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Understanding the Clinical Implications of Low Penetrant Genes and Breast Cancer Risk

  • Breast Cancer (WJ Gradishar, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion statement

Since the 2013 Supreme Court declaration, panel testing for hereditary cancer syndromes has evolved into the gold standard for oncology germline genetic testing. With the advent of next-generation sequencing, competitive pricing, and developing therapeutic options, panel testing is now well integrated into breast cancer management and surveillance. Although many established syndromes have well-defined cancer risks and management strategies, several breast cancer genes are currently classified as limited-evidence genes by the National Comprehensive Cancer Network (NCCN). Follow-up for individuals with mutations in these genes is a point of contention due to conflicting information in the literature. The most recent NCCN guidelines have stratified management based on gene-specific cancer risks indicating that expanding data will allow for better recommendations as research progresses. The evolving management for these genes emphasizes the clinicians’ need for evidence-based understanding of low penetrance breast cancer genes and their implications for patient care. This article reviews current literature for limited evidence genes, detailing cancer risks, association with triple-negative breast cancer, and recommendations for surveillance. A brief review of the challenges and future directions is outlined to discuss the evolving nature of cancer genetics and the exciting opportunities that can impact management.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Easton DF, Pharoah PD, Antoniou AC, Tischkowitz M, Tavtigian SV, Nathanson KL, et al. Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med. 2015;372(23):2243–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Karam R, Conner B, LaDuca H, McGoldrick K, Krempely K, Richardson ME, et al. Assessment of Diagnostic Outcomes of RNA Genetic Testing for Hereditary Cancer. JAMA Netw Open. 2019;2(10):e1913900.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jorge S, McFaddin AS, Doll KM, Pennington KP, Norquist BM, Bennett RL, et al. Simultaneous germline and somatic sequencing in ovarian carcinoma: mutation rate and impact on clinical decision-making. Gynecol Oncol. 2020;156(3):517–22.

    Article  CAS  PubMed  Google Scholar 

  4. Daly MB, Pal T NCCN clinical practice guidelines in oncology (NCCN Guidelines) Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. 2020. In: nccn.org. https://www.nccn.org/professionals/physician_gls/pdf/genetics_bop.pdf. Accessed 23 Feb 2021

  5. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Sniadecki M, Brzezinski M, Darecka K, Klasa-Mazurkiewicz D, Poniewierza P, Krzeszowiec M, et al. BARD1 and breast cancer: the possibility of creating screening tests and new preventive and therapeutic pathways for predisposed women. Genes (Basel). 2020;11(11).

  7. Tung N, Domchek SM, Stadler Z, Nathanson KL, Couch F, Garber JE, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol. 2016;13(9):581–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Kurian AW, Hughes E, Handorf EA, Gutin A, Allen B, Hartman A-R, et al. Breast and ovarian cancer penetrance estimates derived from germline multiple-gene sequencing results in women. JCO Precision Oncol. 2017;1:1–12.

    Google Scholar 

  9. • Suszynska M, Klonowska K, Jasinska AJ, Kozlowski P. Large-scale meta-analysis of mutations identified in panels of breast/ovarian cancer-related genes - Providing evidence of cancer predisposition genes. Gynecol Oncol. 2019;153(2):452–62. This meta-analysis looks at 37 genes and offers evidence supporting the association of some genes with breast/ovarian cancer. The study also outlines risk estimates and provides information to help interpret management for individuals with gene mutations.

    Article  CAS  PubMed  Google Scholar 

  10. Couch FJ, Shimelis H, Hu C, Hart SN, Polley EC, Na J, et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017;3(9):1190–6.

    Article  PubMed  PubMed Central  Google Scholar 

  11. •• Breast Cancer Association C, Dorling L, Carvalho S, Allen J, Gonzalez-Neira A, Luccarini C, et al. Breast cancer risk genes - association analysis in more than 113,000 women. N Engl J Med. 2021;384(5):428–39. This large case-control study examines the association of 34 cancer genes with a risk for breast cancer and separately analyzes the odds ratio for protein-truncating and rare missense variants.

