Melanoma UCLA Anti-PD-1 Cohort (Hugo et al. 2016)

Overview

Prospective cohort of 38 metastatic cutaneous melanoma patients treated with anti-PD-1 antibodies (pembrolizumab or nivolumab) at UCLA. Pretreatment biopsies were collected and profiled by whole-exome sequencing (all 38) and RNA-seq (28-tumor subset). The cohort was the primary discovery set for the Innate anti-PD-1 Resistance (IPRES) transcriptomic signature. Transcriptome data are deposited as GEO accession GSE78220. PMID:26997480

Composition

  • Cancer type: SKCM (metastatic cutaneous melanoma)
  • 38 patients: 21 responders and 17 non-responders (irRECIST criteria; mixed-response cases excluded)
  • 14 of 38 patients had prior MAPK-inhibitor therapy
  • Specimens: 32 pretreatment tumors, 2 pretreatment tumor-derived cultures, 3 early on-treatment non-responding tumors, 1 early on-treatment responding tumor; all with patient-matched normals
  • Assay: Illumina HiSeq 2000, 2×100 bp; median exome coverage 140×; RNA-seq on 28-tumor subset with sufficient RNA quality PMID:26997480

Assays / panels (linked)

Papers using this cohort

  • PMID:26997480 — Hugo et al. 2016, Cell — “Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma”; primary discovery study for this cohort.

Notable findings derived from this cohort

  • Mutational load (median 495 vs 281 non-synonymous SNVs in responders vs non-responders) trended higher in responders but was not significantly predictive (Mann-Whitney P=0.30); high mutational load was prognostic for longer overall survival. PMID:26997480
  • BRCA2 loss-of-function nsSNVs enriched in responders: 28% (6/21) vs 6% (1/17) non-responders (Fisher P=0.002, OR=6.2 vs 6% melanoma background rate in 469-tumor cohort); BRCA2-mutant tumors had significantly higher overall mutational loads. PMID:26997480
  • IPRES (Innate anti-PD-1 Resistance) co-enrichment of 26 transcriptomic signatures covering mesenchymal transition, ECM remodeling, angiogenesis, hypoxia, and wound healing defined a non-responder subset (9/13 non-responders vs 1/15 responders; OR=4.6, P=0.013). PMID:26997480
  • No recurrent copy-number alterations exclusive to either responder group. PMID:26997480
  • Key IPRES mesenchymal-transition transcripts up-regulated in non-responders: AXL, ROR2, WNT5A, LOXL2, TWIST2, TAGLN, FAP; immunosuppressive cytokines IL10, VEGFA, VEGFC; monocyte chemoattractants CCL2, CCL7, CCL8, CCL13. PMID:26997480
  • IPRES program detected across multiple TCGA cancer types (PAAD, LUAD, COAD, ccRCC) and was enriched in metastatic vs primary SKCM (90/282 metastatic vs 6/69 primary in skcm_tcga_pub_2015; P=3.9e-5, OR=0.2). PMID:26997480
  • IPRES was NOT enriched in non-responders to anti-CTLA-4 in the skcm_dfci_2015 cohort, indicating mechanistic distinction between anti-PD-1 and anti-CTLA-4 innate resistance. PMID:26997480

Sources

  • cBioPortal studyId: mel_ucla_2016
  • GEO accession: GSE78220 (transcriptome data)
  • Hugo W et al. “Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma.” Cell. 2016;165(1):35-44. PMID:26997480. DOI: 10.1016/j.cell.2016.02.065.

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