbourne, RN Clinical Director Women and Children Services Waccamaw Hospital, SC

Cyndi Gale Roller, PhD, RN, CNP, CNM Program Director, Women’s Health College of Nursing Kent State University, OH

Joan Zaccardi, MS, DrNP Administrative Practice Manager Urogynecology Arts of New Jersey

CO-EDITOR-IN-CHIEF

Sue Jasulaitis, RN, MS Clinical Research Manager Fertility Centers of Illinois, Chicago

CO-EDITOR-IN-CHIEF

Debra Moynihan, WHNP-BC, MSN Women’s Health Nurse Practitioner Carolina OB/GYN, Myrtle Beach, SC

July/AugusT 2012 l VOLUME 4, NUMBER 2

5

In This Issue www.infertilityrepronewS.Com PUBLISHING STAFF

Publisher Russell Hennessy russell@novellushc.com 732-992-1888 Editorial Director Kristin Siyahian kristin@greenhillhc.com Editorial Assistant Jennifer Brandt Senior Copy Editor Bjarne Hansen Senior Production Manager Marie RS Borrelli

new AgentS proVe potent AgAinSt Her2-poSitiVe BreASt CAnCer Researchers seek to resolve outstanding issues regarding testing

CultiVAting perSonAliZeD meDiCine CliniCAl ACumen in tHe mAnAgement of BreASt CAnCer An interview with Edith Perez, MD

SCreening for oVAriAn CAnCer Symptoms are often passed off as nothing other than symptoms of getting older, gaining weight, or related to menopause

mAle fertility Age and semen characteristics affect the achievement of pregnancy in in vitro fertilization treatments with donated oocytes

SCreening for BlADDer CAnCer Bladder cancer remains a significant healthcare problem with high recurrence rates

iVf in SAme-SeX CoupleS The challenges of IVF are unique for same-sex couples and range from legal and contractual hurdles to treatment coordination

Quality Control Director Barbara Marino Business Manager Blanche Marchitto Editorial Contact: Telephone: 732-992-1536 Fax: 732-656-7938 MISSION STATEMENT Infertility & Reproductive News is the official publication of the American Academy of OB/GYN and Infertility Nurses. Infertility & Reproductive News provides practical, authoritative, cutting-edge information on the physiologic, medical, and psychological aspects of women’s health, focusing on the role of the infertility practitioner, including nurses, MDs, PhDs, NPs, and PAs, in patient care. Our journal offers a forum for nurses, nurse practitioners, physician assistants, physicians, administrators, researchers, and all others involved in infertility and women’s health to discuss the entire scope of current and emerging diagnostic and therapeutic options, as well as counseling and patient followup for women throughout their reproductive years and beyond. Infertility & Reproductive News promotes peer-to-peer collaboration among all infertility professionals toward the advancement of integrated services for optimal delivery of patient care and offers continuing education for all clinicians involved in these interrelated fields of women’s reproduction.

Infertility & Reproductive News, ISSN 2153-6562 (print); ISSN 2153-6546 (online), is published

by Novellus Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831. Copyright ©2012 by Novellus Healthcare Communications, LLC. All rights reserved. Infertility & Reproductive News is a trademark of Novellus 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.

The ideas and opinions expressed in Infertility & Reproductive News do not necessarily reflect those of the Editorial Board, the Editors, or the Publisher. Publication of an advertisement or other product mentioned in Infertility & Reproductive News should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the Editors nor the Publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

SUBSCRIPTIONS/CHANGE OF ADDRESS should be directed to CIRCULATION DIRECTOR, Infertility & Reproductive News, 241 Forsgate Drive, Suite 205D, Monroe Twp, NJ 08831; Fax: 732-656-7938.

OBG0212

6

ONS Annual Congress

new Agents prove potent...

In spite of a decade or so of established treatment with trastuzumab, questions still remain regarding the appropriate population to treat. In addition, many patients who respond to the drug eventually experience drug resistance and recurrence. Researchers are seeking to better understand resistance, and the pipeline is rife with agents that are effective upon trastuzumab failure, said Abueg.

Four proteins make up the members of the HER family of cell surface receptors: HER1, HER2, HER3, and HER4.

Trastuzumab targets HER2, the preferred partner for binding with the other members (heterodimerization) or itself (homodimerization) to create a signaling cascade.

Trastuzumab’s dual-kill mechanism includes antibody-dependent cellular toxicity and the prevention of intracellular cell signaling, which induces apoptosis and prevents proliferation.

Resistance that develops is associated with alternate signaling pathways, which are being targeted by new agents in development.

“The key to understanding and ultimately mitigating this resistance lies in the HER2 signaling pathway,” she said.

Her2 testing: issues of Concern The accuracy of immunohistochemical (IHC) staining and scoring by fluorescence in situ hybridization (FISH) has become questionable, and provocative data are leading to a reexamination of current practice patterns, she said. In the pivotal studies, community pathology and central reference lab results have been discordant some 18% to 34% of the time. The implication is that a “fairly good number” of patients either receive trastuzumab unnecessarily or miss out on its benefits altogether, she said.

The American Society of Clinical

July/AugusT 2012 l VOLUME 4, NUMBER 2

Oncology and the College of American Pathologists have issued revised guidelines for HER2 testing. The most recent recommendation is to prescribe antiHER2 treatment when the FISH result is ≥2.0, and to retest when FISH is 1.8 to 2.2. This recommendation is now, however, compulsory.

The other testing issue is the level of predictability of IHC and FISH, according to information from the pivotal trastuzumab studies. Consistent benefit from trastuzumab was observed in every subset (including patients who were actually HER2 negative), and FISH score strength was not predictive of this.

Even some FISH-negative patients benefited from the drug.

“The clinical implication is whether the HER2 ‘sensitive’ population can be expanded,” Abueg explained. Clinical trials are evaluating trastuzumab in the IHC 1+ and FISH-negative populations. overcoming resistance with new Agents The powerful new agents under investigation are designed specifically to attack the proposed mechanisms of trastuzumab resistance.

Lapatinib, of course, is already established for use after progression with trastuzumab. The ALTTO study is evaluating whether the adjuvant use of lapatinib in combination with trastuzumab, prior to the development of resistance, will be more effective than either agent alone. In the neoadjuvant NeoALLTO trial, the combination produced a 51% pathologic complete response rate,1 and the hope is that this type of activity will be observed in the adjuvant setting, she said.

Even more promising could be 4 investigational agents: • Neratinib, which works similarly to lapatinib, blocks HER2, HER1, and

Continued from page 1

HER4, and inhibits intracellular cell signaling • Everolimus, an mTOR inhibitor proven in other cancers • Pertuzumab, a monoclonal antibody that blocks HER2/HER1 and HER2/ HER3 dimerization and binds at a different site than trastuzumab • T-DM1 (trastuzumab emtansine), an antibody-drug conjugate with highly targeted delivery Each is backed by very encouraging data, but T-DM1 has elicited the most excitement, and for good reason, she noted.

In a phase 2 open-label study, T-DM1 resulted in a median progression-free survival of 14 months versus 9 months with trastuzumab and docetaxel, reducing the risk of disease progression by 41% and proving to be very well tolerated.2 In 2010, the FDA declined to grant accelerated approval and called for phase 3 trials to be completed.

Additional studies (EMILIA, MARIANNE, THERESA) are under way.

“I have a patient on one of these trials who had an 11-cm liver metastasis and pulmonary nodules after multiple lines of treatment. Last week, she received her 47th cycle of T-DM1. Her tumor is now 1.1 cm and has been stable for two and a half years,” Abueg reported. While thrombocytopenia can be problematic, it has remained grade 1 for this patient. “I think this is a stunning result,” she commented. n references 1. Baselga J, Bradbury I, Eidtmann H, et al; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012;379: 633-640.

2. Hurvitz S, Dirix L, Kocsis J, et al. Trastuzumab emtansine (T-DM1) vs trastuzumab plus docetaxel (H+T) in previously untreated HER2-positive metastatic breast cancer (MBC): primary results of a randomized, multicenter, open-label phase II study (TDM4450g /BO21976). Presented at the 2011 European Multidisciplinary Cancer Conference. Stockholm, Sweden.

