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 Journal Article


Authors: Voss, M. H.; Chen, D.; Reising, A.; Marker, M.; Shi, J.; Xu, J.; Ostrovnaya, I.; Seshan, V. E.; Redzematovic, A.; Chen, Y. B.; Patel, P.; Han, X.; Hsieh, J. J.; Ari Hakimi, A.; Motzer, R. J.
Article Title: 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
Abstract: 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 II trial of everolimus versus sunitinib. Patients and Methods: 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). Results: Among 184 everolimus-treated patients with RCC 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 versus absence of mutations in TSC1, TSC2, or mTOR progression-free survival (PFS) neither differed on univariate analysis (HR, 1.0; P 1⁄4 0.895) nor on multivariate testing stratified by MSKCC risk group and other established prognostic factors (HR, 1.1; P 1⁄4 0.806). Everolimus-treated patients with retained (n 1⁄4 50) versus lost (n 1⁄4 50) PTEN IHC expression had median PFS of 5.3 months versus 10.5 months (HR, 2.5; P < 0.001). Such differences were not seen with sunitinib (10.9 months vs. 10.3 months; HR, 0.8; P 1⁄4 0.475). 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. © 2018 American Association for Cancer Research.
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 2
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-01-15
Start Page: 506
End Page: 514
Language: English
DOI: 10.1158/1078-0432.Ccr-18-1833
PUBMED: 30327302
PROVIDER: scopus
DOI/URL:
Notes: Article -- Export Date: 1 February 2019 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Venkatraman Ennapadam Seshan
    282 Seshan
  2. Robert Motzer
    707 Motzer
  3. Martin Henner Voss
    122 Voss
  4. Yingbei Chen
    220 Chen
  5. Abraham Ari Hakimi
    127 Hakimi
  6. Jianing Xu
    9 Xu