Optimizing Cancer Screening With MCED Technologies: From Science to Practical Application - Module 1 - Science Behind Cancer Screening
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Dive into the world of multicancer early detection (MCED) in this exclusive three-module microlearning series. In Module 1, explore the scientific foundations of blood-based cancer screening, including current challenges and the exciting potential of MCED technologies. Learn how these innovative tests use biomarkers to detect multiple cancers through a single, convenient screening, breaking down barriers like low awareness and limited access to screening facilities. 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). However, cancers that are not routinely screened for account for 78% of all cancer deaths in the United States, and even among cancers that do have standard tests, factors such as low awareness, lack of available facilities, and inconvenience often impede screening (ACS, 2024; Pinsky & Berg, 2012; USPSTF, 2024; Chien et al, 2020; Siegel et al, 2019). Multicancer early detection (MCED) is a novel form of blood-based testing that utilizes cancer biomarkers in the blood to detect multiple types of cancer in 1 test (ACS, 2024). In Module 1 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 scientific basis for existing and emerging blood-based cancer screening tests, the current gaps in cancer screening, and how MCED tests can help fill this gap. 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 1 - Science Behind Cancer Screening
- 1. Optimizing Cancer Screening With MCED Technologies: From Science to Practical Application 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 Module 1: Science Behind Cancer Screening
- 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. 2024 American Cancer Society (ACS) Facts and Figures ACS, 2024. ~2.0 million new cancer cases are expected in the United States in 2024 Excludes basal cell and squamous cell skin cancer (reporting not required) ~611,720 deaths from cancer are expected in the US in 2024 = 1,680 deaths/day Cancer is the second most common cause of death in the US (#1: heart disease) ~42/100 men and ~40/100 women in the US will develop cancer in their lifetime 5-year overall cancer survival Today: 69% White; 65% Black 1960s: 39% White; 27% Black
- 5. Death by Cancer Subtype in the United States ACS, 2024. Estimated Deaths, 2024 Males Females Lung and Bronchus 65,790 20% Prostate 35,250 11% Colon and rectum 28,700 9% Pancreas 27,270 8% Liver and intrahepatic bile duct 19,120 6% Leukemia 13,640 4% Esophagus 12,880 4% Urinary bladder 12,290 4% Non-Hodgkin lymphoma 11,780 4% Brain and other nervous system 10,690 3% All sites 322,800 100% Lung and Bronchus 59,280 21% Breast 42,250 15% Pancreas 24,480 8% Colon and rectum 24,310 8% Uterine corpus 13,250 4% Ovary 12,740 4% Liver and intrahepatic bile duct 10,720 4% Leukemia 10,030 3% Non-Hodgkin lymphoma 8,360 3% Brain and other nervous system 8,070 3% All sites 288,920 100%
- 6. Unmet Needs in Cancer Screening Pinsky & Berg, 2012; Pham et al, 2018. Example: lung cancer screening 70% of lung cancers occur in people who do not qualify for lung cancer screening Among the patients who do qualify, 1.9% are getting screened in the US Centers for Medicare & Medicaid Services (CMS) created the Lung Cancer Screening Registry of low-dose computed tomography (LDCT) screens in 2016 ~7.6 million eligible smokers/former smokers Only 141,260 LDCT screens were performed across 1,796 accredited centers in 2016
- 7. Unmet Needs in Cancer Screening (cont.) Chien et al, 2020; Siegel et al, 2019. Even among cancers that we do screen for, many people are not receiving screenings Inconvenience, missing work Discomfort Lack of awareness Fear of radiation exposure Lack of nearby radiology facility Oversight by medical team
- 8. USPSTF Recommendations for Cancer Screening USPSTF = United States Preventive Services Task Force. USPSTF, 2024; CMS, 2015; CMS, 2023; Congress.gov, 1997; USPSTF, 2018; CMS, 2022. Cancer Grade Population Modality/ Recommendation Pathway and Outcome Cervical A Women aged 21-65 years Regular screening (3-5 years) using cervical cytology and/or human papillomavirus (HPV) tests HPV testing: USPSTF Centers for → Medicare & Medicaid Services (CMS) National Coverage Determination (NCD) Colon A/B Adults aged 45-75 years Regular annual screening, multiple effective methods available Legislation CMS NCD → Also has USPSTF “A” rating Breast B Women aged 40-74 years Biennial screening mammography Mandate for coverage with no cost sharing (Balanced Budget Act of 1997, Section 4101) Lung B Adults aged 50-80 years, with a history of smoking Annual LDCT screening USPSTF CMS NCD → Prostate C Men aged 55-69 years Periodic prostate-specific antigen screening on a case-by-case basis Not applicable (N/A)