September 23-27, 2011. Abstract 5001.

Ovarian Cancer

Screening for ovarian Cancer... representing about 3% of all cancers that occur in women. It is the ninth most frequent type of cancer diagnosed in American women (Table 1).

Ovarian cancer is more common in women over 50 to 60 years of age (depending on the source), and uncommon in women younger than 40 years. types of ovarian Cancer Epithelial ovarian cancer is the most frequently diagnosed type of ovarian cancer, accounting for approximately 90% of ovarian cancers.2 The epithelium is the covering of the ovary. As the tumor grows on the surface of the ovary, it can shed cells like seeds directly into the abdominal cavity, a process called seeding. The shed cells can implant or seed themselves into other tissue and organs in the abdominal and pelvic cavities and form new tumors in these sites.

Germ cell ovarian tumors grow in the egg-producing cells of the ovary.

These tumors are uncommon, seen approximately 5% of the time, and often benign. Germ cell tumors occur most often in girls, teenagers, and young women. If the germ cell tumor is cancerous, a high percentage of patients can be cured with surgery and chemotherapy.

Sex cord tumors form in the connective or stromal tissue cells of the ovaries. Sex cord tumors generally occur in women younger than 40 years but can occur in older women. These tumors are generally slower growing and do not spread rapidly. risk factors of ovarian Cancer Although the causes of epithelial ovarian cancer are still being uncovered, researchers have identified a number of factors that increase a woman’s odds of developing epithelial ovarian cancer. Much less is known about risk factors for germ cell and stromal tumors.

Risk factors for epithelial ovarian cancer can be divided into 3 categories: genetic factors, age, and hormonal/reproductive factors.

Genetic Risk Factors The most significant risk factor for ovarian cancer is having an inherited mutation in 1 or both of 2 genes called breast cancer gene 1 (BRCA1) and breast cancer gene 2 (BRCA2). These genes were originally identified in families with multiple cases of breast cancer, which is how they got their name; they are responsible for about 10% of ovarian cancers.3 The second genetic link that increas-

es the risk of developing ovarian cancer involves an inherited syndrome called hereditary nonpolyposis colorectal cancer (HNPCC). Individuals in HNPCC families are at increased risk for cancers of the uterus, colon, ovary, stomach, and small intestine.

Age as a Risk Factor The risk of ovarian cancer increases with age, with a median age at diagnosis of 63 years.1 Hormonal and Reproductive Risk Factors One of the leading causation theories of ovarian cancer is that of incessant ovulation.3 When the ovum leaves the ovary during the ovulatory cycle, there is an increased risk of wounding to the epithelial layer of the ovary. The more ovulatory cycles that occur, the greater the chance for a mutation to occur in the epithelial cells. Under this causative theory, early menstruation, late menopause, and nulliparity would increase a women’s risk of ovarian cancer, while late menstruation, early menopause, pregnancy and breast-feeding, and use of oral contraceptive medication would be protective.

Epithelial ovarian cancer is the most frequently diagnosed type of ovarian cancer, accounting for approximately 90% of ovarian cancers.

Pituitary gonadotropin hormones are also thought to affect the risk of ovarian cancer. This theory submits that during ovulation there is a surge of hormones produced by the pituitary gland, which in turn increase the stimulation of estrogen.3 This increase in estrogen can affect the epithelial cells of the ovary, causing them to develop into inclusion cysts that may transform into cancerous tumors.3 Decreasing of risk of ovarian Cancer Protective Factors Several factors are seen to protect a woman against ovarian cancer. The

Continued from page 1

Table 1

The Most Common Cancers Among American Women

Type

Estimated New Cases 2012

Estimated Death Rate 2012

226,870 109,690 70,040 47,130 43,210 31,970 32,000 24,520 22,280

39,510 72,590 25,220 8010 1000 8620 3120 4920 15,500

1. Breast 2. Lung and bronchus 3. Colon and rectum 4. Uterine 5. Thyroid 6. Non-Hodgkin lymphoma 7. Melanoma of the skin 8. Kidney and renal pelvis 9. Ovarian

Source: American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012.

risk of ovarian cancer is decreased at a rate of 12% for every pregnancy. Also, if the last birth is between the ages of 30 and 35 years, a woman’s risk of ovarian cancer can be reduced by as much at 58% compared with a woman who has never been pregnant.3 Women who have breast-fed their babies for 18 months or more have a reduced risk of ovarian cancer due to the suppression of ovulation, resulting in a decrease in the gonadotropin levels.

Tubal ligations may alter growth factors and hormonal levels, thereby decreasing the risk of epithelial ovarian cancers, as well as preventing carcinogens and inflammatory factors from reaching the ovary from the uterus. Likewise, a hysterectomy decreases the risk of ovarian cancer, with the added benefit of making it easier to examine the ovaries during the pelvic examination.

Progesterone plays a role in the risk of ovarian cancer. When a woman experiences a higher level of progesterone, either through pregnancy or the use of oral contraceptive pills, it is thought to cause a change in the cell cycle and induce apoptosis of the cells of the epithelium of the ovary. The protection offered by the increase in progesterone is thought to last long after the progesterone levels return to normal.3 Available Screening tests for ovarian Cancer A number of screening tests have been evaluated, and the 2 that have remained and are consistently referenced in the literature are the CA125 blood test and the use of transvaginal ultrasound (TVU).

CA125 tests for a protein produced by the cancerous epithelial cells of the ovaries. Approximately 90% of women with epithelial ovarian cancer have an elevation of this marker. Unfortunately, in the majority of these

women the cancer is at an advanced stage when diagnosed. Studies have also shown that CA125 is not a reliable marker for ovarian cancer, as it can be elevated in 2% to 3% of the postmenopausal population who do not have ovarian cancer. Many factors can cause a rise in CA125, including inflammation of the peritoneum, pelvic infection, or another cancer.4 TVU has proven to be the most promising imaging test to screen for ovarian cancer. There is some indication that the combination of the CA125 blood test and the TVU may have increased sensitivity.4 organizational recommended Screening guidelines for ovarian Cancer A number of guidelines have been published for ovarian cancer screening. There is agreement among these bodies that there is insufficient evidence to indicate that routine screening of the general public will result in fewer deaths from ovarian cancer.

There are, however, indications for scheduled screening for those at an increased risk of developing ovarian cancer. Table 2 provides a summary of the most recent guidelines.

National Comprehensive Cancer Network (NCCN) Recommendations The NCCN defines women at high risk for developing ovarian cancer as those who have a family history of ovarian cancer, a BRCA mutation, or a personal history of breast cancer. It recommends that these women begin screening between the ages of 30 and 35 or 5 to 10 years before the age when a family member was diagnosed with ovarian cancer. Screening should be done every 6 months utilizing a combination of CA125 and TVU. The NCCN also recommends that highrisk women consider a prophylactic Continued on page 8

July/AugusT 2012 l VOLUME 4, NUMBER 2

7

Ovarian Cancer

Screening for ovarian Cancer...

Table 2

Continued from page 7

benefits of an earlier diagnosis are yet to be seen.

