Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Current Treatment Options in Oncology
Published in: Current Treatment Options in Oncology 10/2021

01-10-2021 | Breast Cancer | Breast Cancer (WJ Gradishar, Section Editor)

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

Authors: Anusha Vaidyanathan, MS, CGC, Virginia Kaklamani, MD DSc

Published in: Current Treatment Options in Oncology | Issue 10/2021

Login to get access

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.
Literature
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
4.
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
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.
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.PubMedCrossRef
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.PubMedPubMedCentralCrossRef
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.CrossRef
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.CrossRefPubMed
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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.PubMedCentralCrossRefPubMed
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
28.
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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.PubMedPubMedCentralCrossRef
32.
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.CrossRef
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.PubMedCrossRef
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.PubMedCrossRef
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.
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.PubMedCentralCrossRefPubMed
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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.PubMedCrossRefPubMedCentral
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedCrossRef
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.PubMedCrossRef
49.
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.PubMedCrossRef
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.PubMedCrossRef
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.PubMedPubMedCentralCrossRef
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.PubMedPubMedCentralCrossRef
Metadata
Title
Understanding the Clinical Implications of Low Penetrant Genes and Breast Cancer Risk
Authors
Anusha Vaidyanathan, MS, CGC
Virginia Kaklamani, MD DSc
Publication date
01-10-2021
Publisher
Springer US
Published in
Current Treatment Options in Oncology / Issue 10/2021
Print ISSN: 1527-2729
Electronic ISSN: 1534-6277
DOI
https://doi.org/10.1007/s11864-021-00887-4

Other articles of this Issue 10/2021

Current Treatment Options in Oncology 10/2021 Go to the issue

Lower Gastrointestinal Cancers (AB Benson, Section Editor)

Lessons Learned in Managing Patients with Colorectal Cancer During the COVID-19 Pandemic

Breast Cancer (WJ Gradishar, Section Editor)

Treatment Strategies for Oligometastatic Breast Cancer

Palliative and Supportive Care (MP Davis, Section Editor)

Cancer or COVID-19? A Review of Recommendations for COVID-19 Vaccination in Cancer Patients

Upper Gastrointestinal Cancers (JD Berlin, Section Editor)

Immunotherapy in Hepatocellular Carcinoma

Lung Cancer (TA Leal, Section Editor)

Neoadjuvant Chemoimmunotherapy in Patients with Resectable Non-small Cell Lung Cancer

Head and Neck Cancer (JL Geiger, Section Editor)

Management of Laryngeal Dysplasia and Early Invasive Cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits