Prevalence of BRCA1/2 pathogenic variants in triple negative breast cancer patients stratified according to age at diagnosis.

Abstract

e13677 Background: Triple negative breast cancer (TNBC) is strongly associated with germline BRCA1 pathogenic/likely pathogenic variants (PV/LPVs), with up to 28% TNBC patients being BRCA1 PV/LPV carriers. More recently, PALB2 variants have also been shown to be associated with TNBC. Genetic testing in Slovenian hereditary breast and ovarian cancer (HBOC) patients yields consistently high BRCA1/2 detection rates. Four BRCA1 PVs are particularly common, suggesting possible founder effects. Our aim was to analyze the results of panel based genetic testing in Slovenian TNBC patients, with an emphasis on BRCA1/BRCA2 mutational spectrum and detection rates depending on age at diagnosis. Methods: We evaluated the results of genetic testing, performed using a multi-gene panel in 1000 consecutive breast cancer cases. Only 210 patients with TNBC were included in further analysis. We analyzed the mutational spectrum and BRCA1/2 detection rates in TNBC patients stratified according to age at diagnosis. Results: In 80/210 (38.1%) TNBC patients PV/LPVs in BRCA1/2 were identified. Of these, the majority (74/80) were BRCA1-positive. The following variants: c.181T > G, c.5266dupC, c.1687C > T, and c.844_850dupTCATTAC were identified in 64.4% of BRCA1 carriers. BRCA1/2 detection rate decreased with age at diagnosis but was still 18.2% after age 60 (for BRCA1/2 detection rates stratified according to age at diagnosis see table). In 12/210 (5.7%) TNBC patients PV/LPVs in three other genes were identified (3.3% PALB2, 1.4% CHEK2, and 1% ATM). Conclusions: Prevalence of PVs in BRCA1 appears very high in Slovenian TNBC patients and warrants further population-based allele frequency studies with implications for future population screening. High rates of BRCA1/BRCA2 PVs in patients older than 60 years at diagnosis justify testing all TNBC patients, especially in view of treatment options which now include PARP inhibitors. PALB2 was the second most commonly mutated gene in our patients. [Table: see text]

Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer

“…Comparable rates of PVs in patients aged 60 years or older with TNBC have been reported in other populations (13-18%), indicating that age alone should not be used as an exclusion criterion for GCRA in TNBC patients. 25,35 On the other hand, mutational status was not found to be statistically associated with the distribution of disease stage, which is consistent with previous literature. 36 As expected, carriers of PVs experienced a two-fold rate of second primary malignancies than non-carriers (22 vs. 9%).…”

Assessment of pathogenic variation in gynecologic cancer genes in a national cohort

“…Another study included a large sample of 32.544 unaffected women as controls and reported the prevalence of pathogenic variants in 12 breast-cancer-related genes (11 the same as in our study) to be 1.63% 6 , which is a reasonably similar result considering the lower number of genes included. The differences between studies may be partially explained by differences in the methodological approach, most importantly in gene selection and classification methodology, different sample sizes of the previous studies, as well as unique population characteristics such as the presence of Slovenian founder BRCA2 variant in our study 44 and high burden of BRCA1 pathogenic variants in the Slovenian population 8 .…”

“…Our results support the claim that the burden of BRCA pathogenic variants in the unaffected population might be higher than traditionally estimated. Furthermore, we report two unique features of the Slovenian population: a high prevalence of pathogenic variants in the BRCA1 gene compared to the control population, which is reflected in high detection rates of pathogenic variants in BRCA genes in Slovenian HBOC patients as well 8 and a higher burden of pathogenic BRCA1 variants compared to BRCA2 pathogenic variants in the Slovenian population. In most populations, the BRCA2 pathogenic variants prevail 6 , however, a higher burden of BRCA1 pathogenic variants has been previously described in cancer patient populations from a few eastern and central European countries 56 .…”

“…Furthermore, genomic data varies between populations, even between different European populations 17 . For instance, it has been shown that genetic testing in Slovenian patients with breast and ovarian cancer consistently yields very high BRCA1 and BRCA2 detection rates compared to patients from other populations 8 . It is imperative that population-specific studies are conducted to gain insight into the genetic diversity of pathogenic findings in specific populations.…”