Background: Among women with invasive breast cancer, the clinical significance of BRCA1 and BRCA2 variants of unknown significance (VUS) remain uncertain. A closer analysis of the somatic mutational profiles of women with invasive breast cancer and BRCA1 or 2 VUS could provide a better understanding of the pathogenesis of the disease and potentially allow for the development of targeted treatment regimens. We hypothesized that breast cancers with BRCA1/2 VUS will have different somatic genomic profiling patterns and tumor mutational burden (TMB) compared with BRCA1/2 wildtype (WT).
Methods: We compared the tumor molecular profiling patterns for breast cancer with somatic BRCA1/2 VUS to BRCA1/2 WT using a multiplatform profiling service (Caris Life Sciences) consisting of next generation sequencing (NGS), protein expression (immunohistochemistry [IHC]) and gene amplification (fluorescence or chromogenic in situ hybridization [FISH or CISH]). We also determined the differences in TMB between VUS and WT. We defined ER/PR/Her2 status based on IHC and/or CISH results. DNA or mutation results with >1% frequency were analyzed using Chi Square test; p<0.05 was considered statistically significant.
Results: Among 4,172 breast cancer specimens available in the Caris database acquired from more 800 participating institutions between 2013 and 2018, 125 (3%) and 341 (5.5%) had VUS in BRCA1 and BRCA2 respectively. Women with BRCA1 VUS were more likely to have tumors that are hormone receptor (HR) negative, Her2/neu positive (6.1%) compared to triple negative, triple positive or HR positive, Her2 negative (3.6%, 3.6% and 2.3% respectively) (p-value=0.0096) however BRCA2 VUS were more evenly distributed among tumor subtypes. Tumors with either BRCA1 or BRCA2 VUS were more likely to have a high TMB compared to WT (mean TMB 10.3 mut/Mb vs. 7.5 mut/Mb, p=7.2 × 10−7). Compared to WT tumors, tumors with BRCA1 or BRCA2 VUS were more likely to have pathogenic mutations in RB1 (6.4% vs 3.9%) and TP53 (62.5% vs 56%) and less likely to have GATA3 mutations (5.9% vs 8.8%) and PIK3CA amplifications (0.3% vs 35.3 %%). Furthermore, BRCA1/2 VUS cancers were 3 times more likely to have FGFR2 amplification (P=0.0065). There was no difference in AR or PD-L1 expression between VUS and WT, however breast cancer associated with BRCA1/2 VUS had a significantly less WT1 amplification compared to WT (0.3% vs 72.9%, p value <0.001).
Conclusion: Our results suggest that breast cancer associated with BRCA 1 or 2 VUS may be phenotypically and genetically different than WT. Our findings suggest the potential for different responses to immune and targeted therapies, which should be investigated in future prospective studies.External Link