PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases.

Etay Ziv,David B Solit,Joseph P Erinjeri,E Nadia Petre,Rona Yaeger,Stephen B Solomon,Michael Bergen,F Ed Boas,Constantinos T Sofocleous,Hooman Yarmohammadi

doi:10.18632/oncotarget.15278

Etay Ziv, David B Solit + Show 8 more

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https://doi.org/10.18632/oncotarget.15278

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Abstract

PurposeTo establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization.Materials and MethodsRetrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk.ResultsSixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP.ConclusionsPI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.

Highlights

Patients with metastatic colorectal cancer have poor prognosis with 5-year survival rates between 10-20%[1]
Materials and Methods: Retrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the mitogen-activated protein kinase (MAPK)/phosphatidylinositol 3-kinase (PI3K) pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1)
Mutation in the PI3K pathway was a significant predictor of longer time to local progression (TTLP) in both univariate (p=0.031, subdistribution hazard ratio (sHR) 0.31, 95% confidence interval (CI): 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis

Summary

Introduction

Patients with metastatic colorectal cancer (mCRC) have poor prognosis with 5-year survival rates between 10-20%[1]. Improvements in survival over the past ten years may be in part due to the introduction of molecular therapies including monoclonal antibodies targeted against receptor tyrosine kinases (RTK) such as the epidermal growth factor receptor (EGFR)[2]. Despite these improvements, patients with mutations in downstream effectors of the EGFR signaling pathway may not respond to these anti-EGFR antibodies [3]. Two well-established downstream effectors of EGFR are the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) signaling pathways (see Figure 1). Mutations of the MAPK and PI3K signaling pathways may predict worse outcome independent of anti-EGFR antibody treatment [8, 9]

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