Laura Gardner

Genome-Wide Association Studies for Taxane-Induced Peripheral Neuropathy in ECOG-5103 and ECOG-1199

Purpose: Taxane-induced peripheral neuropathy (TIPN) is an important survivorship issue for many cancer patients. Currently, there are no clinically implemented biomarkers to predict which patients might be at increased risk for TIPN. We present a comprehensive approach to identification of genetic variants to predict TIPN. Experimental Design: We performed a genome-wide association study (GWAS) in 3,431 patients from the phase III adjuvant breast cancer trial, ECOG-5103 to compare genotypes with TIPN. We performed candidate validation of top SNPs for TIPN in another phase III adjuvant breast cancer trial, ECOG-1199. Results: When evaluating for grade 3–4 TIPN, 120 SNPs had a P value of <10−4 from patients of European descent (EA) in ECOG-5103. Thirty candidate SNPs were subsequently tested in ECOG-1199 and SNP rs3125923 was found to be significantly associated with grade 3–4 TIPN (P = 1.7 × 10−3; OR, 1.8). Race was also a major predictor of TIPN, with patients of African descent (AA) experiencing increased risk of grade 2–4 TIPN (HR, 2.1; P = 5.6 × 10−16) and grade 3–4 TIPN (HR, 2.6; P = 1.1 × 10−11) compared with others. An SNP in FCAMR, rs1856746, had a trend toward an association with grade 2–4 TIPN in AA patients from the GWAS in ECOG-5103 (OR, 5.5; P = 1.6 × 10−7). Conclusions: rs3125923 represents a validated SNP to predict grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN. Clin Cancer Res; 21(22); 5082–91. ©2015 AACR.

Genome-wide association study for anthracycline-induced congestive heart failure

Purpose: Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anticancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk-to-benefit ratio for each patient. Herein, we present a genome-wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive anthracycline. Experimental Design: We performed a genome-wide association study in 3,431 patients from the randomized phase III adjuvant breast cancer trial E5103 to identify single nucleotide polymorphism (SNP) genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. Results: When evaluating for cardiologist-adjudicated CHF, 11 SNPs had a P value <10−5, of which nine independent chromosomal regions were associated with increased risk. Validation of the top two SNPs in E1199 revealed one SNP rs28714259 that demonstrated a borderline increased CHF risk (P = 0.04, OR = 1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (P = 0.018, OR = 4.2). Conclusions: rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials. Clin Cancer Res; 23(1); 43–51. ©2016 AACR.

Charcot-Marie-Tooth gene, SBF2, associated with taxane-induced peripheral neuropathy in African Americans.

Purpose Taxane-induced peripheral neuropathy (TIPN) is one of the most important survivorship issues for cancer patients. African Americans (AA) have previously been shown to have an increased risk for this toxicity. Germline predictive biomarkers were evaluated to help identify a priori which patients might be at extraordinarily high risk for this toxicity. Experimental design Whole exome sequencing was performed using germline DNA from 213 AA patients who received a standard dose and schedule of paclitaxel in the adjuvant, randomized phase III breast cancer trial, E5103. Cases were defined as those with either grade 3-4 (n=64) or grade 2-4 (n=151) TIPN and were compared to controls (n=62) that were not reported to have experienced TIPN. We retained for analysis rare variants with a minor allele frequency <3% and which were predicted to be deleterious by protein prediction programs. A gene-based, case-control analysis using SKAT was performed to identify genes that harbored an imbalance of deleterious variants associated with increased risk of TIPN. Results Five genes had a p-value < 10−4 for grade 3-4 TIPN analysis and three genes had a p-value < 10−4 for the grade 2-4 TIPN analysis. For the grade 3-4 TIPN analysis, SET binding factor 2 (SBF2) was significantly associated with TIPN (p-value=4.35 x10−6). Five variants were predicted to be deleterious in SBF2. Inherited mutations in SBF2 have previously been associated with autosomal recessive, Type 4B2 Charcot-Marie-Tooth (CMT) disease. Conclusion Rare variants in SBF2, a CMT gene, predict an increased risk of TIPN in AA patients receiving paclitaxel.

Impact of Genetic Ancestry on Outcomes in ECOG-ACRIN-5103

Purpose Racial disparity in breast cancer outcomes exists between African American and Caucasian women in the United States. We have evaluated the impact of genetically determined ancestry on disparity in efficacy and therapy-induced toxicity for breast cancer patients in the context of a randomized, phase III adjuvant trial. Patients and Methods This study compared outcomes between 386 patients of African ancestry (AA) and 2473 patients of European ancestry (EA) in a randomized, phase III breast cancer trial; ECOG-ACRIN-E5103. The primary efficacy endpoint, invasive disease free survival (DFS) and clinically significant toxicities were compared including: anthracycline-induced congestive heart failure (CHF), taxane-induced peripheral neuropathy (TIPN), and bevacizumab-induced hypertension. Results Overall, AAs had significantly inferior DFS (p=0.002; HR=1.5) compared with EAs. This was significant in the estrogen receptor-positive subgroup (p=0.03); with a similar, non-significant trend for those who had triple negative breast cancer (TNBC; p=0.12). AAs also had significantly more grade 3-4 TIPN (OR=2.9; p=2.4 ×10-11) and grade 3-4 bevacizumab-induced hypertension (OR=1.6; p=0.02), with a trend for more CHF (OR=1.8; p=0.08). AAs had significantly more dose reductions for paclitaxel (p=6.6 ×10-6). In AAs, dose reductions in paclitaxel had a significant negative impact on DFS (p=0.03); whereas in EAs, dose reductions did not impact outcome (p=0.35). Conclusion AAs had inferior DFS with more clinically important toxicities in ECOG-ACRIN-E5103. The altered risk to benefit ratio for adjuvant breast cancer chemotherapy should lead to additional research with the focus centered on the impact of genetic ancestry on both efficacy and toxicity. Strategies to minimize dose reductions for paclitaxel, especially due to TIPN, are warranted for this population.

Abstract 5401: Assessment of whole genome amplification for whole exome sequencing in detecting genetic mutation

Whole exome sequencing (WES) has been widely used for studying genetic mutations in DNA coding regions to elucidate cancer etiology and for identifying biomarkers to optimize chemotherapy. However, these studies can be limited when only small amount of DNA is available. Whole genome amplification (WGA) technology can be combined with WES to make these studies technically possible. Here, we evaluated WGA using a phi 29 polymerase prior to library preparation for WES in samples with various DNA concentrations. WES was performed by targeted exon amplification followed by massively parallel sequencing. We compared the base calls of single nucleotide variants for individual same samples with or without WGA prior to library construction to determine the concordance rate of variant calls. We also assessed genetic variant call rate in the same samples with or without WGA. The number of variants obtained ranged from 159,851,999 to 390,784 in the non-amplified samples and from 353,215 to 384,118 in the same amplified samples. The average concordance rate of identical variants in the samples with or without WGA was 96.5%. Our results indicate that WGA in prior to WES can increase detection efficiency of single nucleotide variants in samples with relatively small amount of DNA and/or low DNA concentration. Citation Format: Crystal Xue, Laura Gardner, Guanglong Jiang, Fei Shen, Bryan Schneider. Assessment of whole genome amplification for whole exome sequencing in detecting genetic mutation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5401. doi:10.1158/1538-7445.AM2017-5401