Organizational Ovarian Cancer Screening Recommendations5-11 High Risk

Increased Risk

General Population

National Comprehensive Cancer Network5

Screening every 6 months with TVU and CA125 at 30-35 years of age; or 5-10 years before age at diagnosis of ovarian cancer in family members

Does not recommend routine screening

National Cancer Institute6

Inadequate evidence

US Department of Health & Human Services7

Preventive counseling in early 20s by gynecologic oncologist or geneticist; discuss salpingooophorectomy following completion of childbearing

Insufficient evidence to recommend routine screening

US Preventive Services Task Force8

Screening with TVU and CA125 may be helpful

Does not recommend routine screening

Memorial Sloan-Kettering Cancer Center9

TVU and CA125 testing starting at 30-40 years of age; consider salpingo-oophorectomy following completion of childbearing

American College of Obstetricians and Gynecologists10,11

TVU and CA125 every 6 months, beginning at 30-35 years of age, or 5-10 years before the earliest age at diagnosis of ovarian cancer in relative

Inadequate evidence

Genetic counseling may be of value

Inadequate evidence

Annual gynecologic/ pelvic examination

Does not recommend routine screening

Abbreviation: TVU, transvaginal ultrasound.

salpingo-oophorectomy at the completion of childbearing.5 National Cancer Institute Recommendations The National Cancer Institute has made the following statement of benefit: There is inadequate evidence to determine whether routine screening for ovarian cancer with the serum marker CA125, TVU, or pelvic examinations would result in a decrease in mortality from ovarian cancer.6 US Department of Health & Human Services Recommendations The US Department of Health & Human Services guidelines are evidence-based, using the American College of Radiology and the Scottish Intercollegiate Guidelines Network guidelines.7 The US Department of Health & Human Services is in agreement with the NCCN that there is insufficient evidence to recommend routine screening for ovarian cancer for the general population and that a prophylactic oophorectomy should be consid-

8

ered when childbearing is no longer desired. For women at high risk for developing ovarian cancer, preventive counseling should be started in their early 20s by a gynecologic oncologist or geneticist. The benefits of oral contraceptive use and genetic testing should be addressed and considered.

US Preventive Services Task Force Recommendations The US Preventive Services Task Force recommendations found that while screening for ovarian cancer using TVU and CA125 would be beneficial for women determined to be at high risk for ovarian cancer, the risks outweigh the benefits for those who have no signs or symptoms.8 Memorial Sloan-Kettering Cancer Center Recommendations Memorial Sloan-Kettering Cancer Center has posted detailed recommendations for ovarian cancer screening. It divided high-risk women into 2 groups: 1) those with a 3 to 6 times increased risk, and 2) those with a known genetic mutation, and provided

July/AugusT 2012 l VOLUME 4, NUMBER 2

recommendations for each group.9 American College of Obstetricians and Gynecologists (ACOG) Recommendations ACOG does not recommend routine screening for ovarian cancer in women who are at low risk of developing ovarian cancer.10 However, in women who are at high risk for developing ovarian cancer, screening is recommended utilizing CA125 and TVU.10 Women at high risk are defined as those who are of Ashkenazi Jewish descent, have a BRCA1 or BRCA2 mutation, or have a family history suggestive of a hereditary cancer syndrome.11 Screening should begin between the ages of 30 and 35 years and take place every 6 months. If the woman has a relative with ovarian cancer, screening should begin 5 to 10 years before the age of diagnosis of that family member.11 new research recommendations Two screening trials show benefits in terms of diagnosing ovarian cancer at an earlier stage. However, survival

PLCO Screening Recommendations A large screening trial called the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial took place across the United States between November 1993 and July 2001. It randomized 78,216 women, aged 55 to 74 years, to undergo usual care or annual screening. The screening arm included TVU at the time of the initial examination, followed by annual TVU for a length determined by the study. The screening arm also specified yearly CA125 drawn for 4 years. The usual care group underwent a routine pelvic examination with palpation of the ovaries.

Buys and colleagues recently published the long-term results of the trial.12 In the intervention group, 212 ovarian cancers were diagnosed, with 118 deaths as a result of ovarian cancer. In the usual care group, 176 ovarian cancers were diagnosed, with 100 deaths.

There was no statistically significant difference in overall survival between the groups. There was very little difference in the stage of ovarian cancer being diagnosed between the groups.

In the screening arm, 69% of the cancers were diagnosed at a late stage versus 78% in the usual care group.12 The authors concluded that screening did not impact survival.

University of Kentucky Ovarian Cancer Screening Trial The University of Kentucky Ovarian Cancer Screening Trial resulted in an algorithm used to determine the screening and frequency of tests based on outcome after 37,293 women were screened between January 1987 and June 2011.13 Using the algorithm, 47 invasive epithelial ovarian cancers and 15 borderline tumors (also referred to as tumors of low malignant potential) were detected.

Of the 47 patients diagnosed with invasive cancer, 70% had early-stage disease (stage I or II), and 30% had advanced stage (stage III). In contrast, of the 2560 unscreened women who were diagnosed and entered into the Kentucky Tumor Registry during this time, 27% had stage I/II disease, and 46% had stage III disease. The screening group also had advanced-stage cancer diagnosed at stage IIIA and IIIB more consistently than the control group, which tended to have a higher incidence of stage IIIC ovarian cancer.13 The authors concluded that Continued on page 9

Bladder Cancer

Screening for Bladder Cancer... leather, as well as exposure to paints, solvents, and arsenic; certain previous infections of the bladder; older age; and a positive personal or family history of BC.1,3,5,6 It has been hypothesized that BC risk is related to the concentration of carcinogens in urine and the amount of time urothelial tissues are exposed to such causative agents. Therefore, increasing hydration as well as nocturia may be protective.1 Screening/early Detection There are currently no guidelines for BC screening of asymptomatic adults.

The American Cancer Society reviews its data annually and continues to recommend against screening for BC in patients at average risk.1,3,5 The US Preventive Services Task Force, upon review of the evidence of benefits versus harms of screening for BC in low-risk, asymptomatic individuals, and further based on their statement from 2004, states that the evidence is insufficient to recommend screening.3 Healthcare professionals, nonetheless, need to individualize their approach to care. Healthcare professionals need to consider the potential harms of screening for BC, including the possibility of false-positive results, which may lead to unnecessary diagnostic procedures. This can be the source of great stress and anxiety for patients. On the other hand, early detection of disease and, if possible, the identification of more aggressive cancers that require immediate interventions may have an important effect on morbidity and mortality. Therefore, screening some individuals may prove beneficial. However, current data do not provide certainty that earlier, less toxic therapies improve outcomes versus waiting to use more

toxic treatment in those with symptomatic or advanced tumors.3 For the asymptomatic individual, incidental microhematuria is often found on routine urinalysis and workup for other planned interventions, such as elective surgeries and annual physical exams.

Occult blood found in the urine often prompts the patient to visit a urologist for further workup, generally urine cytology, cystoscopy, and imaging – the gold standard. For those at risk, this gold standard is employed for screening/early detection, minimally every 3 months, depending on interventions. Not only are these tests uncomfortable and embarrassing, but they are not always sensitive enough to detect cancer. Because superficial BC can be missed or may not be of metastatic potential, the standard is not enough to effect positive outcomes. For example, cystoscopy can miss flat tumors or carcinoma in situ, leading to 10% to 30% false-negative results.7 Consequently, the limitations of cytology and the invasiveness of cystoscopy have generated interest and investigation into various noninvasive diagnostic tools.8 In order for a diagnostic tool – ie, a screening method, biomarker, or tumor marker – to be effective, several elements must be in place. First, the disease prevalence must be an obvious healthcare issue, and diagnosing early would seem of benefit. Second, there should be acceptable treatments available. Third, the tool should be minimally invasive or noninvasive and cost-effective, or at least not prohibitively expensive.

Fourth, the tool must be useful in the asymptomatic population, with high sensitivity (true positives and no falsenegatives) and high specificity (true negatives and no false-positives), as opti-

Continued from page 1

mum sensitivity is crucial for screening and high specificity is imperative for disease confirmation. Lastly, the tool must also be acceptable to the population who will be assessed.1,9,10 Approved markers Clinical application of markers includes screening, confirmation of diagnosis, classification and staging, prognosis, monitoring response, surveillance, and early detection of disease recur-

Tumor markers are generally substances secreted by the tumor, overexpressed by malignant cells, or secreted by the host in response to malignancies.

rence.9 However, the definition of markers useful for these applications is broad.

Tumor markers are generally substances secreted by the tumor, overexpressed by malignant cells, or secreted by the host in response to malignancies. These can be hormones, proteins, enzymes, receptors, and genomic alterations.9-11 It is hypothesized that the levels of these markers reflect tumor burden, thus increasing with malignancy and progression of disease and decreasing in response to treatment and with remission.

For BC, there are a few US Food and Drug Administration (FDA)-approved markers available for use in the clinical setting, although currently they are utilized by discerning clinicians for complementary use alongside more standard interventions. Nevertheless, the use of these markers is not currently included in algorithms of recommended screening guidelines. Listed below are several FDA-approved markers for screening of BC: Nuclear matrix protein (NMP22) is a nuclear mitotic apparatus protein, released into urine as BC cells die. It is responsible for chromatid regulation and cell separation during replication.

