1932

Abstract

The new generation of cancer early detection tests holds remarkable promise for revolutionizing and changing the paradigm of cancer early detection. Dozens of cancer early detection tests are being developed and evaluated. Some are already commercialized and available for use, most as a complement to and not in place of existing recommended cancer screening tests. This review evaluates existing single- and multi-cancer early detection tests (MCEDs), discussing their performance characteristics including sensitivity, specificity, positive and negative predictive values, and accuracy. It also critically looks at the potential harms that could result from these tests, including false positive and negative results, the risk of overdiagnosis and overtreatment, psychological and economic harms, and the risk of widening cancer inequities. We also review the large-scale, population-based studies that are being launched in the United States and United Kingdom to determine the impact of MCEDs on clinically relevant outcomes and implications for current practice.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-med-050522-033624
2024-01-29
2024-04-16
Loading full text...

Full text loading...

/deliver/fulltext/med/75/1/annurev-med-050522-033624.html?itemId=/content/journals/10.1146/annurev-med-050522-033624&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    American Cancer Society 2023. Cancer Facts & Figures 2023 Atlanta, GA: Am. Cancer Soc.
  2. 2.
    NORC 2023. Percent of cancers detected by screening: all cancer, all ages. Cancer Detection Tool NORC Chicago, IL.: https://cancerdetection.norc.org/. Accessed Aug. 12, 2023
    [Google Scholar]
  3. 3.
    Sabatino SA, Thompson TD, White MC et al. 2021. Cancer screening test receipt—United States, 2018. Morb. Mortal. Wkly. Rep. 70:2935
    [Google Scholar]
  4. 4.
    Hubbard RA, Kerlikowske K, Flowers CI et al. 2011. Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study. Ann. Intern. Med. 155:48192
    [Google Scholar]
  5. 5.
    Ibáñez-Sanz G, Garcia M, Milà N et al. 2019. Adverse Effects on Colorectal Cancer Screening in Catalonia (EACC) Study Working Group. False-positive results in a population-based colorectal screening program: cumulative risk from 2000 to 2017 with biennial screening. Cancer Epidemiol. Biomarkers Prev. 28:190916
    [Google Scholar]
  6. 6.
    Petitti DB, Lin JS, Burda BU. 2018. Overdiagnosis in prostate cancer screening decision models: a contextual review for the US Preventive Services Task Force AHRQ Publ. No. 17-05229-EF-3 Agency Healthc. Res. Qual. North Bethesda, MD:
  7. 7.
    Toft EL, Kaae SE, Malmqvist J, Brodersen J. 2019. Psychosocial consequences of receiving false-positive colorectal cancer screening results: a qualitative study. Scand. J. Prim. Health Care 37:14554
    [Google Scholar]
  8. 8.
    Lafata JE, Simpkins J, Lamerato L et al. 2004. The economic impact of false-positive cancer screens. Cancer Epidemiol. Biomarkers Prev. 13:212632
    [Google Scholar]
  9. 9.
    Black WC. 2009. Overdiagnosis: an underrecognized cause of confusion and harm in cancer screening. J. Natl. Cancer Inst. 92:128082
    [Google Scholar]
  10. 10.
    Srivastava S, Koay EJ, Borowsky AD et al. 2019. Cancer overdiagnosis: a biological challenge and clinical dilemma. Nat. Rev. Cancer 19:34958
    [Google Scholar]
  11. 11.
    Kim SY, Kim HS, Park HJ. 2019. Adverse events related to colonoscopy: global trends and future challenges. World J. Gastroenterol. 25:190204
    [Google Scholar]
  12. 12.
    Dasari A, Grothey A, Kopetz S. 2018. Circulating tumor DNA-defined minimal residual disease in solid tumors: opportunities to accelerate the development of adjuvant therapies. J. Clin. Oncol. 36:343740
    [Google Scholar]
  13. 13.
    Pantel K, Alix-Panabieres C. 2019. Liquid biopsy and minimal residual disease—latest advances and implications for cure. Nat. Rev. Clin. Oncol. 16:40924
    [Google Scholar]
  14. 14.
    Dinan MA, Curtis LH, Hammill BG et al. 2010. Changes in the use and costs of diagnostic imaging among Medicare beneficiaries with cancer 1999–2006. JAMA 303:162531
