Optimizing Cancer Screening With MCED Technologies: From Science to Practical Application Module 2: Clinical Evidence for MCED Testing
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Join us for Module 2 of our CME microlearning series as experts explore the transformative potential of multicancer early detection (MCED) tests. With nearly 2 million new cancer cases expected in 2024, the importance of early detection is more critical than ever. This module dives into the latest clinical trial data on MCED tests for gynecologic, gastrointestinal, and hematologic cancers, discussing how these advancements could revolutionize cancer screening and improve patient outcomes. Charles Vega, MD, is a Clinical Professor in Department of Family Medicine at the University of California (UC) Irvine. He is also Director of the UC Irvine Program in Medical Education for the Latino Community and Assistant Dean for Culture and Community Education at the UC Irvine School of Medicine. Dr. Vega specializes in Family Medicine, and his academic interests focus on access to quality medical care for underserved populations and the development of training programs to promote compassionate healthcare. He has given over 200 invited presentations at national and regional conferences, and he has authored more than 1,000 continuing medical education reviews. STATEMENT OF NEED Approximately 2 million new cancer cases are expected in the United States in 2024, with an anticipated 611,720 deaths (ACS, 2024). Screening is associated with earlier stage at diagnosis and improved outcomes (Kim et al, 2011; Plumb et al, 2016). Multicancer early detection (MCED) is an emerging form of blood-based testing that utilizes cancer biomarkers in the blood to screen for multiple cancers simultaneously (ACS, 2024). Currently, numerous clinical trials are investigating the sensitivity and specificity of MCED tests, their performance in different populations, their impact on patients, and their implementation into the clinical setting (Lennon et al, 2020; Rubinstein et al, 2024; Gao et al, 2023; Schrag et al, 2022; Lennon et al, 2023; Nicholson et al, 2023). In Module 2 of this activity, Dr. Charles Vega, Clinical Professor of Family Medicine in the School of Medicine at the University of California, Irvine, will discuss the latest clinical trial data of MCED tests in gynecologic, gastrointestinal, and hematologic cancers and the insights into the future of MCED that these trials aim to provide. TARGET AUDIENCE Oncologists, gastroenterologists, obstetrician-gynecologists, hematologists, advanced practice providers, and other healthcare providers involved in cancer screening
Optimizing Cancer Screening With MCED Technologies: From Science to Practical Application Module 2: Clinical Evidence for MCED Testing
- 1. Charles Vega, MD Clinical Professor, Family Medicine, School of Medicine Director, UC Irvine Program in Medical Education for the Latino Community (PRIME-LC) Associate Dean, School of Medicine University of California, Irvine Optimizing Cancer Screening With MCED Technologies: From Science to Practical Application Module 2: Clinical Evidence for MCED Testing
- 2. Disclosures Consultant: Boehringer Ingelheim, GlaxoSmithKline i3 Health has mitigated all relevant financial relationships
- 3. Learning Objectives MCED = multicancer early detection. Differentiate MCED tests from other blood-based screening tests Explain how MCED testing complements existing screening and diagnostic methods in gastrointestinal, gynecologic, and hematologic cancers Assess current and emerging data supporting the use of MCED tests in clinical practice Discuss tactics to promote the widespread adoption of cancer screening in the community Apply practical tools and strategies for integrating the latest cancer screening technologies into the clinical workflow
- 4. a USPSTF-recommended screening includes breast, cervical, and colorectal cancer, and 27% of lung cancer based on estimated proportion of lung cancers that occur in screen-eligible individuals older than 40 years. ACS, 2024; Pinsky & Berg, 2012. 78% 22% Deaths due to cancers with standard screeninga Deaths due to cancers without standard screeninga Cancers without screening tests account for 78% of all cancer deaths in the US (in 2024, age 50-79 years) Cancers With and Without Standard Screening