Approximately 70% of BC carcinomas are positive for NMP22. The NMP22 BladderChek (NMP22BC) test kit detects antibodies in voided urine and thus is noninvasive. The overall sensitivity and specificity reported for this test are 50% to 90% and 60% to 90%, respectively. The FDA has approved this test for screening and monitoring of BC; note, however, that it is not currently included in screening guidelines.10-12 In their nonrandomized study (N=203) comparing the sensitivity and specificity of urine cytology, NMP22BC, and UroVysion fluorescence in situ hybridization (FISH) (see below) in the detection of BC, Kehinde and colleagues concluded that NMP22BC appeared to be more cost-effective, more rapid, and relatively higher in sensitivity and specificity over urine cytology.13 They suggested that NMP22BC should replace urine cytology as the gold standard, although it should be coupled with cystoscopy.

According to Sagnak and colleagues, in their small study (N=164) looking at Continued on page 10

Ovarian Cancer

Screening for ovarian Cancer...

Continued from page 8

using an algorithm to determine screening can result in ovarian cancers being detected at an earlier stage, which will hopefully lead to an overall survival benefit.

Conclusion The ability to effectively screen for ovarian cancer remains elusive. The sensitivity and specificity for our current screening methods, either CA125 or TVU, remain too low to achieve meaningful benefit for early diagnosis or reduction in mortality. Recent

research studies utilizing CA125 and TVU together as a multimodal screening program, taking into account other risk factors such as age, parity, and family history, may lead to an algorithm that will lead to more cancers being detected at an early stage. It has yet to be determined if detecting ovarian cancer at an earlier stage will lead to a statistically significant increase in overall survival. n references 1. American Cancer Society. Ovarian cancer. www.ca ncer.org. Accessed January 11, 2012.

2. Hartmann LC, Loprinzi C. Mayo Clinic Guide to Women’s Cancers. Rochester, MN: Mayo Clinic Health Information; 2005.

3. Vo C, Carney M. Ovarian cancer hormonal and environmental risk effect. Obstet Gynecol Clin North Am. 2007;34:687-700.

4. Clarke-Pearson DL. Screening for ovarian cancer.

N Engl J Med. 2009;361:170-177.

5. National Comprehensive Cancer Network. Genetic screening for ovarian cancer. www.nccn.org. Accessed December 4, 2011.

6. National Cancer Institute. Ovarian cancer screening. www.cancer.gov. Accessed November 7, 2011.

7. United States Department of Health & Human Services. Screening for ovarian cancer. www.guideline. gov/syntheses/synthesis.aspx?id=16420&searchovari an+cancer+screening. Accessed November 18, 2011.

8. U.S. Preventive Task Force. Screening for ovarian cancer. www.uspreventiveservicestaskforce.org/3rdu spstf/ovariancan/ovcanrs.htm. Accessed February 20, 2012.

9. Memorial Sloan-Kettering Cancer Center. Ovarian cancer screening guidelines. www.mskcc.org. Accessed November 7, 2011.

10. American College of Obstetricians and Gynecologists Committee on Gynecologic Practice.

Committee Opinion No. 477: the role of the obstetrician-gynecologist in the early detection of epithelial ovarian cancer. Obstet Gynecol. 2011;117:742-746.

11. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 103. Hereditary breast and ovarian cancer syndrome. Obstet Gynecol. 2009;113:957-966.

12. Buys SS, Partridge E, Black A, et al. Effect of screening on ovarian cancer mortality: the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Randomized Controlled Trial. JAMA. 2011;305:2295-2303.

13. van Nagell JR Jr, Miller RW, DeSimone CP, et al.

Long-term survival of women with epithelial ovarian cancer detected by ultrasonographic screening. Obstet Gynecol. 2011;118:1212-1221.

July/AugusT 2012 l VOLUME 4, NUMBER 2

9

Bladder Cancer

Screening for Bladder Cancer... patients with asymptomatic hematuria, an ultrasound of the upper urinary tract coupled with the NMP22BC test for lower urinary tract investigation was found to be a better first-line screening tool than urine cytology, as it was more sensitive and less expensive. This combination of noninvasive testing also helped guide next steps, instead of going directly to cystoscopy.4

Several promising, noninvasive urine tests are currently being investigated for use in various stages of the BC continuum (eg, screening, surveillance, monitoring).

Two other recent studies evaluated the performance of NMP22BC over urine cytology, due in part to its rapid response and lesser expense. Both Weber et al14 and Smrkolj et al15 concluded that NMP22BC was more sensitive than urine cytology and suggested its use as a replacement for cytology; neither research group was able to suggest its use as a replacement for cystoscopy, however.

Bladder tumor–associated analytes (BTAs) are composed of collagen, fibronectin, laminin, and proteoglycan, which are components of basement membrane, released when bladder tumor cells attach to the bladder wall. BTA is elevated in approximately 30% of lowgrade and 60% of high-grade tumors.

The BTA assay detects H-related protein in voided urine. The overall sensitivity and specificity for this test are reported to be 57% to 83% and 60% to 92%, respectively. The FDA has approved the BTA assay for monitoring of disease, along with cystoscopy.10-12 UroVysion is a multitarget FISH assay that detects aneuploidy in chromo-

10

somes 3, 7, and 17 as well as loss of the 9p21 locus of the p16 tumor suppressor gene (P16). The FDA has approved this test for both screening and monitoring of BC, as it outperforms urine cytology in sensitivity. The high cost and need for large volumes of urine to detect tumor exfoliation, however, have prevented wider use of this test.10,12 ImmunoCyt combines cytology with immunofluorescence assay. It detects cellular biomarkers for BC in exfoliated urothelial cells for a high molecular weight form of carcinoembryonic antigen and 2 bladder tumor–associated mucins. The test is expensive and requires training to perform. It may perform better than cytology but should be coupled with cystoscopy. It is FDA approved for monitoring BC.10,12 investigational urine markers Several promising, noninvasive urine tests are currently being investigated for use in various stages of the BC continuum (eg, screening, surveillance, monitoring). The high rate of disease recurrence in BC requires lifelong surveillance, generally with cystoscopy (painful, embarrassing, expensive), along with urine cytology (not very sensitive). Thus, the use of noninvasive markers will significantly improve disease management.

Whether these markers can and will move into the cancer screening arena, ongoing investigation will reveal. Listed below are a few of the urine markers being investigated 2,7,12,16,17: • The Aurora kinase A gene (AURKA) encodes a serine/threonine kinase associated with aneuploidy and chromosome instability • BLCA-1 and BLCA-4 are nuclear transcription factors present in BC • Human carcinoembryonic antigenrelated cell adhesion molecule 1 (CEACAM1) is a cell adhesion molecule with proangiogenic activity • Epigenetic urinary markers analyze gene methylation • Fibroblast growth factor receptor 3 (FGFR3) is mutated in 50% to 70% of primary bladder tumors and might be associated with good prognosis • Urinary hyaluronic acid (HA), a non-

July/AugusT 2012 l VOLUME 4, NUMBER 2

•

•

•

•

Continued from page 9

sulfated glycosaminoglycan, has been shown to yield 92% sensitivity and 93% specificity for BC detection Microsatellite analysis allows for the evaluation of heterogeneity in chromosomes 9, 4p, 8p, 11p, and 17p MicroRNAs (miRNAs) are noncoding RNAs that posttranscriptionally regulate gene expression Survivin, a novel member of the inhibitor of apoptosis gene family, is overexpressed in human cancers and can be detected in urine Telomerase is a ribonucleoprotein enzyme that acts in chromosomal instability by synthesizing telomere

The FDA has approved a number of these markers, which utilize voided urine, but currently none has been incorporated into screening guidelines.

