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Genetic variation in EPHA contributes to sensitivity to paclitaxel‐induced peripheral neuropathy
Author(s) -
Marcath Lauren A.,
Kidwell Kelley M.,
Vangipuram Kiran,
Gersch Christina L.,
Rae James M.,
Burness Monika L.,
Griggs Jennifer J.,
Van Poznak Catherine,
Hayes Daniel F.,
Smith Ellen M. Lavoie,
Henry N. Lynn,
Beutler Andreas S.,
Hertz Daniel L.
Publication year - 2020
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/bcp.14192
Subject(s) - paclitaxel , confidence interval , medicine , peripheral neuropathy , coefficient of variation , chemotherapy , minor allele frequency , oncology , missense mutation , toxicity , allele , gastroenterology , allele frequency , biology , mutation , genetics , endocrinology , chemistry , chromatography , gene , diabetes mellitus
Aims Chemotherapy‐induced peripheral neuropathy (PN) is a treatment limiting toxicity of paclitaxel. We evaluated if EPHA genetic variation ( EPHA4 , EPHA5 , EPHA6 , and EPHA8 ) is associated with PN sensitivity by accounting for variability in systemic paclitaxel exposure (time above threshold). Methods Germline DNA from 60 patients with breast cancer was sequenced. PN was measured using the 8‐item sensory subscale (CIPN8) of the patient‐reported CIPN20. Associations for 3 genetic models were tested by incorporating genetics into previously published PN prediction models integrating measured paclitaxel exposure and cumulative treatment. Significant associations were then tested for association with PN‐related treatment disruption. Results EPHA5 rs7349683 (minor allele frequency = 0.32) was associated with increased PN sensitivity (β‐coefficient = 0.39, 95% confidence interval 0.11–0.67, p = 0.007). Setting a maximum tolerable threshold of CIPN8 = 30, optimal paclitaxel exposure target is shorter for rs7349683 homozygous (11.6 h) than heterozygous (12.6 h) or wild‐type (13.6 h) patients. Total number of missense variants (median = 0, range 0–2) was associated with decreased PN sensitivity (β‐coefficient: −0.42, 95% confidence interval −0.72 to −0.12, P = .006). No association with treatment disruption was detected for the total number of missense variants or rs7349683. Conclusion Isolating toxicity sensitivity by accounting for exposure is a novel approach, and rs7349683 represents a promising marker for PN sensitivity that may be used to individualize paclitaxel treatment.