ASCO 2017: Comprehensive genomic profiling (CGP) of advanced papillary renal cell carcinoma (PRCC) to reveal distinctions from TCGA dataset

Chicago, IL ( Prior studies assessing the biologic characterization of papillary renal cell carcinoma (PRCC) utilizing the TCGA (The Cancer Genome Atlas) dataset were limited by the fact that only 3% of the 161 patient samples assessed were patients with metastatic disease. As the majority were localized m0 disease, the authors of this study wanted to focus their attention on patients with advanced PRCC.

To that effect, in this study, fresh frozen paraffin-embedded (FFPE) tissue from 169 patients with advanced or metastatic PRCC from multiple institutions were collected. Then, diagnosis and PRCC subtyping was centrally confirmed by 2 board-certified pathologists to ensure validity. DNA was extracted and comprehensive genomic profiling (CGP) was performed in a CLIA-certified central laboratory.

Of the 169 pts, 39 (23%) were type 1, 108 (64%) were type 2 and 22 (13%) were unclassified. Sixty-seven samples (39%) were from a metastatic site biopsy while 102 were from the kidney (61%) itself. Across the board, approximately 2.4 genomic alterations were noted.

When looking at the subtypes, commonly altered gene mutations were MET (33%: 8 activating mutations, 5 amplifications), TERT (30%), CDKN2A/B (13%), and EGFR (8%) in Type 1 PRCC, and CDKN2A/B (18%), TERT (18%), NF2 (13%), (13%), and MET (7.4%, 5 mutations, 3 amplifications) in Type 2 patients.

Genomic alterations in the MET gene was significantly associated with type 1 PRCC (p = 0.0002) while mutations in NF2 and in SWI/SNF complex genes were both significantly associated with type2 PRCC (p = 0.02 and p = 0.007, respectively). When compared to the TCGA dataset, which contained less aggressive disease, the authors noted that there were a higher frequencies of MET and NF2 gene mutations, genomic alterations in SWI/SNF with type 2 PRCC, and CDKN2A/B alteration in both type 1 and type 2 disease.

When comparing biopsies from metastatic sites to primary tumor specimens, metastases had lower MET alterations than primary tumors (type 1: 15% vs 38%; type 2: 4% vs 10%).

Ultimately, the authors conclude that the genomic alteration profile is significantly different between advanced for localized PRCC, as revealed by the differences between their cohort and the TCGA cohort. They hope these findings lead to potentially new targets for PRCC.

1. While the prior studies were primarily m0 patients, it is quite possible that they also included locally advanced or N+ disease. This was not made clear by the authors of this abstract, nor was it able to be assessed.
2. The authors never clearly define what “advanced” PRCC is.

Discussion Points:
Metastatic PRCC, when compared to clear cell RCC, is much less common. PRCC tends to be a more locally aggressive disease. As such, the volume of metastatic PRCC that a single-institution is likely to see is quite low. Therein lies the importance of multi-institutional studies. Future multi-institutional studies are needed to assess any potential actionable medications – the SWOG 1500 study compares conventioned VEGF inhibition (sunitinib) against MET inhibition (cabozantinib, crizotinib, savolinib) in PRCC patients.

Presented By: Sumanta K. Pal

Co-Authors: Daniel M. Geynisman, Siraj Mahamed Ali, Evgeny Yakirevich, Phil Stephens, Jeffrey S. Ross, Vincent A. Miller, Jon Chung, Toni K. Choueiri

Institution(s): City of Hope Comprehensive Cancer Center, Duarte, CA; Fox Chase Cancer Center, Philadelphia, PA; Foudation Medicine, Inc., Cambridge, MA; The Warren Alpert Medical School of Brown University, Providence, RI; Albany Medical College, Albany, NY; Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA