Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal anti-inflammatory drug therapy in colorectal cancer.
OBJECTIVE
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin.


METHODS
We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status.


RESULTS
We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2; 95% CI, 0.53 to 2.72; P = .66; (P)INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87; 95% CI, 0.64 to 1.16; P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11; 95% CI, 0.001 to 0.832; P = .027; (P)INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92; 95% CI, 0.60 to 1.42; P = .71).


CONCLUSIONS
Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.
Enric Domingo, David N. Church, Rajarajan Ramamoorthy, and Ian P.M. Tomlinson, The Wellcome Trust Centre for Human Genetics, University of Oxford; David N. Church, David J. Kerr, and Rachel Midgley, Oxford Cancer Centre, Churchill Hospital; Yoko Yanagisawa, Elaine Johnstone, David J. Kerr, and Rachel Midgley, University of Oxford, Oxford; Rajarajan Ramamoorthy and Brian Davidson, University College London, Royal Free Hospital, London, United Kingdom; and Oliver Sieber, Ludwig Colon Cancer Initiative Laboratory, Ludwig Institute for Cancer Research, Melbourne, Victoria, Australia.
Enric
E
Domingo
David N
DN
Church
Oliver
O
Sieber
Rajarajan
R
Ramamoorthy
Yoko
Y
Yanagisawa
Elaine
E
Johnstone
Brian
B
Davidson
David J
DJ
Kerr
Ian P M
IP
Tomlinson
Rachel
R
Midgley
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D058534:Class I Phosphatidylinositol 3-Kinases; D003082:Colectomy; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D051546:Cyclooxygenase 2 / Q000032:analysis; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D007783:Lactones / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018579:Patient Selection; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D013450:Sulfones / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007783:Lactones; D013450:Sulfones; C116926:rofecoxib; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D001241:Aspirin