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Identification of a SNP cluster associated with taxane-induced peripheral neuropathy risk in patients being treated for breast cancer using GWAS data derived from a large cooperative group trial

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Abstract

Background

Chemotherapy-induced peripheral neuropathy (CIPN) is a common toxicity of taxanes for which there is no effective intervention. Genomic CIPN risk determination has yielded promising, but inconsistent results. The present study assessed the utility of a collective SNP cluster identified using novel analytics to describe taxane-associated CIPN risk.

Methods

We analyzed GWAS data derived from ECOG-5103, first identifying SNPs that were most strongly associated with CIPN using Fisher’s ratio (FR). We then ranked ordered those SNPs which discriminated CIPN-positive (CIPN +) from CIPN-negative phenotypes based on their discriminatory power and developed the cluster of SNPs which provided the highest predictive accuracy using leave-one-out cross-validation (LOOCV).

Results

Using aggregated genotype data obtained from the previously reported ECOG-5103 clinical trial (in which two different arrays were used, HumanOmniExpress (727,227 SNPs) and HumanOmni1-Quad1 (1,131,857 SNPs)), we identified a 267 SNP cluster which was associated with a CIPN + phenotype with an accuracy of 96.1%.

Conclusions

A cluster of SNPs was identified which prospectively discriminated patients most likely to develop symptomatic CIPN following taxane exposure as part of a breast cancer chemotherapy regimen. Validation using an independent patient cohort should be performed.

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Abbreviations

CIPN :

Chemotherapy-induced peripheral neuropathy

GWAS :

Standard genome-wide association studies

SNP:

Single-nucleotide polymorphisms

HOQ1 :

HumanOmni1-Quad1

HOE :

Holdout experiment

LOOCV :

Leave-one-out cross-validation

CDF :

Cumulative distribution function

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Acknowledgements

We thank Dr. Antonio Wolff (Johns Hopkins University), Dr. Kathy Miller (Indiana University), Dr. George Sledge (Stanford University), and Anne O’Neill (Harvard/Dana Farber) and all the patients who participated in ECOG 5103 for providing access to the data that were used to analyze the reported results in this manuscript.

Funding

This work was supported by grants from the Division of Cancer Prevention, National Cancer Institute (R01CA238946-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. School of Medicine, Yale University, New Haven, CT, USA

    Maryam Lustberg

  2. Harvard School of Dental Medicine, Boston, MA, USA

    Xuan Wu & Stephen Sonis

  3. Primary Endpoint Solutions, Waltham, MA, USA

    Juan Luis Fernández-Martínez, Enrique J. de Andrés-Galiana, Jeffrey Leibowitz & Stephen Sonis

  4. Mathematics Department, University of Oviedo, Oviedo, Spain

    Juan Luis Fernández-Martínez

  5. Computer Science Department, University of Oviedo, Oviedo, Spain

    Enrique J. de Andrés-Galiana

  6. Indiana University School of Medicine, Indianapolis, IN, USA

    Santosh Philips & Bryan Schneider

  7. Brigham and Women’s Hospital, Boston, MA, USA

    Jeffrey Leibowitz & Stephen Sonis

  8. Dana-Farber Cancer Institute, Boston, MA, USA

    Stephen Sonis

Authors
  1. Maryam Lustberg
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  2. Xuan Wu
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Contributions

SS and MBL conceived the study concept and wrote the manuscript and edited the manuscript. XW participated in the design of the study, data collection, and analysis, and drafted the manuscript. JLFM and E. J. d. A. G. participated in data analysis, algorithm, and interpretation. SP and BS participated in the design of the study; data analysis and implementation of machine learning algorithm interpretation. JL participated in data collection and data analysis. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Maryam Lustberg.

Ethics declarations

Ethics approval and consent to participate

This is a secondary analysis of a completed clinical trial ECOG 5103. ECOG-ACRIN E5103 was previously approved, including additional secondary analyses of genomic data, by the Central Institutional Review Board (CIRB) for the National Cancer Institute (NCI) and conducted in accordance with Good Clinical Practice guidelines as defined by the International Conference on Harmonisation. All patients provided IRB-approved written informed consent. This study was monitored by the ECOG-ACRIN Data Safety Monitoring Committee and the NCI. The current secondary analysis has been approved by the ECOG Executive Board. The National Cancer Institute Central Institutional Review Board (IRB) approved the protocol the IRB of record for a subset of institutions; the remaining sites used their own individual IRBs. Written informed consent was obtained from all participants. Secondary analyses were in accordance with original consent and IRB approval and were further approved by the ECOG Executive Board.

Competing interests

Dr. Sonis reports personal fees from Biomodels, LLC, and personal fees from Primary Endpoint Solutions, LLC, outside of the submitted work. As an employee of Biomodels and PES, he is involved in assisting industry, government, and academics in the study and enablement of drugs, biologicals, and devices to treat patients for a broad range of indications including cancer and toxicities of cancer therapy. He does not have equity or receive payment from any of the companies’ clients. The other authors have no relevant disclosers.

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Lustberg, M., Wu, X., Fernández-Martínez, J.L. et al. Identification of a SNP cluster associated with taxane-induced peripheral neuropathy risk in patients being treated for breast cancer using GWAS data derived from a large cooperative group trial. Support Care Cancer 31, 139 (2023). https://doi.org/10.1007/s00520-023-07595-9

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