Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer
| Autor: | Fotios Loupakis, Sara Lonardi, Chiara Cremolini, Afsaneh Barzi, Yuji Miyamoto, Shivani Soni, Satoshi Okazaki, Marta Schirripa, Mitsukuni Suenaga, Wu Zhang, Toshiharu Yamaguchi, Shu Cao, Martin D. Berger, Heinz-Josef Lenz, Alfredo Falcone |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Oncology Male Cancer Research Organoplatinum Compounds Colorectal cancer medicine.medical_treatment Leucovorin medicine.disease_cause 030226 pharmacology & pharmacy Cohort Studies 0302 clinical medicine FOLFOX Antineoplastic Combined Chemotherapy Protocols CDX2 Transcription Factor Stage (cooking) 610 Medicine & health FOLFOXIRI Middle Aged Progression-Free Survival Bevacizumab Oxaliplatin medicine.anatomical_structure Cohort FOLFIRI Molecular Medicine Female KRAS Fluorouracil Colorectal Neoplasms Adjuvant medicine.drug Adult medicine.medical_specialty Enterocyte Antineoplastic Agents Polymorphism Single Nucleotide Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Predictive Value of Tests Internal medicine Genetics medicine Biomarkers Tumor Humans Clinical significance neoplasms Gene Aged Pharmacology Polymorphism Genetic business.industry Membrane Proteins medicine.disease digestive system diseases 030104 developmental biology Enterocytes business |
| DOI: | 10.48350/159175 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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