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

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.

The Link between the Multiverse of Immune Microenvironments in Metastases and the Survival of Colorectal Cancer Patients

“…Beside genetic changes, the host immune response could influence the metastatic process (Angelova et al, 2018). Associations of mutations with increased immune infiltrate, cytolytic activity, and prolonged survival were previously described in primary tumors (Edelbauer et al, 2010;Manceau et al, 2015;Mlecnik et al, 2016a;Nosho et al, 2010;Rooney et al, 2015;Ziv et al, 2017). In such tumors, Immunoscore outperformed tumor molecular factors, such as microsatellite instability status in predicting survival (Mlecnik et al, 2016a).…”

Signal transduction pathway mutations in gastrointestinal (GI) cancers: a systematic review and meta-analysis

“… + ? * + + 137 118 Ho 2017 Hong Kong + + + * + + 138 119 Hänninen 2018 Finland + + + * + + 139 120 Mizuno 2018 USA + + + * + + 140 121 Yang 2018 China + + + * + + 141 …”

Genomics and Interventional Oncology in Metastatic Liver Cancer

“…A more recent study completed by our group determined that 49 Ziv et al determined that those patients with PI3K pathway mutations had longer time to local progression after treatment with Y-90 radioembolization. 50 Melucci et al showed in a study where biopsy samples were collected prospectively that survivin, p53, and Bcl-2 expression decreases after Y-90 radioembolization treatment and that levels may elucidate the radiosensitivity of colorectal liver metastases. 51 Fahmueller et al determined that high mobility group box 1 protein levels at 24 hours post-Y-90 treatment were significantly higher in those patients with disease progression.…”