Tumor genomic, transcriptomic, and immune profiling characterizes differential response to first-line platinum chemotherapy in high grade serous ovarian cancer

Cancer Med. 2021 May;10(9):3045-3058. doi: 10.1002/cam4.3831. Epub 2021 Apr 3.

Abstract

Background: In high grade serous ovarian cancer (HGSOC), there is a spectrum of sensitivity to first line platinum-based chemotherapy. This study molecularly characterizes HGSOC patients from two distinct groups of chemotherapy responders (good vs. poor).

Methods: Following primary debulking surgery and intravenous carboplatin/paclitaxel, women with stage III-IV HGSOC were grouped by response. Patients in the good response (GR) and poor response (PR) groups respectively had a progression-free intervals (PFI) of ≥12 and ≤6 months. Analysis of surgical specimens interrogated genomic and immunologic features using whole exome sequencing. RNA-sequencing detected gene expression outliers and inference of immune infiltrate, with validation by targeted NanoString arrays. PD-L1 expression was scored by immunohistochemistry (IHC).

Results: A total of 39 patient samples were analyzed (GR = 20; PR = 19). Median PFI for GR and PR patient cohorts was 32 and 3 months, respectively. GR tumors were enriched for loss-of-function BRCA2 mutations and had a significantly higher nonsynonymous mutation rate compared to PR tumors (p = 0.001). Samples from the PR cohort were characterized by mutations in MGA and RAD51B and trended towards a greater rate of amplification of PIK3CA, MECOM, and ATR in comparison to GR tumors. Gene expression analysis by NanoString correlated increased PARP4 with PR and increased PD-L1 and EMSY with GR. There was greater tumor immune cell infiltration and higher immune cell PD-L1 protein expression in the GR group.

Conclusions: Our research demonstrates that tumors from HGSOC patients responding poorly to first line chemotherapy have a distinct molecular profile characterized by actionable drug targets including PARP4.

Keywords: genomic profiling; high grade serous; immune profiling; ovarian carcinoma; platinum resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • B7-H1 Antigen / metabolism
  • Carboplatin / administration & dosage
  • Class I Phosphatidylinositol 3-Kinases / genetics
  • Cystadenocarcinoma, Serous / drug therapy
  • Cystadenocarcinoma, Serous / genetics*
  • Cystadenocarcinoma, Serous / immunology*
  • Cystadenocarcinoma, Serous / pathology
  • Cytoreduction Surgical Procedures
  • Female
  • Gene Amplification
  • Gene Expression Profiling
  • Genes, BRCA1
  • Genes, BRCA2
  • Genes, p53
  • Humans
  • MDS1 and EVI1 Complex Locus Protein / genetics
  • Middle Aged
  • Mutation
  • Neoplasm Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / immunology*
  • Ovarian Neoplasms / pathology
  • Paclitaxel / administration & dosage
  • Progression-Free Survival
  • Repressor Proteins / metabolism
  • Retrospective Studies
  • Time Factors
  • Transcriptome / genetics*
  • Treatment Outcome
  • Whole Exome Sequencing

Substances

  • B7-H1 Antigen
  • CD274 protein, human
  • EMSY protein, human
  • MDS1 and EVI1 Complex Locus Protein
  • MECOM protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • PARP4 protein, human
  • Repressor Proteins
  • Carboplatin
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Paclitaxel