PTEN Expression, Not Mutation Status for TSC1, TSC2 or mTOR, Correlates With Outcome on Everolimus in Patients With Renal Cell Carcinoma Treated on RECORD-3

Purpose: Genomic alterations in key components of PI3K/mTOR pathway have been proposed as candidate predictive markers for rapalog therapy in renal cell carcinoma (RCC). We tested this hypothesis in patients from a randomized phase 2 trial of everolimus vs sunitinib. Experimental Design: Archival specimens collected at baseline were analyzed with targeted next-generation sequencing (NGS). Focus of interest were alterations in key PI3K pathway components. PTEN expression was assessed by immunohistochemistry (IHC). Association between molecular findings and treatment outcomes was investigated; same associations were tested for 2 everolimus-treated trial cohorts in gastric and hepatocellular carcinoma (HCC). Results: Among 184 everolimus-treated RCC patients with NGS data, mutation rates in genes of interest were 6% (TSC1), 4.4% (TSC2), and 8.2% (mTOR); 44% harbored alterations in ≥1 PI3K pathway component. For subjects with presence vs. absence of mutations in TSC1, TSC2, or mTOR progression-free survival (PFS) neither differed on univariate analysis (HR, 1.0; P=.895) nor on multivariate testing stratified by MSKCC risk group and other established prognostic factors (HR, 1.1; P=.806). Everolimus-treated patients with retained (n=50) vs lost (n=50) PTEN IHC expression had median PFS of 5.3 vs 10.5 months (HR, 2.5; P<0.001). Such differences were not seen with sunitinib (10.9 vs 10.3 months; HR, 0.8; P=.475). Molecular findings did not correlate with outcomes in gastric and HCC cohorts. Conclusions: Association between mutation status for TSC1/TSC2/mTOR and therapeutic outcome on everolimus was not confirmed. Clinically meaningful differences in PFS were seen based on PTEN expression by IHC, lost in >50% of patients.

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