The correlation reported previously, as well as our current findings, suggest that further investigations are warranted to understand the possible linkage of the ER gene locus to hereditary breast cancer.

BRCA1 has been implicated in numerous DNA repair pathways that maintain genome integrity, however the function responsible for its tumor suppressor activity in breast cancer remains obscure. To identify the most highly conserved of the many BRCA1 functions, we screened the evolutionarily distant eukaryote Saccharomyces cerevisiae for mutants that suppressed the G1 checkpoint arrest and lethality induced following heterologous BRCA1 expression. A genome-wide screen in the diploid deletion collection combined with a screen of ionizing radiation sensitive gene deletions identified mutants that permit growth in the presence of BRCA1. These genes delineate a metabolic mRNA pathway that temporally links transcription elongation (SPT4, SPT5, CTK1, DEF1) to nucleopore-mediated mRNA export (ASM4, MLP1, MLP2, NUP2, NUP53, NUP120, NUP133, NUP170, NUP188, POM34) and cytoplasmic mRNA decay at P-bodies (CCR4, DHH1). Strikingly, BRCA1 interacted with the phosphorylated RNA polymerase II (RNAPII) carboxy terminal domain (P-CTD), phosphorylated in the pattern specified by the CTDK-I kinase, to induce DEF1-dependent cleavage and accumulation of a RNAPII fragment containing the P-CTD. Significantly, breast cancer associated BRCT domain defects in BRCA1 that suppressed P-CTD cleavage and lethality in yeast also suppressed the physical interaction of BRCA1 with human SPT5 in breast epithelial cells, thus confirming SPT5 as a relevant target of BRCA1 interaction. Furthermore, enhanced P-CTD cleavage was observed in both yeast and human breast cells following UV-irradiation indicating a conserved eukaryotic damage response. Moreover, P-CTD cleavage in breast epithelial cells was BRCA1-dependent since damage-induced P-CTD cleavage was only observed in the mutant BRCA1 cell line HCC1937 following ectopic expression of wild type BRCA1. Finally, BRCA1, SPT5 and hyperphosphorylated RPB1 form a complex that was rapidly degraded following MMS treatment in wild type but not BRCA1 mutant breast cells. These results extend the mechanistic links between BRCA1 and transcriptional consequences in response to DNA damage and suggest an important role for RNAPII P-CTD cleavage in BRCA1-mediated cancer suppression.

Background: Trastuzumab treatment, both adjuvant and metastatic, has resulted in an improved survival for HER2 positive breast cancer patients. Cardiotoxicity of trastuzumab has been demonstrated in clinical trials, but predictive determinants of cardiotoxicity are lacking. We aimed to examine the incidence of cardiac events and identify potential predictive factors in African American and older women treated with trastuzumab, two cohorts that are under-represented in the trastuzumab trials.Methods: HER2 positive breast cancer patients who received trastuzumab, and were African American (cohort 1) or ≥ 55 years of age (cohort 2) were identified by a search of our breast database. Cohort 2 included only those women who received adjuvant trastuzumab since they were more likely to have been treated with an anthracycline similar to the patients on the two large adjuvant trastuzumab trials (B-31 & N9831) that identified age > 50 as a risk factor. Cardiac event was defined as any decline in left ventricular ejection fraction (LVEF) by > 10% points from baseline or drop to < 50%, Grade III/IV New York Heart Association congestive heart failure (CHF), new onset angina/myocardial infarction, significant arrhythmia or sudden cardiac death during trastuzumab treatment. Uni and multi variable models were fitted to examine association between potential risk factors and a cardiac event.Results: 123 patients were included in this analysis (Cohort 1 N= 66, Cohort 2 N = 57). Select patient characteristics for cohort 1 and 2 respectively include: median age: 57 (range 27-82) & 66 (range 55-82), patients with prior anthracycline exposure: 67% & 68%, median cumulative anthracycline dose: 240mg/m2 in both cohorts, patients with at least one preexisting risk factor (hypertension, hyperlipidemia, diabetes, obesity, coronary artery, cerebrovascular, or valvular disease, diastolic dysfunction and left ventricular hypertrophy): 80% & 79% with median number of risk factors being 2 (0-7) in both cohorts. Incidence of any cardiac event was 38% in cohort 1(N=25, 19 (30%) with LVEF decline > 10%, 16 (24%) with LVEF <50%, 7 (11%) with Grade III/IV CHF, 1 each with arrhythmia, angina and sudden cardiac death) and 39% in cohort 2 (N= 22, 17 (31%) with LVEF decline >10%, 9 (16%) with LVEF <50%, 4 (7%) with Grade III/IV CHF, 2 with angina and 1 with arrhythmia). Of the variables analyzed, only hypertension was associated with an increased risk of having a cardiac event in cohort 1(OR 3.8, p= 0.02). None of the variables attained significance in cohort 2. Total number of preexisting risk factors and age, both analyzed as continuous variables, did not predict an increased risk in either cohort.Conclusion: A high rate of cardiac events, both asymptomatic and symptomatic was observed during trastuzumab treatment in African American women and those older than 55, majority of whom had preexisting comorbidities. Phase III trastuzumab trials by excluding patients with significant comorbidities do not reflect the risk of treatment for such patients and clinicians should consider this during decision making. Further research for predictive markers is needed to identify patients at higher risk of experiencing a cardiac event. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5087.

