Homologous recombination deficiency status predicts response to platinum-based chemotherapy in Chinese patients with high-grade serous ovarian carcinoma

Patient Characteristics

A total of 249 HGSOC patients were included in this study. The first patient in this prospective study was enrolled on January 6, 2016, and the last patient was enrolled on September 25, 2018. Nine patients with failure of quality control of sample or sequencing data or lost follow-up information were further removed for data analysis. Patient characteristics and clinical data are summarized in Table 1. The median age at diagnosis was 53 years (ranger 36–83 years). 76.7% of the patients have been diagnosed with FIGO stage III and 42 patients were FIGO IV stage (17.5%). All patients underwent surgical removal and then received platinum-based chemotherapy. One hundred and ten patients achieved R0 resection with no macroscopic disease (45.8%). Pt-sensitive patients with a platinum-free interval (PFI) of over six months accounted for 82.5 percent of the entire cohort (198/240).

Table 1 Clinical characteristics of HRR Cohort (n = 240)

HRR gene panel test was successfully performed in all 240 HGSOC patients (HRR cohort). Average coverage alignment to the target regions was 832 (range: 645–1103) for tumor and 322 (range 282–366) for matched normal. Average percentage of reads mapped to the target region was 54.3 (range: 48.7%—58.4%)% for tumor and 57.6% (range: 50.3%-62.3%) for matched normal. Germline and somatic deleterious BRCA1/2 mutations were observed in 31.2% of the overall HRR cohort (75 out of 240), including 53 mutations in BRCA1, and 22 mutations in BRCA2 (Table 1, Fig. 1). All mutations have been previously identified in the BIC database, or are designated as deleterious, based on the nature of the mutation (nonsense, frameshift, alternate splicing, or deletion). Sixty patients (25%) had at least one deleterious mutation in a candidate HRR gene. The specific HRR mutations identified in the 14 non-BRCA HRR genes were: BLM (10, 17%), FANCD2 (7, 12%), RBBPB (6, 8%), FANCM (5, 8%), RAD51D (5, 8%), ATM (4, 7%), ATR (4, 7%), MRE11A (4, 7%), NBN (4, 7%), BRIP1 (3, 5%), CHEK2 (3, 5%), RAD51C (3, 5%), BARD1 (1, 2%), FANCG (1, 2%) (Supplementary Figure S1).

Fig. 1figure 1

Distribution of deleterious mutations detected in BRCA1 and BRCA2 genes. Sticks represent mutation positions. The number represents the number of samples with the mutation (the unmarked represents 1). The colors of the bar represent the functional domains of BRCA

HRD Score association with BRCA1/2 and HRR mutation

A subset of 118 patients from the HRR cohort had adequate DNA and underwent HRD test. All 118 patients (HRD cohort) had evaluable HRD scores, with a median of 41.5 (Fig. 2A). Of these, 17.8% (21/118) had apparent biallelic alterations in BRCA, based on presence of LOH or two detectable pathogenic alterations, and these cases had a mean HRD score of 42.7 compared to a mean of 38.5 for cases lacking evidence of biallelic alteration (p = 0.28; Fig. 2A). We also found patient with somatic pathogenicity had a higher HRD score than germline ones in BRCA1-deleterious patients (BRCA1: medium HRD score 62.1 vs 39.9, p = 0.031) (Fig. 2B). Subsequently, we investigated the connection between the HRD score and candidate HRR pathway gene mutations other than BRCA mutations. There was no significant difference in the HRD score among the HRR gene mutation groups (Supplementary Figure S2).

Fig. 2figure 2

HRD score distribution in HRD cohort (n = 118) stratified by BRCA deficiency status (A) and BRCA mutation (B)

HRR mutation, HRD Status, and response to platinum-based chemotherapy

Next, we validated HRD with platinum chemotherapy efficacy in the HRD cohort. Table 1 outlines patient and tumor characteristics stratified by the platinum response. The proportions of Pt-sensitive patients in the HRD cohort were 79.7% (94 out of 118). The Pt-sensitive patients showed higher HRD scores than Pt resistant ones, but this was not significant (median: 42.6 vs. 31.6, p = 0.086, Fig. 3A). (Pt)-sensitive rate was higher in HRD + BRCAm tumors (n = 36) and in HRD + BRCAwt tumors (n = 40) compared with 74% in the HRD-BRCAwt tumors (n = 42) (HRD + BRCAm: 97%, p = 0.004 and HRD + BRCAwt: 90%, p = 0.04) (Fig. 3B). We also found Pt-sensitive patients tend to be enriched in patients with BRCA mutations (BRCA: 93.6% vs 75.4%, p < 0.001) (Fig. 3C).

