Low fHR scores correlate with better primary therapy response and with longer PFI. A, For patients with chemo-naïve samples, the median of fHR scores is lower in CR and PR groups compared with SD/PD (Mann–Whitney test, two-tailed). Only patients with fHRP tumors had SD/PD after primary therapy. B, The median of fHR scores was lower in CR and PR groups compared with SD/PD also for patients with fHR score from IDS/NACT-treated sample (Mann–Whitney test, two-tailed). C, Proportions of CR, PR, and SD/PD are significantly different between fHRP and fHRD groups (Fisher exact test, two-tailed). D and E, PFI and OS significantly correlate with lower fHR scores (linear regression). F, Multivariate hazard ratio analysis for PFI with fHR status and prognostic clinical parameters. The fHRD status and success of cytoreduction significantly correlated with longer PFI (Cox proportional hazards regression). Blue = fHRD, red = fHRP.
ARTICLE ABSTRACT
Deficiency in homologous recombination (HR) repair of DNA damage is characteristic of many high-grade serous ovarian cancers (HGSC). It is imperative to identify patients with homologous recombination–deficient (HRD) tumors as they are most likely to benefit from platinum-based chemotherapy and PARP inhibitors (PARPi). Existing methods measure historical, not necessarily current HRD and/or require high tumor cell content, which is not achievable for many patients. We set out to develop a clinically feasible assay for identifying functionally HRD tumors that can predict clinical outcomes.
We quantified RAD51, a key HR protein, in immunostained formalin-fixed, paraffin-embedded (FFPE) tumor samples obtained from chemotherapy-naïve and neoadjuvant chemotherapy (NACT)-treated HGSC patients. We defined cutoffs for functional HRD separately for these sample types, classified the patients accordingly as HRD or HR-proficient, and analyzed correlations with clinical outcomes. From the same specimens, genomics-based HRD estimates (HR gene mutations, genomic signatures, and genomic scars) were also determined, and compared with functional HR (fHR) status.
fHR status significantly predicted several clinical outcomes, including progression-free survival (PFS) and overall survival (OS), when determined from chemo-naïve (PFS, P < 0.0001; OS, P < 0.0001) as well as NACT-treated (PFS, P < 0.0001; OS, P = 0.0033) tumor specimens. The fHR test also identified as HRD those PARPi-at-recurrence–treated patients with longer OS (P = 0.0188).
We developed an fHR assay performed on routine FFPE specimens, obtained from either chemo-naïve or NACT-treated HGSC patients, that can significantly predict real-world platinum-based chemotherapy and PARPi response.See related commentary by Garg and Oza, p. 2957