1068 Background: TNBC are mostly “basal-like” tumors, that have been shown to overexpress Secreted Protein Acidic and Rich in Cysteine (SPARC). Endothelial transcytosis of nab-P via albumin- gp60 -cav1 and binding of albumin to SPARC results in high intratumoral levels of nab-P. Exploiting this and the dysfunctional DNA repair in basal tumors, we hypothesized that nab-P + C would produce high rates of pCR in TNBC, further enhanced by antiangiogenesis properties of B. Methods: Eligible women had operable TNBC ≥ 2 cm. pCR in the breast and pCR in the breast + nodes were primary & secondary end points respectively. We needed 57 evaluable patients to demonstrate 40% pCR vs. 25% (P0) in a single stage phase II design (α: 0.05, β: 0.2).Schema: C AUC 6 d1 + nab-P 100mg/m2d 1, 8 & 15 Q 28 d x 4 cycles followed by AC d1, Q14d x 4 cycles preoperatively with B 10mg/kg Q 14d for the first 6 cycles of preoperative chemotherapy, resuming postoperatively to complete 1 year of treatment.Baseline tumor biopsies & serial serum/blood samples were collected. Results: Due to slow accrual, study was closed after 42 patients. They were women between 35 and 68 years of age (median 52); 51% were African American and 46% were node positive. Safety population: N=41. Four patients came off study prior to surgery while 7 are still on pre-op treatment. Grade ¾ hematologic AEs: neutropenia (Gr3: 56%; Gr4:24%) febrile neutropenia (4%), thrombocytopenia (32%), anemia (22%). 7 patients had SAEs, with 1 grade 5 event. To date, thirty of 31 patients who had surgery (efficacy population) are considered evaluable per protocol. In-breast pCR rates are 55% (17/31) and 56% (17/30) and the rates of pCR breast + nodes are 52% (16/31) and 53% (16/30), for the efficacy and evaluable populations respectively. Conclusions: Majority of the patients in our study achieved a pCR, which is among the highest rates reported compared to anthracyclines+ taxanes without B in TNBC. Correlative analyses are planned. An ongoing randomized intergroup study is evaluating the individual contributions of carboplatin & bevacizumab to pCR in TNBC. Clinical trial information: NCT00777673.

Purpose: This phase II neoadjuvant study investigated whether nab paclitaxel, carboplatin and bevacizumab given before neoadjuvant doxorubicin/cyclophosphamide (AC) produced higher pathologic complete response (pCR) rates in triple- negative breast cancer (TNBC) compared with historical results achieved with standard anthracycline/taxane regimens. Patients and Methods: Eligible patients with operable TNBC ≥2 cm received four cycles of carboplatin (area under the curve 6, day 1) plus nab-paclitaxel (100 mg/m2, days 1, 8 and 15) every 28 days, followed by four 14-day cycles of AC neoadjuvantly, with bevacizumab 10 mg/kg every 14 days for the rst 6 cycles of neoadjuvant chemotherapy, resuming postoperatively to complete 1 year of antibody treatment. In breast pCR and pCR (breast + nodes) were primary and secondary endpoints, respectively. Results: Due to slow accrual, the study was closed after enrollment of 42 of 60 planned patients. Of the 38 patients who underwent surgery (ef cacy population), 22 (58%) achieved an in-breast pCR and 19 (50%) achieved a pCR (breast + nodes). Neutropenia was the most common Grade 3/4 adverse event (57% Grade 3 and 31% Grade 4), but only 1 patient required hospitalisation and IV antibiotics for neutropenic fever. Other Grade 3/4 events included anaemia (24%), thrombocytopenia (29%) and peripheral neuropathy (Grade 3, 5%). Conclusion: Our results demonstrate a substantially higher pCR rate, both in-breast and breast + nodes, with the combination of nab paclitaxel plus carboplatin followed by AC, with concurrent bevacizumab, versus historic pCR rates with anthracycline-taxane regimens alone, supporting further investigation of this regimen, preferably in molecularly driven subsets, for the neoadjuvant treatment of patients with TNBC. Key words: Bevacizumab, breast cancer, carboplatin, nab-paclitaxel, neoadjuvant, triple-negative