Clinicopathological Features And Prognosis Of Ovarian High-grade Serous Carcinoma With Homologous Recombination Deficiency

Background and objectivesOvarian cancer is one of the leading causes of gynecologic cancer deaths worldwide,and ovarian high-grade serous carcinoma is the most common pathologic subtype of malignant epithelial ovarian tumors.Homologous recombination repair(HRR)can repair DNA doublestand breaks in a high-fidelity way.Homologous recombination deficiency(HRD)is associated with genetic or epigenetic abnormalities in the molecules involved in the HRR pathway.Conventional treatment for ovarian cancer includes tumor cytoreductive surgery and systemic treatment with paclitaxel and platinum,but the recurrence rate is high.Novel medication polyADP ribose polymerase(PARP)inhibitors have been shown to be effective as first-line maintenance therapy in patients with advanced ovarian cancer.HRD is an important predictive and prognostic biomarker in ovarian cancer.Ovarian cancer with HRD is sensitive to PARP inhibitor.Carcinoma cells with HRD rely on other less accurate repair methods to repair damaged DNA duplexes,resulting in specific,quantifiable genomic alterations.HRD test is a next generation sequencing(NGS)technology and consists of two components: the qualitative detection of breast cancer susceptibility gene(BRCA)1/2 mutation and Genomic Instability Score(GIS)that is referred to as HRD score.The results of HRD tests include HRD positive(presence of HRD)and HRD negative(absence of HRD).Currently,there has been no studies on the clinicopathological features and prognosis of ovarian high-grade serous carcinoma with HRD.In this study,we explore the relationship between HRD and the clinicopathological features and prognosis of ovarian high-grade serous carcinoma,which aims to screen the candidates for HRD tests,guide the treatment with PARP inhibitors and assess the prognosis of patients.Materials and Methods36 cases of ovarian high-grade serous carcinoma were collected from January 2021 to June2022 in the Second Hospital of Jilin University.Clinicopathological and survival data were collected.Immunohistochemical staining was applied to detect the expression of immunohistochemical markers ER,PR,Ki67,p53,WT1,PMS2,MLH1,MSH6 and MSH2.Specimens from all cases were tested using NGS technology.Clinicopathological evaluation was according to the diagnostic criteria of ovarian high-grade serous carcinoma in the 5th edition of the World Health Organization(WHO)Classification of the Female Genital Tumors.Solid,endometrial-like,transitional features(SET features)and papillary-like,micropapillarylike and slit-like features and the expression of immunohistochemical markers were recorded.The relationship between different HRD status and the clinicopathological features and prognosis of high-grade serous carcinoma patients were analyzing by SPSS 29.0.The KaplanMeier and COX proportional risk regression models were performed on the survival data to analyze the differences in prognosis.Results1.A total of 36 patients,aged ranging from 42 to 74 years old,with an average age of55.64 ± 7.37 years old.Onset age < 55 years in 16 cases(44.4%),onset age ≥ 55 years in 20cases(55.6%);Ten cases(27.8%)were premenopausal,26 cases(72.2%)were postmenopausal;The number of pregnancies < 2 in 12 cases(33.3%),≥ 2 in 24 cases(66.7%).There are 16 cases(44.4%)without a history of abortion,20 cases(55.6%)with a history of abortion.Initial symptoms and signs: abdominal pain or distension in 14 cases(38.9%),abdominal mass in 13cases(36.1%),abnormal vaginal bleeding or fluid flow in 5 cases(13.9%),dysuria,ascites or cervical lymph node enlargement in 4 cases(11.1%).Tumor diameter was 2.5 to 20 cm,median diameter was 6.00(3.50,9.00)cm,< 6 cm in 17 cases(47.2%),≥ 6 cm in 19 cases(52.8%);22(61.1%)patients presented with lymphatic metastasis;14(38.9%)patients did not present with lymphatic metastasis.FIGO stage Ⅰ + Ⅱ in 5 cases(13.9%);Ⅲ + Ⅳ 31 in cases(86.1%).2.Morphologically,13 cases(36.1%)had the classic morphology of ovarian high-grade serous carcinoma;23 cases(63.9%)showed the SET features;10 cases(27.8%)had no maplike or comedo-like necrosis;26 cases(72.2%)had map-like or comedo-like necrosis.ER positive proportion < 10% in 8 cases(22.2%),10%–20% in 12 cases(33.3%),20%–50% in 10cases(27.8%),> 50% in 6 cases(16.7%);PR positive proportion < 10% in 12 cases(33.3%),10%–20% in 12 cases(33.3%),20%–50% in 7 cases(19.4%),> 50% in 5 cases(13.9%);Ki67positive < 70% in 14 cases(38.9%),≥ 70% in 22 cases(61.1%);p53 protein mutant-type overexpression in 30 cases(83.3%);p53 protein mutant-type absence in 6 cases(16.7%);WT1negative in 3 cases(8.3%);WT1 positive in 33 cases(91.7%);All the PMS2,MLH1,MSH6,MSH2 were positive in 36 cases(100%).3.Results of HRD tests: HRD negative in 12 cases(33.3%),HRD positive in 24 cases(66.7%).HRD score ≥ 41 with BRCA1/2 mutation in 6 cases;HRD score ≥ 41 without BRCA1/2mutation in 18 cases;HRD score < 41 with BRCA1/2 mutation in 0 cases;HRD < 41 without BRCA1/2 mutation in 12 cases.LST had the highest contribution to HRD score in 28 cases(77.8%),TAI had the highest contribution to HRD score in 8 cases(22.2%).LOH had the lowest contribution to HRD score in all cases(100%).BRCA1 germline mutation in 2 cases(5.6%)and somatic mutation in 2 cases(5.6%),BRCA2 germline mutation in 2 cases(5.6%).4.Statistical analysis of the clinicopathological features of the HRD positive and negative groups showed a significant difference in SET features between the two groups(P < 0.05).Statistical analysis of the clinicopathological features of different BRCA1/2 mutation status in the HRD positive group showed a significant difference in the number of pregnancies between the two subgroups(P < 0.05).5.The follow-up was ranging from 5 to 41 months,with a median follow-up time of 17(13–22)months.10 patients(27.8%)had recurrence or metastasis;1 patient died(2.8%),total poor prognosis in 11 cases(30.6%).6.The results of univariate analysis showed that p53 protein mutant-type absence was significantly associated with shorter OS(P < 0.05).7.The results of multifactorial survival analysis showed that HRD negative in ovarian high-grade serous carcinoma was associated with shorter PFS and HRD negative could be an independent risk prognostic factor.Conclusion1.HRD positive rate was as high as 66.7%,BRCA1/2 mutations rate was 16.7% and the frequency of BRCA1/2 germline mutations were higher than BRCA1/2 somatic mutations in ovarian high-grade serous carcinoma.2.Comparing with HRD negative cases,HRD positive cases had more frequent SET features in ovarian high-grade serous carcinoma,which might help to screen the HRD tests candidate population.3.HRD negative in ovarian high-grade serous carcinoma was significantly associated with shorter PFS and HRD negative could be an independent risk prognostic factor.