The purpose of this study is to determine the biologic impact of short-term lipophilic statin exposure on in situ and invasive breast cancer through paired tissue, blood and imaging-based biomarkers. A perioperative window trial of fluvastatin was conducted in women with a diagnosis of DCIS or stage 1 breast cancer. Patients were randomized to high dose (80 mg/day) or low dose (20 mg/day) fluvastatin for 3–6 weeks before surgery. Tissue (diagnostic core biopsy/final surgical specimen), blood, and magnetic resonance images were obtained before/after treatment. The primary endpoint was Ki-67 (proliferation) reduction. Secondary endpoints were change in cleaved caspase-3 (CC3, apoptosis), MRI tumor volume, and serum C-reactive protein (CRP, inflammation). Planned subgroup analyses compared disease grade, statin dose, and estrogen-receptor status. Forty of 45 patients who enrolled completed the protocol; 29 had paired Ki-67 primary endpoint data. Proliferation of high grade tumors decreased by a median of 7.2% (P = 0.008), which was statistically greater than the 0.3% decrease for low grade tumors. Paired data for CC3 showed tumor apoptosis increased in 38%, remained stable in 41%, and decreased in 21% of subjects. More high grade tumors had an increase in apoptosis (60 vs. 13%; P = 0.015). Serum CRP did not change, but cholesterol levels were significantly lower post statin exposure (P<0.001). Fluvastatin showed measurable biologic changes by reducing tumor proliferation and increasing apoptotic activity in high-grade, stage 0/1 breast cancer. Effects were only evident in high grade tumors. These results support further evaluation of statins as chemoprevention for ER-negative high grade breast cancers.

Background: I-SPY 2 is a multicenter, phase 2 screening trial using adaptive randomization within biomarker subtypes to evaluate a series of novel agents/combinations when added to standard neoadjuvant therapy (paclitaxel q wk x 12, doxorubicin & cyclophosphamide q 2-3 wk x 4, T/AC) vs. T/AC (control arm) for women with high-risk stage II/III breast cancer. The primary endpoint is pathologic complete response (pCR) at surgery. Our goal is to identify/graduate regimens that have ≥85% Bayesian predictive probability of success (statistical significance) in a 300-patient biomarker-linked Phase 3 neoadjuvant trial. Experimental regimens can "graduate" in at least 1 of 10 possible signatures defined by hormone-receptor (HR) & HER2 status & MammaPrint (MP), with a maximum number of 120 total patients enrolled. We report final efficacy results of the oral PARP inhibitor veliparib (V, ABT-888) in combination with carboplatin (carbo), 1 of 7 experimental regimens evaluated in the trial to date. Methods: Women with tumors ≥2.5 cm by clinical exam and ≥2 cm by imaging are eligible for screening. Tumors that are MP low/HR+/HER2-are ineligible for randomization. MRI scans (baseline, 3 weeks after start of therapy, at completion of weekly T, and prior to surgery) were used in a longitudinal statistical model to improve the efficiency of adaptive randomization. V+carbo was assigned to HER2-tumors only, which limits its possible signatures to: all HER2-, HR+/HER2-, HR-/HER2-. For these 3 signatures we provide estimated pCR rates with associated 95% Bayesian probability intervals for V+carbo and concurrently randomized controls. Analysis is intent to treat with patients who switched to non-protocol therapy regarded as non-pCRs. For each signature we provide probabilities of superiority for V+carbo over control and Bayesian predictive probabilities of success in a neoadjuvant Phase 3 trial equally randomized between V+carbo and control. Results: When V+carbo met the 85% predictive probability criterion in HR-/HER2-and all HER2-, this regimen graduated and accrual to V+carbo was stopped. V+carbo was assigned to 72 patients, and there were 62 concurrently randomized controls (44 HER2-controls). The following table shows final results based on available pCR information. Two patients assigned to V+carbo withdrew consent during treatment and are not included in the table.

The majority of clinical trials of neo-adjuvant therapy for breast cancer have been conducted in resource-rich countries. We chose Nigeria, a resource-poor country, as the major site for a phase II feasibility open-label multicenter clinical trial designed to evaluate the efficacy, safety, and tolerability of neo-adjuvant capecitabine in locally advanced breast cancer (LABC). Planned treatment consisted of 24 weeks of capecitabine at a dose of 1,000 mg/m2 twice daily (2,000 mg/m2 total per day). The primary endpoints were overall, partial, complete clinical response rate (OCR, PCR, CCR) and complete pathologic response (cPR). A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first three cycles of therapy, PCR were seen in five of 16 patients (31%; 95% CI 11–59%). Of the remaining 11 patients, eight had no response (NR) or stable disease (SD), and three had progressive disease (PD). Seven patients proceeded with further therapy of which had SD. OCR at the end of eight cycles was 44% (95% CI 20–70%). Clinical response and radiologic response by ultrasonomammography were highly concordant (spearman correlation 0.70). The most common adverse effect was Grade 1 hand–foot syndrome, which was seen in 75% of patients. Despite several limitations, we successfully carried out this phase II feasibility study of neo-adjuvant capecitabine for LABC in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.

