Abstract B114: Effect of spatial and temporal inter-tumoral heterogeneity on homologous recombination deficiency scores in high grade serous ovarian cancer
Authors: Christie Elizabeth L. , Lorentzen Marc , Liu Maiqi , Burdett Nikki , Curry Edward , Kwok Chun Hei , Pandey Ahwan , Nixon Katherine , Ploski Jennifer , Clark James J. , McNeish Iain , Bowtell David D.L. , Krell Jonathan , Fotopoulou Christina , Cunnea Paula 
Published: March 2024

Abstract
High-grade serous ovarian cancer (HGSC) is the most common and lethal subtype of ovarian cancer. Extensive genomic instability and heterogeneity are characteristics of HGSC, with near-ubiquitous TP53 loss-of-function mutations, defects in homologous recombination (HR) repair, and extensive copy number aberrations contributing to the vast genomic heterogeneity observed. Most patients relapse and acquire resistance to platinum or PARP inhibitor (PARPi)-based therapy. Diverse mechanisms leading to therapy resistance and lack of predictive biomarkers means that matching the best treatment options to patients is difficult. Testing tumors for HR-Deficiency (HRD) status is now a clinical test to predict PARPi sensitivity in HGSC. We aimed to determine the influence of spatial and temporal heterogeneity on HRD status in HGSC. Patients (n=59) at Hammersmith Hospital (HH) underwent maximal-effort upfront cytoreduction for advanced HGSC, had their tumor dissemination mapped and tumor biopsies collected (range 4-15). Paired relapse samples were collected for 10 patients. Tumor DNA was extracted (n=5 tumors per case, plus relapse), Illumina Human OmniExpress genotyping performed for 59 cases and whole genome sequencing (WGS; 30x depth) performed for 21 cases. Allele-specific copy number (CN) was quantified using ASCAT. Multi-site CN data was also accessed from two cohorts (GSE38787, GSE40546). Tumors that failed QC or had an aberrant cell fraction &lt;0.3 were excluded. HR scores were estimated in each cohort using different genomic instability score (GIS) or mutational signature-based algorithms and relevant cut-offs were applied to determine HRD and HR-Proficient (HRP) tumors. Variations in HR scores were observed across the cohorts with a proportion of patients presenting with a mixed HR score, displaying both HRD and HRP scores in their tumors: HH cohort (20%, 11/54 patients); GSE38787 (17%, 4/24 patients); and GSE40546 (28%, 4/14 patients) using a scarHRD algorithm. In the HH cohort (n=45), we examined if mixed HR status was associated with survival and demonstrated that patients with HR-mixed or all HRP tumors had poorer progression-free (p=0.0052) and overall survival (p=0.00092) than patients with all HRD tumors. Applying different approaches to the HH WGS data (scarHRD, CHORD, &gt;63 score cut-off), approximately 20% of patients demonstrated HR-mixed scores in their tumors in each approach. However, depending on the approach chosen to define HRD, different cases showed HR-mixed scores, 2/21 mixed cases overlapped between the different algorithms applied with tumors changing from HRD to HRP and vice versa depending on the approach applied. Differences in HR-deficiency/proficiency scores suggests that HR status may not be consistent across advanced disseminated HGSC, indicating that a single tumor biopsy may not accurately depict spatial HGSC tumor biology. HR score variations in different methods (GIS or mutational signatures) indicates that these tests are not analogous for defining HRD and thus PARPi suitability.
Citation Format: Elizabeth L. Christie, Marc Lorentzen, Maiqi Liu, Nikki Burdett, Edward Curry, Chun Hei Kwok, Ahwan Pandey, Katherine Nixon, Jennifer Ploski, James J. Clark, Iain McNeish, David D.L. Bowtell, Jonathan Krell, Christina Fotopoulou, Paula Cunnea. Effect of spatial and temporal inter-tumoral heterogeneity on homologous recombination deficiency scores in high grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B114.