    Article  Google Scholar 

  12. Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015;33(4):304–11.

    Article  CAS  PubMed  Google Scholar 

  13. •• Shimelis H, LaDuca H, Hu C, Hart SN, Na J, Thomas A, et al. Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing. J Natl Cancer Inst. 2018;110(8):855–62. This study examines the outcome of a 21 cancer gene panel test performed in women with triple-negative breast cancer (TNBC). The odds ratio, lifetime cancer risks, and overall breast cancer risks in the Caucasian and African American populations are outlined.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Hu C, Polley EC, Yadav S, Lilyquist J, Shimelis H, Na J, et al. The contribution of germline predisposition gene mutations to clinical subtypes of invasive breast cancer from a clinical genetic testing cohort. J Natl Cancer Inst. 2020;112(12):1231–41.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. • Hu C, Hart SN, Gnanaolivu R, Huang H, Lee KY, Na J, et al. A population-based study of genes previously implicated in breast cancer. N Engl J Med. 2021;384(5):440–51. This case-control study based on data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium outlines prevalence and breast cancer risks for 28 genes in the US population.

    Article  PubMed  PubMed Central  Google Scholar 

  16. • Angeli D, Salvi S, Tedaldi G. Genetic predisposition to breast and ovarian cancers: how many and which genes to test? Int J Mol Sci. 2020;21(3). This review summarizes the recent evidence for cancer predisposition genes and discusses the high, moderate, low, and emerging evidence genes. The study also offers insights into emerging prevention and therapies.

  17. Easton DF, Lesueur F, Decker B, Michailidou K, Li J, Allen J, et al. No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing. J Med Genet. 2016;53(5):298–309.

    Article  CAS  PubMed  Google Scholar 

  18. Weber-Lassalle N, Hauke J, Ramser J, Richters L, Gross E, Blumcke B, et al. BRIP1 loss-of-function mutations confer high risk for familial ovarian cancer, but not familial breast cancer. Breast Cancer Res. 2018;20(1):7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Seal S, Thompson D, Renwick A, Elliott A, Kelly P, Barfoot R, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006;38(11):1239–41.

    Article  CAS  PubMed  Google Scholar 

  20. Byrnes GB, Southey MC, Hopper JL. Are the so-called low penetrance breast cancer genes, ATM, BRIP1, PALB2 and CHEK2, high risk for women with strong family histories? Breast Cancer Res. 2008;10(3):208.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Zhang G, Zeng Y, Liu Z, Wei W. Significant association between Nijmegen breakage syndrome 1 657del5 polymorphism and breast cancer risk. Tumour Biol. 2013;34(5):2753–7.

    Article  CAS  PubMed  Google Scholar 

  22. Hauke J, Horvath J, Gross E, Gehrig A, Honisch E, Hackmann K, et al. Gene panel testing of 5589 BRCA1/2-negative index patients with breast cancer in a routine diagnostic setting: results of the German Consortium for Hereditary Breast and Ovarian Cancer. Cancer Med. 2018;7(4):1349–58.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Li N, McInerny S, Zethoven M, Cheasley D, Lim BWX, Rowley SM, et al. Combined tumor sequencing and case-control analyses of RAD51C in breast cancer. J Natl Cancer Inst. 2019;111(12):1332–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yang X, Song H, Leslie G, Engel C, Hahnen E, Auber B, et al. Ovarian and breast cancer risks associated with pathogenic variants in RAD51C and RAD51D. J Natl Cancer Inst. 2020;112(12):1242–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Tung N, Lin NU, Kidd J, Allen BA, Singh N, Wenstrup RJ, et al. Frequency of germline mutations in 25 cancer susceptibility genes in a sequential series of patients with breast cancer. J Clin Oncol. 2016;34(13):1460–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ma D, Chen SY, Ren JX, Pei YC, Jiang CW, Zhao S, et al. Molecular features and functional implications of germline variants in triple-negative breast cancer. J Natl Cancer Inst. 2020.

