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Research Highlight | January 15, 2019

Study reveals genomic differences between long- and short- term survivors of high-grade serous ovarian cancer, advancing potential for individualized treatments

Researchers may be one step closer to creating personalized treatments for patients with an extremely deadly form of ovarian cancer thanks to a new study by a Toronto group funded by TFRI.

The study, published in Genome Medicine (October 2018), maps the clinical and genomic differences between two sub-groups of patients with high-grade serous ovarian cancer (HGSOC): those who respond exceptionally well to the standard-of-care treatment of cytoreductive surgery and platinum-based chemotherapy, known as exceptional long-term (LT) survivors, and those who quickly build resistance to it, short-term (ST) survivors.

“In this pilot study, we sought to identify clinical and molecular factors that distinguish HGSOC patients who share similar clinical characteristics and pathology at diagnosis with exceptional survival outcomes, either LT or ST, through integrated analysis of clinical features, germline variants, somatic genomic alterations, and tumour immune microenvironment,” reads the paper.

Using samples from 20 LT survivors and 21 ST survivors collected at the Princess Margaret Cancer Centre in Toronto, the team was able to determine several key differences between the groups, including an elevated mutation burden, biallelic inactivation of BRCA1 or BRCA2, and increased CD4+ and CD8+ lymphocytic infiltration in the tumour microenvironment in LT survivors. These findings suggest that exceptional long- or short-term survival is determined by a concert of clinical, molecular, and microenvironment factors.

The team also found the ESR1-CCDC170 gene fusion present in tumours from two HGSOC patients with extremely short survival, which could point to this fusion as a potential biomarker for treatment resistance and aggressive disease.

While these findings will now need to be validated using a larger cohort, researchers are hopeful that they will help bring them closer to tailoring treatments for these patients based on their individual genetic and clinical landscapes.

“Identifying mechanisms involved in the response or resistance to treatment is essential to devising precision treatment plans, and future strategies will likely rely on multiple clinical and immunogenomic factors,” reads the paper. “This analysis of exceptional responders in HGSOC has the potential to contribute to our understanding of the biology of ovarian cancer, with the goal of improving the survival of patients.”

Trevor Pugh is a TFRI-funded researcher who co-lead the study.

Landscape of genomic alterations in high-grade serous ovarian cancer from exceptional long- and short-term survivors

Yang SYC, Lheureux S, Karakasis K, Burnier JV, Bruce JP, Clouthier DL, Danesh A, Quevedo R, Dowar M, Hanna Y, Li T, Lu L, Xu W, Clarke BA, Ohashi PS, Shaw PA, Pugh TJ, Oza AM

This work was supported by a Terry Fox Translational Research Program Grant to iTNT: The Immunotherapy Network.