Abstract P3-07-30: Molecular profiling comparison of BRCA1/2-mutated and BRCA1/2 non-mutated triple-negative breast cancer (TNBC)
Authors: Arguello D , Abbott B , Reddy S , Gatalica Z , Obeid E , Goldstein L 
Published: May 2016

Background: Triple-negative breast cancer (TNBC) is one type of breast cancer that remains challenging because of its aggressive nature and the lack of effective targeted therapy for it. Molecular profiling has revealed different subtypes, indicating a potential for promising targeted therapy such as androgen blockade and PARP inhibition in some TNBCs. The purpose of this study is to identify differences in BRCA1/2 mutated and non-mutated TNBC to shed light on potential therapeutic options in both subtypes, utilizing a multiplatform approach.

Methods: A cohort of 386 triple-negative breast cancer specimens were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (next generation sequencing [NGS]), protein expression (immunohistochemistry [IHC]) and gene amplification (fluorescence or chromogenic in situ hybridization [FISH or CISH]). Primary and metastatic specimens were evaluated. Tumor specimens with any BRCA1 and/or BRCA2 mutation (i.e. pathogenic or variant of unknown significance) were categorized as "BRCA1/2-mutated", while all others were considered "BRCA1/2 non-mutated".

Results: In our cohort, 16.3% (63/386) of specimens were BRCA1/2-mutated while 83.7% (323/386) had no BRCA1/2 alteration detected. Amongst the highest rates of protein expression in BRCA1/2-mutated and non-mutated specimens were biomarkers like TOPO1 (63.5% and 63.4%), EGFR (65.2% and 67.4%), and the immune checkpoint biomarker, PD-1 (65.1% and 61.9%), with non-statistically significant differences. Differences noted between BRCA1/2-mutated and non-mutated specimens were detected by IHC in AR (11.1% versus 22.0%, p=0.0585) and PTEN (47.6% versus 59.6%, p=0.0941), with both trending but not achieving statistical significance. The highest overall mutation rate in both BRCA1/2-mutated and non-mutated were TP53 (80.6% and 73.1%, p=0.2659). Differences were also noted between BRCA1/2-mutated and non-mutated specimens by NGS in APC (6.3% versus 1.9%, p = 0.0644) and PIK3CA (11.1% versus 25.8%, p = 0.0137), with PIK3CA being statistically significant.

Conclusion: Multiplatform tumor profiling identified differences in molecular profiles between BRCA1/2 mutated and BRCA1/2 non-mutated TNBC. Our findings raise the possibility for future investigation of potential combination therapeutic targeted therapy. Increased AR overexpression in BRCA1/2 non-mutated specimens is consistent with reports from other institutions. Further studies utilizing tumor profiling to elucidate the biological differences in in TNBC subtypes are warranted, to optimally include patients on clinical trials with specific targeted therapy and possibly improve treatment options.

Citation Format: Arguello D, Abbott B, Reddy S, Gatalica Z, Obeid E, Goldstein L. Molecular profiling comparison of BRCA1/2-mutated and BRCA1/2 non-mutated triple-negative breast cancer (TNBC). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-30.