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.

Background: BC that arises in BRCA1/2 mutation carriers is characterized by defective homologous recombination DNA repair. Given the clinical potential for DNA repair-targeted therapeutics, Myriad Genetics has developed a tumor DNA-based assay that can identify underlying defects in the homologous recombination pathway, regardless of etiology, including identification of BRCA1/2 mutation carriers with high sensitivity. This study was designed to assess ability of the HRD score to predict pathologic response to neoadjuvant platinum-based therapy in early-stage triple-negative and BRCA1/2 mutation-associated BC. Methods: The HRD score was assessed in a cohort of 55 fresh frozen tumors from pts with clinical stage I-IIIA triple-negative and BRCA1/2 mutation-associated BC enrolled onto a single-arm, phase II study of neoadjuvant gemcitabine, carboplatin and iniparib. Following neoadjuvant therapy (4 cycles=11; 6 cycles=44), pathologic response was assessed using the residual cancer burden (RCB) index by a central pathologist. Twenty-nine tumors were obtained from responders (RCB 0/1) and 26 tumors were from non-responders (RCB 2/3). The HRD score was derived by count of the number of LOH regions (>15 Mb and < whole chromosome) observed in the tumor genome. Association of response to treatment and HRD score was performed by the Mann-Whitney U test. Results: Germline BRCA1/2 mutation status was known in all pts and 13/55 tumors were from carriers of deleterious BRCA1 (n = 9), BRCA2 (n = 3) or BRCA1&2 (n = 1) mutations. Two mutation carriers had ER+/PR+(>5%) BC. The mean HRD score for responders is 16.5 and no differences were noted between germline BRCA1/2 mutants vs. non-mutants. The mean HRD score for non-responders is 11.4. Among carriers of BRCA1/2 mutations, 12/13 achieved a favorable response. The one BRCA1 mutation carrier non-responder with TNBC had a low HRD score of 8. This pt was previously treated with chemotherapy twice 12 years prior for primary and locally recurrent contralateral TNBC. The p-value for association between response to treatment and HRD score by the Mann-Whitney U test is 0.004. If BRCA1/2 deficient samples are excluded, the association between response to treatment and HRD score remains significant (p = 0.02). Multivariate analysis that includes HRD score, BRCA1/2 genotype, age, stage, tumor grade, PAM50 subtype, ER/PR status, and cycles of therapy will be presented together with data from an additional 35 pts. Enrollment to the therapeutic trial is complete and final clinical results will be separately presented. Conclusion: The HRD score is significantly correlated with pathologic response to platinum-based chemotherapy in early-stage triple-negative and BRCA1/2 mutation-associated BC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD09-04.

Background: Aberrant signaling via the PI3K pathway is a common alteration in breast cancer (BC), with frequent activating mutations in the PIK3CA gene helical (exon 9) and catalytic (exon 20) domains. These mutations occur across all BC subtypes with an overall incidence of 36%, with the highest frequency (∼45%) in luminal A/ER+ tumors. Lobular phenotype is common among luminal A tumors. We examined associations between lobular histology and molecular features among BC samples submitted for comprehensive molecular analyses for The Cancer Genome Atlas (TCGA). Design: Experts in breast pathology reviewed digital slides of breast cancer samples submitted for comprehensive molecular profiling to the TCGA. Tumors were graded, subtyped and scored for additional histopathologic features. We tested pairwise associations between lobular features and components of grade, PAM50-derived molecular subtype and mutational status for BRAC1/2, PIK3CA, TP53 and CDH1 by performing Chi-Square analysis for comparisons with a categorical variable and the Mann-Whitney test for comparisons with an ordinal variable Results: A total of 1132 images were scored from 589 unique cases in TCGA. For cases with multiple scorers (43% of cases), we summarized scores by taking the median (for ordinal variables) or the consensus diagnosis (for categorical variables). A total of 567 cases had a consensus diagnosis for lobular features, all of which had pathological information on components of histologic grade and 540 of which had data for TP53, CDH1, and PIK3CA mutations. 110/567 (19%) of cases were classified as invasive lobular or invasive mammary carcinoma with lobular features. The lobular cases had significantly less nuclear pleomorphism (p = 3.3 e -12), lower mitotic index (p = 3.4e-16), less tubule formation (p = 3.9e-8), increased association with lobular carcinoma in situ (p < 2.2 e-16), decreased stromal inflammation (p = 1.5e-7), and decreased necrosis (p = 4.4e-11) compared with cases without lobular features. Cases with lobular features were highly enriched for CDH1 mutations with 19% of cases with lobular features having CDH1 mutations, compared with only 1% of cases without lobular features (p = 2.4 e-14). The lobular features cases were more likely to have PIK3CA mutations (p = 0.01), with 33% of the lobular features cases having PIK3CA mutations, compared with 21% of the non-lobular cases. The lobular features cases were less likely to have TP53 mutations (p = 0.02), with 13% of lobular features cases having TP53 mutations as compared with 24% of the non-lobular feature cases. Lobular status was associated with PAM50 molecular subtype (Chi-square p = 0.002) with the lobular cases significantly less likely to be basal molecular subtype and more likely to be Luminal-A. Conclusions: PIK3CA mutations are enriched in invasive lobular carcinomas and invasive mammary carcinomas with lobular features. These associations point to the possibility that PIK3CA mutations as well as CDH1 alterations are important drivers of invasive lobular carcinomas. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-05-10.