  27. Harkness EF, Barrow E, Newton K, Green K, Clancy T, Lalloo F, et al. Lynch syndrome caused by MLH1 mutations is associated with an increased risk of breast cancer: a cohort study. J Med Genet. 2015;52(8):553–6.

    Article  CAS  PubMed  Google Scholar 

  28. Gupta S, Weiss J (2020) Genetic/familial high-risk assessment: colorectal. In: NCCN Clinical Practice Guidelines in Oncology. https://www.nccn.org/professionals/physician_gls/pdf/genetics_colon.pdf. Accessed 20 Feb 2021

  29. Win AK, Young JP, Lindor NM, Tucker KM, Ahnen DJ, Young GP, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012;30(9):958–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Engel C, Loeffler M, Steinke V, Rahner N, Holinski-Feder E, Dietmaier W, et al. Risks of less common cancers in proven mutation carriers with lynch syndrome. J Clin Oncol. 2012;30(35):4409–15.

    Article  PubMed  Google Scholar 

  31. Espenschied CR, LaDuca H, Li S, McFarland R, Gau CL, Hampel H. Multigene panel testing provides a new perspective on Lynch syndrome. J Clin Oncol. 2017;35(22):2568–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Win AK, Lindor NM, Jenkins MA. Risk of breast cancer in Lynch syndrome: a systematic review. Breast Cancer Res. 2013;15(2):R27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Roberts ME, Jackson SA, Susswein LR, Zeinomar N, Ma X, Marshall ML, et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med. 2018;20(10):1167–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Goldberg M, Bell K, Aronson M, Semotiuk K, Pond G, Gallinger S, et al. Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry. J Med Genet. 2017;54(11):742–6.

    Article  CAS  PubMed  Google Scholar 

  35. • Lu HM, Li S, Black MH, Lee S, Hoiness R, Wu S, et al. Association of breast and ovarian cancers with predisposition genes identified by large-scale sequencing. JAMA Oncol. 2019;5(1):51–7. This large-scale exome sequencing analysis of individuals with breast or ovarian cancer outlines cancer association. The study also offers a case-control analysis and describes pathogenic variants associated with breast cancer and the different subtypes.

    Article  PubMed  Google Scholar 

  36. Yi D, Xu L, Luo J, You X, Huang T, Zi Y, et al. Germline TP53 and MSH6 mutations implicated in sporadic triple-negative breast cancer (TNBC): a preliminary study. Hum Gen. 2019;13(1):4.

    Article  Google Scholar 

  37. ten Broeke SW, Brohet RM, Tops CM, van der Klift HM, Velthuizen ME, Bernstein I, et al. Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk. J Clin Oncol. 2015;33(4):319–25.

    Article  PubMed  Google Scholar 

  38. Mills AM, Dill EA, Moskaluk CA, Dziegielewski J, Bullock TN, Dillon PM. The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma. Am J Surg Pathol. 2018;42(2):183–91.

    Article  PubMed  Google Scholar 

  39. • MacInnis RJ, Knight JA, Chung WK, Milne RL, Whittemore AS, Buchsbaum R, et al. Comparing five-year and lifetime risks of breast cancer in the prospective family study cohort. J Natl Cancer Inst. 2020. This study discusses the utility of the absolute 5-year cancer risk model compared to the lifetime risk model to direct breast cancer screening decisions.

  40. Turnbull C, Sud A, Houlston RS. Cancer genetics, precision prevention and a call to action. Nat Genet. 2018;50(9):1212–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Manahan ER, Kuerer HM, Sebastian M, Hughes KS, Boughey JC, Euhus DM, et al. Consensus guidelines on genetic testing for hereditary breast cancer from the American Society of Breast Surgeons. Ann Surg Oncol. 2019;26(10):3025–31.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Kurian AW, Ward KC, Howlader N, Deapen D, Hamilton AS, Mariotto A, et al. Genetic testing and results in a population-based cohort of breast cancer patients and ovarian cancer patients. J Clin Oncol. 2019;37(15):1305–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Young EL, Feng BJ, Stark AW, Damiola F, Durand G, Forey N, et al. Multigene testing of moderate-risk genes: be mindful of the missense. J Med Genet. 2016;53(6):366–76.

