Reference Detail

Ref Type Journal Article
PMID (30327302)
Authors Voss MH, Chen D, Reising A, Marker M, Shi J, Xu J, Ostrovnaya I, Seshan V, Redzematovic A, Chen YB, Patel P, Han X, Hsieh JJ, Hakimi AA, Motzer RJ
Title 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.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol
Issue
Date 2018 Oct 16
URL
Abstract Text 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.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).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.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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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PTEN loss renal cell carcinoma predicted - sensitive Everolimus Clinical Study - Cohort Actionable In a retrospective analysis, loss of PTEN expression was associated with improved progression-free survival compared to PTEN positive (10.5 vs 5.3 months) in renal cell carcinoma patients treated with Afinitor (everolimus) (PMID: 30327302). 30327302