Distinct Ovarian Cancer Evolution States Might Help In Personalized Treatment

Researchers from the University of Helsinki in Finland have made significant progress in understanding the evolutionary states of tumors in patients with ovarian high-grade serous carcinoma (HGSC). The team conducted whole genome sequencing on 510 samples from patients participating in the DECIDER study, including samples from ovaries, fallopian tubes, metastases, and other tissues. The study identified three distinct evolutionary clusters of tumors based on clonal complexity and divergence. 

As per Cancer Cell, Cluster 1, known as the “evolving state,” represented the youngest state in evolutionary time and showed aberrations in MAPK and ERBB2 signaling. Tumors in this state were more stable and had fewer subclones. Patients with tumors in this state had the best response to therapy, with longer times to relapse or death. 

Cluster 2, termed the “maintaining state,” consisted of polyclonal tumors with multiple subclones. These tumors were enriched with subclonal aberrations in the PI3K/AKT pathway and were associated with the shortest times to relapse and worst survival odds. 

Cluster 3, the “adaptive state,” was the most evolved state and exhibited a high number of clones and mutations in various signaling cascades, including NOTCH and WNT pathways. 

Furthermore, the study revealed two distinct evolutionary trajectories connecting the three states. Patients whose tumors evolved directly to the adaptive state had better survival outcomes than those whose tumors evolved via the maintaining state, which initially involved changes in the PI3K/AKT signaling and cell cycle pathways. 

The researchers also investigated the potential of PI3K inhibitors as a treatment for HGSC. They exposed HGSC organoid lines to different PI3K inhibitors and observed significant cytotoxicity with alpelisib and umbralisib, particularly with alpelisib, indicating the relevance of the PI3K/AKT pathway in a specific subset of patients with HGSC. 

The current standard-of-care for HGSC involves debulking surgery followed by platinum/paclitaxel chemotherapy. However, PI3K inhibitors have not yet progressed to clinical use for ovarian cancers, despite their approval for other cancer types. The researchers emphasized the need for further investigation and clinical intervention trials guided by cancer genomics to explore the potential of PI3K inhibitors for HGSC treatment. 

The study also made an unexpected finding that tubo-ovarian samples, considered the site-of-origin tumor, had significantly more unique subclones compared to metastasis sites. This discovery suggests that studies primarily relying on these samples may be challenging to reproduce in other cohorts. 

Moving forward, the researchers aim to analyze samples taken during or after chemotherapy to understand how tumor genomes change during treatment and relapses. Additionally, they are exploring the possibility of identifying the three evolutionary states from circulating tumor DNA sequencing data, as multi-site whole-genome sequencing is currently not feasible in clinical settings.