    [Google Scholar]
  15. 15.
    Vlahiotis A, Griffin B, Stavros AT, Margolis J. 2018. Analysis of utilization patterns and associated costs of the breast imaging and diagnostic procedures after screening mammography. Clinicoeconom. Outcomes Res. 10:15767
    [Google Scholar]
  16. 16.
    Johnson DA, Barclay RL, Mergener K et al. 2014. Plasma Septin9 versus fecal immunochemical testing for colorectal cancer screening: a prospective multicenter study. PLOS ONE 9:e98238
    [Google Scholar]
  17. 17.
    Church TR, Wandell M, Lofton-Day C et al. 2014. PRESEPT Clinical Study Steering Committee, investigators and study team. Prospective evaluation of methylated SEPT9 in plasma for detection of asymptomatic colorectal cancer. Gut 63:31725
    [Google Scholar]
  18. 18.
    CMS 2021. Screening for colorectal cancer—blood-based biomarker tests Decision memo CAG-00454N Cent. Medicare Medicaid Serv. Baltimore, MD:
  19. 19.
    Lamb YN, Dhillon S. 2017. Epi proColon® 2.0 CE: a blood-based screening test for colorectal cancer. Mol. Diagn. Ther. 21:22532
    [Google Scholar]
  20. 20.
    Imperiale TF, Ransohoff DF, Itzkowitz SH et al. 2014. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 370:128797
    [Google Scholar]
  21. 21.
    US Prev. Serv. Task Force 2021. Screening for colorectal cancer: US Preventive Services Task Force recommendation statement. JAMA 325:196577
    [Google Scholar]
  22. 22.
    Wolf AMD, Fontham ETH, Church TR et al. 2018. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J. Clin. 68:25081
    [Google Scholar]
  23. 23.
    Valouev A, Zotenko E, Snyder M et al. 2022. Development of a highly sensitive multicancer, targeted, cell-free DNA epigenomic assay for integrated screening of lung and colorectal cancer. J. Clin. Oncol. 40:3542 Abstr.)
    [Google Scholar]
  24. 24.
    Jeeyun L, Kim HC, Kim ST et al. 2021. Multimodal circulating tumor DNA (ctDNA) colorectal neoplasia detection assay for asymptomatic and early-stage colorectal cancer (CRC). J. Clin. Oncol. 39:3536 (Abstr.)
    [Google Scholar]
  25. 25.
    D'Auria K, Chang Y, Multhaup M et al. 2022. Validation of a multi-modal blood-based test for the detection of colorectal cancer with sub single molecule sensitivity. J. Clin. Oncol. 40:3627 Abstr.)
    [Google Scholar]
  26. 26.
    Kim S-T, Raymond VM, Park JO et al. 2019. Combined genomic and epigenomic assessment of cell-free circulating tumor DNA (ctDNA) improves assay sensitivity in early-stage colorectal cancer (CRC). Cancer Res 79:916 Abstr.)
    [Google Scholar]
  27. 27.
    Westesson O, Axelrod H, Dean J et al. 2020. Integrated genomic and epigenomic cell-free DNA (cfDNA) analysis for the detection of early-stage colorectal cancer. Cancer Res 80:2316 Abstr.)
    [Google Scholar]
  28. 28.
    Guardant Health 2022. Guardant Health announces positive results from pivotal ECLIPSE study evaluating a blood test for the detection of colorectal cancer Press Release, Dec. 15 Guardant Health Palo Alto, CA: https://investors.guardanthealth.com/press-releases/press-releases/2022/Guardant-Health-announces-positive-results-from-pivotal-ECLIPSE-study-evaluating-a-blood-test-for-the-detection-of-colorectal-cancer/default.aspx
  29. 29.
    Chung D, Gray DM, Greenson J et al. 2023. Clinical validation of cell free DNA blood-based test for colorectal cancer screening in an average risk population. Gastroenterology 164:6 Suppl.S1573
    [Google Scholar]
  30. 30.
    Han YD, Oh TJ, Chung T-H et al. 2019. Early detection of colorectal cancer based on presence of methylated syndecan-2 (SDC2) in stool DNA. Clin. Epigenet. 11:51
    [Google Scholar]
  31. 31.
    Kim CW, Kim H, Kim HR et al. 2021. Colorectal cancer screening using a stool DNA-based SDC2 methylation test: a multicenter, prospective trial. BMC Gastroenterol 21:173
    [Google Scholar]
  32. 32.
    Crook T, Leonard R, Mokbel K et al. 2022. Accurate screening for early-stage breast cancer by detection and profiling of circulating tumor cells. Cancers 14:3341
    [Google Scholar]
  33. 33.
