Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer

Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer Ying-Cheng Chiang, Hsien-Neng Huang, Kuan-Ting Kuo, Wuh-Liang Hwu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4601529/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 30 Jan, 2025 Read the published version in Journal of Ovarian Research → Version 1 posted 8 You are reading this latest preprint version Abstract Background The homologous recombination deficiency (HRD) test is an important tool for identifying patients with epithelial ovarian cancer (EOC) benefit from the treatment with poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). Using whole exome sequencing (WES)-based platform can provide information of gene mutations and HRD score; however, the clinical value of WES-based HRD test was less validated in EOC. Methods We enrolled 40 patients with EOC in the training cohort and 23 in the validation cohort. The WES-based HRD score was calculated using the scarHRD software. We first evaluated the concordance of the HRD status defined by the Myriad MyChoice CDx and then assessed the value of HRD on clinical prognosis in patients with EOC. Results The HRD score defined by the WES-based test was positively correlated with that of the Myriad MyChoice® CDx test (r = 0.82, p < 0.01) in the training cohort. In compared to HRD status of Myriad test, the sensitivity, specificity, positive predictive value, and negative predictive value of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively. Patients with positive HRD status defined by WES-based scarHRD test and Myriad MyChoice® CDx test were both highly associated with platinum sensitive response (both Fisher's exact test, p = 0.002) as well as the superior progression-free survival (both log-rank p = 0.002). The multi-variate Cox regression model incorporated with optimal debulking surgery showed that the recurrence risk was decreased in the patients with positive HRD status, either defined by Myriad MyChoice® CDx test (Hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14–0.79, p = 0.013) or WES-based test Myriad MyChoice® CDx test (HR 0.34, 95% CI 0.14–0.80, p = 0.014). Nine patients had mutations in the genes involved in HR DNA repair, and all of them were positive for HRD. In the validation group, 23 patients were defined as positive HRD by WES-based testing. Six positive HRD patients and 5 negative HRD patients received maintenance PARPi. The median responsive interval of PARPi was 17 months in positive HRD patients and 3 months in negative HRD patients. Conclusions The WES-based test is a feasible option for determining the HRD status in EOC patients. Epithelial ovarian cancer Homologous recombination deficiency test Whole-exome sequencing scarHRD Figures Figure 1 Figure 2 Figure 3 Introduction Epithelial ovarian cancer (EOC) is a major cause of cancer-related death in women [ 1 , 2 ]. Owing to the lack of specific symptoms and screening tools for identifying early-stage disease, most EOC patients are diagnosed at an advanced stage, where the disease would have spread beyond the pelvis, with a 5-year survival of less than 50% [ 3 ]. Most advanced-stage EOC patients relapse after a good response to primary treatments, including debulking surgery and adjuvant platinum-based chemotherapy, and the response to salvage chemotherapy is generally unsatisfactory, leading to poor prognosis [ 3 , 4 ]. Precision medicine is an evolving area in EOC that depends on the distinct genetic or molecular features of cancer, which are the targets of therapy. Maintenance PARPi therapy is a good example of an EOC [ 5 , 6 ]. Accumulation of DNA damage caused by replication errors, oxidative stress, ultraviolet light, radiation, or cytotoxic agents can lead to genomic instability. DNA damage response (DDR) pathways repair single-strand breaks (SSBs) or double-strand breaks (DSBs) in damaged DNA and DDR dysfunction is associated with carcinogenesis [ 7 ]. Homologous recombination repair (HRR) is an error-proof DNA repair pathway involving several genes, such as BRCA1/2 , which restores the original sequence at the DSB sites [ 7 ]. Homologous recombination deficiency (HRD) is a condition in which when HRR is impaired, DSBs are repaired by error-prone pathways, such as non-homologous end joining (NHEJ), single-strand annealing, or microhomology-mediated end joining, which causes errors in the sequence of the repaired DNA [ 7 ]. Poly (adenosine diphosphate-ribose) polymerase (PARP) participates in SSBs repair by binding to DNA strand breaks. PARP inhibitor (PARPi) therapy is based on “synthetic lethality,” in which DSBs induced by PARPi are repaired by error-prone pathways, leading to genomic instability and subsequent apoptosis in HRD cancer cells [ 8 ]. The dilemma is that the most promising target drugs benefit only in a subpopulation, and it is important to select the right patients for targeted therapy. A cost-effective analysis suggested