Predictive and prognostic analysis of PIK3CA mutation in stage III colon cancer intergroup trial
Shuji Ogino1, Xiaoyun Liao, Yu Imamura
1Affiliations of authors: Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA (SO, XL, YI, MY, NJM, KN, RJM, JAM, CSF); Department of Pathology (SO), Channing Division of Network Medicine, Department of Medicine (DS, CSF), and Department of Surgery (MMB), Brigham and Women's Hospital and Harvard Medical School, Boston, MA (SO); Department of Epidemiology (SO, DS) and Department of Biostatistics (DS) , Harvard School of Public Health, Boston, MA; Alliance Statistics and Data Center, Duke University Medical Center, Durham, NC (DN); Memorial Sloan-Kettering Cancer Center, New York, NY (LBS); Hôpital du Sacré-Coeur de Montréal, Montreal, Canada (RW); Loyola University Stritch School of Medicine, Maywood, IL (AH); current: Edward Cancer Center, Naperville, IL (AH); Northwestern University, Chicago, IL (ABB); Toledo Community Hospital Oncology Program, Toledo, OH (RBM); Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH (RMG).
Background:
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.
Methods:
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.
Results:
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).
Conclusions:
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.
Insights
PIK3CA mutations do not impact stage III colon cancer prognosis or predict response to irinotecan-based chemotherapy. Further research is needed to understand PIK3CA
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Somatic mutations in the PIK3CA gene activate the PI3K-AKT pathway, contributing to various cancers, including colorectal cancer.
- PIK3CA is a key oncogene implicated in cancer development and progression.
Purpose of the Study:
- To investigate the prognostic and predictive value of PIK3CA mutations in stage III colon cancer.
- To determine if PIK3CA mutation status influences survival or response to adjuvant chemotherapy.
Main Methods:
- Analysis of 627 stage III colon cancer patients from a randomized adjuvant chemotherapy trial.
- Detection of PIK3CA mutations in exons 9 and 20 using polymerase chain reaction and pyrosequencing.
- Cox proportional hazards models assessed prognostic and predictive roles, adjusting for clinical and molecular features (KRAS, BRAF, MSI).
Main Results:
- PIK3CA mutation status was not significantly associated with recurrence-free, disease-free, or overall survival.
- No significant interaction was observed between PIK3CA and KRAS/BRAF mutation status in survival analyses.
- PIK3CA mutation status did not predict differential response to irinotecan-based (IFL) versus fluorouracil/leucovorin (FU/LV) chemotherapy.
Conclusions:
- Tumor PIK3CA mutation status does not correlate with prognosis in stage III colon cancer.
- PIK3CA mutations are not a predictive biomarker for response to irinotecan-based adjuvant chemotherapy in this patient cohort.
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