ORLANDO—Protein expression markers predict disease-specific survival (DSS) in clear cell renal cell carcinoma (ccRCC), according to research (Abstract 406) presented during the 2015 Genitourinary Cancers Symposium.1
“We have identified and validated proteomic signatures which cluster ccRCC patients into five prognostic groups,” reported lead study author Samuel D. Kaffenberger, MD, of the Memorial Sloan Kettering Cancer Center in New York, NY. “Furthermore, two distinct mTOR-activated clusters—one with high receptor tyrosine kinase (RTK) activity and one with increased mTOR pathway genomic alterations—were revealed, which may have prognostic and therapeutic implications.”
The study authors ”sought to leverage reverse phase protein array (RPPA) data from The Cancer Genome Atlas (TCGA)” with an independently developed proteomic platform to identify druggable targets and pathways associated with prognosis in ccRCC, Dr. Kaffenberger said.
They conducted pathway analysis for differentially expressed proteins and assessed associations with clinicogenomic factors and DSS.
“RPPA clustering of 324 patients from the ccRCC TCGA [cohort] revealed five robust clusters characterized by alterations in specific pathways and divergent prognoses,” Dr. Kaffenberger explained.
Both clusters 1 and 2 showed evidence of downstream upregulation of mTOR.
Cluster 1 was characterized by poor DSS, decreased expression of RTK and upregulation of the mTOR pathway, and was associated with mTOR pathway genomic alterations, sarcomatoid histology, and the ccB prognostic mRNA signature (all Ps <0.001).
Cluster 2 was characterized by increased expression of RTKs “and interestingly, had upregulation of the mTOR pathway with excellent DSS,” Dr. Kaffenberger noted. Whereas cluster 1 was associated with worse survival, cluster 2 was associated with superior DSS. After accounting for stage and grade in multivariate analysis, cluster designations remained independently associated with DSS (hazard ratio=0.23 for cluster 2; 95% CI 0.08-0.68; P=0.008).”
“Cluster 1 was associated with universal downregulation of the RTK pathway,” Dr. Kaffenberger noted. “Conversely, cluster 2, which was also associated with upregulation of the mTOR pathway, was associated with universal upregulation of the RTK pathways.”
The study authors subsequently performed an external validation analysis with a separate cohort of 189 patients, using a different proteomics platform—a panel of phosphoproteins (pHER1, pHER2, pHER3, pSHC, pMEK, pAKT) that were highly discriminant between clusters 1 and 2, Dr. Kaffenberger reported.
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In the external validation cohort, patients with mTOR pathway activation were segregated into two groups: those with coincident high-RTK activation (83 patients) and those with low RTK activation (13 patients). A univariate comparison of DSS in these high- versus low-RTK score groups found a significant difference: DSS hazard ratio=0.19 (95% CI: 0.05-0.082; P=0.03).
“We found that we were able to accurately stratify patients with clear cell RCC based purely upon protein expression, and furthermore, we found that this stratification was independently prognostic,” Dr. Kaffenberger concluded. “We validated this data with a separate patient cohort and a separate proteomics plastform.”
Following the external validation analysis, RPPA was adapted to predict responses to mTOR inhibitor (mTORi) therapy, using a novel RPPA antibody panel. Preliminary results suggest the novel RPPA panel can predict response to mTOR inhibition, and the researchers are now pursuing study of a larger cohort of mTORi responders.
- Kaffenberger SD, Ciriello G, Winer AG. Proteomic stratification of clear cell renal cell carcinoma utilizing The Cancer Genome Atlas (TCGA) with external validation. 2015 Genitourinary Cancers Symposium. Abstract 406.