Rapid-fire talks

Saturday May 25, 2024 from 11:30 to 12:00

Room: Imperial

> Rapid-fire 08 (POS-26) High grade serous ovarian cancer (HGSOC): Tracking response to therapies in plasma and at single cell resolution

Farhia Kabeer

Post doctoral fellow
Pathology and Laboratory Medicine
University of British Columbia

Abstract

High grade serous ovarian cancer (HGSOC): Tracking response to therapies in plasma and at single cell resolution

Farhia Kabeer1,2, Naila Adam1,2, Branden Lynch2, Tsz Yin Lam1, Amal El-Naggar1, Janine Sanz2, Amy Lum2, Goldman Lam1, Lorena Zoltan1, Stephanie Lapadat1, Vinci Au2, Caroline Baril2, Sean Beaty2, Daniel Lai2, Andy Mungall2, Richard Moore2, Samuel Aparicio1,2, Andrew Roth1,2, David Huntsman1,2, Yvette Drew1,2,3.

1Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada; 2Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada; 3Division of Medical Oncology, Faculty of Medicine, UBC, Vancouver, BC, Canada

Introduction: HGSOC is characterized by TP53 loss and genomic instability. Despite PARP inhibitor success, chemotherapy remains first-line for advanced BRCA mutant and HRD HGSOC. Its impact on tumor heterogeneity and response to targeted therapies remains unclear. We investigated how HGSOC evolves under treatment by examining single-cell genomic changes in PDX models and circulating tumor DNA (ctDNA) from the same HGSOC patients. We aimed to understand if the molecular changes seen in PDX’s could be assessed through ctDNA and whether ctDNA can be used for tracking clonal tumor dynamics over time.

Methods: 11 treatment naive HGSOC PDX were developed in immunodeficient mice. Two lines (one BRCA mutant) have been treated with platinum (cisplatin) or targeted PARP inhibitor (olaparib). Single-cell whole-genome sequencing (scWGS) conducted on PDX and original tumors identified copy number events, enabling cell clustering and clone identification. Hierarchical clustering was utilized to determine clonal structure pre and post-treatment, and a phylogenetic tree was computed.  Additionally plasma samples matched to PDX’s underwent WGS for ctDNA analysis.

Results: From scWGS data of PDX, we observed initial clonal heterogeneity leading to emergent clones in later passages. Evolving CN changes were found on chromosomes 19, 8, and 3, along with TP53 loss of heterozygosity on Chr17p. Despite normal ploidy, focal CN alterations are visible in all plasma samples. In patient 1, gains and amplifications appeared on chromosomes 3 and 8, with losses on 4, 15, and 16. Bulk tumor CN profiles of patient 1 and corresponding PDXs largely matched those derived from the same patient’s plasma.

Conclusion: Through genome sequencing at both single-cell tumor and plasma sample levels, we captured diversification between HGSOC tumors, particularly PDXs after drug exposures. ctDNA shows promise as an alternative to conventional tissue sampling measuring treatment associated with genomic changes. 

Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship. Michael Smith Health Research BC Postdoctoral Trainee Award. Carraresi Foundation OVCARE Research Grant.

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