Comprehensive HRD testing in epithelial ovarian cancer: A further step toward personalized therapy decisions.
Authors: Reimer Daniel Uwe , Schnaiter Simon , Wimmer Katharina , Schamschula Esther , Leitner Katharina , Pietzner Klaus , Sehouli Jalid , Marth Christian , Fiegl Heidi , Zeimet Alain G 
Published: June 2023

e17591

Background: HRD testing in ovarian cancer to date is predominately based on dichotomizing scores defining HR-deficiency and -proficiency. We herein provide a new comprehensive approach to test HR-status, which aims to assess HRD in a qualitative and quantitative manner. Methods: In addition to a 153-gene NGS panel, quantitative HRD was assessed in a “real-life” collective of 108 “high-grade”, stage III/IV ovarian cancer specimens. The readout of the assay integrates a LoH score, based on the algorithm of Swisher et al. and an Aneuploidy Normalized Telomeric Imbalance- (ANTI) score, adapted from the Birkbak et al. Telomeric Allelic Imbalance- (TAI) score. Besides numerical HRD values, clinical thresholds for both parameters were determined based on platinum-response at first recurrence according to platinum-free interval, and integrated into a HRD score ( [LoH/optimal cutoff] + [ANTI/optimal cutoff]) resulting in an optimal clinical cutoff of 1.95 (40. percentile). Results: All BRCAmut tumor specimens (n = 42) exhibited HRD scores above the derived cutoff (median: 3.00 (95%CI 2.65; 3.80)). Tumors with HRD scores above the cutoff were associated with improved PFS and OS in the whole collective (HR 0.334 (0.210–0.532) and 0.237 (0.123-0.459), respectively) and in the subgroup of BRCAwt patients (n = 66) (HR 0.282 (0.142–0.563) and 0.160 (0.048–0.536), respectively). In addition, a high HRD score was associated with a longer platinum-free interval ( < 6 mo: 1.32 (0.92–1.44), ≥ 6 mo: 2.09 (1.18–3.24)). Residual disease after primary debulking surgery (n = 81) was associated with lower HRD scores (p = 0.029) which was apparently not based on differences in the amount or localization of intraperitoneal tumor spread (p = 0.802). However, patients exhibiting miliary, confluent tumor spread had significantly lower HRD scores compared to a more nodular and, more easy to remove type of carcinomatosis (median: 1.09 (95%CI 0.81; 1.40) and 2.83 (95%CI 2.07; 3.51); p < 0.001). In neoadjuvant treated patients (n = 27) morphologically assessed vitality in remaining disease at the time of interval debulking surgery inversely correlated with HRD scores (p < 0.001), whereby highest HRD scores were assessed in the 3% of patients exhibiting a complete pathologic response. In addition, comparing testing performance to the CA-125 ELIMination Rate Constant K (KELIM) score revealed a notably higher correlation of HRD to residual tumor vitality (-0.900; p < 0.001 versus -0.614; p < 0.001). Conclusions: Clinical validation of the herein provided new comprehensive HRD test in a “real-life” collective underscores its relevance in predicting ovarian cancer patients’ clinical outcome. From the clinical point of view, furthermore, our test is relevant to predict ( i) response to neoadjuvant treatment, and ( ii) surgical outcome. Its a priori integration could be a further step towards a more precise therapy decision strategy.