Early Cancer Detection in Primary Care by Integritas Communications

© 2022 Global Education Group and Integritas Communications. All rights reserved. No part of this eHealth Source may be used or reproduced in any manner whatsoever without written permission except in the case of brief quotations embedded in articles or reviews. Integritas Communications 95 River Street, Suite 5B Hoboken, NJ 07030 www.integritasgrp.com www.exchangecme.com

FACULTY Lincoln D. Nadauld, MD, PhD Vice President Chief, Precision Health and Academics Intermountain Healthcare St. George, Utah

Lincoln Nadauld founded the Intermountain Precision Genomics program with a vision of nding solutions to improve health and disease through genomics and precision medicine without increasing costs. With his vision in mind, he oversees the clinical implementation of precision genomics across Intermountain’s 24 hospitals and 160 physician clinics. Dr. Nadauld serves as Intermountain Healthcare’s Chief Academic Of cer. In addition, he facilitates genomic research to better understand the human genome. Dr. Nadauld conceived of and is leading the recently announced Heredigene Population Study—a collaborative effort with deCODE Genetics in Iceland to collect and perform wholegenome sequencing on 500,000 participants in the Intermountain system. Dr. Nadauld’s work in founding Intermountain Precision Genomics was recognized with the Utah Governor’s 32nd Annual Science Medal for Industry, which is the highest civilian award to be bestowed by the state of Utah to honor signi cant contributions to science and technology. Dr. Nadauld also received the 2020 C2 Catalyst for Precision Medicine award, honoring those who improve personalized treatment for cancer patients. He is married with ve children and enjoys attending their many activities and events as well as water sports, shing, and other athletic pursuits.

Charles P. Vega, MD, FAAFP Clinical Professor, Family Medicine Director, UC Irvine Program in Medical Education for the Latino Community Associate Dean, School of Medicine University of California, Irvine Irvine, California Chuck Vega grew up in Northern California and completed his undergraduate degree at Harvard University. He attended medical school at the University of Wisconsin – Madison and completed residency training in Family Medicine at the University of California – Irvine (UCI). He stayed on as faculty in the Department of Family Medicine at UCI and now holds the title of Health Sciences Clinical Professor. He is the Executive Director of UCI’s Program in Medical Education for the Latino Community and won a Macy Faculty Scholarship to improve patient-centered health education at UCI. He currently serves as Assistant Dean for Culture and Community Education at UCI.

Dr. Vega has seen patients and taught medical students and residents at UCI’s Family Health Center – Santa Ana for the past 20 years. This clinic is a federally quali ed health center and the largest safety-net clinic for Orange County. Dr. Vega’s academic interests are focused on access to quality, compassionate medical care for underserved populations, and the development of training programs to promote this vision of health care.

PREAMBLE Target Audience The educational design of this activity addresses the needs of primary care physicians, nurse practitioners, physician assistants, and obstetricians, as well as geriatricians involved in early cancer detection.

Program Overview

Despite signi cant advances in therapy, cancer continues to impose enormous medical, economic, and social burdens. In the United States, approximately 1700 people die from cancer each day, making it the leading cause of mortality in people younger than 80 years old. The costs of treating cancer, including drugs, hospitalization, and ambulatory care, exceed $157 billion annually. Indirect costs, including lost productivity and absenteeism, add nearly another $100 billion to the tally. Early detection is an essential step in reducing the burdens of cancer. Identifying cancer at its earliest stages improves outcomes by allowing therapy to begin sooner, decreasing treatment costs and complexity, reducing morbidity and mortality, and improving quality of life. Liquid biopsy–based multi-cancer early detection (MCED) tests have been developed to support population-based screening of asymptomatic individuals for dozens of cancer types. This multimedia educational activity has been designed to help primary care clinicians—the most important facilitators of preventive health care and cancer screening—understand the technology behind MCED tests, interpret data from clinical trials, engage in shared decision-making to determine which patients

should be tested, and plan for follow-up examinations in response to positive tests.

Educational Objectives After completing this activity, the participant should be better able to: • Discuss the bene ts, limitations, and potential harms of current cancer screening recommendations and protocols • Describe recent advances in liquid biopsy approaches including the latest understanding of cell-free DNA for the early detection of multiple cancer types • Evaluate recent clinical data on available and emerging noninvasive multi-cancer screening tests and their utility in early cancer detection • Design a practical protocol for integration of patient counseling and multi-cancer screening into work ow protocols in the primary care setting

Physician Accreditation Statement

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

Physician Credit Designation Global Education Group designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurse Practitioner Continuing Education This activity has been planned and implemented in accordance with the Accreditation Standards of the American Association of Nurse Practitioners (AANP) through the joint providership of Global Education Group and Integritas Communications. Global Education Group is accredited by the American Association of Nurse Practitioners as an approved provider of nurse practitioner continuing education. Provider number: 110121. This activity is approved for 1.0 contact hour (which includes 0.0 hour(s) of pharmacology).

Instructions to Receive Credit In order to receive credit for this activity, the participant must review the activity as well as successfully complete the posttest, with 70% or better, and evaluation form.

Global Contact Information For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

Fee Information & Refund/Cancellation Policy There is no fee for this educational activity.

Disclosure of Con icts of Interest Global Education Group (Global) adheres to the policies and guidelines, including the Standards for Integrity and Independence in Accredited CE, set forth to providers by the Accreditation Council for Continuing Medical Education (ACCME) and all other professional organizations, as applicable, stating those activities where continuing education credits are awarded must be balanced, independent, objective, and scienti cally rigorous. All persons in a position to control the content of an accredited continuing education program provided by Global are required to disclose all nancial relationships with any ineligible company within the past 24 months to Global. All nancial relationships reported are identi ed as relevant and mitigated by Global in accordance with the Standards for Integrity and Independence in Accredited CE in advance of delivery of the activity to learners. The content of this activity was vetted by Global to assure objectivity and that the activity is free of commercial bias. All relevant nancial relationships have been mitigated. The faculty have the following relevant nancial relationships with ineligible companies: Lincoln D. Nadauld, MD, PhD

Stock Option Holder: Invitae

Charles P. Vega, MD, FAAFP Consulting fees: GlaxoSmithKline; Johnson & Johnson

The planners and managers have the following relevant nancial relationships with ineligible companies: Kristin Delisi, NP

Nothing to disclose

Lindsay Borvansky

Nothing to disclose

Andrea Funk

Nothing to disclose

Liddy Knight

Nothing to disclose

Ashley Cann

Nothing to disclose

Jim Kappler, PhD

Nothing to disclose

Disclosure of Unlabeled Use This educational activity may contain discussion of published and/ or investigational uses of agents that are not indicated by the US Food and Drug Administration. Global Education Group (Global) and Integritas Communications do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the of cial prescribing information for each product for discussion of approved indications, contraindications, and warnings.

Disclaimer

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own

professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

INTRODUCTION

VIDEO: Introduction to the Multi-Cancer Early Detection eHealth Source Approximately 20 million new cancer cases are diagnosed worldwide each year, with nearly 2 million occurring in the United States.1,2 Cancer is the second leading cause of death in the United States.2 Patients with cancer diagnosed at a localized stage have a 5-year relative survival rate that is 3 times higher than those whose cancer is diagnosed at a distant stage.3 Therefore, increasing the detection of cancer at early stages is an important public health initiative to reduce cancer-associated morbidity and mortality.4,5 However, population-level screening recommendations for asymptomatic individuals are only available for breast, prostate, cervical, colorectal, and lung cancers.6 Newer genomic technologies that can detect signals circulating in the

References 1.

International Agency for Research on Cancer. Global Cancer Observatory. https:// gco.iarc.fr/. Accessed April 1, 2022.

2. American Cancer Society. Cancer Facts & Figures, 2022. Atlanta: American Cancer Society; 2022. www.cancer.org/research/cancer-facts-statistics/all-cancer-factsgures/cancer-factsgures-2022.html. Accessed April 11, 2022. 3. Clarke CA, et al. Projected reductions in absolute cancer–related deaths from diagnosing cancers before metastasis, 2006–2015. Cancer Epidemiol Biomarkers Prev. 2020;29(5):895-902. 4. Miles A, et al. A perspective from countries using organized screening programs. Cancer. 2004;101(suppl 5):1201-1213. 5. US Department of Health and Human Services, Of ce of Disease Prevention and Health Promotion. Healthy People 2030. https://health.gov/healthypeople/objectivesand-data/browse-objectives/cancer. Accessed April 1, 2020. 6. Hackshaw A, et al. Estimating the population health impact of a multi-cancer early detection genomic blood test to complement existing screening in the US and UK. Br J Cancer. 2021;125(10):1432-1442.

7. Hackshaw A, et al. New genomic technologies for multi-cancer early detection: rethinking the scope of cancer screening. Cancer Cell. 2022;40(2):109-113.

blood from multiple cancer types represent a potential paradigm shift for cancer screening.6 Analyzing methylation patterns in circulating cell-free DNA has been shown to be effective for the early detection of cancers.7 With one assay currently available in the United States and others on the horizon, primary care providers should be familiar with the data surrounding various multi-cancer early detection (MCED) tests. Incorporating these modalities into primary care practice necessitates identi cation of patients who are likely to bene t, standardization of testing processes, consideration of MCED tests together with other screening modalities, and strategies to address positive results.

THE NEED FOR IMPROVED EARLY DETECTION ACROSS CANCER TYPES Cancer Epidemiology and Mortality Nearly 40% of Americans will receive a cancer diagnosis at some point during their lifetimes.1 In 2022, approximately 1.9 million new cancer cases will be diagnosed in the United States, most frequently among people between 65 and 74 years old (mean age at diagnosis, 66 years).2,3 In the United States, the most common cancers are found in the breast, male and female genital systems, lung and bronchus, and lower gastrointestinal tract, including the colon and rectum (Figure 1.1).2 Although the mortality rate for all cancer sites combined has declined 32.1% since 1990, cancer remains the second leading cause of death in the United States, with projections of more than 600,000 lives lost in 2022.4

Factors In uencing Cancer Survival

The average 5-year relative survival rate for patients with any malignancy is 67.7%, although a number of factors in uence the chances of survival in a given individual.2 Patient-speci c characteristics include age and race (Figure 1.2).5 In general, patients who receive a diagnosis at a younger age are likely to survive longer than older patients.1,2 For instance, likelihood of surviving 5 or 10 years postdiagnosis is 1.4 times higher for patients younger than 50 years of age compared with those 65 years of age or older.5 Additionally, after adjusting for sex, age, and disease stage at diagnosis, the risk of death is 33% higher for Black patients and 51% higher for Indigenous American patients compared with White patients.6 While the underlying causes are not fully understood, these disparities by race have persisted over time and can be at least partially explained by differences in the timely receipt of recommended treatments.6-8

Disease-speci c factors, such as tumor site and disease stage, also profoundly in uence survival (Figures 1.2 and 1.3).5 The 5-year relative survival rate for thyroid cancer is 98.3%, whereas it is just 10.8% for pancreatic cancer. Moreover, the stage at which a tumor is diagnosed directly impacts the associated morbidity and mortality; cancers at earlier stages are more likely to be resectable and/or responsive to less aggressive therapies.9 Overall, when tumors are detected at a localized stage, the 5-year relative survival is 91.1%, whereas the average 5-year relative survival for cancers detected at a distant stage is only 30.1%.10 Further, over a 5-year period, cancers with distant metastases account for only 18% of new cases but 45% of cancer-related deaths.11 Given the ongoing trend of an aging US population and projections for signi cant increases in cancer incidence in the coming years, strategies to ensure early diagnosis across diverse patient populations are vital to lessen the burdens of cancer.12

Current Approaches to Screening

Currently, there are recognized screening approaches for only a limited number of cancers, including colonoscopy for colorectal cancer, prostate-speci c antigen test for prostate cancer, lowdose computed tomography (LDCT) for lung cancer, mammography for breast cancer, and cervical cytology for cervical cancer.13 Screening recommendations are based on individual risk status for each cancer type and are associated with many challenges, although the guidelines are frequently updated and may differ based on the issuing agency.14 Current screening

recommendations from the US Preventive Services Task Force (USPSTF) are summarized in Table 1.1.

