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.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2018 Oct 16 [Epub ahead of print]
Martin H Voss, David Chen, Albert Reising, Mahtab Marker, Jiayuan Shi, Jianing Xu, Irina Ostrovnaya, Venkatraman Seshan, Almedina Redzematovic, Ying-Bei Chen, Parul Patel, Xia Han, James J Hsieh, A Ari Hakimi, Robert J Motzer
GU oncology, Memorial Sloan Kettering Cancer Center ., Novartis Pharmaceuticals Corporation, East Hanover, New Jersey, USA., Oncology Precision Medicine, Novartis Oncology., Statistics, Novartis Oncology., Global Biometric Sciences, Bristol-Myers Squibb Company., Human Oncology Pathogenesis Program, Memorial Sloan Kettering Cancer Center., Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center., Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center., Memorial Sloan Kettering Cancer Center., Department of Pathology, Memorial Sloan Kettering Cancer Center., Oncology, Novartis Oncology., Novartis Oncology., Medicine, Washington University., Surgery - Urology Service, Memorial Sloan Kettering Cancer Center., Department of Medicine, Memorial Sloan Kettering Cancer Center.