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Clinical Trial
. 2016 Jul 8;11(7):e0158984.
doi: 10.1371/journal.pone.0158984. eCollection 2016.

The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study

Leila Dorling  1 , Siddhartha Kar  1 , Kyriaki Michailidou  1   2 , Louise Hiller  3 , Anne-Laure Vallier  4 , Susan Ingle  4 , Richard Hardy  4 , Sarah J Bowden  5 , Janet A Dunn  3 , Chris Twelves  6 , Christopher J Poole  3 , Carlos Caldas  4   7   8 , Helena M Earl  4   7 , Paul D P Pharoah  1 , Jean E Abraham  1   4   7
Affiliations
Clinical Trial

The Relationship between Common Genetic Markers of Breast Cancer Risk and Chemotherapy-Induced Toxicity: A Case-Control Study

Leila Dorling et al. PLoS One. .

Abstract

Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.

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Conflict of interest statement

Competing Interests: The original tAnGo and Neo-tAnGo trials were supported by funding from commercial sources Eli Lilly Limited, Bristol Myers Squibb, and Pfizer. The funders made no contribution to the design, analysis and reporting of the work described in this manuscript. Further, this does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Distribution of polygenic risk scores in the PGSNPS cohort.
A) Non-weighted polygenic risk score. B) Weighted polygenic risk score.
Fig 2
Fig 2. Scatter plot comparing variant-associated odds ratios for breast cancer risk, published by the Breast Cancer Association Consortium (BCAC), with odds ratios for neutropenia risk estimated in the Pharmacogenetic SNPs (PGSNPS) study.
Fig 3
Fig 3. Kaplan-Meier plot comparing relapse-free survival in patients carrying >90 risk alleles to those carrying <80 risk alleles.
See this image and copyright information in PMC

References

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