Pharmacogenetic interaction analysis for the efficacy of systemic treatment in metastatic colorectal cancer.
BACKGROUND
Pharmacogenetic markers related to drug metabolism and mechanisms of action could help to better select patients with metastatic colorectal cancer (mCRC) for treatment. Genetic interaction analysis is used as a rational tool to study the contribution of polygenic variation in relation to drug response.


METHODS
A selection of 17 polymorphisms in genes encoding drug targets, pathway molecules and detoxification enzymes was analyzed in 279 previously untreated mCRC patients treated with capecitabine, oxaliplatin and bevacizumab (CAPOX-B). Multifactor dimensionality reduction analysis was used to identify a genetic interaction profile for progression-free survival (PFS).


RESULTS
Median PFS was 10.9 [95% confidence interval (CI) 9.4-12.4] months. A genetic interaction profile consisting of the TYMS enhancer region and VEGF +405G>C polymorphisms was significantly associated with PFS. Median PFS was 13.3 (95% CI 11.4-15.3) and 9.7 (95% CI 7.6-11.8) months for the beneficial and unfavorable genetic profiles, respectively, corresponding to a hazards ratio for PFS of 1.58 (95% CI 1.14-2.19). None of the studied polymorphisms were individually associated with PFS.


CONCLUSIONS
Our results support a genetic interaction between the TYMS enhancer region and VEGF +405G>C polymorphisms as a predictor of the efficacy of CAPOX-B in mCRC patients.
Department of Clinical Pharmacy & Toxicology.
J
J
Pander
Department of Clinical Pharmacy & Toxicology.
J A M
JAM
Wessels
Department of Clinical Oncology, Leiden University Medical Center, Leiden.
H
H
Gelderblom
Department of Clinical Pharmacy & Toxicology.
T
T
van der Straaten
Department of Medical Oncology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
C J A
CJA
Punt
Department of Clinical Pharmacy & Toxicology. Electronic address: h.j.guchelaar@lumc.nl.
H-J
HJ
Guchelaar
D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004742:Enhancer Elements, Genetic; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D058011:Multifactor Dimensionality Reduction; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011110:Polymorphism, Genetic; D016016:Proportional Hazards Models; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D009944:Organoplatinum Compounds; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D013940:Thymidylate Synthase; D005472:Fluorouracil