- 5. Single vs Multicancer Screening USPSTF, 2024; USPSTF, 2018. “1 test, many cancers” approach “1 test, 1 cancer” approach Low-dose CT (lung cancer) • Breast cancer • Lung cancer • Colon cancer • Prostate cancer • Cervical cancer Lymphoid neoplasm Plasma-cell neoplasm Ovarian cancer Bladder cancer Gastrointestinal cancer Liver cancer Pancreatic cancer Head and neck cancer Anorectal cancer Uterine cancer Kidney cancer Melanoma Thyroid Myeloid neoplasm Sarcoma Multiple other cancers Screened cancers Low-dose CT (lung cancer) Blood-based
- 7. Clinical Trials ESMO = European Society of Medical Oncology; PET-CT = positron emission tomography-computed tomography; GI = gastrointestinal. Clinicaltrials.gov, 2023a; Bryce et al, 2023; Klein et al, 2021; Clinicaltrials.gov, 2022b; Liu et al, 2020; Clinicaltrials.gov, 2022a; Schrag et al, 2022; Schrag et al, 2023; Clinicaltrials.gov, 2023b; Tisi et al, 2023; Lennon et al, 2023; Lennon et al, 2020; Nicholson et al, 2023. How close are liquid biopsies to the clinical setting? No MCED tests are currently approved by the FDA. SUMMIT NCT03934866 ~25,000 participants ♂♀ Additional performance in a population with no known active cancer diagnosis and clinical utility in a high-risk population PATHFINDER NCT04241796 6,622 participants ♂♀ Evaluate implementation of test in clinical practice (results published at ESMO 2022) STRIVE NCT03085888 99,481 participants ♀ Confirm performance in a population with no known active cancer diagnosis CCGA NCT02889978 15,254 participants ♂♀ Demonstrate feasibility of detecting cancer and predicting tissue of origin with minimal false positives DETECT-A 10,006 participants ♀ Demonstrate feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention SYMPLIFY 6,238 participants ♂♀ Performance in a population with symptoms potentially due to gynecological, lung, or GI cancers
- 8. a % of participants diagnosed with cancer due to MCED signal detection. NNS = number needed to screen. Schrag et al, 2022. Primary objective: time to achieve diagnostic resolution Time to achieve diagnostic resolution (confirm whether cancer is present or not): median of 79 days Diagnostic resolution achieved within 3 months for 73% Secondary objective: MCED test performance Methylation-Based MCED in Asymptomatic Adults, Interventional Test Metric Result Number Cancer signal detected 1.4% 92/6,621 Specificity 99.1% 6,253/6,290 Positive predictive value 38.0%-43.1% 35/92 Negative predictive value 98.6% 6,235/6,321 NNS to detect 1 cancer 189 6,621/35 Yielda 0.5% 35/6,621 Test not currently approved by the FDA. PATHFINDER: Results
- 9. PATHFINDER: Notes Rubinstein et al, 2024. 1/4 of participants had history of cancer 20% of cancer detected was recurrent disease 40% of cancer detected at stage I or II 57% of early cancer detected was hematologic NNS to detect 1 additional early cancer: 473 121 participants diagnosed with cancer without a positive test Methylation-Based MCED in Symptomatic Adults, Interventional
- 10. DETECT-A: The Multi-Biomarker Approach w/u = workup. Lennon et al, 2020; Cohen et al, 2018; Gainullin et al, 2024. 10,006 women between 65 and 75 years of age without cancer history Multi-biomarker approach Aneuploidy Proteins DNA methylation Mutations 26 cancers detected; 65% localized or regional Specificity: 99% Sensitivity: 27% 62% of participants with false-positive blood test had no further w/u after PET-CT 1,239 tests to detect 1 early-stage cancer Test has been modified; now in ASCEND 2 trial with 11,000 participants Multi-Biomarker MCED in a Low-Risk Group, Interventional
- 11. THUNDER: Results MCDBT = multi-cancer detection blood test. Gao et al, 2023; Burning Rock, 2023. MCDBT-1 MCED test Breakthrough device designation by FDA in 2023 Early detection of esophageal, liver, lung, ovarian, and pancreatic cancers >10,000 subjects enrolled in PREDICT and PRESCIENT studies to study other cancers Methylation-Based MCDBT-1 Case-Control Study THUNDER Test Metric Result Specificity 98.9% Sensitivity 69.1%
