Mutation Rates in Cancer Susceptibility Genes in Patients With Breast Cancer With Multiple Primary Cancers

Affiliations

PMID: 32954205
PMCID: PMC7496037 (available on 2021-08-19)
DOI: 10.1200/PO.19.00301

Abstract

Purpose: Women with breast cancer have a 4%-16% lifetime risk of a second primary cancer. Whether mutations in genes other than BRCA1/2 are enriched in patients with breast and another primary cancer over those with a single breast cancer (S-BC) is unknown.

Patients and methods: We identified pathogenic germline mutations in 17 cancer susceptibility genes in patients with BRCA1/2-negative breast cancer in 2 different cohorts: cohort 1, high-risk breast cancer program (multiple primary breast cancer [MP-BC], n = 551; S-BC, n = 449) and cohort 2, familial breast cancer research study (MP-BC, n = 340; S-BC, n = 1,464). Mutation rates in these 2 cohorts were compared with a control data set (Exome Aggregation Consortium [ExAC]).

Results: Overall, pathogenic mutation rates for autosomal, dominantly inherited genes were higher in patients with MP-BC versus S-BC in both cohorts (8.5% v 4.9% [P = .02] and 7.1% v 4.2% [P = .03]). There were differences in individual gene mutation rates between cohorts. In both cohorts, younger age at first breast cancer was associated with higher mutation rates; the age of non-breast cancers was unrelated to mutation rate. TP53 and MSH6 mutations were significantly enriched in patients with MP-BC but not S-BC, whereas ATM and PALB2 mutations were significantly enriched in both groups compared with ExAC.

Conclusion: Mutation rates are at least 7% in all patients with BRCA1/2 mutation-negative MP-BC, regardless of age at diagnosis of breast cancer, with mutation rates up to 25% in patients with a first breast cancer diagnosed at age < 30 years. Our results suggest that all patients with breast cancer with a second primary cancer, regardless of age of onset, should undergo multigene panel testing.

Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). Joseph VijaiPatents, Royalties, Other Intellectual Property: Title: Diagnosis & Treatment of ERCC3-Mutant Cancer; inventors: Joseph Vijai, Sabine Topka, Kenneth Offit; US National Stage Patent Application No.: 16/493,214; filing date: September 11, 2019 (Inst)Kasmintan A. SchraderConsulting or Advisory Role: Pfizer, AstraZeneca Research Funding: AstraZeneca (Inst)Mark E. RobsonConsulting or Advisory Role: Change Health Care Research Funding: AstraZeneca (Inst), InVitae (Inst), AbbVie (Inst), Pfizer (Inst), Merck (Inst) Travel, Accommodations, Expenses: AstraZeneca, Pfizer, Merck Other Relationship: Research to Practice, Clinical Care Options, Physician Education Resource Uncompensated Relationships: Merck, Pfizer, Daiichi Sankyo, Epic Sciences Open Payments Link: https://openpaymentsdata.cms.gov/physician/612669/summaryJames M. FordResearch Funding: Genentech (Inst), AstraZeneca (Inst), Puma Biotechnology (Inst), Pfizer (Inst)Judy E. GarberConsulting or Advisory Role: Novartis (I), GTx (I), Helix BioPharma, Konica Minolta, Aleta BioTherapeutics (I), H3 Biomedicine (I), Kronos Bio (I) Research Funding: Novartis (I), Ambry Genetics, Invitae Genetics, Myriad Genetics Other Relationship: Susan G. Komen for the Cure (I), American Association for Cancer Research, Diane Helis Henry Medical Foundation (I), James P. Wilmot Foundation (I), Adrienne Helis Malvin Medical Research Foundation (I), Breast Cancer Research Foundation, Facing our Risk of Cancer EmpoweredPayal D. ShahStock and Other Ownership Interests: Johnson & Johnson (I), Novartis (I), Novo Nordisk (I), Pfizer (I), Merck (I), Amgen, Johnson & Johnson, Novo Nordisk Consulting or Advisory Role: Tmunity TherapeuticsAngela R. BradburyConsulting or Advisory Role: AstraZeneca, MerckAngela M. DeMicheleConsulting or Advisory Role: Context Therapeutics, Pfizer (I) Research Funding: Pfizer (Inst), Genentech (Inst), Calithera Biosciences (Inst), Menarini (Inst), Silicon Biosystems (Inst)Jeffrey N. WeitzelSpeakers’ Bureau: AstraZenecaFergus J. CouchConsulting or Advisory Role: AstraZeneca Speakers’ Bureau: Ambry Genetics, QIAGEN Research Funding: Grail Travel, Accommodations, Expenses: Grail, QIAGEN Other Relationship: Ambry GeneticsSusan M. DomchekHonoraria: AstraZeneca, Clovis Oncology, Bristol Myers Squibb Research Funding: AstraZeneca (Inst), Clovis Oncology (Inst) Open Payments Link: https://openpaymentsdata.cms.gov/physician/917904 No other potential conflicts of interest were reported.