Bene ts and Limitations of Current Modalities

The association between available and recommended cancer screening programs and changes in incidence and death rates were analyzed recently. The percentage of lung cancers diagnosed at a localized stage increased by 8% in the 5 years following the USPSTF recommendation to perform annual LDCT for

high-risk individuals.15 Moreover, mortality was reduced by 39% compared with no intervention.16 Recent updates to lung cancer screening recommendations increased the eligible population from 14.1% to 20.6%-23.6% of the population, and early models predict that lung cancer deaths averted and life-years gained are likely to increase.17 The overall mortality rate for colorectal cancer has decreased by approximately 2% per year since 2010.2 However, the mortality rate among adults less than 50 years of age has increased by about 1.2% annually, as this population was not included in colorectal cancer screening recommendations.5 The mortality rates for breast and prostate cancers continue to decline after initial rapid reductions when mammography screening and PSA testing were introduced, respectively.2,18

Although current screening modalities have demonstrated clinical bene ts for certain patient populations, there are several limitations to their use and capacity to impact change (Supplementary video 1). Recommended population-level screening approaches (breast, cervical, colorectal, and lung cancers) address cancers that, in total, account for about a third of new diagnoses and just under 38% of deaths.2 Additionally, even among patients who are eligible, many are not screened in line with available recommendations.19 About a third of patients who are eligible for breast, cervical, and colorectal cancer screening are not up to date.20-22 Moreover, current screening methods employ a “one organ at a time” approach, which requires use of different (and often expensive) modalities for each cancer type.23 In addition, heterogeneous screening modalities may be logistically inef cient and interfere with practice integration, patient compliance, and scheduling.23 Disparities in cancer screening are well documented, with the lowest rates observed for various racial and ethnic minorities, uninsured people, patients who do not have a usual source of care, individuals without a

college education, and individuals who live below the national poverty line.20-22,24 Geographic access to screening facilities also affects the utilization of lung, breast, and colorectal cancer screenings.25-30 Efforts to improve early cancer detection—and apply them broadly and equitably—are necessary to further reduce the morbidity and mortality associated with cancer.

VIDEO 1: Limitations of Current Cancer Screening Strategies

Key Takeaways • Cancer continues to impose high public health and economic burdens, both of which are projected to increase in the coming years • The morbidity and mortality associated with cancer are lower when malignancies are diagnosed at earlier stages than at later stages

• Population-level screening recommendations for asymptomatic adults have been published for breast, lung, colorectal, cervical, and prostate cancer, although adherence rates are below national target levels

References 1.

National Cancer Institute (NCI), Division of Cancer Control and Population Sciences (DCCPS). Understanding cancer: Cancer statistics. https://www.cancer.gov/aboutcancer/understanding/statistics. Accessed April 11, 2022.

Siegel RL, et al. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.

Surveillance, Epidemiology, and End Results (SEER) Program. DevCan database: SEER 21. Percent of new cases by age group: cancer of any site, 2014-2018. NCI, DCCPS. Released April 2021, based on the Nov 2020 submission. https:// seer.cancer.gov/statfacts/html/all.html. Accessed March 1, 2022.

Murphy SL, et al. Mortality in the United States, 2020. NCHS Data Brief. Hyattsville, MD: National Center for Health Statistics. 2021;427:1-8.

SEER*Explorer: An interactive website for SEER cancer statistics. Surveillance Research Program, NCI. https://seer.cancer.gov/explorer/. Accessed March 1, 2022.

Jemal A, et al. Annual report to the nation on the status of cancer, 1975–2014, featuring survival. J Natl Cancer Inst. 2017;109(9):djx030.

Fedewa SA, et al. Delays in adjuvant chemotherapy treatment among patients with breast cancer are more likely in African American and Hispanic populations: a national cohort study 2004-2006. J Clin Oncol. 2010;28(27):4135-4141.

Freedman RA, et al. The association of race/ethnicity, insurance status, and socioeconomic factors with breast cancer care. Cancer. 2011;117(1):180-189.

Schiffman JD, et al. Early detection of cancer: past, present, and future. Am Soc Clin Oncol Educ Book. 2015:57-65.

10. SEER Program SEER*Stat Database. Incidence—SEER 18 Regs Research Data + Hurricane Katrina Impacted Louisiana Cases (2000-2018), NCI, DCCPS Surveillance Research Program. Released April 2021, based on the Nov 2020 submission. https:// seer.cancer.gov/explorer/. Accessed March 2, 2022. 11.

Clarke CA, et al. Projected reductions in absolute cancer–related deaths from diagnosing cancers before metastasis, 2006–2015. Cancer Epidemiol Biomarkers Prev. 2020;29(5):895-902.

12. Weir HK, et al. Cancer incidence projections in the United States between 2015 and 2050. Prev Chron Dis. 2021;18:E59.

13. US Preventive Services Task Force. Published Recommendations for Cancer. www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstfand-b-recommendations. Accessed March 1, 2022. 14. Corley DA, et al. Reducing variation in the “standard of care” for cancer screening: recommendations from the PROSPR Consortium. JAMA. 2016;315(19):2067-2068. 15. SEER Program SEER*Stat Database. North American Association of Central Cancer Registries (NAACCR) incidence data-cancer in North America analytic le, 1995-2018, with race/ethnicity, custom le with county. NCI, DCCPS Surveillance Research Program. Released April 2021, based on the Nov 2020 submission. https:// seer.cancer.gov/explorer/. Accessed March 2, 2022. 16. Pastorino U, et al. Prolonged lung cancer screening reduced 10-year mortality in the MILD trial: new con rmation of lung cancer screening ef cacy. Ann Oncol. 2019;30(7):1162-1169. 17.

Meza R, et al. Evaluation of the bene ts and harms of lung cancer screening with low-dose computed tomography: modeling study for the US Preventive Services Task Force. JAMA. 2021;325(10):988-997.

18. Tsodikov A, et al. Reconciling the effects of screening on prostate cancer mortality in the ERSPC and PLCO trials. Ann Intern Med. 2017;167(7):449-455. 19. Sabatino SA, et al. Cancer screening test receipt—United States, 2018. MMWR Morb Mortal Wkly Rep. 2021;70(2):29-35. 20. Joseph DA, et al. Vital signs: colorectal cancer screening test use—United States, 2018. MMWR Morb Mortal Wkly Rep. 2020;69(10):253-259. 21. American Cancer Society. Breast cancer facts & gures 2019-2020. 2019. https:// www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/ breast-cancer-facts-and- gures/breast-cancer-facts-and- gures-2019-2020.pdf. Accessed March 2, 2022. 22. NCI. Online summary of trends in us cancer control measures: prostate cancer screening. 2021. https://progressreport.cancer.gov/detection/prostate_cancer. Accessed March 1, 2022. 23. Ahlquist DA. Universal cancer screening: revolutionary, rational, and realizable. NPJ Precis Oncol. 2018;2:23. 24. Liu D, et al. Interventions to reduce healthcare disparities in cancer screening among minority adults: a systematic review. J Racial Ethn Health Disparities. 2021;8(1):107-126. 25. Sahar L, et al. Geographic access to lung cancer screening among eligible adults living in rural and urban environments in the United States. Cancer. 2022;128(8):1584-1594.

