Predictive and Prognostic Analysis of PIK3CA Mutation in Stage III Colon Cancer Intergroup Trial

• Published in: JNCI : Journal of the National Cancer Institute Vol. 105; no. 23; pp. 1789 - 1798
• Main Authors: Ogino, Shuji, Liao, Xiaoyun, Imamura, Yu, Yamauchi, Mai, McCleary, Nadine J., Ng, Kimmie, Niedzwiecki, Donna, Saltz, Leonard B., Mayer, Robert J., Whittom, Renaud, Hantel, Alexander, Benson, Al B., Mowat, Rex B., Spiegelman, Donna, Goldberg, Richard M., Bertagnolli, Monica M., Meyerhardt, Jeffrey A., Fuchs, Charles S.
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 04.12.2013; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Chemotherapy; Chemotherapy, Adjuvant; Class I Phosphatidylinositol 3-Kinases; Clinical outcomes; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - pathology; Colonic Neoplasms - surgery; Colorectal cancer; Disease-Free Survival; Female; Fluorouracil - administration & dosage; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Kaplan-Meier Estimate; Leucovorin - administration & dosage; Male; Medical sciences; Microsatellite Instability; Middle Aged; Multivariate Analysis; Mutation; Neoplasm Staging; Oncology; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinases - genetics; Polymerase Chain Reaction; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Antineoplastic agent; Relapse; Prognosis; Adjuvant treatment; Calcium folinate; Isomerases; Colon cancer; Cancerology; Genetics; Intestinal disease; Topoisomerase I inhibitor; Fluorouracil; Camptothecin derivatives; Human; Drug combination; Enzyme; Fluoropyrimidine derivatives; Transferases; Treatment efficiency; DNA topoisomerase; Enzyme inhibitor; Malignant tumor; Thymidylate synthase; Survival; 1-Phosphatidylinositol 3-kinase; Colonic disease; Irinotecan; Chemotherapy; Treatment; Antimetabolic; Methyltransferases; Pyrimidine derivatives; Digestive diseases; Locally advanced stage; Mutation; Cancer
• ISSN: 0027-8874; 1460-2105; 1460-2105
• DOI: 10.1093/jnci/djt298

Somatic mutations in PIK3CA (phosphatidylinositol-4,5-bisphosphonate 3-kinase [PI3K], catalytic subunit alpha gene) activate the PI3K-AKT signaling pathway and contribute to pathogenesis of various malignancies, including colorectal cancer. We examined associations of PIK3CA oncogene mutation with relapse, survival, and treatment efficacy in 627 stage III colon carcinoma case subjects within a randomized adjuvant chemotherapy trial (5-fluorouracil and leucovorin [FU/LV] vs irinotecan [CPT11], fluorouracil and leucovorin [IFL]; Cancer and Leukemia Group B 89803 [Alliance]). We detected PIK3CA mutation in exons 9 and 20 by polymerase chain reaction and pyrosequencing. Cox proportional hazards model was used to assess prognostic and predictive role of PIK3CA mutation, adjusting for clinical features and status of routine standard molecular pathology features, including KRAS and BRAF mutations and microsatellite instability (mismatch repair deficiency). All statistical tests were two-sided. Compared with PIK3CA wild-type cases, overall status of PIK3CA mutation positivity or the presence of PIK3CA mutation in either exon 9 or 20 alone was not statistically significantly associated with recurrence-free, disease-free, or overall survival (log-rank P > .70; P > .40 in multivariable regression models). There was no statistically significant interaction between PIK3CA and KRAS (or BRAF) mutation status in survival analysis (P(interaction) > .18). PIK3CA mutation status did not appear to predict better or worse response to IFL therapy compared with FU/LV therapy (P(interaction) > .16). Overall tumor PIK3CA mutation status is not associated with stage III colon cancer prognosis. PIK3CA mutation does not appear to serve as a predictive tumor molecular biomarker for response to irinotecan-based adjuvant chemotherapy.