DFCI ccRCC Immunotherapy Response Cohort (2019)

Overview

Prospective discovery cohort of 35 patients with metastatic clear cell renal cell carcinoma (CCRCC) enrolled on a nivolumab (anti-PD-1) trial at Dana-Farber Cancer Institute. Pre-treatment paired tumor/normal whole-exome sequencing (mean coverage 128x tumor / 91x normal) was performed to identify genomic correlates of response to immune checkpoint blockade. A separate validation cohort of 63 ccRCC patients treated with anti-PD-(L)1 ± anti-CTLA-4 was also analyzed. The study is deposited in cBioPortal as ccrcc_dfci_2019. PMID:29301960

Composition

  • Discovery cohort: 35 metastatic CCRCC patients on a prospective nivolumab trial; pre-treatment tumor/normal pairs sequenced by whole-exome sequencing. PMID:29301960
  • Validation cohort (not in cBioPortal study): 63 metastatic CCRCC patients treated with anti-PD-1 (nivolumab) or anti-PD-L1 (atezolizumab) alone or combined with anti-CTLA-4 (ipilimumab); PBRM1 status from WES (n=49) or panel sequencing (n=14). PMID:29301960
  • Clinical endpoint: Composite response — clinical benefit (CB) = CR/PR by RECIST 1.1 or SD with any objective tumor reduction lasting ≥6 months; no clinical benefit (NCB) = PD by RECIST 1.1 with discontinuation within 3 months; intermediate benefit (IB) = remainder. PMID:29301960
  • Reference expression data: TCGA KIRC ccRCC and the Sato (Kyoto University) untreated ccRCC cohort used for RNA-seq comparisons. PMID:29301960

Assays / panels (linked)

  • whole-exome-seq — paired tumor/normal, mean 128x (tumor) / 91x (normal) coverage
  • rna-seq — on-study tumor transcriptomics for pathway enrichment analysis (GSEA)

Papers using this cohort

  • PMID:29301960 — Miao et al. 2018, Science — “Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma”

Notable findings derived from this cohort

  • PBRM1 was the only recurrently mutated gene (by MutSig2CV) in which truncating/LOF mutations were enriched in CB vs. NCB tumors: 9/11 vs. 3/13 (Fisher’s exact p=0.012, q=0.086). PMID:29301960
  • All discovery-cohort truncating PBRM1 alterations co-occurred with deletion of the non-mutated allele on chromosome 3p, producing complete biallelic LOF; most mutations were predicted to be clonal by ABSOLUTE. PMID:29301960
  • Patients with biallelic PBRM1 loss had significantly prolonged OS (log-rank p=0.0074) and PFS (p=0.029) vs. PBRM1-intact patients on anti-PD-1. PMID:29301960
  • Median nonsynonymous tumor mutation burden was modest (82/exome) and did not differ between CB and NCB groups; PD-L1 IHC was also not predictive in this cohort. PMID:29301960
  • GSEA of PBRM1-LOF tumors (n=18 vs. n=14 intact) confirmed up-regulation of hypoxia and IL6/JAK-STAT3 hallmark gene sets. PMID:29301960
  • VHL LOF — the most commonly mutated ccRCC gene — did not correlate with immune-related gene expression, indicating the signal is PBRM1-specific. PMID:29301960
  • PFS benefit from PBRM1 LOF was more pronounced in previously-treated (VEGF-inhibitor pre-exposed) patients than in treatment-naive patients (p=0.009). PMID:29301960

Sources

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