Mutation rates in cancer susceptibility genes in patients with breast cancer with multiple primary cancers

Kara N. Maxwell, Brandon M. Wenz, Abha Kulkarni, Bradley Wubbenhorst, Kurt D’Andrea, Benita Weathers, Noah Goodman, Joseph Vijai, Jenna Lilyquist, Steven N. Hart, Thomas P. Slavin, Kasmintan A. Schrader, Vignesh Ravichandran, Tinu Thomas, Chunling Hu, Mark E. Robson, Paolo Peterlongo, Bernardo Bonanni, James M. Ford, Judy E. GarberSusan L. Neuhausen, Payal D. Shah, Angela R. Bradbury, Angela M. DeMichele, Kenneth Offit, Jeffrey N. Weitzel, Fergus J. Couch, Susan M. Domchek, Katherine L. Nathanson

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)916-925
Number of pages10
JournalJCO Precision Oncology
StatePublished - 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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