PTEN Expression, Not Mutation Status in TSC1, TSC2 , or mTOR , Correlates with the Outcome on Everolimus in Patients with Renal Cell Carcinoma Treated on the Randomized RECORD-3 Trial

• Published in: Clinical cancer research Vol. 25; no. 2; pp. 506 - 514
• Main Authors: Voss, Martin H., Chen, David, Reising, Albert, Marker, Mahtab, Shi, Jiayuan, Xu, Jianning, Ostrovnaya, Irina, Seshan, Venkatraman E., Redzematovic, Almedina, Chen, Ying-Bei, Patel, Parul, Han, Xia, Hsieh, James J., Hakimi, A. Ari, Motzer, Robert J.
• Format: Journal Article
• Language: English
• Published: United States 15.01.2019
• Subjects: Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - therapeutic use; Biomarkers, Tumor; Carcinoma, Renal Cell - diagnosis; Carcinoma, Renal Cell - drug therapy; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - mortality; Everolimus - administration & dosage; Everolimus - adverse effects; Everolimus - therapeutic use; Female; Gene Expression; Humans; Kaplan-Meier Estimate; Kidney Neoplasms - diagnosis; Kidney Neoplasms - drug therapy; Kidney Neoplasms - genetics; Kidney Neoplasms - mortality; Male; Middle Aged; Mutation; Neoplasm Metastasis; Neoplasm Staging; Prognosis; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Retreatment; TOR Serine-Threonine Kinases - genetics; Treatment Outcome; Tuberous Sclerosis Complex 1 Protein - genetics; Tuberous Sclerosis Complex 2 Protein - genetics
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-1833

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 II trial of everolimus versus 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 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 patients with RCC with NGS data, mutation rates in genes of interest were 6% ( ), 4.4% ( ), and 8.2% ( ); 44% harbored alterations in ≥1 PI3K pathway component. For subjects with presence versus absence of mutations in , or progression-free survival (PFS) neither differed on univariate analysis (HR, 1.0; = 0.895) nor on multivariate testing stratified by MSKCC risk group and other established prognostic factors (HR, 1.1; = 0.806). Everolimus-treated patients with retained ( = 50) versus lost ( = 50) PTEN IHC expression had median PFS of 5.3 months versus 10.5 months (HR, 2.5; < 0.001). Such differences were not seen with sunitinib (10.9 months vs. 10.3 months; HR, 0.8; = 0.475). Molecular findings did not correlate with outcomes in gastric and HCC cohorts. Association between mutation status for / / 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.