E5103 Correlative Studies

ECOG-ACRIN E5103 (E5103) was a phase III adjuvant breast cancer trial that randomized 4994 patients with node-positive or high-risk node-negative breast cancer to intravenous doxorubicin and cyclophosphamide every 2 or 3 weeks (at the discretion of treating physician), for four cycles of adriamycin and cyclophosphamide (AC) followed by 12 weeks of weekly paclitaxel (80 mg/m2) alone (Arm A), or to the same chemotherapy with either concurrent bevacizumab (Arm B), or concurrent plus sequential bevacizumab (Arm C). To develop predictive genetic biomarkers for chemotherapy efficacy and toxicities, we have successfully performed genome-wide genotyping and whole exome sequencing in the germline (blood) DNA of 3215 and 672 patients, respectively, from the E5103 trial to investigate the association of genetic variants with chemotherapy efficacy and toxicities. Case and control studies were performed with genome-wide analyses (GWAS) and whole exome analyses (WES) across all arms of E5103 to identify genotypes at single-nucleotide polymorphisms (SNPs) and deleterious gene mutations that were associated with paclitaxel-induced peripheral neuropathy (TIPN). Through GWAS, we have identified a SNP, rs3125923, and through WES, Cytochrome P450 oxidoreductase (POR), that was significantly associated with grade 3-4 TIPN.]]>
Cases: Cases were defined as those experiencing Grade 2-4 TIPN as assessed by the Common Toxicity Criteria Adverse Events (CTCAE) version 3.0. We separately assessed those with the more extreme phenotype of grade 3-4. Cases included patients who received at least one dose of paclitaxel and the neuropathy event occurred during treatment or within 3 months of the last dose of therapy. Controls: Controls included patients who met all the following: Received all planned doses of paclitaxelHad follow-up for at least 3 months after the last dose of the drugDid not meet any of the case definitions as outlined above andPatients who had either paclitaxel or bevacizumab held or modified for any reason (i.e. disease progression or other toxicity) were excluded as controls. ]]>