26. Tailor TD, et al. Geographic access to CT for lung cancer screening: a census tractlevel analysis of cigarette smoking in the United States and driving distance to a CT facility. J Am Coll Radiol. 2019;16(1):15-23.

27. Jewett PI, et al. Geographic access to mammography facilities and frequency of mammography screening. Ann Epidemiol. 2018;28(2):65-71. 28. Engelman KK, et al. Impact of geographic barriers on the utilization of mammograms by older rural women. J Am Geriatr Soc. 2002;50(1):62-68. 29. Elkin EB, et al. Geographic access and the use of screening mammography. Med Care. 2010;48(4):349-356. 30. Alyabsi M, et al. Colorectal cancer screening uptake: differences between rural and urban privately-insured population. Front Public Health. 2020;8:532950.

THE SCIENCE OF LIQUID BIOPSY Introduction to Liquid Biopsy Identifying and effectively treating malignancies as early as possible is critical to improving outcomes across cancer types. Historically, tissue biopsy has been considered the “gold standard” for tumor diagnosis and classi cation.1 Tissue samples obtained via biopsy can help determine whether cancer is present, categorize the tumor type and stage, and detail biomarker expression for insights into patient prognosis and potential treatment options. Tissue biopsies, however, are not without limitations as they can be invasive, costly, risky, and potentially painful.2 Moreover, these procedures require that the tumor is accessible and only provide detailed information about cancer at the site and the time of biopsy.2 To accelerate tumor diagnoses and support the potential for personalized medicine across all stages of cancer care, there is need for noninvasive, highly sensitive methods that can screen multiple organs simultaneously with high speci city and evaluate the spatial and temporal heterogeneity of cancer development.3

To address some of the limitations associated with tissue biopsy, liquid biopsy has emerged as a noninvasive approach for cancer screening and characterization across all tumor stages.2 With just 6 to 20 mL of blood collected in a routine blood draw, single and serial sampling with liquid biopsy can produce real-time information about cancer diagnoses, patient prognoses, potential treatment responses and resistance, recurrence/metastases, and biologic risk strati cation (Supplementary video 2).4,5 However, this

technology is relatively new and its use needs to be standardized and harmonized across laboratories.3

VIDEO 2: Applications of Liquid Biopsy in Oncology

Testing Modalities of Liquid Biopsy

Various analyses with liquid biopsy can be performed to detect different classes of mutations and other abnormalities in cancer cells, providing insights into gene expression, tumor heterogeneity, prognosis, and potential responses to treatment (Figure 2.1).6 Thus, liquid biopsy can be used to identify and genetically pro le tumors throughout the body by examining certain markers in blood. These markers include circulating tumor cells, platelets with altered gene expression pro les after exposure to a tumor (tumoreducated platelets), extracellular membrane-encapsulated vesicles containing tumor-speci c proteins and other compounds that are released from malignant cells, and cell-free circulating nucleic acids.7-9 The last—which include cell-free DNA (cfDNA),

circulating tumor DNA, and cell-free RNA—have been extensively studied as markers for detection of new or residual cancer, minimally invasive molecular pro ling, and identi cation of resistance mutations.7,10,11 cfDNA in particular is present in all patients, and has become the basis for new cancer screening modalities.5

The clinical utility of analyzing cfDNA obtained via liquid biopsy as a cancer screening method in people who have not already received a cancer diagnosis is expanding. In healthy individuals, cfDNA is found in plasma at an average concentration of 30 ng/mL (range: 0-100 ng/mL), with the level depending on patient age, overall health status, and degree of physical activity.12 These cfDNA fragments average approximately 250 to 320 base pairs in

length and predominantly originate from lymphoid and myeloid cells.13 This suggests that the primary source mechanism is apoptosis of hematopoietic cells, although other active DNA release and cellular breakdown processes—such as necrosis, pyroptosis, mitotic catastrophe, autophagy, phagocytosis, and erythroblast enucleation—are known to contribute to cfDNA levels.14 In patients with cancer, tumor cell apoptosis and necrosis increase average cfDNA concentrations approximately sixfold to 180 ng/mL (range: up to 1000 ng/mL), with levels varying based on tumor type and location.12 The sizes of these DNA fragments also differ; fragments from those with cancer are typically smaller, averaging about 90-150 base pairs in length.13 Thus, ongoing efforts have sought to use advances in molecular technologies to evaluate cfDNA for cancer-related genetic alterations, cfDNA length pro les, and epigenetic modi cations that are speci c for various malignancies.14

DNA Methylation in Cancer

Research has helped characterize genetic aberrations associated with various cancer types, which can include acquired or germline mutations in tumor-suppressor genes, oncogenes, or DNA-repair genes.15 In addition to numerous genetic changes, cancer is also associated with epigenetic changes, which regulate genomic function and activity by altering the 3-dimensional conformation of the genome and/or protein-DNA interactions or through chemical modi cations on DNA strands.16,17 One well-characterized epigenetic change that has been investigated as a tumor biomarker is DNA methylation.18 Changes in DNA methylation that can contribute to tumorigenesis or progression include focal hypomethylation or global hypermethylation.18,19 Focal hypomethylation results in disordered chromosomes during cell

division and activation of transposable genomic elements, which can in turn lead to additional tumor-promoting genetic damage.19,20 Global hypermethylation can occur in the promotors or other regulatory regions of tumor suppressor genes, thereby silencing their expression and eliminating the tumor-suppressing activities of the encoded proteins (Figure 2.2).21

Evaluating DNA methylation has been proposed as a modality to screen for cancers because this epigenetic change has been shown to occur early in tumorigenesis and is highly pervasive across tumor types.22 Moreover, many different malignancies exhibit a high degree of concordance in DNA methylation patterns across tissues or within the tissue of origin.22-24 Therefore, DNA methylation patterns are indicative of individual cell types and produce a type ngerprint or tissue-speci c marker that indicates the origin of cfDNA.25 For example, DNA methylation patterns in cfDNA derived from lung cancer patients have a distinct pattern

compared with the methylation pattern of cfDNA from patients with colon cancer. Each cancer type generally has a distinct methylation pattern that is unique and identi able in the cfDNA from those cancers. This is con rmed in cfDNA obtained from patients with different cancer types.25 The ability to use noninvasive blood draws and a single molecular analysis to detect numerous cancer types early during tumorigenesis makes methylation-based cfDNA testing an attractive option for cancer screening because it can simultaneously detect the presence of cancer and provide a prediction about the tissue of origin (Supplementary video 3).