- 12. CCGA: Preferentially Detecting Aggressive Cancers Chen et al, 2021. Addressing overdiagnosis in screening Methylation-Based MCED Case-Control Study: Overall Survival By Stage All Stages
- 13. What Happens After a False-Positive MCED Result? PET = positron emission tomography. Lennon et al, 2023. DETECT-A cohort of 9,911 women 98 with false-positive test Negative PET and targeted workup w/o evidence of cancer at 1 year Median follow up: 4.3 years 96 women without incident cancer 1 case of stage 1 breast cancer; 1 case of stage 3 ovarian cancer
- 14. SYMPLIFY: MCED for Symptomatic Patients gyn = gynecologic; NHS = National Health Service; PPV = positive predictive value; NPV = negative predictive value. Nicholson et al, 2023. Adults with symptoms (gyn, lung, GI) presenting to NHS in UK, offered methylation-based MCED test 5,851 tested and 5,461 with results through 9 months after test Median age: 61.9 years 66.1% female Cancer diagnosis: 6.7% PPV 75.5%, NPV 97.6% Sensitivity 66.3%, specificity 98.4% Site of origin 85.2% accurate Greatest accuracy: upper GI cancer Methylation-Based MCED Observational Study
- 15. Sensitivity by Tumor Type: CCGA Study Klein et al, 2021. Cancer Class Sensitivity, Proportion of True Positives Liver/bile duct 93.5% Head and neck 85.7% Esophagus 85.0% Pancreas 83.7% Ovary 83.1% Colon/rectum 82.0% Anus 81.8% Cervix 80.0% Urothelial tract 80.0% Lung 74.8% Plasma cell neoplasm 72.3% Gallbladder 70.6% Stomach 66.7% Cancer Class Sensitivity, Proportion of True Positives Sarcoma 60.0% Lymphoma 56.3% Other 50.8% Melanoma 46.2% Lymphoid leukemia 41.2% Bladder 34.8% Breast 30.5% Uterus 28.0% Myeloid neoplasm 20.0% Kidney 18.2% Prostate 11.2% Thyroid 0.0%
- 16. Sensitivity for GI Cancers: CCGA Study Klein et al, 2021. Cancer Class Sensitivity, Proportion of True Positives Liver/bile duct 93.5% Head and neck 85.7% Esophagus 85.0% Pancreas 83.7% Ovary 83.1% Colon/rectum 82.0% Anus 81.8% Cervix 80.0% Urothelial tract 80.0% Lung 74.8% Plasma cell neoplasm 72.3% Gallbladder 70.6% Stomach 66.7% Cancer Class Sensitivity, Proportion of True Positives Sarcoma 60.0% Lymphoma 56.3% Other 50.8% Melanoma 46.2% Lymphoid leukemia 41.2% Bladder 34.8% Breast 30.5% Uterus 28.0% Myeloid neoplasm 20.0% Kidney 18.2% Prostate 11.2% Thyroid 0.0%
- 17. Sensitivity for Gynecologic Cancers: CCGA Study Klein et al, 2021. Cancer Class Sensitivity, Proportion of True Positives Liver/bile duct 93.5% Head and neck 85.7% Esophagus 85.0% Pancreas 83.7% Ovary 83.1% Colon/rectum 82.0% Anus 81.8% Cervix 80.0% Urothelial tract 80.0% Lung 74.8% Plasma cell neoplasm 72.3% Gallbladder 70.6% Stomach 66.7% Cancer Class Sensitivity, Proportion of True Positives Sarcoma 60.0% Lymphoma 56.3% Other 50.8% Melanoma 46.2% Lymphoid leukemia 41.2% Bladder 34.8% Breast 30.5% Uterus 28.0% Myeloid neoplasm 20.0% Kidney 18.2% Prostate 11.2% Thyroid 0.0%
- 18. Sensitivity for Hematologic Cancers: CCGA Study Klein et al, 2021. Cancer Class Sensitivity, Proportion of True Positives Liver/bile duct 93.5% Head and neck 85.7% Esophagus 85.0% Pancreas 83.7% Ovary 83.1% Colon/rectum 82.0% Anus 81.8% Cervix 80.0% Urothelial tract 80.0% Lung 74.8% Plasma cell neoplasm 72.3% Gallbladder 70.6% Stomach 66.7% Cancer Class Sensitivity, Proportion of True Positives Sarcoma 60.0% Lymphoma 56.3% Other 50.8% Melanoma 46.2% Lymphoid leukemia 41.2% Bladder 34.8% Breast 30.5% Uterus 28.0% Myeloid neoplasm 20.0% Kidney 18.2% Prostate 11.2% Thyroid 0.0%
- 19. Controversy Remains… What about effects on cancer-related morbidity and mortality? Is sensitivity for early cancer sufficient? Will MCEDs provide a false sense of security? Will cost-to-benefit be acceptable? What is the ideal screening interval for MCEDs?
- 20. Key Takeaways Traditional cancer screening misses most cases of cancer that cause mortality MCEDs offer opportunity to screen for over 50 types of cancer High specificity; less sensitivity but refinement is ongoing Sensitivity is variable based on type of cancer—more to come Large population-based studies are underway—need to establish screening interval/guidelines
- 21. Thank you! To learn more, check out modules 1 and 3 of this activity!
