Related Experiment Video
Updated: Nov 10, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Tumor genomic, transcriptomic, and immune profiling characterizes differential response to first-line platinum
Johanne I Weberpals1,2, Trevor J Pugh3,4,5, Paola Marco-Casanova6
1Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, ON, Canada.
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.