VIDEO 3: Key Aspects of Liquid Biopsy and Multi-Cancer Screening Tests

Key Takeaways

• Genetic and epigenetic changes drive cancer tumorigenesis, growth, and metastasis

• Liquid biopsy is a relatively new, noninvasive technique that examines circulating biomarkers to provide information across all stages of cancer care: diagnosis, prognosis, treatment, and monitoring • Analyzing methylation pro les in cfDNA to identify and localize multiple cancer types has emerged as a promising new technique for population-level cancer screening • Multi-cancer screening modalities should accurately detect cancers in different organ systems, localize tumor sites, and demonstrate clinical utility based on analytical and clinical validation

References Sharma S, et al. Precision diagnostics: integration of tissue pathology and genomics in cancer. Pathology. 2021;53(7):809-817.

Rodríguez J, et al. When tissue is an issue the liquid biopsy is nonissue: a review. Oncol Ther. 2021;9(1):89-110.

Pinzani P, et al. Updates on liquid biopsy: current trends and future perspectives for clinical application in solid tumors. Clin Chem Lab Med. 2021;59(7):1181-1200.

Mathai RA, et al. Potential utility of liquid biopsy as a diagnostic and prognostic tool for the assessment of solid tumors: implications in the precision oncology. J Clin Med. 2019;8(3):373.

Aarthy R, et al. Role of circulating cell-free DNA in cancers. Mol Diagn Ther. 2015;19(6):339-350.

Cisneros-Villanueva M, et al. Cell-free DNA analysis in current cancer clinical trials: a review. Br J Cancer. 2022;126(3):391-400.

Ahlquist DA. Universal cancer screening: revolutionary, rational, and realizable. NPJ Precis Oncol. 2018;2:23.

Salvianti F, et al. The pre-analytical phase of the liquid biopsy. N Biotechnol. 2020;55:19-29.

Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. Science. 2020;367(6478):eaau6977.

10. Galbiati S, et al. Microarray approach combined with ddpcr: an useful pipeline for the detection and quanti cation of circulating tumour dna mutations. Cells. 2019;8(8):769. 11.

Wan JCM, et al. Liquid biopsies come of age: towards implementation of circulating tumour DNA. Nat Rev Cancer. 2017;17(4):223-238.

12. Fernández-Lázaro D, et al. Liquid biopsy as novel tool in precision medicine: origins, properties, identi cation and clinical perspective of cancer's biomarkers. Diagnostics (Basel). 2020;10(4):215. 13. Aucamp J, et al. The diverse origins of circulating cell-free DNA in the human body: a critical re-evaluation of the literature. Biol Rev Camb Philos Soc. 2018;93(3):1649-1683. 14. Grabuschnig S, et al. Putative origins of cell-free DNA in humans: a review of active and passive nucleic acid release mechanisms. Int J Mol Sci. 2020;21(21):8062. 15. Persi E, et al. Mutation-selection balance and compensatory mechanisms in tumour evolution. Nat Rev Genet. 2021;22(4):251-262. 16. Nakagawa H, Fujita M. Whole genome sequencing analysis for cancer genomics and precision medicine. Cancer Sci. 2018;109(3):513-522. 17.

Kondo Y. Epigenetic cross-talk between DNA methylation and histone modi cations in human cancers. Yonsei Med J. 2009;50(4):455-463.

18. Locke WJ, et al. DNA methylation cancer biomarkers: translation to the clinic. Front Genet. 2019;10:1150. 19. Prada D, et al. Satellite 2 demethylation induced by 5-azacytidine is associated with missegregation of chromosomes 1 and 16 in human somatic cells. Mutat Res. 2012;729(1-2):100-105. 20. Daskalos A, et al. Hypomethylation of retrotransposable elements correlates with genomic instability in non–small cell lung cancer. Int J Cancer. 2009;124(1):81-87. 21. Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21(35):5427-5440. 22. Zhang J, Huang K. Pan-cancer analysis of frequent DNA co-methylation patterns reveals consistent epigenetic landscape changes in multiple cancers. BMC Genomics. 2017;18(suppl 1):1045. 23. Hoadley KA, et al. Cell-of-origin patterns dominate the molecular classi cation of 10,000 tumors from 33 types of cancer. Cell. 2018;173(2):291-304.e296. 24. Yang X, et al. Comparative pan-cancer DNA methylation analysis reveals cancer common and speci c patterns. Brief Bioinform. 2017;18(5):761-773.

25. Moss J, et al. Comprehensive human cell-type methylation atlas reveals origins of circulating cell-free DNA in health and disease. Nat Commun. 2018;9(1):5068.

RECENT DATA AND CLINICAL UTILITY OF BLOOD-BASED MULTICANCER SCREENING Evaluating Test Results

Over the last decade, signi cant scienti c and clinical research has focused on developing numerous multi-cancer early detection (MCED) tests and modalities (Table 3.1). To assess and compare results from clinical trials evaluating these strategies—and subsequently to interpret and share testing results with patients— clinicians need a good understanding of the sensitivities, speci cities, and positive and negative predictive values associated with various MCED tests (Figure 3.1).1 The sensitivity of a test describes its ability to detect a true positive sample (eg, a patient with a particular cancer), whereas speci city relates to the ability of the test to detect a true negative (eg, a patient who does not have that particular cancer).1 As examples, a test with a sensitivity of 98% would produce 2 false-negative results for every 100 samples from patients with cancer, whereas a speci city of 98% would result in 2 false-positive signals for every 100 samples from patients with no cancer. Positive predictive values (PPVs), which can be thought of as an assessment of the utility of the test in clinical practice, are measured as the percentage of all positive samples that are true positives.1 Negative predictive values (NPVs) are the opposite—the percentage of all negative samples that are true negatives.1 Understanding the clinical relevance of these values is critical

when interpreting test results and communicating them to patients (Supplementary video 4).

VIDEO 4: The Importance of Accuracy and Interpreting Results for Multi-Cancer Screening

Clinical Data for MCED Tests Circulating Cell-Free Genome Atlas (CCGA) Study

The CCGA study was a prospective, case-controlled, observational study of more than 15,000 participants to determine whether genome-wide sequencing of circulating cell-free DNA (cfDNA) in combination with machine learning could detect and localize a large number of cancer types with a speci city high enough to support general population–based screening.2 In the 3-part study, a blood liquid biopsy was obtained (along with tumor tissue when possible) from patients with newly diagnosed but untreated cancer and people with no known cancer diagnosis.3,4 The initial proof-of-concept portion of the study showed that examining cfDNA methylation patterns outperformed sequencing approaches focused on genetic mutations or chromosome

changes for detecting multiple cancer types.5,6 Moreover, the results demonstrated that the cfDNA-based blood test detected multiple cancers at various stages with high speci city, including some potentially lethal malignancies that currently lack national screening recommendations and are associated with lower mortality risks when they are diagnosed at earlier stages.4

The second part of the CCGA study sought to further validate the methylation-based assay, which was able to detect more than 50 cancer types.7 Results showed a speci city of 99.8% in the training set of samples (used to re ne the parameters of the test) and 99.3% in the validation set of samples (used to validate the test based on results from the training set) (Figure 3.2).7 Speci city values for both data sets increased with disease stage, meaning that the tests were more speci c for more advanced cancers. The sensitivity of the test was also consistent for the training set (55.2% across all cancers and stages) and the validation set (54.9%) and increased for higher stage cancers.7 The performance of the test across tumor types, including cancers associated with high mortality and without established screening paradigms, is shown in Figure 3.3.7

Finally, part 3 of the CCGA study sought to further validate the selected test clinically using an independent validation set of samples from just over 4000 patients. The speci city of the test for detecting cancer was 99.5%, whereas the sensitivity was 67.6% for a prespeci ed group of cancers that account for the majority of cancer deaths in the United States, and 40.7% for all cancers (Figure 3.4).8 Overall, the CCGA study showed that results with the methylation-based test show a high degree of speci city and accuracy for the tissue of tumor origin across many different cancer types.

PATHFINDER Study

The PATHFINDER study is a prospective, interventional, return-ofresults study involving approximately 6600 participants aged 50 years or older who were examined with the methylation-based assay re ned during the CCGA study (now referred to as the Galleri® test).9,10 In an interim analysis of the study, 1.4% of participants (92/6629) had a cancer signal detected using the MCED-E version of the test.11 Of those with a positive signal, 63 participants (68%) had achieved diagnostic resolution in time to be included in the primary analysis.11 To con rm a cancer diagnosis, imaging tests were performed in over 90% (57/63) of participants and 48% underwent an invasive diagnostic procedure.11 Cancer diagnosis was con rmed in 27 patients (43%), yielding a PPV of 44.6%. Additionally, cancer signal origin was predicted with 96.3% accuracy.11 In the version of the test re ned

for screening (MCED-Scr), a positive cancer signal was detected in 0.9% (57/6516), of which 40 were also detected in the previous version. Of these participants, 30 reached diagnostic resolution (including 19 with cancer and 11 without).11 In this analysis, the other 17 positive signals were termed “discordant positive” samples and were assumed to be false-positive results).11 A minimal conservative PPV for MCED-Scr was calculated to be 40.4%.11 In addition, the Galleri test is currently being investigated in large clinical trials for a number of different populations, including women attending mammography screening (STRIVE), smokers and former smokers at high risk of lung cancer attending low-dose computed tomography screening (SUMMIT), and patients eligible for other guideline-recommended cancer screenings (PATHFINDER 2). The Galleri test was granted breakthrough designation by the US Food and Drug Administration (FDA) and is available under a waiver for high-complexity testing by the Clinical Laboratory Improvement Amendments of 1988 (CLIA).12

THUNDER Studies

The THUNDER and THUNDER II substudies are prospective, observational trials to develop and validate the ELSA-seq methylation-based MCED test of cfDNA, which speci cally targets cancers of the lung, colon/rectum, liver, ovary, pancreas, and esophagus.7,13 Similar to the CCGA study, these trials included training and validation sets.13 Reported results include a speci city of 99.5% for the training set and 98.3% for the validation set, whereas the sensitivity of the test was 79.9% and 80.6% in the training and validation sets, respectively.7,13 This assay is being examined in 2 ongoing prospective trials: the PREDICT and PRESCIENT studies.

Taizhou Longitudinal Study (TLZ) In the longitudinal TLZ study, 123,115 healthy participants provided plasma samples for long-term storage and were then monitored for cancer occurrence.14 The PanSeer DNA methylation test was used to examine cfDNA from 605 asymptomatic individuals in this group, 191 of whom received a diagnosis of stomach, esophageal, colorectal, lung, or liver cancer within 4 years of the blood draw.14 Plasma from 223 additional patients with diagnosed cancers was also assayed. In this preliminary analysis, the PanSeer test detected 88% of cancers in postdiagnosis patients with a speci city of 96%.14 Further, cancer was detected in 95% of the asymptomatic patients who later received a cancer diagnosis.14

Key Takeaways • Speci city, sensitivity, PPV, and NPV are important parameters to consider when interpreting clinical data for MCED testing • Methylation-based multi-cancer screening tests include method to evaluate genome-wide methylation patterns, targeted methylation sequences, or methylation in combination with other cfDNA analyses • Currently, the only commercially available methylation-based MCED assay is the Galleri test, which detects more than 50 cancer types, with a reported PPV of 44.6% and 96.3% accuracy for the cancer signal origin

References Hackshaw A, et al. New genomic technologies for multi-cancer early detection: rethinking the scope of cancer screening. Cancer Cell. 2022;40(2):109-113.

Trevethan R. Sensitivity, speci city, and predictive values: foundations, pliabilities, and pitfalls in research and practice. Front Public Health. 2017;5.

Liu M, et al. Plasma cell-free DNA (cfDNA) assays for early multi-cancer detection: the circulating cell-free genome atlas (CCGA) study. Ann Oncol. 2018;29(suppl 8):viii14.

Klein EA, et al. Development of a comprehensive cell-free DNA (cfDNA) assay for early detection of multiple tumor types: The Circulating Cell-free Genome Atlas (CCGA) study. J Clin Oncol. 2018;36(suppl 15):12021.

Oxnard GR, et al. LBA77 - Simultaneous multi-cancer detection and tissue of origin (TOO) localization using targeted bisul te sequencing of plasma cell-free DNA (cfDNA). Ann Oncol. 2019;30(suppl 5):912.

