P3-14-08: A Phase II Study of Gemcitabine and Carboplatin (GC) Plus Iniparib (BSI-201) as Neoadjuvant Therapy for Triple-Negative and BRCA1/2 Mutation-Associated Breast Cancer.

Abstract

Background The combination of gemcitabine, platinum and inhibition of DNA repair results in synergistic chemosensitivity in triple-negative and BRCA1-deficient breast cancer cell lines. This study was designed to assess efficacy, safety and predictors of response to iniparib, a small molecule whose mechanism of action is under investigation, in combination with GC in early-stage triple-negative and BRCA1/2 mutation-associated BC. Methods: This single-arm, phase II study (NCT00813956) enrolled patients with clinical stage I-IIIA (T ≥1cm by MRI) estrogen receptor-negative (≤ 5%), progesterone receptor-negative (≤ 5%), and HER2−negative or BRCA1/2 mutation-associated BC. Neoadjuvant gemcitabine (1000 mg/m2; IV; D1, 8), carboplatin (AUC 2; IV; D1, 8), and iniparib (5.6 mg/kg; IV; D1, 4, 8, 11) were given every 21 days for 4 cycles, until the protocol was amended to increase the treatment duration to 6 cycles with enrollment of 36 patients. The protocol was further amended to increase the patient number with expansion to additional centers. Prior to expansion, reporting of interim safety and efficacy results was specified. The primary endpoint is pathologic complete response (pCR), defined as the absence of invasive carcinoma in the breast and axilla. Pathologic response was assessed using the residual cancer burden (RCB) index. Secondary endpoints included safety, radiographic response by MRI, breast conservation eligibility and correlation of baseline gene expression with response. Results: The pre-expansion cohort consisted of 13 patients assigned to 4 cycles of treatment and 36 patients assigned to 6 cycles of treatment. Among these 49 patients (50 tumors), median tumor size is 35 mm, and median age is 48 years. The overall pCR rate is 34% (95% CI = 22–48); the pCR rate at 6 cycles is 41% (95% CI = 26–57). RCB 0/I was observed in 5/13 pts (38%; 95% CI = 18–64) treated with 4 cycles; 21/37 (57%; 95% CI = 41–71) treated with 6 cycles; and 9/9 pts (100%) with known BRCA1/2 mutations. Two pts experienced disease progression, two locoregional relapse, and three distant relapse. Among 45 tumors with Affymetrix-based RNA microarray gene expression data, 39/45 (87%) are classified as basal-like, 3/45 (7%) luminal B, and 3/45 (7%) normal breast-like. Most common G3/4 adverse events include neutropenia (31%), anemia (10%), and elevated ALT/AST (10%). Alopecia and chemotherapy-induced amenorrhea were uncommon. Analyses of secondary endpoints are ongoing and will be presented. Conclusions: Preoperative GC plus iniparib is active in the treatment of early-stage triple-negative and BRCA1/2 mutation-associated breast cancer. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-08.

BRCAness Predicts Resistance to Taxane-Containing Regimens in Triple Negative Breast Cancer During Neoadjuvant Chemotherapy

“…26 However, this finding has not been confirmed by other investigators, possibly because of the poor reproducibility of the BRCA1 antibody assays. A homologous recombination deficiency assay reported in 2013, 27 which performs genome-wide, single-nucleotide polymorphism analysis using Affymetrix molecular inversion probe arrays of DNA sequencing, is also effective for selecting likely responders to neoadjuvant carboplatin, gemcitabine, and iniparib.…”

Tackling the Diversity of Triple-Negative Breast Cancer

“…The basal-like 2 subtype, in contrast, was shown to be associated with gene expression patterns enriched for genes related to growth factor signaling. Basal-like 1 cancer cell lines are enriched for sensitivity to specific DNA-damaging agents such as cisplatin (31), although initial preliminary clinical data did not identify a clear association between this subtype and sensitivity to neoadjuvant gemcitabine and carboplatin chemotherapy (35).…”

“…A number of groups have suggested that cancers defective in BRCA1/2 mutations have a characteristic pattern of genomic instability that is definable in terms of loss of heterozygosity (51,52), patterns of deletions flanked by microhomology (53), or the presence and frequency of large-scale transitions assessed by microarraybased comparative genomic hybridization (54). These approaches have been assessed in small, independent studies, suggesting that these genomic classifiers may identify sporadic cancers that are more sensitive to platinum chemotherapy (35,55), potentially identifying a group of sporadic cancers that have BRCAness.…”

“…It should be noted that mesenchymal stem-like cancers are also likely to lack expression of basal cytokeratins, suggesting that two subtypes of TNBC are enriched for basal-cytokeratin-negative TNBCs (31). Emerging data suggest that luminal AR cancers may have a lower pathologic complete response (path CR) rate to neoadjuvant chemotherapy, compared with other TNBC subtypes (35). Given the paucity of data, it is, perhaps, too early to conclude that this implies less benefit from chemotherapy.…”

Triple Negative Breast Cancer in BRCA1 Mutation Carriers With a Complete Radiologic Response to Neoadjuvant Paclitaxel: A Case Report

“…19 In the PrECOG 0105 study, BRCA mutation carriers had a greater pCR rate than did noncarriers to a platinum-containing regimen combined with a PARP inhibitor. 20 Studies exploring the response specifically to taxane-based therapies have demonstrated mixed results. In the metastatic setting, ER-negative, BRCA1-associated breast tumors were less sensitive to taxanes than sporadic tumors.…”