Conclusions BC is a major healthcare concern, both in the United States and worldwide. More than 70,000 individuals are expected to be diagnosed in the United States this year. To date, there are no agreed-upon guidelines, based on evidence, for screening of the asymptomatic population. Problematic as well is the invasiveness of diagnostics, once workup is begun. Even microhematuria, often an incidental finding, requires further investigation. The current gold standard for diagnosis of BC is urine cytology, cystoscopy, and imaging.

Many tumor markers and biomarkers are being investigated for diagnosing and following BC in a noninvasive way. The FDA has approved a number of these markers, which utilize voided urine, but currently none has been incorporated

into screening guidelines. Large randomized clinical trials are required to provide greater evidence on sensitivity and specificity for new markers and combinations of interventions for asymptomatic populations at variable risks. Better data for stratifying risk will enable improved algorithms for directing interventions.

Until reliable markers or combinations of interventions are validated, cystoscopy remains the gold standard. n references 1. Shelton G. Bladder cancer. In: Yarbro CH, Wujcik D, Gobel BH, eds. Cancer Nursing Principles and Practice. 7th ed. Sudbury, MA: Jones and Bartlett; 2010:1080-1090.

2. Datta A, Adelson M, Mogilevkin Y, et al.

Oncoprotein DEK as a tissue and urinary biomarker for bladder cancer. BMC Cancer. 2011;11:1-7.

3. Moyer VA; US Preventive Services Task Force.

Screening for bladder cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2011;155:246-251.

4. Sagnak L, Ersoy H, Gucuk O, et al. Diagnostic value of a urine-based tumor marker for screening lower urinary tract in low-risk patients with asymptomatic microscopic hematuria. Urol Int. 2011;87:35-41.

5. American Cancer Society. Cancer Facts & Figures 2012. Atlanta, GA: American Cancer Society; 2012. www.cancer.org. Accessed January 20, 2012.

6. Roobol MJ, Bangma MD, el Bouazzaoui S, et al.

Feasibility study of screening for bladder cancer with urinary molecular markers (the BLU-P project). Urol Onc. 2010;28:686-690.

7. Murali A, Kasman L, Voelkel-Johnson C. Adenoviral infectivity of exfoliated viable cells in urine: implications for the detection of bladder cancer. BMC Cancer.

2011;11:168.

8. Tanaka MF, Sonpavde G. Diagnosis and management of urothelial carcinomas of the bladder. Postgrad Med. 2011;123:43-55.

9. Handy B. The clinical utility of tumor markers.

Labmedicine. 2009;40:99-103.

10. Viale PH. Cancer diagnosis and staging. In: Gobel BH, Triest-Robertson S, Vogel WH, eds. Advanced Oncology Nursing Certification Review and Resource Manual. Pittsburgh, PA: Oncology Nursing Society; 2009:77-147.

11. DeMoranville VE, Best ME. Tumor marker tests.

Encyclopedia of Surgery Web site. www.surgeryencyclope dia.com/St-Wr/Tumor-Marker-Tests.html. Accessed April 17, 2012.

12. Tilki D, Burger M, Dalbagni G, et al. Urine markers for detection and surveillance of non-muscle-invasive bladder cancer. Eur Urol. 2011;60:484-492.

13. Kehinde EO, Al-Mulla F, Kapila K, et al.

Comparison of the sensitivity and specificity of urine cytology, urinary nuclear matrix protein-22 and multitarget fluorescence in situ hybridization assay in the detection of bladder cancer. Scand J Urol Nephrol. 2011; 45:113-121.

14. Weber CM, Cauchi M, Patel M, et al. Evaluation of a gas sensor array and pattern recognition for the identification of bladder cancer from urine headspace. Analyst.

2011;136:359-364.

15. Smrkolj T, Mihelič M, Sedlar A, et al. Performance of nuclear matrix protein 22 urine marker and voided urine cytology in the detection of urinary bladder tumors.

Clin Chem Lab Med. 2011;49:311-316.

16. Van Tilborg AAG, Bangma CH, Zwarthoff EC. Bladder cancer biomarkers and their role in surveillance and screening. Int J Urol. 2009;16:23-30.

17. Zuiverloon TCM, Tjin SS, Busstra M, et al.

Optimization of nonmuscle invasive bladder cancer recurrence detection using a urine based FGFR3 mutation assay. J Urol. 2011;186:707-712.

Fertility

male fertility Declines rapidly After Age 40

By Wayne Kuznar

A

man’s age and semen characteristics affect the achievement of pregnancy in in vitro fertilization (IVF) treatments with donated oocytes, Brazilian researchers have found.

In their retrospective analysis, male age older than 41 years was found to reduce the odds of pregnancy, while enhanced sperm morphology criteria increased the chances of pregnancy.

Their findings were reported at the 2011 meeting of the American

Society for Reproductive Medicine.

Led by Paula Fettback, nurse researcher at the Huntington Reproductive Center in São Paulo, Brazil, the team looked at outcomes from 570 IVF treatments with oocyte donors at their institution. The use of oocyte donors allowed them to isolate the influence of the male’s age on IVF success.

Donor eggs were from women 18 to 30 years of age with a body mass index of 28 kg/m2 or less. All oocyte donors and their recipients underwent physical,

endocrine, transvaginal ultrasonography, and infectious disease evaluation.

There was no significant difference in the number of embryos transferred, the percentage of top-quality embryos transferred, and the recipient’s age between the group that achieved pregnancy and the group that did not achieve pregnancy.

The mean age of the men whose partners achieved pregnancy was 41 years, while the mean age of those for whom IVF was unsuccessful was 45

years. Fertility declined by up to 7% with each additional year of age for the male partner – the chances of pregnancy declined from 60% at age 41 to 35% at age 45 years.

The percent of normal strict morphology according to Kruger’s criteria was also significantly higher in those achieving pregnancy versus those not achieving pregnancy (3.5% vs 2.2%). “Every 1% increase in Kruger’s strict morphology criteria increased the chances of pregnancy by 22%,” said Fettback. n

iVf often Chosen for family Building in Same-Sex Couples

By Wayne Kuznar

S

ame-sex couples are increasingly using in vitro fertilization (IVF) for family building. The challenges of IVF are unique for same-sex couples and range from legal and contractual hurdles to treatment coordination. Outcomes for same-sex couples, however, appear to be at least as good as those of age-matched typical IVF patients, says Donna Cunningham, BS, BSc. At the 2011 meeting of the American Society for Reproductive Medicine, she related the experience with infertility treatments for same-sex couples at the Reproductive Science Center of New England in Lexington, Massachusetts. The center began infertility treatments for same-sex female couples in 1988 and same-sex male couples in 1998.

female Couples The use of IVF in lesbian couples is advantageous when 1 or both partners have an infertility factor and when gonadotropin stimulation and/or intrauterine insemination have been unsuccessful. “IVF allows for the possibility that both partners can participate in the reproductive effort,” said Cunningham, senior embryologist at the center.

Because Massachusetts is an insurance-mandated state for infertility treatment, infertility testing and treatment must be covered by insurers who provide pregnancy-related benefits.

Some insurance companies will cover IVF after 12 months of medically supervised exposure to sperm or if

female infertility is documented. Most patients do not have coverage for treatment (because most choose not to proceed with 12 months of medically supervised IVF), while some have limited coverage for diagnostic testing and medications. The approximate cost of IVF with donor sperm is $13,000 per cycle.

Sixty lesbian couples undergoing assisted reproductive technology at her institution were appraised for treatment cycle outcomes. All used commercially purchased donor sperm. The 60 couples initiated 86 IVF cycles resulting in an average of 10.3 oocytes retrieved. An average of 2.0 embryos were transferred.

The average age of the partner providing the eggs was 36.5 years.

The pregnancy rate per initiated cycle was 51.9%, compared with a rate of 41.0% for the typical IVF population, said Cunningham. The implantation rate was 28.0%.

Reciprocal IVF is an option in which partners reciprocate in their roles – 1 partner undergoes ovarian stimulation and serves as the oocyte source, and the other is the gestational mother, said Cunningham. The cost per cycle of reciprocal IVF is $21,000.

