Tissue based biomarkers in non-clear cell RCC: Correlative analysis from the ASPEN clinical trial

Abstract

Biomarkers are needed in patients with non-clear cell renal cell carcinomas (NC-RCC), particularly papillary renal cell carcinoma, in order to inform on initial treatment selection and identify potentially novel targets for therapy. We enrolled 108 patients in ASPEN, an international randomized open-label phase 2 trial of patients with metastatic papillary, chromophobe, or unclassified NC-RCC treated with the mTOR inhibitor everolimus (n=57) or the vascular endothelial growth factor (VEGF) receptor inhibitor sunitinib (n=51), stratified by MSKCC risk and histology. The primary endpoint was overall survival (OS) and secondary efficacy endpoints for this exploratory biomarker analysis were radiographic progression-free survival (rPFS) defined by intention-to-treat using the RECIST 1.1 criteria and radiographic response rates. Tissue biomarkers (n=78) of mTOR pathway activation (phospho-S6 and -Akt, c-kit) and VEGF pathway activation (HIF-1α, c-MET) were prospectively explored in tumor tissue by immunohistochemistry prior to treatment and associated with clinical outcomes. We found that S6 activation was more common in poor-risk NC-RCC tumors and S6/Akt activation was associated with worse PFS and OS outcomes with both everolimus and sunitinib, while c-kit was commonly expressed in chromophobe tumors and associated with improved outcomes with both agents. C-MET was commonly expressed in papillary tumors and was associated with lower rates of radiographic response but did not predict PFS for either agent. In multivariable analysis, both pAkt and c-kit were statistically significant prognostic biomarkers of OS. No predictive biomarkers of treatment response were identified for clinical outcomes. Most biomarker subgroups had improved outcomes with sunitinib as compared to everolimus.

Advances in non‐clear cell renal cell carcinoma management: From heterogeneous biology to treatment options

“…97 Moreover, tissue-based biomarker analyses of ASPEN trial demonstrated that c-kit expression was associated with a favorable response to everolimus, whereas c-MET expression was associated with a poor response to sunitinib or everolimus. 98 Genomic analysis of patients in the RECORD-3 study 99 found that among patients treated with frontline sunitinib, PFS was longer in those with KDM5C mutations (20.6 months) than in those with PBRM1 mutations (11 months) or BAP1 mutations (8.1 months). 100 The incidence of these genetic mutations in patients with various subtypes of nccRCC is not well reported.…”

“…Analysis of plasma angiokines of patients in the ASPEN trial while on treatment found associations between the presence of osteopontin, thrombospondin‐2, VCAM‐1, hepatocyte growth factor and TIMP‐1 with poor‐risk disease and worse prognosis 97 . Moreover, tissue‐based biomarker analyses of ASPEN trial demonstrated that c‐kit expression was associated with a favorable response to everolimus, whereas c‐MET expression was associated with a poor response to sunitinib or everolimus 98 . Genomic analysis of patients in the RECORD‐3 study 99 found that among patients treated with frontline sunitinib, PFS was longer in those with KDM5C mutations (20.6 months) than in those with PBRM1 mutations (11 months) or BAP1 mutations (8.1 months) 100 .…”

PD-L1 expression and its prognostic value in metastatic papillary renal cell carcinoma: Results from a GETUG multicenter retrospective cohort

“…Albiges et al's study of over 90 sporadic pRCC samples found high MET expression (46 % of type 2 pRCC and 81 % of type 1 pRCC) [33]. We also sought to characterize carbonic anhydrase IX (CAIX) expression, as it is regulated by the hypoxia-inducible factor 1 alpha, a factor that also induces angiogenesis via the VEGF pathway [31,34,35]. Moreover CAIX is often overexpressed in ccRCC, and its low expression is a poor prognostic factor [36].…”

“…Regarding angiogenesis markers, c-MET, through the HGF (Hepatocyte Growth Factor)/c-MET pathway, has been described not only as a promoter of cell proliferation and anti-apoptotic activity, but also as an angiogenic factor [29][30][31]. This c-MET pathway is frequently activated in pRCC, and several data sources, such as The Cancer Genome Atlas (TCGA), containing 161 localized pRCCs, reported 81 % of MET alterations in type 1 pRCC [32].…”