- 9. SEER, 2024. Local vs Metastatic Breast Cervical Colon Esophagus Liver Lung M elanom a M yelom a O vary Pancreas Prostate Thyroid U terus -20.00% 0.00% 20.00% 40.00% 60.00% 80.00% 100.00% Localized Metastatic Survival % 5-Year Overall Survival by Cancer Type
- 10. 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
- 11. Screening Improves Outcomes Kim et al, 2011; Plumb et al, 2016. Screening is associated with earlier stage at diagnosis and improved outcomes
- 13. 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
- 14. The Power of Aggregate Prevalence Ahlquist, 2018. Number needed to screen (NNS) to detect 1 cancer Among gastrointestinal (GI) cancers, only colorectal cancer (CRC) is considered prevalent enough for population screening NNS = 167 for colorectal cancer NNS = 500 for pancreatic cancer NNS = 1,000 for esophageal cancer NNS for all GI cancers = 83 NNS for all cancers = 33
- 15. The Power of Aggregate Prevalence (cont.) Ahlquist, 2018. Positive predictive value (PPV) PPV = given a positive test, what is the probability of actually having cancer? Determined by specificity and prevalence Aggregate prevalence rates of all cancers vs single-organ screening means a much higher PPV is achievable
- 16. The Power of Aggregate Prevalence for Selected Cancers Ahlquist, 2018. PPV (%) Prevalence (%) Specificity 99% 97% 95% Esophagus Stomach 0 20 40 60 80 0 1 2 3 NNS Prevalence (%) Esophagus (1,000) Stomach (833) Liver (588) Pancreas (500) Colorectal (167) Pan-GI (83) Universal (33) 0 200 400 600 800 1,000 0 1 2 3 Colorectal Pan-Gl Liver Pancreas Universal
- 17. Cumulative False-Positive Rate From Single-Cancer Screening Pinsky et al, 2015; Melnikow et al, 2018; US FDA, 2013; Lehman et al, 2017. Each false positive requires follow-up tests or interventions Cumulative risks are not well understood at the population level because current paradigms only evaluate 1 cancer at a time A 60-year-old female with a history of smoking screened for 4 cancers would have a 43.6% false-positive rate (FPR) 12.8% FPR for low-dose computed tomography 7.4% FPR for cervical screening 13.4% FPR for stool-based colon cancer screening 10.0% FPR for mammography
- 18. Origins and Alterations in Circulating Tumor DNA (ctDNA) Wan et al, 2017. /indels Gains/losses of chromosomal regions Gene fusions and breakpoints Epigenetic changes Viral DNA Point mutations, insertions, and deletions Secretion Necrosis Apoptosis Apoptotic bodies DNA mutations Copy number alterations Rearrangements Methylation changes Exosomal DNA
- 19. Blood-Based Screening PCR = polymerase chain reaction. Gao et al, 2023; Bryce et al, 2023; Clinicaltrials.gov, 2022b; Schrag et al, 2023; Clinicaltrials.gov, 2023b; Nicholson et al, 2023; Gainullin et al, 2024; Putcha et al, 2022; Guardantcomplete.com; Foundationmedicine.com; Cellsearchctc.com; Natera.com; Invitae.com. Test Technology Trial(s) Multicancer early detection and localization of cancers in the colorectum, esophagus, liver, lung, ovary, and pancreas Cell-free DNA (cfDNA) methylation-based technology THUNDER Multicancer early detection and localization test for 50+ types of cancer cfDNA methylation-based technology CCGA, STRIVE, PATHFINDER, SUMMIT, SYMPLIFY Multicancer early detection cfDNA methylation and protein-based technology ASCEND 2 Early detection of colorectal cancer Multiomic technology PREEMPT CRC Liquid biopsy for detection of solid tumor biomarkers from cell-free DNA Next-generation sequencing to detect alterations in 74 genes using circulating tumor DNA (ctDNA) - Liquid biopsy with comprehensive genomic profiling of solid tumor biomarkers from cfDNA Next-generation sequencing to detect alterations in 311 genes using ctDNA - Circulating tumor cell count to predict tumor response and survival in patients with metastatic solid tumors Circulating tumor cell count - Minimal residual disease and recurrence detection for solid tumors cfDNA sequencing by PCR based on a previously acquired molecular signature - Genetic testing for hereditary cancer risk Sequencing of 48 genes for changes linked to hereditary cancer - No MCED screening test is approved by the FDA.