- 22. References American Cancer Society (ACS) (2024). Cancer Facts & Figures, 2024. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/2024-cancer-facts- figures.html Bryce AH, Thiel DD, Seiden MV, et al (2023). Performance of a cell-free DNA-based multi-cancer detection test in individuals presenting with symptoms suspicious for cancers. JCO Precis Oncol, 7:e2200679. DOI:10.1200/PO.22.00679 Burning Rock Dx (2023). Burning Rock received FDA breakthrough device designation for its OverC™️multi-cancer detection blood test. Available at: https://us.brbiotech.com/news/2023/burning-rock-received-fda-breakthrough-device-designation-for-its-overc-multi-cancer-detection-blood-test/ Chen X, Dong Z, Hubbell E, et al (2021). Prognostic significance of blood-based multi-cancer detection in plasma cell-free DNA. Clin Can Res, 27(15):4221-4229. DOI:10.1158/1078- 0432.ccr-21-0417 Clinicaltrials.gov (2022a). Assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. NLM identifier: NCT04241796. Clinicaltrials.gov (2022b). The STRIVE study: development of a blood test for early detection of multiple cancer types. NLM identifier: NCT03085888. Clinicaltrials.gov (2023a). The circulating cell-free genome atlas study (CCGA). NLM identifier: NCT02889978. Clinicaltrials.gov (2023b). The SUMMIT study: a cancer screening study (SUMMIT). NLM identifier: NCT03933866. Cohen JD, Li L Wang X, et al (2018). Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science, 359(6378):926-930. DOI:10.1126/science.aar3247 Gainullin V, Hwang HJ, Hogstrom L, et al (2024). Performance of a multi-analyte, multi-cancer early detection (MCED) blood test in a prospectively-collected cohort. Cancer Res, 84(suppl_7). Abstract LB100. DOI:10.1158/1538-7445.AM2024-LB100 Gao Q, Lin YP, Lin BS, et al (2023). Unintrusive multi-cancer detection by circulating cell-free DNA methylation sequencing (THUNDER): development and individual validation studies. Ann Oncol, 34(5):486-495. DOI:10.1016/j.annonc.2023.02.010 Klein EA, Richards D, Cohn A, et al (2021). Clinical validation of a targeted methylation-based multi-cancer early detection test using an independent validation set. Ann Oncol, 32(9):1167-1177. DOI:10.1016/j.annonc.2021.05.806 Lennon AM, Buchanan AH, Rego SP, et al (2023). Outcomes in participants with a false positive multi-cancer early detection (MCED) test: results from >4 years follow-up from DETECT- A, the first large, prospective interventional MCED study. J Clin Oncol, 41(suppl_16). Abstract 3039. DOI:10.1200/JCO.2023.41.16_suppl.3039
- 23. References (cont.) Lennon AM, Buchanan AH, Kinde I, et al (2020). Feasibility of blood testing combined with PET-CT to screen for cancer and guide intervention. Science, 369(6499):eabb9601. DOI:10.1126/science.abb9601 Liu MC, Oxnard GR, Klein EA, et al (2020). Sensitive and specific multi-cancer detection and localization using methylation signatures in cell-free DNA. Ann Oncol, 31(6):745-759. DOI:10.1016/j.annonc.2020.02.011 Nicholson BD, Oke J, Virdee PS (2023). Multi-cancer early detection test in symptomatic patients referred for cancer investigation in England and Wales (SYMPLIFY): a large-scale, observational cohort study. Lancet Oncol, 24(7):733-743. DOI:10.1016/S1470-2045(23)00277-2 Pinsky PF & Berg CD (2012). Applying the National Lung Screening Trial eligibility criteria to the US population: what percent of the population and of incident lung cancers would be covered? J Med Screen, 19(3):154-156. DOI:10.1258/jms.2012.012010 Rubinstein WS, Patriotis C, Dickherber A, et al (2024). Cancer screening with multicancer detection tests: a translational science review. CA Cancer J Clin, 74(4):368-382. DOI:10.3322/caac.21833 Schrag D, Beer TM, McDonnell III CH, et al (2023). Blood-based tests for multicenter early detection (PATHFINDER): a prospective cohort study. Lancet, 402(10409):1251-1260. DOI:10.1016/S0140-6736(23)01700-2 Schrag D, McDonnell III CH, Nadauld L, et al (2022). A prospective study of a multi-center early detection blood test. Ann Oncol, 33(suppl_7):S417-S426. DOI:10.1016/annonc/annonc1061 Tisi S, Creamer AW, Dickson J, et al (2023).Prevalence and clinical characteristics of non-malignant CT detected incidental findings in the SUMMIT lung cancer screening cohort. BMJ Open Respir Res, 10(1):e001664. DOI:10.1136/bmjresp-2023-001664 US Preventive Services Task Force (2018). Prostate cancer: screening. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/prostate-cancer-screening US Preventive Services Task Force (2024). A & B Recommendations. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation-topics/uspstf-a-and-b- recommendations#bcf
Editor's Notes
- #8: New ESMO slide