that PARPi should be reserved for EOC patients with positive HRD status [ 9 , 10 ]. To stratify EOC patients for PARPi is currently based on the HRD status, and Myriad MyChoice® CDx test was one commercial test suggested by US Food and Drug Administration (FDA) and European Medicines Agency (EMA) [ 5 , 6 ]. HRD is a highly sensitive biomarker to PARPi or platinum-based chemotherapy [ 11 , 12 ]. However, the currently available FDA-approved HRD tests are not economical and feasible for real-world applications; establishing a method that most laboratories can perform is more consistent with clinical needs. A recent concept has shifted from single-nucleotide polymorphism (SNP) sequencing to whole-genome sequencing (WGS) or whole-exome sequencing (WES) [ 13 ]. Compared to SNP sequencing, WES provides more useful information about actionable genetic variants, microsatellite instability, and even tumor mutational burden for immune checkpoint blockade therapy. Some studies have demonstrated a very good correlation in HRD status between Myriad MyChoice® CDx testing and the WGS/WES method for breast cancer [ 13 , 14 ]. However, the clinical significance of WES-based HRD analysis for EOC has not yet been validated. In this study, we used a training cohort to develop a WES-based HRD test for EOC patients and evaluated its concordance with the results of the Myriad MyChoice® CDx test in the HRD status. We also assessed the prognostic and predictive value of HRD, which was defined using a WES-based test in EOC patients. We then confirmed the performance of the HRD test in the validation cohort to demonstrate its ability to guide PARPi therapy. Methods Patients and specimens The study protocol was approved by the National Taiwan University Hospital Research Ethics Committee (201807116RINA), and the study was performed in accordance with the guidelines and regulations. As shown in Figs. 1 , 40 and 23 patients were included in the training and validation groups, respectively. Specimens were retrieved from formalin-fixed paraffin-embedded (FFPE) tissues obtained from the primary debulking surgery. After pathologists’ review, FFPE specimens with a tumor purity of more than 20% were sliced at a thickness of 5–10 µm and sent for experiments. Clinical data were obtained from patients’ medical records, including age, cancer stage, tumor grade, residual tumor size after debulking surgery, pathological reports, adjuvant treatments, and outcomes. All the patients underwent primary debulking surgery and adjuvant platinum-based chemotherapy. For debulking surgery, R0 resection was defined as no gross residual tumor following surgery, R1 resection as a maximal residual tumor size of < 1 cm following surgery, and R2 resection as a maximal residual tumor size ≥ 1 cm. Stage was defined based on the International Federation of Gynecology and Obstetrics (FIGO) criteria, and tumor grade was defined based on the International Union Against Cancer criteria [ 15 ]. Cancer recurrence was defined as biopsy-proven disease, abnormalities reported in imaging studies (including computed tomography or magnetic resonance imaging), or continuously elevated levels of cancer antigen 125 (CA-125; more than twice the upper normal limit) for at least two consecutive tests with a monthly interval. Patients were designated as “platinum-sensitive” when the tumor recurs beyond 6 months after completing primary treatment, and “platinum-resistant” when the tumor recurred within 6 months after completing primary treatment. Progression-free survival (PFS) was defined as the interval from the date of completion of the primary treatment to the date of confirmed recurrence, progression, or last follow-up. Overall survival (OS) was defined as the interval from the date of diagnosis to the date of EOC or the last follow-up. DNA extraction and library preparation Genomic DNA was isolated from FFPE specimens using a Quick-DNA FFPE extraction kit (Zymo Research, CA, USA), according to the manufacturer’s instructions. A total of 100-ng ng DNA per sample was used for library preparation. DNA fragmentation and library construction were performed using the KAPA HyperPlus Kit for next-generation sequencing (NGS) DNA Library Preparation. An exome library was generated using Roche KAPA HyperExome Probes (Roche, Basel, Switzerland). Sequencing and bioinformatics The samples were sequenced using Illumina NovaSeq with paired-end reads of 300 nucleotides, and the analysis algorithm was in accordance with our previous protocol [ 16 ]. Raw sequencing data were aligned with the reference human genome (December 2013, GRCh38) using Burrows-Wheeler Aligner software (version 0.5.9) [ 16 ]. The SAM tools (version 0.1.18) were used for data conversion, sorting, and indexing [ 16 ]. We used the Genome Analysis Toolkit (GATK; version 4) Mutect2 for variant calling, including nonsynonymous variants, small insertion/deletions (indels), and variants of splicing boundaries [ 16 ]. After variant