- 20. Methylation Biology Dor & Cedar, 2018. Each cell type in the body has a unique pattern of methylation (fingerprint) Methylation-based technology can generate a tissue of origin DNA Methyl Methyl Methyl Methyl Methyl Methyl Methyl
- 21. Circulating Tumor Nucleic Acids Crowley et al, 2013; Elazezy & Joosse, 2018. Origins of cell-free DNA (cfDNA) Apoptosis Necrosis Phagocytosis Active secretion cfDNA is enclosed in vesicles Protects from degradation Prevents activation of immune system Half-life 0.5 to 2.5 hours cfDNA is cleared from blood Via nuclease digestion Renal excretion (urine)
- 22. Workup of Positive Blood-Based Screen With Cancer Signal Origin CT = computed tomography. Slide courtesy of Sana Raoof, MD, PhD. CRC Blood work + whole-body CT Lung Breast Liver Head and neck Ovarian Esophageal Gastric Multiple myeloma Lymphoma Indeterminate Endoscopy Pancreatic Imaging Blood work and physical exam Biopsy Imaging Treat
- 23. Key Takeaways There’s a 40% lifetime risk of cancer in US adults—major cause of morbidity and mortality Current screening is available for 5 types of cancer, but 78% of cancer deaths are due to cancer without screening recommendations Blood-based testing is able to detect over 50 types of cancer with a single test Different mechanisms of blood-based testing are being studied Tests are commercially available
- 24. Thank you! To learn more, check out modules 2 and 3 of this activity!
- 25. References Ahlquist DA (2018). Universal cancer screening: revolutionary, rational, and realizable. npj Precision Oncology, 2:23. DOI:10.1038/s41698-018-0066-x 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 Cellsearchctc.com (2024). How does the CellSearch® System work? Available at: https://www.cellsearchctc.com/about-cellsearch/how-cellsearch-ctc-test-works Centers for Medicare & Medicaid Services National Coverage Determination (2015). National Coverage Determination: screening for cervical cancer with human papillomavirus (HPV). Available at: https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=365 Centers for Medicare & Medicaid Services National Coverage Determination (2022). National Coverage Determination: lung cancer screening with low dose computed tomography (LDCT). Available at: https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=364 Centers for Medicare & Medicaid Services National Coverage Determination (2023). National Coverage Determination: Colorectal Cancer Screening Tests. Available at:https://www.cms.gov/medicare-coverage-database/view/ncd.aspx?NCDId=281 Chien SY, Chuang MC & Chen IP (2020). Why people do not attend health screenings: factors that influence willingness to participate in health screening for chronic diseases. Int J Environ Res Public Health, 17(10):3495. DOI:10.3390/ijerph17103495 Clinicaltrials.gov (2022b). The STRIVE study: development of a blood test for early detection of multiple cancer types. NLM identifier: NCT03085888. Clinicaltrials.gov (2023b). The SUMMIT study: a cancer screening study (SUMMIT). NLM identifier: NCT03933866. Congress.gov (1997). H.R.2015 – balanced budget act of 1997. Available at: https://www.congress.gov/bill/105th-congress/house-bill/2015 Crowley E, Nicolantonio FD, Loupakis F & Bardelli A (2013). Liquid biopsy: monitoring cancer-genetics in the blood. Nature Reviews Clinical Oncology, 10:472-484. DOI:10.1038/nrclinonc.2013.110 Dor Y & Cedar H (2018). Principles of DNA methylation and their implications for biology and medicine. Lancet, 392(10149):777-786. DOI:10.1016/S0140-6736(18)31268-6
