Background: TN and BRCA1-deficient breast tumors share clinicopathologic characteristics and are highly sensitive to DNA-damaging agents. This single-arm phase II study was designed to assess efficacy and safety of iniparib, whose mechanism of action is under investigation, in combination with GC in early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. Our objective was to use multi-omic profiling of breast tumors to identify markers associated with therapy response.
Methods: Fresh-frozen breast tumor core biopsies were collected under ultrasound guidance (n=75 tumors from 74 patients (one patient with bilateral tumors)) prior to treatment. Tumor RNA and DNA was extracted, as well as matched peripheral whole blood DNA for germline comparison. Affymetrix U133 plus 2.0 array was used for whole genome expression analysis and Affymetrix Molecular Inversion Probe (MIP) was used for copy number variation analysis on 75 tumors. After normalization, we used the PARADIGM algorithm, a pathway-based approach for combining multi-omics data types on individual tumors.
Results: We identified pathway features that correspond to pathologic response, assessed using the residual cancer burden (RCB) index. All patients were tested for BRCA germline mutation and 16 (22%) patients were positive. Overall, a low RCB (0,1) was observed in 43 (58%) patients and a high RCB (2,3) in 31 (42%) patients. Pathway-based analysis of these breast tumors revealed significant alterations in 459 of 1466 (31%) of the cancer-related pathways. Gene set enrichment analysis on the PARADIGM results identified differentially expressed pathways in tumors with RCB 0 (65 pathways at p<0.05) versus RCB 3 (37 pathways at p<0.05). Tumors with complete pathologic response (RCB 0) were significantly enriched for immune-related pathways, including multiple interleukin signaling pathways. This signature appears to be primarily driven by increased signaling through SHC1, GRB2, PTPN6 and JAK2. Tumors that were least responsive (RCB 3) to therapy were enriched for NOTCH and WNT signaling cascades, primarily WNT1, CTBP1, CCND1 and APC.
Conclusions: Using a pathway-based approach, predictors of pathologic response to GC plus iniparib were identified from pre-treatment tumor biopsies. Tumors with complete pathologic response were enriched for immune-related pathways, including interleukin signaling pathways. Least responsive tumors to this therapy were enriched for NOTCH and WNT signaling pathways. We plan to validate these findings in external datasets. Platinum-based therapies are under clinical investigation for TN and BRCA1/2-associated breast cancer and identification of response predictors can guide patient selection.
Citation Format: Shaveta Vinayak, Stephen C. Benz, Charles J. Vaske, Melinda L. Telli, James M. Ford. Multi-omic profiling to predict response to gemcitabine/ carboplatin (GC) plus iniparib (BSI-201) as neoadjuvant therapy for triple-negative (TN) and BRCA1/2 mutation-associated breast cancer using a pathway-based approach. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2826. doi:10.1158/1538-7445.AM2014-2826