    O'Neill K, Syed N, Crook T et al. 2023. Profiling of circulating glial cells allows accurate blood-based diagnosis of glial malignancies. medRxiv 2022.07.06.22277300
  34. 34.
    Limaye S, Chowdhury S, Rohatgi N et al. 2023. Accurate prostate cancer detection based on enrichment and characterization of prostate cancer specific circulating tumor cells. Cancer Med 12:911627
    [Google Scholar]
  35. 35.
    Hudnut AG, Hubbell E, Venn O, Church TR. 2023. Modeled residual current cancer risk after clinical investigation of a positive multi-cancer early detection test result. Cancer 129:205663
    [Google Scholar]
  36. 36.
    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. 31:74559
    [Google Scholar]
  37. 37.
    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:eabb9601
    [Google Scholar]
  38. 38.
    Chen X, Gole J, Gore A et al. 2020. Non-invasive early detection of cancer four years before conventional diagnosis using a blood test. Nat. Commun. 11:3475
    [Google Scholar]
  39. 39.
    Wang HY, Chen CH, Shi S et al. 2020. Improving multi-tumor biomarker health check-up tests with machine learning algorithms. Cancers 12:1442
    [Google Scholar]
  40. 40.
    Akolkar D, Patil D, Crook T et al. 2020. Circulating ensembles of tumor-associated cells: a redoubtable new systemic hallmark of cancer. Int. J. Cancer 146:348594
    [Google Scholar]
  41. 41.
    Gaya A, Crook T, Plowman N et al. 2021. Evaluation of circulating tumor cell clusters for pan-cancer noninvasive diagnostic triaging. Cancer Cytopathol 129:22638
    [Google Scholar]
  42. 42.
    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. 32:116777
    [Google Scholar]
  43. 43.
    Chen X, Dong Z, Hubbell E et al. 2021. Prognostic significance of blood-based multi-cancer detection in plasma cell-free DNA. Clin. Cancer Res. 27:422129
    [Google Scholar]
  44. 44.
    Nadauld LD, McDonnell CH 3rd, Beer TM et al. 2021. The PATHFINDER study: assessment of the implementation of an investigational multi-cancer early detection test into clinical practice. Cancers 13:3501
    [Google Scholar]
  45. 45.
    GRAIL 2022. GRAIL announces final results from the PATHFINDER multi-cancer early detection screening study at ESMO Congress 2022 News Release, Sept. 11 GRAIL Menlo Park, CA:
  46. 46.
    Schrag D, McDonnell CH III, Nadauld L et al. 2022. A prospective study of a multi-cancer early detection blood test (Abstract 9030). Ann. Oncol. 33:S961
    [Google Scholar]
  47. 47.
    Lee JM, Ichikawa L, Valencia E et al. 2017. Performance benchmarks for screening breast MR imaging in community practice. Radiology 285:4452
    [Google Scholar]
  48. 48.
    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. 19:15456
    [Google Scholar]
  49. 49.
    FDA 2014. Premarket approval (PMA): Cologuard summary of safety and effectiveness data Premarket Approval Applic. No. P130017, US Food Drug Adm. US Dep. Health Hum. Serv. Silver Spring, MD:
    [Google Scholar]
  50. 50.
    Cohen JD, Li L, Wang Y et al. 2018. Detection and localization of surgically resectable cancers with a multi-analyte blood test. Science 359:92630
    [Google Scholar]
  51. 51.
    Grubb RL 3rd, Pinsky PF, Greenlee RT et al. 2008. Prostate cancer screening in the Prostate, Lung, Colorectal and Ovarian cancer screening trial: update on findings from the initial four rounds of screening in a randomized trial. BJU Int. 102:152430
    [Google Scholar]
  52. 52.
    Natl. Lung Screening Trial Res. Team, Aberle DR, Adams AM, Berg CD et al. 2011. Reduced lung-cancer mortality with low-dose computed tomographic screening. N. Engl. J. Med. 365:395409
    [Google Scholar]
  53. 53.
    Croswell JM, Kramer BS, Kreimer AR et al. 2009. Cumulative incidence of false-positive results in repeated, multimodal cancer screening. Ann. Fam. Med. 7:21222
    [Google Scholar]
  54. 54.
    Bettegowda C, Sausen M, Leary RJ et al. 2014. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci. Transl. Med. 224:224ra24
    [Google Scholar]
  55. 55.
    Liles EG, Coronado GD, Perrin N et al. 2017. Uptake of a colorectal cancer screening blood test is higher than of a fecal test offered in clinic: a randomized trial. Cancer Treat. Res. Commun. 10:2731