calling, ANNOVAR was used for annotation of the genetic variants [ 16 , 17 ]. ClinVar, dbSNP (version 150), Exome Sequencing Project 6500 (ESP6500), and 1000 Genomes variant datasets (ExAC and gnomAD) were used to filter common variants in the sequencing results. Pathogenic/likely pathogenic variants, which were defined by guidelines for the interpretation of sequencing variants, were considered deleterious and used for further analysis [ 18 ]; variants of uncertain significance were not enrolled. In the WES-based test, we focused on pathogenic variants of genes involved in DDR pathways, including BRCA genes (Supplementary Table S1 ) [ 16 , 19 ]. WES-based HRD test We used scarHRD software to measure the HRD score, which is a combination of loss of heterozygosity (LOH)[ 11 ], the number of chromosomal regions with allelic imbalance extending to the telomere (TAI)[ 20 ], and large-scale state transition (LST)[ 21 ]. The LOH score was defined as the number of LOH regions greater than 15 Mb in length. TAI refers to the unequal contribution of parental allele sequences extending to the end of the chromosome. LST is defined as a chromosomal break between adjacent regions, each of which is at least 10 Mb, and the distance between them is not larger than 3 Mb. The scarHRD is an R package program downloaded from the website ( https://github.com/sztup/scarHRD ) [ 22 ]. The positive HRD status of the specimen was defined under the following two conditions. First, deleterious variants of BRCA1 or BRCA2 were detected. Second, the HRD score of the specimen calculated using scarHRD software was ≥ 50, which reflected the score of 42 of the Myriad MyChoice® CDx test by linear regression analysis (Fig. 2 B). Myriad MyChoice® CDx test The Myriad MyChoice® CDx test is an NGS-based diagnostic test that is conducted using DNA isolated from FFPE specimens. This test performed (1) qualitative detection of single-nucleotide variants (SNVs), insertions and deletions (indels), and large genomic rearrangement variants in protein-coding regions and intron/exon boundaries of BRCA1 / 2 genes and (2) determination of the genomic instability score (GIS), which is an algorithmic measurement of LOH, TAI, and LST. Positive HRD status was defined as pathogenic or likely deleterious mutations in BRCA1/2 or GIS ≥ 42. Statistical analysis The chi-square test and Fisher’s exact test were used to calculate significant differences in the variables between the groups. The sensitivity and specificity of the WES-based scarHRD test were assessed using the Myriad MyChoice CDx test as a reference. The correlation between the HRD status and clinical outcomes was analyzed. PFS and OS were estimated using Kaplan-Meier analysis and log-rank tests. The HRD status on the risk of recurrence and death was evaluated using univariate and multivariate Cox proportional hazards regression models with corresponding 95% confidence intervals (CI). All p values were two-sided, and less than 0.05 were considered statistically significant. Results Clinicopathologic characteristics of the training cohort There were 40 patients with EOC in the training group, and their clinical characteristics are shown in Table 1. The median age was 56.5 years old, and the median pretreatment CA-125 value was 889 U/ml. All patients had advanced-stage (FIGO stages III and IV) high-grade serous EOC. All patients underwent primary debulking surgery, with R0 resection in 13 and R1 resection in 27. All patients received adjuvant platinum-based and paclitaxel chemotherapy, and 23 (57.5%) patients were platinum-sensitive. The median follow-up duration was 60 months. The Tumor recurred in 31 (77.5%) patients, and 21 (52.5%) patients died due to EOC. Establish the of WES-based HRD The HRD scores and deleterious gene mutations detected in these two tests are shown in Figure 2A. In the WES-based scarHRD test, the HRD scores of 40 patients ranged from 17 to 90. In the Myriad MyChoice CDx test, the HRD scores of 40 patients ranged from 3 to 84. A linear regression model was applied to analyze the correlation between the WES-based scarHRD score and the Myriad MyChoice CDx HRD score (Figure 2B). The WES-based scarHRD score was strongly correlated with the Myriad MyChoice CDx × HRD score (correlation coefficient (r): 0.82, p<0.001). Based on the regression model, we defined positive HRD status as BRCA gene mutation or a score of ≥50 in our WES-based scarHRD test, which is equal to a score of 42 in the Myriad MyChoice® CDx test. Overall, 32 patients had a positive HRD status (score > 50) in the WES-based test and 30 patients had a positive HRD status according to the Myriad MyChoice® CDx test (score > 42). For DDR gene mutations, BRCA1 mutation was noted in two patients, BRCA2 in two patients, ATM in one patient, CHEK2 in one patient, RAD51C in two patients, FANCG in one patient, and MSH6 in one patient (Supplementary Table S2). All patients with DDR mutations had a positive HRD status. In addition, we confirmed