Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

Breast Cancer Res Treat. 2023 Jul;200(1):63-72. doi: 10.1007/s10549-023-06870-x. Epub 2023 Mar 1.


Purpose: Herein, we report the frequency and distribution of germline pathogenic variants (PVs) among females with breast cancer (BC) and at least one other non-BC who underwent multi-gene panel testing (MGPT). Among females with PVs diagnosed first with BC or ovarian cancer (OC), we sought to enumerate the frequency of subsequent PV-associated cancers.

Methods: Females with BC and cancer of ≥ 1 other site (multiple primary cancers, MPC) who underwent MGPT through Ambry Genetics from March 2012 to December 2016 were included if they had testing of at least 21 genes of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53). Phenotypic data were abstracted from test requisition forms and clinical notes.

Results: Of 6,617 evaluable patients, most were White (70.8%) and median age at first cancer, second cancer, and MGPT was 49 (interquartile range [IQR]: 18), 59 (IQR: 16), and 63 (IQR: 16) years, respectively. PVs were found among 14.1% (932/6617) of the overall cohort and in 16.4% (440/2687) of females who were diagnosed first with BC. Among those, 55.2% (243/440) had an actionable PV associated with a subsequent cancer diagnosis including 150 OCs. Of the 2443 females with breast and ovarian cancer, few (n = 97, 9.5%) were diagnosed first with OC, limiting our analysis.

Conclusions: Females with MPC, including BC, have a high frequency of germline PVs (14.1%). These data delineate the opportunities for intercepting subsequent cancers associated with genetic risk among females diagnosed first with BC.

Keywords: Breast cancer; Cancer interception; Genetics; Germline; Multiple primary cancers; Pathogenic variants; Survivorship.

MeSH terms

  • Breast Neoplasms* / epidemiology
  • Breast Neoplasms* / genetics
  • Female
  • Genes, BRCA2
  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • Ovarian Neoplasms* / genetics
  • Protein Serine-Threonine Kinases / genetics


  • Protein Serine-Threonine Kinases