Liu MC, et al. Genome-wide cell-free DNA (cfDNA) methylation signatures and effect on tissue of origin (TOO) performance. J Clin Oncol. 2019; 37(15):abstract 3049.

Liu MC, et al. Sensitive and speci c multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol. 2020;31(6):745-759.

Klein EA, et al. Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol. 2021;32(9):1167-1177.

Beer TM, et al. A prespeci ed interim analysis of the PATHFINDER study: Performance of a multicancer early detection test in support of clinical implementation. J Clin Oncol. 2021;39(15 suppl):3070.

10. Nadauld LD, et al. The PATHFINDER Study: assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. Cancers (Basel). 2021;13(14):3501. 11.

Beer TM, et al. Expanding the way we screen for cancer: a path to a multicancer early detection test. J Oncol Navigation Survivorship. 2021;12(12).

12. Galleri Test website; Menlo Park, CA: Grail LLC. https://www.galleri.com/hcp. Accessed March 18, 2022. 13. Gao Q, et al. Early detection and localization of multiple cancers using a blood-based methylation assay (ELSA-seq). J Clin Oncol. 2021;39(3 suppl):459.

14. Chen X, et al. Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nat Commun. 2020;11(1):3475.

IMPLEMENTING MULTICANCER SCREENING IN PRIMARY CARE PRACTICE Multiple Cancer Early Detection in Primary Care

Liquid biopsy has emerged as a noninvasive approach to facilitate the diagnosis, treatment, and monitoring of a number of different cancers.1 In addition, the possibility of using this technology to assay circulating cell-free DNA (cfDNA) in single blood samples for known molecular signatures of multiple tumors has the potential to dramatically alter cancer screening protocols and accelerate cancer detection.2 The clinical use of liquid biopsy–based screening, however, requires comprehensive strategies to ensure optimal bene ts and minimize potential harms. In the United States, implementing appropriate cancer screening regimens—and therefore the use of novel screening technologies—is predominantly the responsibility of primary care clinicians.3 Thus, these health care providers must be up to date on available screening options, resources, and recommendations while being prepared to work with patients to interpret and act on test results.4

Integrating Multi-Cancer Screening Into Patient Care

Current screening strategies for breast, cervical, colorectal, lung, and prostate cancers are rooted in risk strati cation.4,5 When considering tests that proactively screen for multiple cancers simultaneously, determining the potential clinical utility for individual patients gets decidedly more complex.6 Moreover, while the feasibility and safety of multi-cancer early detection (MCED) tests have been demonstrated in clinical trials and analytical models, real-world evidence and population-wide data are not yet available. The potential bene ts of multi-cancer screening clearly include reduced morbidity and mortality associated with identi ed tumors, whereas potential harms comprise the consequences of false positives (eg, unnecessary follow-on diagnostic workups) or false negatives, which may delay the identi cation and treatment of a malignancy.7 As such, patient counseling prior to screening should include speci c conversations on the likelihood of false positives and false negatives, with the decision to move forward based on shared decision making with each patient (Supplementary video 5).

VIDEO 5: Talking to Patients About False Negatives and False Positives With Multi-Cancer Screening

Communication surrounding the decision to use an MCED test is especially important regarding the potential identi cation of tumors for which there are no widely recommended screening paradigms. There is currently a lack of evidence demonstrating that early identi cation of these forms of cancer in asymptomatic individuals positively affects patient outcomes.8 Guidelines, such as those from the US Preventive Services Task Force, that recommend against screening asymptomatic patients for ovarian, pancreatic, testicular, and thyroid cancers are based on previous screening approaches or population-wide data for cancers with low incidence. Statistical modeling, however, has indicated that adding MCED testing to usual screening protocols could identify nearly 500 additional cancers per year per 100,000 individuals between 50 and 79 years of age, reduce the 5-year mortality rate for the intercepted malignancies (ie, tumors identi ed at an earlier stage) by 39%, and result in an absolute reduction of 26% in all

cancer-related deaths.9 Given these predictions, it is clear that the value of multi-cancer screening must be determined on a caseby-case basis.7

To date, no MCED test has been included in national guidelines or other consensus recommendations. Further, with few exceptions, currently available tests are not covered by commercial or government-sponsored insurance plans. Therefore, when recommending a test, cost to the patient should be addressed, including potential payment options and plans (Supplementary video 6). However, changes may be on the way. The Medicare Multi-Cancer Early Detection Screening Coverage Act of 2021 is, as of April 2022, still being considered in Congress. If passed, this legislation would authorize Centers for Medicare and Medicaid Services to evaluate and cover MCED tests once they are approved by the US Food and Drug Administration.10 Moreover, the Federal government has recently relaunched the Cancer Moonshot initiative, which includes a call to action for Federal agencies (eg, the National Cancer Institute) to develop plans to quickly evaluate the utility and bene ts of MCED tests.11

VIDEO 6: Costs and Coding With Multi-Cancer Screening Tests

For now, it is up to the clinician and patient to determine whether the potential bene ts of screening outweigh the costs and potential harms, and how to best use MCED tests in practice. For example, the Galleri test can be used as supplementation to other recommended screening approaches for patients at an elevated risk of cancer, such as those aged 50 years or older, with the interval between tests based on underlying risk factors.12 Moreover, while individual testing processes may differ and evolve as more tests become available and real-world data continue to accrue, the Galleri test can be ordered by a health care provider via a test requisition form through the mail or electronically.12 One to three specimen collection kits can be shipped upon request from health care providers. Kits include two 10-mL Streck cfDNA BCT® blood collection tubes. Following the collection of whole blood, specimens must be stored between 6°C and 37°C for no more than 7 days before sending to lab for processing.12

Patient-Centered Care After a Positive Test

MCED tests are not intended to replace current cancer screening methods, but rather to be used in conjunction with those strategies. Follow-up for a test that produces a positive signal for cancer should be individualized based on data supporting the speci c test, the invasiveness of additional diagnostic evaluations, the potential ef cacy of available treatments, and other patient-speci c factors. Further workups may include laboratory tests, computerized tomography, bone scans, magnetic resonance imaging, positron emission tomography, ultrasound, Xray, or tissue biopsy. First-line procedures for diagnostic con rmation following a positive cancer signal are included in Table 4.1.2 Monitoring pathways should also be developed for people with positive MCED testing who have no radiologic or clinical evidence of cancer.

Following diagnosis, patients should be promptly seen to discuss potential preventive care, such as ensuring all vaccinations are current, fertility preservation, and any necessary lifestyle changes. Regular follow-up appointments should be scheduled as well to go over recent results, address any symptoms, answer questions, and provide other patient support. Collaboration among health care team members to deliver integrated patient-centered care can improve outcomes in patents with a number of conditions.13 Forming a multidisciplinary network with specialists, including hematologists/oncologists, can help ensure appropriate diagnoses, prompt referrals, and transfer of care. These providers can help interpret ndings from screening tests, serve as a resource to explain additional steps in follow-up evaluations, and design a personalized, data-driven treatment plan (Figure 4.1).14-16

Key Takeaways

• Establishing appropriate cancer screening regimens is an important and challenging responsibility of primary care practitioners

• MCED testing is intended to complement, not replace, current screening strategies • The choice to undergo MCED testing should be a result of shared decision making after counseling the patient on potential bene ts and consequences of testing • Optimally integrating novel cancer screening technologies into clinical practice includes the establishment of work ows surrounding testing logistics, follow-up evaluations, and transitions of care

Scroll to the next page to view a Patient Education tool or click here download a printable version. https://www.exchangecme.com/resourcePDF/mced/2022-MCEDPatientHandout.pdf

And don’t forget to access the MCED Clinical Resource Center for more information on this topic.

https://www.exchangecme.com/MCEDResources

References 1.

Pinzani P, et al. Updates on liquid biopsy: current trends and future perspectives for clinical application in solid tumors. Clin Chem Lab Med. 2021;59(7):1181-1200.

Nadauld LD, et al. The PATHFINDER Study: assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. Cancers (Basel). 2021;13(14):3501.

Wender R, Wolf AMD. Increasing cancer screening rates in primary care. Med Clin North Am. 2020;104(6):971-987.

Smith RA, Oef nger KC. The importance of cancer screening. Med Clin North Am. 2020;104(6):919-938.

Corley DA, et al. Reducing variation in the "standard of care" for cancer screening: recommendations from the PROSPR Consortium. JAMA. 2016;315(19):2067-2068.

Cisneros-Villanueva M, et al. Cell-free DNA analysis in current cancer clinical trials: a review. Br J Cancer. 2022;126(3):391-400.

Putcha G, et al. Multicancer screening: one size does not t all. JCO Precis Oncol. 2021:574-576.

Siegel RL, et al. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33.

Hubbell E, et al. Modeled reductions in late-stage cancer with a multi-cancer early detection test. Cancer Epidemiol Biomarkers Prev. 2021;30(3):460-468.

10. Prevent Cancer Foundation. Multi-cancer early detection coverage and legislation. https://www.preventcancer.org/multi-cancer-early-detection/coverage-andlegislation/. Accessed March 9, 2022. 11.

American Association for Cancer Research. Moonshot redux to focus on prevention, screening. Cancer Discov. 2022;12(4):876.

12. Galleri Test Website; Menlo Park, CA: Grail LLC. https://www.galleri.com/hcp. Accessed March 18, 2022. 13. Saint-Pierre C, et al. Multidisciplinary collaboration in primary care: a systematic review. Fam Pract. 2018;35(2):132-141. 14. Bolle S, et al. Medical decision making for older patients during multidisciplinary oncology team meetings. J Geriatr Oncol. 2019;10(1):74-83. 15. Horlait M, et al. Exploring non-physician care professionals’ roles in cancer multidisciplinary team meetings: A qualitative study. PLoS One. 2022;17(2):e0263611.

16. Soukup T, et al. Successful strategies in implementing a multidisciplinary team working in the care of patients with cancer: an overview and synthesis of the available literature. J Multidiscip Healthc. 2018;11:49-61.

CLINICAL RESOURCE CENTER™ Guidelines US Preventive Services Task Force. Published Recommendations for Cancer. A and B Recommendations www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/ uspstf-and-b-recommendations

Clinician Resources Prevent Cancer Foundation. Multi-cancer early detection coverage and legislation. https://www.preventcancer.org/multi-cancer-early-detection/coverage-andlegislation/

Surveillance, Epidemiology, and End Results (SEER) *Explorer An interactive website for SEER cancer statistics. Surveillance Research Program, National Cancer Institute, Division of Cancer Control and Population Sciences. https://seer.cancer.gov/explorer/.

Galleri Test Website Menlo Park, CA: Grail LLC. https://www.galleri.com/hcp

Suggested Readings Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Chen X, et al. Nat Commun. 2020;11(1):3475. https://www.nature.com/articles/s41467-020-17316-z.pdf

Cell-free DNA analysis in current cancer clinical trials: a review. Cisneros-Villanueva M, et al. Br J Cancer. 2022;126(3):391-400. https://www.nature.com/articles/s41416-021-01696-0.pdf

Projected reductions in absolute cancer–related deaths from diagnosing cancers before metastasis, 2006–2015. Clarke CA, et al. Cancer Epidemiol Biomarkers Prev. 2020;29(5):895-902. https://aacrjournals.org/cebp/article/29/5/895/72197/Projected-Reductions-inAbsolute-Cancer-Related

Modeled reductions in late-stage cancer with a multicancer early detection test. Hubbell E, et al. Cancer Epidemiol Biomarkers Prev. 2021;30(3):460-468. https://aacrjournals.org/cebp/article/30/3/460/72416/Modeled-Reductions-inLate-stage-Cancer-with-a

Clinical validation of a targeted methylation-based multicancer early detection test using an independent validation set. Klein EA, et al. Ann Oncol. 2021;32(9):1167-1177.

https://www.annalsofoncology.org/action/showPdf? pii=S0923-7534%2821%2902046-9

Sensitive and speci c multi-cancer detection and localization using methylation signatures in cell-free DNA. Liu MC, et al. Ann Oncol. 2020;31(6):745-759. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274402/pdf/ nihms-1712146.pdf

The PATHFINDER Study: assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. Nadauld LD, et al. Cancers (Basel). 2021;13(14):3501. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304888/pdf/ cancers-13-03501.pdf

Updates on liquid biopsy: current trends and future perspectives for clinical application in solid tumors. Pinzani P, et al. Clin Chem Lab Med. 2021;59(7):1181-1200. https://www.degruyter.com/document/doi/10.1515/cclm-2020-1685/html

Sensitivity, speci city, and predictive values: foundations, pliabilities, and pitfalls in research and practice. Trevethan R. Front Public Health. 2017;5.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701930/pdf/ fpubh-05-00307.pdf

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