Abstract
Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49–0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44–0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19–0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.
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Acknowledgements
This work was partly supported by the National Cancer Institute (grant number P30CA014089), The Gloria Borges WunderGlo Foundation—The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, Daniel Butler Research Fund and Call to Cure Fund. Mitsukuni Suenaga is the recipient of Takashi Tsuruo Memorial Fund. Martin D. Berger received a grant from the Swiss Cancer League (BIL KLS-3334-02-2014) and the Werner and Hedy Berger-Janser Foundation for cancer research. YM received a grant from Japan Society for the Promotion of Science (S2606). We thank Anne M. O’Rourke, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.
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All authors have read the journal’s policy on disclosure of potential conflicts of interest. CC is a consultant/advisory board member for Roche, Amgen, Bayer, Merck Serono, Servier. AF is a consultant/advisory board member for Bayer, Roche, Amgen, Eli-Lilly, Merck Serono, Bristol-Myers Squibb, Sanofi, and Servier. H-JL is consultant /advisory board member for Bristol-Myers Squibb, Merck Serono, and Bayer. All remaining authors have no conflicts of interest to declare in this work.
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Suenaga, M., Schirripa, M., Cao, S. et al. Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer. Pharmacogenomics J 21, 285–295 (2021). https://doi.org/10.1038/s41397-021-00207-x
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DOI: https://doi.org/10.1038/s41397-021-00207-x