e11554 Background: The majority of clinical trials of neoadjuvant therapy for breast cancer have been conducted in resource-rich countries. We chose Nigeria, a resource-poor country, as the major site for a phase II feasibility open label multicenter clinical trial designed to evaluate the efficacy, safety and tolerability of neoadjuvant capecitabine in locally advanced breast cancer. Methods: Planned treatment consisted of 24 weeks of capecitabine at a dose of 1000mg/m2 twice daily (2000mg/m2 total per day). Each cycle consisted of a 14-day period of therapy followed by a 7-day pause, and patients were evaluated after 3 cycles and taken off study if no response was documented. Responding patients were treated for no more than 8 cycles. The primary endpoints were partial, complete clinical response and pathologic complete response. Results: A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first 3 cycles of therapy, partial clinical responses were seen in 5 of 16 patients (31%; 95% CI 11% - 59%). Of the remaining 11 patients, 8 had no response or stable disease, and 3 had progressive disease. Seven pateints proceeded with further therapy, two of them with stable disease but exactly in the border line of 25% increase. By physical examination, only 2 of the 6 patients had a documented complete clinical response, while by ultrasonomammography, partial responses were observed in 5 patients. Thus, overall response rate at the end of 8 cycles were 31.1% both by clinical examination and by ultrasonomammography. Clinical response by physical examination and radiologic response by ultrasonomammography were highly concordant (the spearman correlation between the two ratios was 0.70). The most common adverse effect was Grade 1 Hand and Foot Syndrome in 75% of patients. Conclusions: Despite several limitations, we successfully carried out this phase II feasibility study of neoadjuvant capecitabine for locally advanced breast cancer in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.

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To date, more than 100 single nucleotide polymorphisms (SNPs) have been found to be associated with breast cancer susceptibility in large genome-wide association studies (GWAS) conducted predominantly in women of European and Asian ancestries. To identify breast cancer susceptibility alleles in populations of African ancestry, we performed a GWAS in 3,686 subjects from Nigeria, Barbados and the United States (Baltimore, Chicago, Detroit, Philadelphia and the Southern Community Cohort Study), using the Illumina HumanOmni2.5 array. Using stringent quality control criteria, a total of 1,657 cases (777 with known estrogen receptor [ER] status) and 2,029 controls were successfully genotyped for 2,116,365 SNPs. Subsequently, imputation was conducted using reference panels from The 1000 Genomes Project and logistic regression models controlling age and global ancestry were applied to examine the association of 78 known breast cancer GWAS index SNPs and 44 iCOGS (Illumina iSelect genotyping array for Collaborative Oncological Gene-Environment Study) SNPs with breast cancer risk in our study population. Only 4 SNPs were statistically significant (unadjusted P&lt;0.01) associated with breast cancer in women of African descent: rs3112612 (16q12.1, P=0.0021), rs3817198 (11p15.5, P=0.0049), rs10069690 (5p15.33, P=0.0056), and rs1978503 (18q21.2, P=0.0066). Additional five SNPs were found to be associated with breast cancer at the unadjusted P&lt;0.05 significance level: rs458685 (12q21.3), rs361147 (4q31.3), rs4322600 (14q31.3), rs616488 (1p36.22), and rs17356907 (12q22). We also observed positive associations for ER-negative breast cancer: rs3817198 (11p15.5, P=0.0029), rs6762644 (3p26.1, P=0.0036), rs10069690 (5p15.33, P=0.0048), and rs3803662 (16q12.1, P=0.0050); and ER-positive breast cancer: rs12355688 (10q22.3, P=0.011), rs1978503 (18q21.2, P=0.020), rs3112612 (16q12.1, P=0.032), and rs4784227 (16q12.1, P=0.038). In conclusion, our observations highlight the necessity of validating previous breast cancer GWAS findings across diverse populations. Different environmental factors, allele frequencies and linkage disequilibrium patterns may influence the genetic risk profiles in different populations. Larger genetic studies in women of African ancestry hold promise to reveal additional risk variants for developing polygenic risk models for breast cancer susceptibility in this population. Citation Format: Yonglan Zheng, Dezheng Huo, Temidayo O. Ogundiran, Adeyinka G. Falusi, Oladosu Ojengbede, Clement Adebamowo, William J. Blot, Wei Zheng, Qiuyin Cai, Lisa B. Signorello, Katherine L. Nathanson, Susan M. Domchek, Timothy R. Rebbeck, Michael S. Simon, Anselm J.M. Hennis, Barbara Nemesure, Suh-Yuh Wu, Maria Cristina Leske, Stefan Ambs, Abayomi Odetunde, Imaria Anetor, Stella Akinleye, Qun Niu, Jing Zhang, Anna Pluzhnikov, Anuar Konkashbaev, Lin Chen, Eric R. Gamazon, Younghee Lee, Nancy J. Cox, Olufunmilayo O. Olopade. Replication of previously identified breast cancer susceptibility loci in a breast cancer case-control study on women of African ancestry. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B11. doi:10.1158/1538-7755.DISP13-B11

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