    [Google Scholar]
  56. 56.
    Clarke CA, Hubbell E, Kurian AW et al. 2020. Projected reductions in absolute cancer-related deaths from diagnosing cancers before metastasis, 2006–2015. Cancer Epidemiol. Biomarkers Prev. 29:895902
    [Google Scholar]
  57. 57.
    Schrag D, McDonnell CH III, Nadauld L et al. 2022. PATHFINDER: a prospective study of a multi-cancer early detection blood test Paper presented at ESMO Congress, Sep. 11 Paris: https://grail.com/wp-content/uploads/2022/09/Schrag_903O_ESMO-2022_Pathfinder-Main_Proferred-Paper-Oral-Presentation.pdf
  58. 58.
    Schrag D, Beer TM, McDonnell CH III et al. 2022. Evaluation of anxiety, distress and satisfaction with a multi-cancer early detection test. Ann. Oncol. 33:241726
    [Google Scholar]
  59. 59.
    Tafazzoli A, Ramsey SD, Shaul A et al. 2022. The potential value-based price of a multi-cancer early detection genomic blood test to complement current single cancer screening in the USA. PharmacoEconomics 40:110717
    [Google Scholar]
  60. 60.
    Swanton C, Neal RD, Johnson PWM et al. 2022. NHS-Galleri trial design: equitable study recruitment tactics for targeted population-level screening with a multi-cancer early detection (MCED) test. J. Clin. Oncol. 40:TPS6606-TPS
    [Google Scholar]
  61. 61.
    Am. Soc. Clin. Oncol. Assoc. Comm. Cancer Cent 2023. ASCO-ACCC initiative to increase racial & ethnic diversity in clinical trials. ASCO. https://old-prod.asco.org/news-initiatives/current-initiatives/cancer-care-initiatives/diversity-cancer-clinical-trials
    [Google Scholar]
  62. 62.
    Exact Sciences 2023. Cologuard offers comprehensive support designed with your practice and patients in mind. Cologuard https://www.cologuardhcp.com/coverage-and-support/specialized-support
    [Google Scholar]
  63. 63.
    Kaiser J. 2022. ‘The complexities are staggering.’ U.S. plans huge trial of blood tests for multiple cancers: National Cancer Institute prevention chief discusses steps toward largest U.S. cancer screening trial ever. Science June 22. https://www.science.org/content/article/complexities-are-staggering-u-s-plans-huge-trial-blood-tests-multiple-cancers
    [Google Scholar]
  64. 64.
    Natl. Cancer Inst. Div. Cancer Prev 2023. Multi-Cancer Detection (MCD) Research https://prevention.cancer.gov/major-programs/multi-cancer-detection-mcd-research
  65. 65.
    Neal RD, Johnson P, Clarke CA et al. 2022. Cell-free DNA–based multi-cancer early detection test in an asymptomatic screening population (NHS-Galleri): design of a pragmatic, prospective randomised controlled trial.. Cancers 14:4818
    [Google Scholar]
  66. 66.
    Owens L, Gulati R, Etzioni R. 2022. Stage shift as an endpoint in cancer screening trials: implications for evaluating multicancer early detection tests. Cancer Epidemiol. Biomarkers Prev. 31:1298304
    [Google Scholar]
  67. 67.
    Davis KV, Hallman MH, DiCarlo M et al. 2022. Factors likely to affect the uptake of genomic approaches to cancer screening in primary care: a scoping review. J. Pers. Med. 12:2044
    [Google Scholar]
  68. 68.
    Assoc. Comm. Cancer Cent 2023. Exploring current perceptions of multi-cancer early detection testing among healthcare providers. Oncol. Issues 38:6670
    [Google Scholar]
  69. 69.
    Ueberroth BE, Marks LA, Borad MJ, Agrwal N. 2022. Multicancer early detection panels (MCEDs) in the primary care setting. Am. J. Med. 135:e14549
    [Google Scholar]
  70. 70.
    Selby K, Elwyn G, Volk RJ. 2023. Multi-cancer early detection tests, primary care, and shared decision making. Ann. Intern. Med. 176:71820
    [Google Scholar]
  71. 71.
    Kessler L, Le Beau MM, Smith RA et al. 2023. The modeling of multicancer early detection (MCED) tests’ residual risk and the challenges of MCED evaluation and implementation. Cancer 129:196668
    [Google Scholar]
/content/journals/10.1146/annurev-med-050522-033624
Loading
/content/journals/10.1146/annurev-med-050522-033624
Loading

Data & Media loading...

Supplemental Material

Supplementary Data

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error