Pharmacogenetic predictors of adverse events and response to chemotherapy in metastatic colorectal cancer: results from North American Gastrointestinal Intergroup Trial N9741.
OBJECTIVE
With three available chemotherapy drugs for advanced colorectal cancer (CRC), response rate (RR) and survival outcomes have improved with associated morbidity, accentuating the need for tools to select optimal individualized treatment. Pharmacogenetics identifies the likelihood of adverse events or response based on variants in genes involved in drug transport, metabolism, and cellular targets.


METHODS
Germline DNA was extracted from 520 patients on the North American Gastrointestinal Intergroup N9741 study. Three study arms were evaluated: IFL (fluorouracil [FU] + irinotecan [IRN]), FOLFOX (FU + oxaliplatin), and IROX (IRN + oxaliplatin). Information on adverse events, response, and disease-free survival was available. Thirty-four variants in 15 candidate genes for analysis based on previous associations with adverse events or outcome were assessed. Genotyping was performed using pyrosequencing.


RESULTS
All variants were polymorphic. The homozygous UGT1A1*28 allele observed in 9% of patients was associated with risk of grade 4 neutropenia in patients on IROX (55% v 15%; P = .002). Deletion in GSTM1 was associated with grade 4 neutropenia after FOLFOX (28% v 16%; P = .02). Patients with a homozygous variant genotype for GSTP1 were more likely to discontinue FOLFOX because of neurotoxicity (24% v 10%; P = .01). The presence of a CYP3A5 variant was significantly associated with RR on IFL (29% v 60%; P = .0074). Most previously published genotype-toxicity or -efficacy relationships were not validated in this study.


CONCLUSIONS
This study provides a platform to evaluate pharmacogenetic predictors of response or severe adverse events in advanced CRC. Pharmacogenetic studies can be conducted in multicenter trials, and our findings demonstrate that with continued research, clinical application is practical.
University of North Carolina Institute for Pharmacogenomics and Individualized Therapy, University of North Carolina, Chapel Hill, NC 27599-7360, USA. hmcleod@unc.edu
Howard L
HL
McLeod
Daniel J
DJ
Sargent
Sharon
S
Marsh
Erin M
EM
Green
Cristi R
CR
King
Charles S
CS
Fuchs
Ramesh K
RK
Ramanathan
Stephen K
SK
Williamson
Brian P
BP
Findlay
Stephen N
SN
Thibodeau
Axel
A
Grothey
Roscoe F
RF
Morton
Richard M
RM
Goldberg
D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005838:Genotype; D006801:Humans; D007674:Kidney Diseases / Q000139:chemically induced; D008875:Middle Aged; D009503:Neutropenia / Q000235:genetics; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic