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

Abstract

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 3431 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 <10−4 from patients of European descent (EA) in ECOG-5103. 30 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. A 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). Conclusion rs3125923 represents a validated SNP to predict Grade 3-4 TIPN. Genetically determined AA race represents the most significant predictor of TIPN.

OATP1B2 deficiency protects against paclitaxel-induced neurotoxicity

“…The predictive strategies have predominantly focused on the search for hereditary biomarkers that could identify patients at increased risk of toxicity through candidate gene or genome-wide association studies (5,11,12). However, the findings from these studies done to date have identified nonoverlapping single or pathway biomarker associations that preclude immediate clinical implementation.…”

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials

“…An analysis of patients with early-stage breast cancer did not show an association between self-reported black race and CIPN; however, a genome-wide association study of patients in the same study found an association between genetically determined African ancestry and taxane-induced CIPN. 7 Similarly, in an analysis from a SWOG adjuvant breast cancer trial, an African American-specific haplotype was associated with an almost threefold increase in risk of CIPN. 17 These studies did not have information on baseline diabetes.…”

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

“…Previously, we reported that compared to all other races, AAs had higher risk of experiencing grade 2-4 TIPN; HR=2.1 (p=9.4 ×10 -15 ) and grade 3-4 TIPN; HR=2.7 (p=7.4 ×10 -13 ), respectively. 17 When assessed for impact of genetic ancestry on the risk of various definitions of hypertension in the bevacizumab containing arms (arms B and C), African ancestry was associated with significantly more grade 3-4 hypertension (OR=1.6; p=0.02), a trend toward more patients with one SBP measurement >160 mmHg (OR=1.4; p=0.07) or one SBP measurement >180 mmHg (OR=2.1; p=0.03); Figure 3. Finally, there was a trend for more AA patients that had CHF (OR=1.8; p=0.08); Figure 3.…”

“…15,17,18 In this study we have compared the likelihood of each of these clinically relevant toxicities between AAs and EAs. We report a numerically higher likelihood for each of these toxicities for AA's; with odds ratios ranging from 1.4-2.9.…”

“…We had previously published biomarker data on each of these toxicities 15,17,18 and set out to compare the frequency of all toxicities between AAs and EAs and to assess the impact of race on dose modifications with the current study. Statistical analysis was performed using R (v3.3.0) and the chi-square test.…”