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Study Unearths Features Found in Long-Term Survivors of Advanced Ovarian Cancer

NEW YORK – An international team has identified a range of tumor and immune features linked to unusually long survival of individuals diagnosed with advanced ovarian cancer.

"Specific combinations of germline and somatic gene alterations, tumor cell phenotypes, and differential immune responses appear to contribute to long-term survival in [high-grade serous ovarian cancers]," co-senior and co-corresponding author David Bowtell from the University of Melbourne and the Peter MacCallum Cancer Center, and his colleagues wrote.

As they reported in Nature Genetics on Thursday, the researchers brought together whole-genome sequence, RNA sequence, and/or genome-wide array-based DNA methylation profiling data for 60 individuals from US and Australian ovarian cancer biobanks who had survived at least 10 years after a diagnosis with advanced high-grade serous ovarian cancer (HGSC), comparing the tumor and immune features with those found in 34 individuals with short-term HGSC survival and in 32 moderate-term survivors. They also considered samples from four patients who experienced cancer recurrence after long-term survival.

"Fewer than half of all patients with advanced-stage high-grade serous ovarian cancers (HGSCs) survive more than five years after diagnosis, but those who have an exceptionally long survival could provide insights into tumor biology and therapeutic approaches," the authors added, noting that "[a] subgroup of patients with HGSC with apparently poor prognosis disease at presentation have a remarkable response to treatment and extraordinary long-term survival, including a small number with incomplete removal of macroscopic disease following surgery."

The patients in the study had been diagnosed with stage IIIC or stage IV HGSC when they were 29 to 81 years old. Sequence data for dozens of the short-, moderate-, or long-term survivors came from the International Cancer Genome Consortium's ovarian cancer analyses or the Multidisciplinary Ovarian Cancer Outcomes Group study.

In particular, the results suggested that survival tended to be stretched out in cases marked by somatic mutations affecting DNA repair genes, along with other alterations prompting pronounced tumor mutational burden and corresponding neoantigen production. Particularly long survival was found among individuals whose tumors were impacted by at least three DNA repair gene changes, though survival also appeared to get a boost in cases with prominent tumor proliferation markers.

Likewise, the combined rate of germline, somatic, and methylation changes affecting homologous recombination genes such as BRCA1, BRCA2, PALB2, or PTEN was lower in the short-term survivors than in the ovarian cancer patients with moderate- or long-term survival.

Even so, mutation status was only part of the long-term survival story. Rather, the investigators found that mutational signatures, expression profiles, methylation clusters, and immune features worked together to influence survival outcomes.

For example, the team saw three distinct survival clusters containing cases marked by mutations in BRCA1, a breast and ovarian cancer risk gene involved in homologous recombination-mediated DNA repair, depending on the broader mutational signatures and past environmental exposures.

And despite past studies linking CCNE1 amplifications to platinum chemotherapy resistance, for example, the researchers noted that a combination of CCNE1 amplifications and higher-than-usual activated CD4 memory T-cell and CD8 T-cell immune activity appeared more common in a subset of HGSC patients with the most favorable outcomes.

"We have identified distinct HGSC subgroups separated by mutational processes, DNA methylation, and immune response, and found that differential outcomes may be associated with compounding lifestyle-related exposures, surgical outcomes, anti-tumor immune activity, cell cycle deregulation, and/or disruption of multiple DNA repair pathways," the authors reported.

While the study focused on cases that were mainly treated with surgery in combination with adjuvant or neoadjuvant chemotherapy, the study's authors noted that further survival clues will likely come from future studies of still larger ovarian cancer patient groups that include homologous recombination-deficient cases treated with PARP inhibitors (PARPi).

"The determinants of long-term survival in HGSC are complex, and progress will depend on detailed discovery studies and validation of specific findings in large, clinically annotated cohorts with long follow-up," the authors wrote.

Even so, they noted that although "most of our patients pre-date the introduction of PARPi, given that response to platinum is predictive of PARPi sensitivity, our findings may also provide insights into long-term PARPi response."

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