MSK Esophagogastric Cancer (Janjigian et al. 2017)

Overview

Janjigian et al. report the first 295 patients with stage IV esophagogastric adenocarcinoma prospectively profiled at MSKCC using the MSK-IMPACT targeted next-generation sequencing assay. With mature clinical annotation including treatment response and survival, this dataset characterizes the genomic landscape of metastatic EGC, evaluates ERBB2 NGS vs IHC/FISH concordance for trastuzumab selection, defines MSI-H as chemotherapy-refractory but immunotherapy-sensitive, and identifies acquired resistance mechanisms to trastuzumab and checkpoint inhibitors. The dataset is committed to AACR Project GENIE and publicly available on cBioPortal. Published in Nature Medicine (2017).

Composition

  • 295 patients with metastatic (stage IV) esophageal, gastric, and gastroesophageal junction adenocarcinoma; 318 tumor samples (some patients with paired pre- and post-treatment biopsies). Consented February 2014–February 2017.
  • Cancer types: Esophagogastric Adenocarcinoma (EGC), spanning ESCA, STAD including DSTAD, and GEJ tumors.
  • Molecular subtypes: CIN subtype dominated (63%); GS tumors 34% (enriched for diffuse histology 32% vs 9%, P=3e-5, and CDH1 mutations 20% vs 7%, P=0.01); MSI-H 3% (9/295).
  • Treatment subsets analyzed: 187 HER2-negative on first-line fluoropyrimidine/platinum; 50 HER2+ on first-line trastuzumab/chemotherapy; 23 paired pre-/post-trastuzumab tumor pairs; 40 patients on immune checkpoint inhibitors.
  • 90% ECOG 0–1 status reflecting specialty care selection.

Assays / panels (linked)

  • MSK-IMPACT — CLIA-certified hybrid-capture targeted NGS, run as IMPACT341, IMPACT410, or IMPACT468 panels on paired tumor/normal blood; mean coverage 744X
  • FACETS — allele-specific copy number and tumor purity estimation
  • MSIsensor — MSI status from sequencing data (MSI-H threshold ≥10)
  • OncoKB — oncogenic effect annotation
  • IHC — HER2 (3+ positive) per CAP/ASCO criteria; B2M protein confirmation
  • FISH — HER2 status per CAP/ASCO criteria
  • EBER-ISH — EBV detection (n=26 immunotherapy-treated patients)

Papers using this cohort

  • PMID:29122777 — Janjigian et al., Nat Med (2017): Genomics of Trastuzumab Resistance in HER2 Positive Advanced Esophagogastric Adenocarcinoma.

Notable findings derived from this cohort

  • 53% of patients had at least one OncoKB-defined potentially actionable alteration. Most frequent oncogenic alterations in the CIN subset: ERBB2 (25%), KRAS (16%), EGFR (8%), ERBB3 (7%), PIK3CA (7%), FGFR2 (5%), MET (5%). Most-mutated genes: TP53 (73%), ARID1A (15%), CDKN2A (12%). PMID:29122777
  • MSI-H tumors (3%) are chemotherapy-refractory but immunotherapy-sensitive. Median PFS on first-line chemotherapy 4.8 months (MSI-H) vs 6.9 months (non-MSI-H), HR=0.4, P=0.027. MSI-H frequency significantly lower than TCGA’s 16% (P=8e-10), attributable to the metastatic-enriched MSK cohort. PMID:29122777
  • HRD/LST is not a platinum-chemotherapy biomarker in EGC. LST score did not predict PFS on first-line platinum (HR=0.99, P=0.947); two longest outlier responders (68 and 104 months) had no BRCA1/BRCA2 alterations. PMID:29122777
  • NGS-based ERBB2 amplification is concordant with IHC/FISH (PPV 90%, NPV 96.9%, concordance 93.7%) and captures dose-dependent response gradient: top-quartile ERBB2-amplification patients had median PFS of 24.3 months on first-line trastuzumab. PMID:29122777
  • Loss of ERBB2 amplification is a common acquired-resistance mechanism: 7/44 (16%) post-trastuzumab samples became ERBB2-negative by NGS with HER2 protein loss confirmed by IHC. PMID:29122777
  • RTK-RAS-PI3K co-alterations shorten trastuzumab PFS (median 8.4 months vs longer in pathway-wildtype); acquired KRAS (2% pre vs 13% post) and PIK3CA (2% pre vs 8.6% post) activating mutations enriched post-trastuzumab. PMID:29122777
  • B2M loss is a recurrent immunotherapy-resistance mechanism: 4/9 (44%) MSI-H tumors carry likely deleterious B2M alterations; acquired exon-1 loss-of-function confirmed by IHC in a patient with acquired resistance to anti-PD-1. PMID:29122777
  • High TMB (>9.7 mut/Mb) supports immunotherapy: top-quartile TMB associated with median OS 16.8 vs 6.62 months and 2-year OS 44% vs 14% (HR=0.40, P=0.058). PMID:29122777
  • EBV+ exceptional response: the single EBV+ patient achieved a complete and durable response (>30 months) to anti-PD-1 therapy. PMID:29122777
  • No primary-vs-metastatic differences in alteration frequencies detected. PMID:29122777

Sources

  • cBioPortal study ID: egc_msk_2017
  • AACR Project GENIE
  • MSK-IMPACT clinical sequencing program

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