Six lesbian couples elected reciprocal IVF, with 6 embryo transfers resulting in 4 pregnancies and live births (3 singletons, 1 twin). male Couples IVF with gestational surrogacy is a reproductive option for male couples, allowing both partners to contribute

gametes and become parents. “It eliminates the genetic tie between the carrier and the child, and it provides therapy for male factor infertility,” said Cunningham. “These men can have infertility just as commonly as our traditional IVF patients.”

Legal and contractual agreements should be considered before males choose IVF with gestational surrogacy; the laws vary widely by state, and an experienced attorney should be retained to help with the legal aspects, she advised.

Treatment coordination is another pretreatment consideration. “These gay male couples who come to us are not infertility patients, so we need to start at the beginning and let them know what’s involved; they’ve never heard of clomiphene citrate, IVF, or embryo transfer,” she said. “You need to start off with basic infertility instruction. Let them know about the psychological evaluation, cycle timing, and travel requirements. We have patients come to us from other countries, and they need to know how many times they need to be there and at what times.”

The financial considerations are the biggest surprise to gay male couples, she said. The approximate cost for a cycle completed to delivery is $90,000 to $120,000. Costs are incurred for the cycle, medication, legal fees, agency fees for the egg donor and the gestational carrier, oocyte donor compensation, and gestational carrier compensation. Total cost can depend on the locations of the donor and carrier.

An elective intracytoplasmic sperm injection (ICSI) option adds $2000 to the cost but virtually guarantees fertilization. Both partners may contribute sperm, but they need to discuss decisions about embryo number (ie, how many, whose embryos will be transferred) and paternity.

At the Reproductive Science Center of New England, 18 gay male couples initiated infertility treatment; most were from the Northeast and there were 2 international couples.

“All 18 couples succeeded in having at least 1 child through IVF and/or frozen embryo transfer,” she said.

Twenty-two fresh IVF cycles were initiated; the average number of oocytes retrieved was 17. Microdrop insemination was performed in 16 cycles, and elective ICSI was used in 6. Both partners’ sperm were used to inseminate eggs in 11 instances, and only 1 partner’s sperm was used in 11. The fertilization rates were 90% when ICSI was used and 75% with traditional IVF. The average number of embryos transferred was 1.86. There were 15 clinical pregnancies achieved (71.5% per transfer). The implantation rate was 51.3%. There were 15 live births (10 singletons and 5 sets of twins).

No frozen embryo transfer cycles were initiated, with 8 embryo transfers taking place. The average number of embryos transferred was 1.75. There were 7 clinical pregnancies (87.5% per embryo transfer), the implantation rate was 64%, and 5 live births (3 singletons, 2 sets of twins) resulted. n

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Breast Cancer

Cultivating personalized medicine...

Continued from page 1

forever the bar of cancer care. What conditions have arisen to make breast cancer the envy of other cancer researchers, and how is this field leveraging its discoveries to unlock new opportunities for researchers and clinicians alike? And most importantly, how can today’s practicing oncologists put into practice the lifesaving techniques of breast cancer personalized medicine, ally them with the conventional medicine that still dominates the field, and cultivate a base of knowledge of this burgeoning, data-heavy field of medical science?

To capture the essence of the breast cancer treatment revolution, we interview Dr Edith Perez, Deputy Director of Mayo Clinic Cancer Center in Florida, Director of the Breast Program, and the Serene M. and Frances C. Durling Professor of Medicine at Mayo Medical School. Translational research is the soul of Dr Perez’s work. Asked what she sees as the vision statement of personalized medicine in breast cancer, she mentions not the advances in science but the lives that will be saved through a new understanding and application of its science. Asked about the “competing” model of predictive modeling vs biomarkers, she instantly embraces it as a welcome and helpful adjunct to biomarkers. This same inclusiveness extends to wellness-based healthcare, to patient-reported outcomes, to the link between the clinical, business, and policy sectors of healthcare in making breast cancer research get traction and stay on course.

And what is that course? Without hesitation, she advances the translational research goal: a new molecular classification of breast cancer that identifies the relevance of types of breast cancer to drive treatment decisions. For Dr Perez, it’s all about treatment. As one of the leading researchers in the area of cancer research that other cancer experts look to as a model of success, we sought her out to give not only an empirical view of the principles and drivers of breast cancer success and future research goals, but also to help define the issues helpful to all cancers. Above all, she applauds the principle of personalized medicine in oncology: to cultivate an understanding by practicing oncologists of the biological basis of cancer and the pharmacodynamic basis of the drugs – biologicals and conventional alike – used to combat it. Asked what the practicing oncologist must glean from the informational overload of this new science to keep up, her advice was immediate and precise: “The practicing oncologist needs to understand genes, the regulation of

12

genes, protein expression, and then metabolomics.”

We turn now to a tour of personalized medicine for the practicing oncologist

by Dr Edith Perez, who describes the strategy and tactics that she and her fellow colleagues are employing to transform what was once a universal killer into a manageable, nonlethal condition.

The OB Nurse How would you define or otherwise describe personalized medicine and its role in the clinical management of breast cancer?

I am very enthusiastic about the way we’re moving because we are all learning about better ways to do the analysis.

– Edith Perez, MD

Dr Perez It’s our ability to identify markers of the tumor of the host that impact pathogenesis so that we can target them to optimize treatments for the individual patients.

The OB Nurse How does predictive modeling assist in this process, compared with the more specific matter of biomarkers?

Dr Perez Predictive modeling can be really fascinating and provide us with some guide of the path that we want to follow. The same applies to preclinical modeling, utilizing cell lines or newer models. In the area of predictive medicine for patients, or personalized medicine, we have realized that all of these models really need to be validated with a robust number of patients who have been followed for an adequate time, along with having appropriate tumor specimens to test these biomarkers.

We can chase a lot of ideas with the-

July/AugusT 2012 l VOLUME 4, NUMBER 2

oretical concepts and preclinical models, and even studies in a small number of patients. But in the area of oncology, certainly in the area of breast cancer, we have come to a realization that these tumors are heterogeneous. There are many genes and proteins that impact the pathogenesis. Thus, we need a fairly large number of patients with appropriate molecular testing to reach definite conclusions.

I’m very enthusiastic, though, about the way the field is moving, but at the same time I’m concerned about the volume of reports that are published in abstract form or peer-review manuscripts every month in this field that may not have a robust number of patients to reach definite conclusions.

The OB Nurse Yes, and that’s what you’re looking for: an enriched patient population.

Dr Perez Yes, and we’ll get to that, but another area that is tremendously important in terms of interpretation of the literature is that it has become easier for journals to prominently publicize and publish material that reflects a possible relationship between a biomarker and patient outcome. It remains difficult to print data of negative associations.

For the needs of patients, reports of negative associations are as important, so that researchers don’t have to keep repeating the same work, as well as acknowledge the work that is done by not only the patients volunteering tumor specimens but also the investigators who have done the calculation work.

I would like to ask for a call to analyze and publicize the data, even if they are negative, because that is the way to advance the field.

The OB Nurse Yes, everyone from the public to the research community is getting this skewed, overly positive perspective on the degree of success – and the ease of success – that’s present in personalized medicine. Without sufficient recognition of the research failures, we will lose the impetus to continue pursuing research areas that are going to overcome these setbacks.

Dr Perez Yes, but I wouldn’t actually use the word failure. When we have hypotheses, it’s our job as scientists and translational investigators to validate the hypothesis or not, and so our obligation is to be able to publish, to report on the information we have provided.

That’s the way I look at the field.

But I am very enthusiastic about the way we’re moving because we are all learning about better ways to do the analysis. We have started to look more carefully at the way the specimens are collected and stored, the need to vali-

date any laboratory testing that we do with appropriate controls, and potentially even have more than one pathologist look at stains or results of gene analysis. And also how carefully we have to analyze the data from these markers in a blinded way in the context of patient outcomes, so that the results that we obtain truly could relate with patient performance.

The OB Nurse You’re seeing basically a success in changing not just prognostic expectations that personalized medicine provides, but even changing the culture of medicine regarding prevention, diagnosis, and treatment?

Dr Perez Well stated. Let me phrase the situation in this way. It is clear that we have made advances over the past 30 to 40 years, but at this time I think we are in a position for the advances to be of much greater magnitude than what we have been able to accomplish.

