Abstract P3-06-09: BRCA mutations and not type 1 tandem duplicator phenotypes are associated with pathological complete response in patients with triple negative breast cancer undergoing neoadjuvant carboplatin/nab-paclitaxel
Authors: Menghi F , Yuan Y , Somlo G , Liu ET 
Published: May 2019

Abstract
Background. We recently described six distinct genomic configurations characterized by large numbers of distributed somatic tandem duplications (TDs) known as Tandem Duplicator Phenotypes (TDPs). Different TDPs feature TDs of different span sizes, and are enriched in TNBC, ovarian, and uterine cancers. Type 1 TDPs (i.e. groups 1, 1/2mix and 1/3mix) feature short span TDs (˜11Kb in size), invariably show abrogation of BRCA1 (via mutation or methylation) and of TP53, and affect ˜40% of TNBCs. We had observed, in limited in vitro and preclinical PDX models, that TDP status correlates with platinum sensitivity (1). Here, we assess TDP status across a cohort of 42 TNBC patients (pts) undergoing neoadjuvant carboplatin and NAB-paclitaxel to test the hypothesis that type 1 TDP status may be predictive of optimal response to platinum-based therapy.
Methods. 42 pts with TNBC were enrolled in a phase II study of neoadjuvant carboplatin/nab-paclitaxel at the City of Hope National Medical Center (NCT01525966).Pathological complete response (pCR) was achieved in 50% of pts (21/42). WGS was performed using standard Illumina protocols. Structural variants were called using Crest, Delly and BreakDancer, and high confidence breakpoints were selected when called by at least two tools and by requiring split-read support. TDP status was ascertained as recently described (2). BRCA1 methylation was determined by methylation-specific PCR.
Results. 45% of the tumors classified as TDP (19/42). Consistent with our previous observation, the vast majority were type 1 TDPs with short span TDs (n=17) and were strongly associated with BRCA1 mutation or methylation (16/17, P= 1.4E-8). However, there was no correlation between TDP status and pCR (OR=1.1, NS). In a more detailed analysis, we found that BRCA1 mutation correlated with pCR rate (6/7 pCR, P=0.01), whereas promoter methylation did not (4/11 pCR, NS). Moreover, both pts with mutant BRCA2 achieved pCR. Thus, as a group, pts with BRCA1/2 mutations (but not BRCA1 methylation) were more likely to achieve pCR than those with wild type BRCA1/2 (OR=11.9, P=1.7E-2). Results were unchanged when using RCB 0 and 1 vs. RCB 2 and 3 as the response criteria.
Conclusions. This study confirmed that reduction of BRCA1 activity via either mutation or methylation robustly associates with type 1 TDPs in TNBC. However, TDP status did not predict good response, suggesting the separation of BRCA effects on genomic instability and platinum sensitivity. This indicates that genomic signature assessments, such as TDP and HRD, may not be sufficient in predicting pCR in TNBC. Importantly, we found that BRCA1/2 mutated TNBC pts were more likely to experience pCR (8/9) compared with pts with either BRCA1 methylation (4/11) or wild type BRCA1/2 (8/21). The exact genetic underpinnings of response in non-BRCA pts are currently under investigation.
References.
1) Menghi et al, The Tandem Duplicator Phenotype is a Prevalent Genome-Wide Cancer Configuration Driven by Distinct Gene Mutations, Cancer Cell (2018).
2) Menghi et al, The tandem duplicator phenotype as a distinct genomic configuration in cancer, Proc Natl Acad Sci (2016).
Citation Format: Menghi F, Yuan Y, Somlo G, Liu ET. BRCA mutations and not type 1 tandem duplicator phenotypes are associated with pathological complete response in patients with triple negative breast cancer undergoing neoadjuvant carboplatin/nab-paclitaxel [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-06-09.