Fig. 3figure 3

HRD score, homologous recombination mutations, and HRD status predict platinum response. The Pt-sensitive patients showed significantly higher HRD scores than Pt-resistant ones (A). Pt-sensitive patients tend to be enriched in patients with HRD or BRCAm (B) and BRCA mutations or non-BRCA HRR pathway gene mutations (C)

Association of BRCA1/2 mutation, HRD score, and HRD status with PFS

The PFS data were analyzed based on BRCA and HRD status in the HRD cohort. Patients with HRD status positive had significantly improved PFS compared with those HRD status was negative (median PFS: 30.5 months vs. 16.8 months, Log-rank p = 0.001) (Fig. 4A). Even for BRCAwt patients, positive HRD also associated with better PFS than the HRD-negative group (median: 27.5 months vs 16.8 months, Log-rank p = 0.010) (Supplementary Figure S3A).

Fig. 4figure 4

Progression-free survival by genetic status. A, the presence of HRD was associated with an improved PFS compared with cases without HRD. B, Similarly, cases with HRR gene or BRCA mutation had longer median PFS than subjects without mutation in HRR gene and BRCA. C, Patients with mutations in the DBD domain of BRCA1 are less sensitive to platinum chemotherapy

Besides, we also evaluated whether HRR gene mutation was a prognostic factor. We found that BRCA mutation group had significant longer PFS than the HRRwt group (BRCAm: medium PFS 30.5 months vs 18.3 months, p = 0.006) (Fig. 4B).

A previous study suggested that mutations in the different functional domains of BRCA might result in differences in cancer prognosis. We defined the functional domain of BRCA1 protein as follows: 1) the N-terminal Really Interesting New Gene (RING) domain: AA 8–96; 2) DNA-binding domain: AA 452–1092; and 3) the BRCA1 C-terminal (BRCT) domain: AA 1646–1736 and 1760–1855. Similarly, functional domains of BRCA2 were defined as 1) RAD51-binding domain (RAD51-BD): AA 900–2000; 2) DBD: AA 2459–3190. Considering these domains, 37 patients of the BRCA mutation group were divided into subgroups depending on the position of BRCA mutations, and their survival outcomes were compared. Patients with pathogenic mutations located in the DBD domain of BRCA1 had improved FPS, compared to those with mutations in other domains. (p = 0.03). Due to the small sample size of some domains, this conclusion needs more research to verify.

Ten covariates (HRD status, residual tumor, tBRCA, HRD score, CA125, HE4, cancer history, HRR, FIGO stage, and Age) were evaluated in the univariable Cox proportional hazards regression model. The univariate analysis identified 4 covariates (HRD status: HR, 0.44; 95% CI [0.29–0.68]; p < 0.001; residual tumor: HR, 0.45; 95% CI [0.29–0.70]; p < 0.001; tBRCA: HR, 0.54; 95% CI [0.33–0.90]; p = 0 0.017; HRD score: HR, 0.64; 95% CI [0.41–0.98]; p = 0 0.04) as potential candidates for the multivariate model at the 0.05 alpha level based on the Wald chi-square statistic (Table 2). On multivariate analysis, residual tumor was again to be significant factors for PFS (HR, 0.47; 95% CI [0.30–0.74]; p = 0.001) (Table 2). We found patients with HRD-positive tumors tended to undergo R0 resection at tumor reductive surgery (Pearson's Chi-squared test, p = 0.03). Thus, having an HRD-positive tumor had a longer median PFS compared withthose who did not undergo R0 resection and were HRD negative whether R0 is achieved or not.(nonR0 & HRD + vs non-R0 & HRD-, P < 0.0083; R0 & HRD + vs non-R0 & HRD-, P < 0.001) (Supplementary Figure S3B).

Table 2 Univariable and multivariable analysis of progression-free survival in HRD cohort (n = 118)

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