Secondly, the 2 basic stories that are most positive in the setting of breast cancer are following the only 2 targets that we currently use for therapeutic decisions, which include the ER and HER2. At the same time we know that we have to move beyond these 2 markers in the context of 24,000 genes, validation of the expression of these genes, then posttranslational modifications approaches.

The OB Nurse What is the degree of the proliferation, if you will, of personalized care in breast cancer compared with other cancers, and what would be the reason for the differences in the degree of personalized medicine proliferation across these cancers?

Dr Perez I think there’s a wide interest in the field of personalized medicine for all malignancies. The one issue in the setting of breast cancer that makes it unique is composed of 2 things.

Number 1, breast cancer is a common disease, and we have had some good therapies that have allowed many patients to survive for longer times than other tumor types, which has then led to an advocacy coming from the patient’s standpoint to get researchers to do research in the setting of breast cancer.

Also a positive for breast cancer has been the fact that some of these therapies that we have found to be beneficial really have impacted the lives of so many, so essentially we have used the low-hanging fruit. Some things have worked very well, so we have a lot of impetus to keep moving in that direction.

But clearly at the same time I’m really very happy that this field of personalized medicine has started to pan out in the

Breast Cancer setting of some lung cancers and also some other cancers, especially melanoma, where we’re starting to see some really fascinating data. But the issue is going to be, are these new data going to impact the 5-year survival of those diseases, which remain way below 20%?

So although the data with the EGFR inhibitors for lung cancer, for the ALK inhibitors for lung cancer, and the data for the BRAF inhibition in the setting of melanoma look very interesting, we need a little bit longer follow-up, whereas in breast cancer, we know that targeting ER, targeting HER2, truly impacts the long-term outcome of patients in addition to having an impact on short-term response or progression-free survival.

Initially it seems like the group of individuals involved in breast cancer is quite cohesive at the global level, but this is happening also with other tumor types. But we have had long-term meetings where research data are discussed on an ongoing basis so that we don’t duplicate work, and at the same time we collaborate with each other to make important data available.

The OB Nurse What would be some of the important examples of personalized medicine algorithms of this type as they’re generally understood? And next, what are some examples of such algorithms that have been discovered by researchers but have failed to be adopted by oncologists expeditiously, and how can we expedite the uptake of that kind of progress for breast cancer patients?

Dr Perez First of all, one of the issues that we have to deal with, and I deal with this all the time, is how to convey the message of the work that is currently being done, as well as the complexity of the work being done, to the physicians who are mainly involved in practice, or to physicians or to philanthropists who we absolutely need for support of some of this innovative work. We have to distill the technical jargon to understandable concepts that can be conveyed to people because they have to be part of the team as we try to solve this puzzle of breast cancer.

The OB Nurse Yes, including the investors.

Dr Perez Absolutely. Then we as scientists also have to keep in mind that the honesty related to our research findings is something that cannot be underestimated. We have to be judicious in the way we report our own data and just absolutely always, always tell the truth, not make more than what we have, not make less than what we have. We’ll always be 100% honest and accurate related to the information we share with others.

We cannot compromise on this issue because we may send confusing mes-

sages to all of these stakeholders as well as all the researchers.

In terms of personalized medicine algorithms, I think probably the most important thing I can say is that we have to work with our pathologists to be able to collect the tumor specimens in a consistent way, and for pathologists to follow algorithms and recommendations that have been generated by expert panels related to exposure of tissues to various elements so that the tissue remains appropriate for testing of these markers.

At the same time it is very important to realize that at least from the treatment standpoint, depending on the data that we get from these molecular profiles, the clinical condition of the patient is also very important. So we don’t manage patients only based on laboratory results. We manage patients based on the prior therapy they may have had, the patient’s overall condition and organ function. We have to put all the pieces together, but I hope that in the next few years we’re going to learn so much about the molecular profile of these tumors that we’ll be able to be a lot smarter related to putting together molecular profiles with patient profiles to come up with the best treatments.

When we think about personalized medicine and molecular markers, there are so many different things that we can look at. We can look at whole genome.

We can look at exomes. We can look at RNA. We can look at proteins. We can look at microRNAs, RNAs that modulate function of genes. So this is a very vast field that speaks to the complexity of what we need to elucidate.

In the area of microRNAs, there are hundreds of RNAs that have now been identified, and RNAs appear to modulate the function of about a third of our genes.

The OB Nurse Given the limitations of personalized medicine, empirical science continues to play a predominant role in cancer care and in research, and we won’t be abandoning this approach anytime soon. Because of the need for personalized medicine and empirical medicine to coexist, we’d welcome your comments to put personalized medicine into an operational perspective.

Dr Perez I think in order to provide personalized medicine there will always be a portion of empiricism, because I don’t know if we are going to be able to devise a treatment that will target all molecular abnormalities that may be driving a tumor for each individual patient.

I think what we’re going to be able to do is subclassify patients based on pathways, and I hope that will give us enough information to be able to have maybe 10 types of breast cancer and

guide therapy based on that. Ideally, if a tumor is found to have 3 abnormalities and we can find 3 drugs that address those abnormalities, then obviously we will be able to provide individualized care to each patient. But I think the way things are going, each breast cancer may have many more than 3 abnormalities, so we may not be able to treat a patient with 20 drugs.

A realistic approach means that, while most of what we do now is empiric, the balance will change. But we’re going to have to be realistic related to whether we will address every target in the tumor. Think about this: It’s more than just being able to identify the abnormalities in the tumor with

I think the way things are going, each breast cancer may have many more than 3 abnormalities, so we may not be able to treat a patient with 20 drugs.

genomic analysis. We need to identify whether they are drivers of tumor growth or metastatic potential.

The OB Nurse Is there any strategic guidance that you might offer practicing oncologists to give appropriate emphasis to personalized medicine in order to integrate it into their clinical strategic process?

Dr Perez I think the guidance is going to be that we are going to need more access to more specimens in the evolution of the disease process to be able to manage patients in an optimal way. Right now we’ve been practically relying on the limited molecular testing that we can do on the original tumor and expect that that will provide us the guide on how to manage patients when they develop relapse, when they go into a metastatic setting, when they develop further progression, so I think that has to be the guide.

We may need to be much more attentive and consistent in our recommendations to obtain biopsies so that we can do this molecular analysis at the different stages of the disease process.

Then people like me and others will figure out the best tools with which to evaluate the molecular changes. But without tissue that can be collated with patient outcome, we will not be able to advance as quickly as we should.

The OB Nurse How would you advise oncologists so that they could develop a sophistication in their understanding of personalized medicine techniques to distinguish real innovation from just novelty?

Dr Perez Very good point. I think it’s going to be up to all of us. I think it’s our responsibility to educate physicians, because the terminology is different from what they learned in medical school. So we need different specimens to do different types of gene sequencing. We need to help them understand the difference between doing an exome analysis versus a whole genome sequencing and the data that we can get. There’s a realization that we’ll need to work together to educate practicing oncologists, and it will be done.

The OB Nurse Can you describe breast cancer patient subgroup risk stratification as part of the personalized medicine revolution? What are the different categories of breast cancer prognostic expression signature sets?

Dr Perez They’re currently being defined. That’s actually one of the challenges in the field. Different people are using different technologies to come up with signatures, and the genes from one signature do not correlate with the genes found with the other mechanisms, so these signatures seem to be nonconsistent, in my opinion. That’s because the platforms used to develop the signatures are different. So I think as we get more and more into understanding the exome, and we get to understand the whole genome sequencing, this will get better, because right now we just have a smatter of signatures and no real clearcut relation between one versus the other. To complicate matters even more, not many studies have been done in which a specific set of tumors has been tested using different techniques to see if the signatures that are derived are the same or different.

The OB Nurse How do they reflect tumor status?

Dr Perez Well, right now we and others are working on redeveloping signatures for what’s ER-positive versus ER-negative breast cancer. I think we will eventually develop signatures for patients with HER2-positive breast cancer that will have a likelihood of responding to trastuzumab or lapatinib or other agents.

Right now the status of the signature is that no one can tell me whether it’s a primary tumor or a metastatic site.

