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End-Stage Ovarian Cancer Marked by Rampant Treatment Resistance, Multiple Clones

NEW YORK – New research by a team from Australia, the US, and Canada has highlighted the molecular alterations found in end-stage cases of high-grade serous ovarian carcinoma (HGSC) marked by homologous recombination (HR) DNA repair defects, uncovering difficult-to-treat polyclonal tumor features and diverse resistance-related mutations.

"HGSC patients typically have a poor prognosis, and acquired resistance to treatment is common," senior and corresponding author Elizabeth Christie, a researcher with the University of Melbourne's Peter MacCallum Cancer Centre and the Sir Peter MacCallum Department of Oncology, explained in an email. "We identified that there was substantial inter- and intra-tumoral heterogeneity and observed multiple mechanisms of treatment resistance, including within individual patients."

As they reported in Nature Genetics on Monday, the researchers used a combination of whole-genome sequencing, targeted deep sequencing of 63 DNA repair- or resistance-related genes, RNA sequencing, array-based methylation profiling, quantitative mass spectrometry-based proteomics, and multicolor immunofluorescence-based immune cell analyses to characterize autopsy samples from 15 individuals with end-stage HR-deficient HGSC marked by germline or somatic mutations in BRCA1, BRCA2, or BRIP1, along with matched normal blood or tissue samples from the patients.

The samples were collected through the "cancer tissue collection after death" (CASCADE) rapid autopsy program, they noted, and included 18 samples per patient, on average, spanning multiple metastatic sites. Christie noted that the CASCADE program, led by David Bowtell at the Peter MacCallum Cancer Centre, enrolls individuals with advanced metastatic disease who consent to undergo rapid autopsy for research following their death.

Although HR-deficient forms of HGSC are known for responding to treatment approaches such as platinum chemotherapy or PARP inhibitors initially, they tend to develop resistance over time. Even so, the suite of resistance mechanisms contributing to HGSC recurrence or progression may be missed by limited sampling strategies, the team wrote, suggesting that more extensive sampling and testing on advanced HGSC could help in addressing advanced disease.

"As comprehensive tumor sampling is not part of routine practice for recurrent, late-stage HGSC, prior studies often analyzed recurrent ascites samples," Christie explained. "As such, we had a limited understanding of the extent of heterogeneity across tumor sites within patients."

Molecular data generated for the new study pointed to the presence of multiple tumor clones and mutational signatures contributing to treatment resistance in the end-stage samples, the researchers reported, with each HGSC patient carrying between two and nine tumor clones found by whole-genome sequencing.

When the team delved into the types of alterations found in these samples, it saw recurrent whole-genome duplications, for example, as well as alterations that restored HR activity in some of the subclones. The combination of immune cell and tumor profiles also revealed clones capable of dodging patients' immune systems.

The results argued against the notion that a single tumor clone drives tumor progression, recurrence, or treatment resistance in individuals with late-stage HGSC, the team noted, while highlighting the importance of attempting to head off the disease before it develops such polyclonal features.

"This finding represents a serious challenge for researchers and clinicians trying to target specific mechanisms of resistance, which, based on our observations, are likely to be subclonal and occurring amongst multiple mechanisms of resistance," Christie noted, adding that this polyclonal resistance pattern "demonstrates the limitations of a single site biopsy and means that measures such as liquid biopsy to profile the tumor landscape are important to explore."

In their preliminary circulating tumor DNA (ctDNA) experiments, including eight patients, the investigators found that targeted ctDNA sequencing picked up HR-related mutation reversions that appeared as early as at the first-line chemotherapy treatment stage in two of the patients.

"The findings of two patients with early, low-frequency reversions detected in ctDNA but with divergent treatment responses highlights the need for detailed longitudinal studies of reversion mutation in patients with HR gene-driven cancer," the authors wrote.