Genetic predisposition in female patients with triple‑negative breast cancer

Abstract

Triple‑negative breast cancer (TNBC) is an immu‑ nohistochemical tumor type characterized by the absence of estrogen, progesterone and human epidermal growth factor receptors. Its complexity renders it difficult to select an effec‑ tive therapy. TNBC accounts for ~15% of all breast cancer cases in the Caucasian population and 35% among African American women; it is most common in women <40 years of age. The present study examined the spectrum and frequency of germline mutations in genes with a high and moderate penetrance in a cohort of women with TNBC. Molecular analysis was performed with a multigene panel of 94 genes for cancer predisposition using next‑generation sequencing. The mean age of the TNBC cohort at the time of diagnosis was 44 years, 14 years younger than the mean age of the non‑TNBC cohort (58 years). The results revealed a high frequency (41.2%) of pathogenic/likely pathogenic variants in susceptible genes in women with TNBC. Pathogenic germline variants in BRCA1/2 were found in 32% of the women (70% of patho‑ genic variants detected), and alterations in other predisposing genes (FANCM, CDKN2A and BLM) were found in 9% of the women. The data of all the patients with TNBC studied revealed a family history of cancer in 30% of the cases; most frequently, this involved relatives with breast cancer (11.8%). In the present study, the most frequent variant detected (in 11.8% of patients with TNBC) was a pathogenic variant in the BRCA1 gene (c.5266dup). The recommendations of genetic counselors for patients with a pathogenic BRCA1/2 germ‑ line variant followed accepted prevention and risk reduction guidelines. By contrast, in the case of a detected pathogenic germline variant in genes with a moderate or low penetrance, the recommendations depended on the assessment of genetic counselors based on age at diagnosis, family history, the gene affected and the pathogenic variant.