High-Grade Ovarian Cancer Shows Survival Gap Between HR-Deficient and Proficient BRCA+ Tumors

Travis Sims, MD, MPH

Improvements in progression-free (PFS) and overall survival (OS) were observed in patients with homologous recombination deficient (HRD), high-grade ovarian cancer, with germline and somatic BRCA mutations, despite prior tumor reduction surgery or treatment with neoadjuvant chemotherapy, according to retrospective findings presented in a poster during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.

The evaluated patient population was comprised of 187 women with advanced high-grade ovarian cancer. In total, 106 patients were positive for germline BRCA mutations, 26 had somatic BRCA mutations and were HRD-positive, and 55 were BRCA-negative and HRD-negative.

By Kaplan-Meier analysis, the median PFS for patients who were identified as germline BRCA-positive was 23.5 months, and 20.2 months among those with somatic BRCA- and HRD-positive disease, compared with 14.9 months in the BRCA and HRD-negative population (P < .001). The median OS observed was 68.8 months in the germline BRCA-positive population and 69.2 months in the somatic BRCA and HRD-positive group versus 42.3 months in the group of patients who were BRCA and HRD negative.

Baseline demographics showed differences in those assessed for PFS and based on the statistics, investigators found that being older, having a specific stage of disease, and prior resection impacted outcomes. Specifically, younger age had significant impact on PFS (HR, 1.02; 95% CI, 1.00-1.04; P = .01), and having stage III disease was shown to improve PFS (19.52 months) compared with stage IV disease, which achieved a median PFS of 18.52 months (HR, 4.7; 95% CI, 1.39-23.4; P = .02).

Further, having an R0 resection at tumor reductive surgery was associated with a longer median PFS of 16.10 months compared with 13.93 months for those who did not undergo R0 resection (HR, 0.41; 95% CI, 0.21-0.83; P = .01). Finally, having a BRCA and HRD-negative tumor correlated with a shorter PFS compared with germline BRCA-positive tumors and somatic BRCA- and HRD-positive tumors.

The assessment of OS showed similar results to the PFS analysis. Patients who were older had poorer outcomes compared to the younger group (HR, 1.07; 95% CI, 1.03-1.10; P < .001), and those who underwent R0 resection at tumor reductive surgery lived longer than those who did not (HR, 0.19; 95% CI, 0.08-0.44; P < .001).

The findings of this analysis could indicate that having high-grade ovarian cancer that is both BRCA- and HRD-negative may be predictive of poor survival outcomes.

In an interview with Targeted Oncology, held during the 2021 ASCO Annual Meeting, Travis Sims, MD, MPH, a fellow in Gynecologic Oncology at The University of Texas MD Anderson Cancer Center, discussed the treatment of HRD-positive ovarian cancer and the retrospective analysis of HRD status and its impact of survival outcomes for this patient population.

TARGETED ONCOLOGY: What is the prevalence of homologous recombination deficiency in ovarian cancer? How does this impact patient outcomes?

SIMS: Nearly 50% of patients with high-grade ovarian cancer harbor germline mutations in BRCA1 or BRCA2, have somatic tumor mutations in BRCA, or have DNA repair genes that are characterized by deficiency in HRD. As a result, recent clinical trials have focused on developing targeted therapies that can take advantage of this. For example, PARP inhibitors have been very popular lately. HRD has been demonstrated to be a response predictor to PARP inhibitor therapy in high-grade ovarian cancer. Although treatment with PARP inhibitors have shown great promise, there continues to be interest in investigating how HRD status can be used to objectively tailor other treatment strategies.

Right now, primary debulking surgery followed by platinum-based chemotherapy continues to be the standard of care for patients with advanced-stage epithelial ovarian cancer. But neoadjuvant chemotherapy is an alternative course of treatment that should be considered for select patients. So, the aim of this study was to compare clinical and survival outcomes in high-grade ovarian cancer stratified by HRD status in patients receiving either primary debulking surgery or neoadjuvant chemotherapy followed by interval debulking surgery.

Can you explain what you investigated retrospectively around HRD status and ovarian cancer? What methods were used to perform this analysis?

We performed a retrospective analysis of all patients with high-grade ovarian cancer from April 2013 to June 2019. Patients were included if they had if germline BRCA and HRD status was known. Clinical outcomes were analyzed and stratified according to 3 groups. The first group included patients with germline BRCA-positive mutations. The second group had patients that were germline BRCA negative but harbored a somatic tumor BRCA mutation or were HRD-positive. In the last group, everybody else was included, for example, those that were BRCA-negative tumors and were HRD negative, and this group is also known as BRCA wild-type, HR-proficient patient.

Progression-free survival and overall survival were estimated using the Kaplan Meier method and stratified by HRD status and modeled via Cox proportional hazard regression.

What were the results that you presented during the 2021 ASCO Annual Meeting?

Out of the 1201 patients that we analyzed, approximately 187 met our inclusion criteria. One-hundred six patients were found toharbor a germline BRCA mutation, 26 were somatic, BRCA positive or HRD positive, and then 55 were BRCA negative and HRD negative.

Patients who had BRCA-negative and HRD-negative tumors tended to be older, White, and had non-serous histology. They also tended to acquire more neoadjuvant chemotherapy cycles and had less complete growth resection at tumor reductive surgery. Patients who had BRCA and HRD-negative tumors also had a worse progressive-free survival, as well as overall survival when compared to the patients with germline BRCA-positive or somatic-BRCA- and HRD-positive tumors on multivariate analysis for progression-free survival. We found that age, stage, R0 resection at tumor reductive surgery, as well as BRCA- and HRD-negative status were significant factors impacting progression-free survival. And on multivariate analysis for overall survival,we again found age and R0 resection status to be significant factors for overall survival.

What are the implications of this research? Do you think these findings can inform future studies?

There are 2 big points that we highlighted in this initial analysis. The first wasn't really all that surprising. It's that women who harbor a germline mutation in BRCA1 or BRCA2 or have a somatic BRCA tumor mutation or HRD-positive disease have an improved progression-free survival and overall survival, regardless of whether they received primary cytoreductive surgery followed by adjuvant chemotherapy, or received neoadjuvant chemotherapy, followed by interval cytoreductive surgery followed by adjuvant chemotherapy. I think the second point, which is something that that we hope to explore further, is that it seems that having BRCA wild-type and being HR-proficient seem to be negative prognostic factors for survival in high-grade ovarian cancer.

Are there any next steps with this research?

The next step is to take the same cohort, and stratify again using same groups, and look at their frontline therapy. More importantly, we will look at their maintenance options and the maintenance therapy that they're receiving.

What other predictive markers do you think are important to explore in these patients?

That’s the question that I think a lot of people are wondering, and at this point, I don't think we can say. The important focus, though, needs to shift towards looking at those other 50% of patients. What I mean by that is looking at those patients that are BRCA wild-type and HR-proficient, because these patients seem to have less targeted therapy options as compared with the other 50% that do have a germline BRCA mutation or are found to be HRD positive.

_Reference:

_{Sims TT, Sood AK, Westin SN, et al. Correlation of HRD status with clinical and survival outcomes in patients with advanced-stage ovarian cancer. J Clin Oncol. 2021; 39: (suppl 15; abstr 5568). doi: 10.1200/JCO.2021.39.15_suppl.5568}