Genomic Biomarkers of a Randomized Trial Comparing First-line Everolimus and Sunitinib in Patients with Metastatic Renal Cell Carcinoma

Abstract

Background Metastatic renal cell carcinoma (RCC) patients are commonly treated with vascular endothelial growth factor (VEGF) inhibitors or mammalian target of rapamycin inhibitors. Correlations between somatic mutations and first-line targeted therapy outcomes have not been reported on a randomized trial. Objective To evaluate the relationship between tumor mutations and treatment outcomes in RECORD-3, a randomized trial comparing first-line everolimus (mTOR inhibitor) followed by sunitinib (VEGF inhibitor) at progression with the opposite sequence in 471 metastatic RCC patients. Design, setting, and participants Targeted sequencing of 341 cancer genes at ~540× coverage was performed on available tumor samples from 258 patients; 220 with clear cell histology (ccRCC). Outcome measurements and statistical analysis Associations between somatic mutations and median first-line progression free survival (PFS1L) and overall survival were determined in metastatic ccRCC using Cox proportional hazards models and log-rank tests. Results and limitations Prevalent mutations (≥ 10%) were VHL (75%), PBRM1 (46%), SETD2 (30%), BAP1 (19%), KDM5C (15%), and PTEN (12%). With first-line everolimus, PBRM1 and BAP1 mutations were associated with longer (median [95% confidence interval {CI}] 12.8 [8.1, 18.4] vs 5.5 [3.1, 8.4] mo) and shorter (median [95% CI] 4.9 [2.9, 8.1] vs 10.5 [7.3, 12.9] mo) PFS1L, respectively. With first-line sunitinib, KDM5C mutations were associated with longer PFS1L (median [95% CI] of 20.6 [12.4, 27.3] vs 8.3 [7.8, 11.0] mo). Molecular subgroups of metastatic ccRCC based on PBRM1, BAP1, and KDM5C mutations could have predictive values for patients treated with VEGF or mTOR inhibitors. Most tumor DNA was obtained from primary nephrectomy samples (94%), which could impact correlation statistics. Conclusions PBRM1, BAP1, and KDM5C mutations impact outcomes of targeted therapies in metastatic ccRCC patients. Patient summary Large-scale genomic kidney cancer studies reported novel mutations and heterogeneous features among individual tumors, which could contribute to varied clinical outcomes. We demonstrated correlations between somatic mutations and treatment outcomes in clear cell renal cell carcinoma, supporting the value of genomic classification in prospective studies.

Genomic alterations as predictors of survival among patients within a combined cohort with clear cell renal cell carcinoma undergoing cytoreductive nephrectomy

“…One possible reason for a survival advantage in patients with KDM5C mutations may be an improved response to VEGF inhibitor therapy. We have recently published data showing prolonged progression-free survival among these patients (20.6 months for patients with KDM5C mutations vs 8.3 months for KDM5C wild-type),[21] and other recent research has yielded similar results [22]. In regard to SETD2 mutations, previous studies have indicated these mutations are associated with advanced or recurrent disease.…”

The SWI/SNF Protein PBRM1 Restrains VHL-Loss-Driven Clear Cell Renal Cell Carcinoma

“…However, a wide range of clinical outcomes has been observed. Interestingly, genomic study of RECORD-3, a large clinical trial randomized kidney cancer patients to either VEGFR or mTORC1 inhibitors, demonstrated that ccRCC with mutant PBRM1 associates with longer progression free survival (PFS) on everolimus, an mTORC1 inhibitor, at 12.8 months than those with wild-type PBRM1 at 5.5 months (Hsieh et al, 2015; Hsieh et al, 2016). In parallel, the Vhl F/F Pbrm1 F/F Ksp-Cre ccRCC and human VHL and PBRM1 mutated ccRCC shared mTORC1 pathway aberration.…”

“…Remarkably, these genes encode chromatin and epigenetic regulatory proteins, and most mutations are predicted to result in functional loss, favoring their roles as tumor suppressors (Hakimi et al, 2013b). PBRM1 , the second most commonly mutated gene in all stages of ccRCC (Hsieh et al, 2016), encodes BRG1-associated factor (BAF) 180, the defining subunit of the ~2 MDa Polybromo BAF (PBAF) SWI/SNF complex (Varela et al, 2011). The SWI/SNF chromatin remodeling complexes are macromolecular machineries, which utilizes ATP to mobilize nucleosome and thereby modulate chromatin structure (Biegel et al, 2014; Clapier and Cairns, 2009).…”

“…PBRM1 loss-of-function is one of the most likely candidates given its high mutation frequency (~40%) in human ccRCC (Hsieh et al, 2016). Here, we created kidney-specific deletion of Pbrm1 and/or Vhl mice to study the tumor suppressor role of PBRM1 and sought to establish a physiological mouse kidney cancer model that recapitulates human ccRCC.…”

Renal cell carcinoma

“…Indeed, owing to the predominance of clear cell histology in metastatic disease (83–88%) 12,13 , tumours with non-clear cell histology have been grouped as ‘nccRCC’ (Table 1) for feasibility in conducting clinical trials 14–16 . Furthermore, recent cancer genomic studies have revealed an overt complexity of intra-tumour 17–19 and inter-tumour 7,20 heterogeneity in ccRCC, which could contribute to the heterogeneous clinical outcomes observed 21–23 .…”