Stratification of Homologous Recombination Deficiency-Negative High-Grade Ovarian Cancer by the Type of Peritoneal Spread into Two Groups with Distinct Survival Outcomes.

Simple Summary: Homologous recombination deficiency plays an important role in high-grade ovarian cancer development and is used as an important marker to predict cancer survival based on the patient's response to treatment. The present study used a new score that we developed to assess homologous recombination deficiency, called the predictive-value integrated genomic instability score. We then looked at two different types of cancer spread (miliary versus non-miliary) and saw that tumors with miliary type tumor spread were negative for homologous recombination deficiency and that patients with miliary type tumor spread had a much poorer likelihood of survival than patients with non-miliary spreading tumors, independent of homologous recombination deficiency. This suggests that the type of tumor spread is the dominant predictor of the response to cancer therapy and homologous recombination deficiency is an indirect marker for the type of tumor spread. Background: Homologous recombination deficiency (HRD) has evolved into a major diagnostic marker in high-grade ovarian cancer (HGOC), predicting the response to poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and also platinum-based therapy. In addition to HRD, the type of peritoneal tumor spread influences the treatment response and patient survival; miliary type tumor spread has a poorer predicted outcome than non-miliary type tumor spread. Methods: Known methods for HRD assessment were adapted for our technical requirements and the predictive-value integrated genomic instability score (PIGIS) for HRD assessment evolved as an outcome. PIGIS was validated in HGOC samples from 122 patients. We used PIGIS to analyze whether the type of tumor spread correlated with HRD status and whether this had an impact on survival. Results: We demonstrated that PIGIS can discriminate HRD-positive from HRD-negative samples. Tumors with a miliary tumor spread are HRD-negative and have a very bad prognosis with a progression-free survival (PFS) of 15.6 months and an overall survival (OS) of 3.9 years. However, HRD-negative non-miliary spreading tumors in our cohort had a much better prognosis (PFS 35.4 months, OS 8.9 years); similar to HRD-positive tumors (PFS 34.7 months, OS 8.9 years). Conclusions: Our results indicate that in a predominantly PARPi naïve cohort, the type of tumor spread and concomitant cytoreduction efficiency is a better predictor of survival than HRD and that HRD may be an accidental surrogate marker for tumor spread and concomitant cytoreduction efficiency. It remains to be determined whether this also applies for sensitivity to PARPi. [ABSTRACT FROM AUTHOR]