- 26. References (cont.) Elazezy M & Joosse SA (2018). Techniques of using circulating tumor DNA as a liquid biopsy component in cancer management. Comput Struct Biotechnol J, 16:370-378. DOI:10.1016/j.csbj.2018.10.002 Foundationmedicine.com (2024). FoundationOne® Liquid CDx. Available at: https://www.foundationmedicine.com/test/foundationone-liquid-cdx 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 Guardantcomplete.com (2024). Guardant360® CDx. Available at: guardantcomplete.com/products/guardant360-cdx Invitae.com (2024). Invitae common hereditary cancers panel. Available at: https://invitae.com/us/providers/test-catalog/test-01102 Kim J, Lee SK, Kim S, et al (2011). Clinicopathologic and prognostic difference of screen detected breast cancer compared with symptomatic breast cancer. Cancer Res, 71(suppl_24). Abstract P5-14-02. DOI:10.1158/0008-5472.SABCS11-P5-14-02 Lehman CD, Arao RF, Sprague BL, et al (2017). National performance benchmarks for modern screening digital mammography: update from the Breast Cancer Surveillance Consortium. Radiology, 283(1):49-58. DOI:10.1148/radiol.2016161174 Melnikow J, Henderson JT, Burda BU, et al (2018). Screening for cervical cancer with high-risk human papillomavirus testing. JAMA, 320(7):687-705. DOI:10.1001/jama.2018.10400 Natera.com (2024). Signatera™️ . Available at: natera.com/oncology/signatera-advanced-cancer detection Nicholson BD, Oke J, Virdee PS, et al (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 Pham D, Bhandari S, Oechsli M, et al (2018). Lung cancer screening rates: data from the lung cancer screening registry. J Clin Oncol, 36(suppl_15). Abstract 6504.DOI:10.1200/JCO.2018.36.15_suppl.6504 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 Pinsky PF, Gierada DS, Black W, et al (2015). Performance of Lung-RADS in the National Lung Screening Trial: a retrospective assessment. Ann Intern Med, 162(7):485-491. DOI:10.7326/M14-2086
- 27. References (cont.) Plumb AA, Ghanouni A, Rees CJ, et al (2017). Patient experience of CT colonography and colonoscopy after fecal occult blood test in a national screening programme. Eur Radiol, 27(3): 1052-1063. DOI:10.1007/s00330-016-4428-x Putcha G, Xu C, Shaukat A & Levin T (2023). Prevention of colorectal cancer through multiomics blood testing: the PREEMPT CRC study. J Clin Oncol, 40(suppl_4). Abstract TPS208. DOI:10.1200/JCO.2022.40.4_suppl.TPS208 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 Siegel RL, Miller KD & Jemal A (2019). Cancer Statistics, 2019. CA Cancer J Clin, 69(1):7-34. DOI:10.3322/caac.21551 Surveillance, Epidemiology, and End Results Program (2024). Cancer Stat Facts. Available at: seer.cancer.gov/statfacts US Food & Drug Administration (2013). Premarket approval (PMA) Cologuard. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P130017 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 Wan JCM, Massie C, Garcia-Corbacho J, et al (2017). Liquid biopsies come of age: towards implementation of circulating tumor DNA. Nat Rev Cancer, 17:223-238. DOI:10.1038/nrc.2017.7
Editor's Notes
- #7: 65.5% lack screening if you include PSA, which is grade C.