    Article  CAS  PubMed  Google Scholar 

  44. Ryu JS, Lee HY, Cho EH, Yoon KA, Kim MK, Joo J, et al. Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer. Cancer Sci. 2020;111(10):3912–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Michailidou K, Lindstrom S, Dennis J, Beesley J, Hui S, Kar S, et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551(7678):92–4.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. •• Yanes T, Young MA, Meiser B, James PA. Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field. Breast Cancer Res. 2020;22(1):21. This review outlines the current evidence for polygenic risk scores and breast cancer risks. It also discusses the challenges and clinical utility of various polygenic risk scoring programs.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Yang S, Axilbund JE, O'Leary E, Michalski ST, Evans R, Lincoln SE, et al. Underdiagnosis of hereditary breast and ovarian cancer in medicare patients: genetic testing criteria miss the mark. Ann Surg Oncol. 2018;25(10):2925–31.

    Article  PubMed  Google Scholar 

  48. •• Beitsch PD, Whitworth PW, Hughes K, Patel R, Rosen B, Compagnoni G, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37(6):453–60. This study debates the utility of guidelines in directing testing for hereditary cancer syndromes, with evidence indicating no statistical difference in detection rates between individuals who do and do not meet NCCN guidelines for hereditary cancer testing.

    Article  PubMed  Google Scholar 

  49. Ohmoto A, Yachida S. Current status of poly(ADP-ribose) polymerase inhibitors and future directions. Onco Targets Ther. 2017;10:5195–208.

    Article  PubMed  PubMed Central  Google Scholar 

  50. •• Tung NM, Robson ME, Ventz S, Santa-Maria CA, Nanda R, Marcom PK, et al. TBCRC 048: phase II study of olaparib for metastatic breast cancer and mutations in homologous recombination-related genes. J Clin Oncol. 2020;38(36):4274–82. This phase II abstract presented at ASCO examines the response to PARP in metastatic breast cancer patients with mutations in homologous recombination repair genes or somatic BRCA1/2 mutations.

    Article  CAS  PubMed  Google Scholar 

  51. Kantidze OL, Velichko AK, Luzhin AV, Petrova NV, Razin SV. Synthetically lethal interactions of ATM, ATR, and DNA-PKcs. Trends Cancer. 2018;4(11):755–68.

    Article  CAS  PubMed  Google Scholar 

  52. Cruz C, Llop-Guevara A, Garber JE, Arun BK, Perez Fidalgo JA, Lluch A, et al. Multicenter phase II study of lurbinectedin in BRCA-mutated and unselected metastatic advanced breast cancer and biomarker assessment substudy. J Clin Oncol. 2018;36(31):3134–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jiang M, Jia K, Wang L, Li W, Chen B, Liu Y, et al. Alterations of DNA damage repair in cancer: from mechanisms to applications. Ann Transl Med. 2020;8(24):1685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. UT Health Science Center San Antonio, 7979 Wurzbach Road, San Antonio, TX, 79229, USA

    Anusha Vaidyanathan MS, CGC & Virginia Kaklamani MD DSc

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  1. Anusha Vaidyanathan MS, CGC
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Correspondence to Anusha Vaidyanathan MS, CGC.

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Anusha Vaidyanathan is the Professional Issues Chair for the Texas Society of Genetic Counselors and the Research Chair for the National Society of Genetic Counselors (Cancer SIG). Both are unpaid positions.

Virginia Kaklamani has received speaker's honoraria and compensation for service as a consultant from Immunomedics, AstraZeneca, Daiichi Sankyo, Seattle Genetics, Puma Biotechnology, Pfizer, and Novartis, and has served on advisory boards for Puma Biotechnology, Radius Health, and Sanofi.

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Vaidyanathan, A., Kaklamani, V. Understanding the Clinical Implications of Low Penetrant Genes and Breast Cancer Risk. Curr. Treat. Options in Oncol. 22, 85 (2021). https://doi.org/10.1007/s11864-021-00887-4

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