Abstract IA09: Impact of genetically determined race on outcomes in E5103
Authors: Schneider Bryan Paul 
Published: March 2017

Abstract
Background: African Americans (AAs) have inferior breast cancer outcomes. AAs have a higher percentage of the poor prognosis triple negative breast cancer subtype and also have inferior relative benefit from chemotherapy when compared to other races. While some of the disparity may be due to socio-economic factors, the underlying biology of the tumor may also play a pivotal role. Using ancestry informative markers, we have evaluated race-specific outcomes and various therapy-induced side effects in the adjuvant breast cancer trial, E5103. We have further explored the roles of germline genetic biomarkers to predict the increased risk for the most common chemotherapy induced toxicity; taxane-induced peripheral neuropathy (TIPN) in AAs.
Methods: E5103 was a phase III adjuvant breast cancer trial that randomized 4,994 patients with node-positive or high risk node-negative breast cancer to intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks for four cycles followed by 12 weeks of weekly paclitaxel alone (Arm A) or to the same chemotherapy with either concurrent bevacizumab (Arm B) or concurrent plus sequential bevacizumab (Arm C). Germline (blood) DNA and clinical data were available from 3394 patients across all arms. Genome-wide analyses were performed in these patients and race was determined by principle components analysis (PCA). Clinical outcome and the occurrence of therapy-induced toxicities were compared in genetically defined AAs against other races. Germline biomarkers were evaluated to predict the risk of TIPN in AAs through a genome wide association study (for common variants) and through whole exome sequencing (for rare variants).
Results: PCA determined 386 AAs among 3394 available patients from E5103. Compared to other races, AA patients had an inferior disease free survival. AAs were also more likely to experience the most common, severe side effects from each of the agents used in E5103, including: CTCAE v 4.0 grade 3-4 TIPN (p=2.4 × 10-11; OR=2.9) and grade 3-4 bevacizumab induced hypertension (p=0.002; OR=1.6). Despite a small number of events, the same trend was observed for anthracycline induced congestive heart failure (p=0.08, OR=1.8). The genome wide study identified several germline biomarkers that impacted the risk of TIPN specific to AAs. Specifically, a SNP in FCAMR demonstrated a trend toward decreased risk of grade 2-4 TIPN in AAs (p-value=2.8 × 10-7). Whole exome sequencing revealed an association between deleterious rare variants in SET binding factor 2 (SBF2) with a marked increased risk of grade 3-4 TIPN in AAs (p-value=4.35 × 10-6).
Conclusion: AA breast cancer patients had an inferior DFS and were more likely to experience bevacizumab-induced hypertension, TIPN, and anthracycline-induced congestive heart failure compared with other races in E5103. Germline biomarkers for predicting the risk of TIPN, pending validation in independent trials, can drastically impact counseling patients for the likelihood of this toxicity.
Citation Format: Bryan Paul Schneider. Impact of genetically determined race on outcomes in E5103. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr IA09.