That’s not the area that we are going to be pursuing. We’re just going to take a tumor wherever it is, try to understand the biology so that we can offer the best therapy for our patients.

The OB Nurse Drilling down one step further. These signature sets, how Continued on page 14

July/AugusT 2012 l VOLUME 4, NUMBER 2

13

Breast Cancer

Cultivating personalized medicine... do they help delineate outcome?

Dr Perez When we find mutations in the signature sets that are important for the pathophysiology of the breast cancer, then we’ll be able to really devise therapeutic strategies using combinations of agents, and that will be directly correlated with improved patient outcome. At least that’s the way I envision this.

The OB Nurse Historically, how reliable are they?

Dr Perez Well, we haven’t had the tools in the past. Right now the best we can do when we have a patient with advanced cancer is to choose any of the drugs that have been approved by regulatory agencies. Each drug has approximately a 20% to 30% activity, and that’s just not good enough. I hope that we’ll get to the point where we’ll be able to do the analysis of the tumors and tell the patient, “hey, your tumor has an 80% chance of benefiting.” Even with that I’m going to be very happy.

The OB Nurse Are these codified in algorithms by the National Comprehensive Cancer Network or American Society of Clinical Oncology?

Dr Perez Not yet, because there are so many signatures that are being published, based on what I consider to be evolving technologies, that they have not been validated by others enough to really have big names yet.

The OB Nurse What are the specific breast cancer patient types – and tumor types? Is the revelation of personalized medicine processes in breast cancer leading to subspecialization based on these patient types and tumor types?

Dr Perez This will happen, but right now they’re really not validated enough for me to tell you that there are going to be 4 subtypes of breast cancer, or 10. I think this is going to require a little bit more work.

Right now we’re still using ER/PR [progesterone receptor] and HER2 to make the decisions for patients.

Everything else is to be validated.

The OB Nurse In what way would this profiling aid the oncologist in risk stratification, in establishing prognostic expectations, and in identifying personalized medicine diagnostic tests and treatment?

Dr Perez Just to give you an example how this is going to be revolutionized: Right now when a new patient is diagnosed with breast cancer, we do surgery and take the tumor out, and then we give adjuvant therapy, or we may decide to give neoadjuvant therapy. But there are essentially about 5 drugs that are used where I think there may be 40 abnormalities in the breast cancer that

14

may be important to drive pathogenesis.

I think in the future we’re going to have many more agents that are really directed toward their normal targets. Instead of having one general recommendation for adjuvant therapy, we may have 10.

Because right now everybody’s treated the same way, bottom line. Everybody gets chemotherapy, that is anthracycline, taxane-based chemotherapy.

That’s it. That is the backbone of treatment for patients with cancer, even with early-stage breast cancer, and we need to be much more specific than you’re seeing, you know, 2 classes of drugs that are most effective.

Right now the best we can do when we have a patient with advanced cancer is to choose any of the drugs that have been approved by regulatory agencies.

The OB Nurse If you could, please discuss the discovery and advancement of the approved biomarkers for breast cancer, and the investigational ones.

Dr Perez In terms of a routine management of patients with breast cancer, there are only 3 markers that are done: ER, PR, and HER2. And it’s not even HER2/neu. HER2/neu refers to the HER2 gene, so we prefer to call it HER2 because HER2 addresses evaluation of the protein or the gene, and we can do either for a therapeutic decision.

We don’t have to do both.

EGFR has been looked at, and it has not panned out yet as a marker to drive therapy in patients with breast cancer.

Regarding p53, certainly we know it’s expressed as abnormal in a majority of tumors, but it’s not tumor-specific enough to guide therapy, and people have tried to look at p53 in the context of anthracyclines, but again nothing specific.

So we just wonder when looking at AKT, looking at pa3 kinase, looking at IGF, are those markers going to be important, but right now we don’t know. MET may be a very important marker in breast cancer. Protein kinase D1 may be important, but again, all these things are a part of research right now. Nodule may be important. But we

July/AugusT 2012 l VOLUME 4, NUMBER 2

Continued from page 13

need to figure out what those markers mean in the context of the physiology of this disease.

The OB Nurse Why are these attracting the most interest and research?

Dr Perez One of the reasons is that companies have drugs that target a particular marker, because the other markers that we haven’t talked a lot about today are the microRNAs, which may control 30% of our genome, and theoretically they could be extremely important. But more work needs to be done in that area.

Another area certainly is phosphorylated proteins, but that is very difficult to test for because phosphorylation occurs, and in 1 minute it’s gone, so you cannot assay for the impact of phosphorylated proteins in the context of tumors. We can do that very well in cell lines, but that’s very different than in humans, so I think that’s going to be a very challenging area to conquer.

The other biomarker of interest has been circulating tumor cells. Before we can really explore this more, we need to first understand if the genomic markers in circulating tumor cells are equivalent to the genomic markers of the tumors that are invading different organs. And secondly, can we assay for a variety of molecular markers in circulating tumor cells when we may have just 5 cells per mL? When is the technology going to be good enough that we can take 2 cells and do enough biomarkers in those 2 cells to be able to drive a better understanding of breast cancer?

If we can avoid having to do invasive biopsies and just assay the circulating tumor cells, that would be great. But before we do this we again need to address those 2 issues: are they the same cells, or is there something different about the cells that decide to shed and be in the circulation compared with the tumors that are invading the liver and causing death?

The OB Nurse What would you regard as landmark research in personalized medicine in breast cancer and the clinical basis for its significance?

Dr Perez The term “personalized medicine” is a very broad term, but essentially the most important biomarker in addition to ER really has been HER2. HER2 was identified, and then we developed a strategy in the metastatic setting to target HER2, clearly improving survival. And then we were able to take that marker and use these agents in the adjuvant setting, and we decreased relapse by 50%, and we are improving survival by 38%. So now by using this biomarker, this is part

of personalized medicine. We’ve been able to change the natural history of HER2-positive breast cancer from a very aggressive type of breast cancer to one that is very manageable and potentially curable.

The OB Nurse Are there any particular clinical, business, or policy factors impeding progress in breast cancer, especially involving personalized medicine?

Dr Perez It’s really time and money, because we need to put enough resources not only to have sequencing machines but to have the patient resources to have enough tumor specimens to not only put the specimens in a machine but also to have the bioinformatics personnel to put the story together. There has to be a focused and concerted effort to devote enough resources to this area in a timely fashion to really get the answers.

The OB Nurse Are there particular areas of consensus and particular areas of controversy concerning biomarkers in particular and personalized medicine in general involving breast cancer that you see as standing out, very obvious ones?

Dr Perez The controversy is, in my opinion, that some people feel a lot of gene work has been done and “it hasn’t translated into anything yet.” Some people have become naysayers because they’re not as involved as some of us are, trying to really make specific advances on this.

I think that is the main controversy.

This is a new field, and people don’t understand it. Breast cancer is a genetic disease, and we really need to unravel the genetics of this disease, what drives gene function, what is the product of those genes, so that we can realize this dream, going back to the dream of personalized medicine for our patients with breast cancer.

The OB Nurse In your research priorities, are you going to focus in one area?

Dr Perez Absolutely, although our interests are very vast. I hope that our work will eventually lead to a new molecular classification of breast cancer and we’ll identify the relevance of types of breast cancer to drive treatment decisions. Along those lines, this finding of fusion genes in breast cancer may be very important. But first of all, we need to identify what the redundant fusion genes are, and number 2, do they have any associated protein products, and can they be utilized for the development of new treatments.

The OB Nurse That gives us a perfect place to end our discussion today.

Thank you for your time.

Dr Perez My pleasure. n

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Editor in Chief

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Stephanie A. Gregory, MD

Professor Vice Chair of Clinical Affairs Department of Hematology and Medical Oncology Winship Cancer Institute Emory University School of Medicine

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The Elodia Kehm Chair of Hematology Professor of Medicine Director, Lymphoma Program Rush University Medical Center/Rush University

Topics include: • Mantle Cell Lymphoma • Follicular Lymphoma

These activities are supported by educational grants from Millennium: The Takeda Oncology Company and Celgene Corporation.

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