Open AccessTumor genomic, transcriptomic, and immune profiling characterizes differential response to first‐line platinum chemotherapy in high grade serous ovarian cancer
Author(s) -
Weberpals Johanne I.,
Pugh Trevor J.,
MarcoCasanova Paola,
Goss Glenwood D.,
Andrews Wright Natalie,
Rath Prisni,
Torchia Jonathon,
Fortuna Alexander,
Jones Gemma N.,
Roudier Martine P.,
Bernard Laurence,
Lo Bryan,
Torti Dax,
Leon Alberto,
Marsh Kayla,
Hodgson Darren,
Duciaume Marc,
Howat William J.,
Lukashchuk Natalia,
Lazic Stanley E.,
Whelan Doreen,
Sekhon Harmanjatinder S.
Publication year - 2021
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.3831
Subject(s) - ovarian cancer , carboplatin , medicine , chemotherapy , debulking , paclitaxel , oncology , immunohistochemistry , serous fluid , exome sequencing , cancer research , cancer , biology , mutation , cisplatin , gene , biochemistry
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.