that the sequencing outcome of BRCA mutations in the cohort found by the Myriad MyChoice® CDx test was recapitulated in our WES-based test. Compared with the positive HRD status in the Myriad MyChoice® CDx test, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively (Supplementary Table S3). Correlation of HRD status to clinical outcomes in the training group In WES-based test, a higher percentage of patients with a platinum-sensitive response had a positive HRD status than that of patients with a platinum-resistant response (95.7% [22/23] vs. 52.9% [9/17], p=0.002, Fisher's exact test, Table 2). Similarly, a higher percentage of patients with a platinum-sensitive response had a positive HRD by Myriad MyChoice® CDx test than that of patients with a platinum-resistant response (95.7% [22/23] versus 52.9% [9/17], p=0.002, Fisher’s exact test, Table 2). There was no significant difference in the percentage of EOC patients with positive HRD status as defined by the two tests according to cancer recurrence and cancer-related death. Patients with EOC who underwent debulking surgery with R0 resection had a longer PFS (p=0.032, log-rank test; Figure 2C) and OS (p=0.013, log-rank test; Supplementary Figure 1A) than those who underwent R1 resection. Patients with a positive HRD status, either by the WES-based test or the Myriad MyChoice® CDx test, had a longer PFS (both p=0.002, log-rank test; Figure 2D & 2E). The predictive value of OS for the two HRD tests was unsatisfactory (Supplementary Figure 1B, C). Debulking surgery with R0 resection (hazard ratio [HR] 0.42, 95% CI 0.18-0.98, p=0.045) and HRD positive status test (WES based HRD: HR 0.29, 95% CI 0.12-0.68; , Myriad MyChoice CDx test: HR 0.28, 95% CI 0.12-0.66) were associated with disease recurrence in univariate analysis. The multivariate Cox regression model showed that a positive HRD status, which was defined by either the WES-based test or the Myriad MyChoice® CDx test, was an independent factor for disease progression after adjustment for R0/R1 resection. However, a positive HRD status in both tests was associated with a better OS trend, which was not statistically significant. The multivariate Cox regression model for the risk of cancer-related death revealed that only debulking surgery with R0 resection was an independent risk factor in the multivariate analysis. Evaluation of WES-based scarHRD test in validation group There were 23 patients in the validation group, all of whom had advanced-stage high-grade serous EOC. The follow-up period was 24 months. The clinical characteristics are shown in Table 4. Twelve patients were positive for HRD status, as defined by the WES-based test. The median age was 57.5 years old in patients with a positive HRD status and 64 years in those with a negative HRD status. The median pretreatment CA-125 level was 1211 U/ml in patients with positive HRD and 1206 U/ml in those with negative HRD. All patients underwent primary debulking surgery, with R0 resection in three patients, R1 in six patients, and R2 in three patients with positive HRD. Among the negative HRD patients, R0 was observed in six patients, R1 in three patients, and R2 in two patients. All patients received adjuvant platinum-based and paclitaxel chemotherapy, and platinum-sensitive response was noted in 12 (100%) patients with positive HRD patients and three (27.2%) of negative HD patients. As shown in Figure 3, six positive and five negative HRD patients received maintenance PARPi. The median interval of PARPi was 17 months in patients with positive HRD and 3 months in those with negative HRD results. Eight patients with positive HRD and five with negative HRD had cancer recurrence, and the median PFS was 14.5 months in patients with positive HRD and 4 months in patients with negative HRD. Discussion We demonstrated a high degree of consistency in HRD assessment using the WES-based method and the Myriad MyChoice® CDx test. Patients with positive HRD status were associated with platinum sensitivity and better PFS than those without HRD. We then validated the performance of the WES-based HRD test in patients with advanced EOC for maintenance PARPi therapy, which showed satisfactory outcomes, suggesting that the WES-based HRD test is a useful tool for the treatment of patients with EOC. The WES-based scarHRD test provides an HRD score representing genomic instability to determine the HRD status of patients with EOC. “Genomic scars” represent a record that reflects the repair of DNA damage in response to harmful exposure through multiple pathways in cells [ 23 ]. Currently available methods for detecting “genomic scars” use SNP-based microarray or NGS to measure large-scale structural lesions in tumor specimens, including LOH, TAI, and LST [ 24 ]. The above three are characteristics of impaired DNA repair activity for DSBs, and the genomic instability score (GIS) combines them to represent the degree of HRD-related genomic instability. Myriad MyChoice® CDx (Myriad Genetics) and Foundation Focus CDx BRCA LOH (Foundation Medicine) are Food and Drug Administration-approved diagnostic HRD tests. Positive HRD status in the Myriad MyChoice® CDx test was determined by BRCA mutation or GIS ≥ 42 in PAOLA-1 [ 25 ] and PRIMA [ 5 ], and by BRCA mutation or GIS ≥ 33 in VELIA [ 26 ]. The cutoff value of GIS was determined retrospectively from exploratory analyses, and these PARPi trials were not prospectively designed to stratify patients by HRD tests. The Foundation HRD test includes BRCA mutations and genomic LOH, calculated as the fraction of genomic regions with LOH by sequencing SNPs in tumor specimens. Moreover, 14% genomic LOH was considered a positive HRD status in the ARIEL2 trial [ 27 ], whereas 16% genomic LOH was considered the threshold in the ARIEL3 trial [ 28 ]. The compatibility between HRD defined by GIS and the percentage of genomic LOH also needs to be determined. Recently, the concept of HRD testing has shifted from SNP-based methods to WGS or WES methods. For example, HRDetect, a WGS-based assay, could predict BRCA deficiency with sensitivity of 98.7% and nearly 100% in 560 breast cancer cases and 73 ovarian cancer cases, respectively, in the validation cohort [ 29 ]. However, the ability of HRDetect to predict the PARPi response in EOC has not been confirmed [ 14 , 30 ]. WGS analyzes the whole genome, whereas WES analyzes all coding regions, which comprise 1%-2% of the genome [ 31 , 32 ]. The original data provided by WGS are quite larger than those provided by WES; therefore, WGS is more time-consuming and expensive than WES [ 33 , 34 ]. Thus, WES is more affordable in clinical practice if WES-based HRD is accurate. The scarHRD is an open-source R program that can be freely downloaded, and WGS or WES data can be used to calculate GIS. The results of our WES-based scarHRD test correlated well with those of the Myriad HRD test, and the WES-based scarHRD test provided a significant predictive value for clinical outcomes. These findings suggest that the WES-based HRD test is suitable for guiding precision oncology research. The cutoff value for HRD in our WES-based scarHRD test was 50, which was different from that of 42 for the Myriad MyChoice® CDx test. The use of different methods and a baseline reference to measure the HRD score may generate different thresholds to define a positive HRD status [ 35 ]. The linear regression model revealed a highly positive correlation between WES-based scarHRD and Myriad HRD scores. Thus, we defined the threshold of our WES-based scarHRD score according to the results of the linear regression analysis when the Myriad HRD score was equal to 42. The positive HRD status defined by our test had satisfactory sensitivity, specificity, and PPV/NPV compared to the HRD status determined by the Myriad MyChoice® CDx test. EOC patients with a positive HRD status according to the WES-based test showed a sensitive response to platinum chemotherapy, favorable PARPi maintenance interval, and better PFS. All evidence demonstrated that the clinical utility of our WES-based scarHRD test to guide PARPi is encouraging. The WES-based test provides information about DDR gene mutations, including BRCA and non-BRCA DDR genes, such as ATM , BRCA1/2 , BRIP1 , MLH1 , MSH2 , MSH6 , PALB2 , RAD51C , and RAD51D , as recommended by the National Comprehensive Cancer Network guidelines for EOC [ 36 ]. The percentage of BRCA1/2 somatic mutations in serous EOC in this study was 7.9% (5/63), consistent with the findings of previous literature [ 37 , 38 ]. Approximately 11–18% of high-grade serous EOC patients have a germline BRCA mutation and another 6–7% of patients with somatic BRCA mutations can be identified from tumor specimens [ 37 , 38 ]. In addition to BRCA mutated EOC patients who receive the greatest benefit from PARPi therapy, patients with non- BRCA HR gene mutations such as ATM , BRIP1 , PALB2 , RAD51C , RAD51D also derive a survival benefit [ 38 , 39 ]. Furthermore, these genes are cancer-predisposing genes, and somatic sequencing of pathogenic variants of the above genes may imply a potential germline origin[ 40 ]. Genetic counseling and cancer prevention are suggested if genetic testing confirms germline origin. Thus, WES is helpful in providing comprehensive management for patients with EOC. The present study had some limitations. First, the number of cases was small, and it is necessary to recruit more participants to confirm the value of WES-based HRD testing further. Second, no prospective randomized trial-designed clinical response to PARPi was observed in this cohort. In the training cohort, we used platinum sensitivity as the clinical surrogate marker to develop our WES-based scarHRD test because platinum sensitivity has been used as an indicator for obtaining GIS [ 11 , 20 , 21 , 24 ]. Our WES-based test showed good predictability for platinum response and progression-free survival (PFS). In the validation cohort, the outcomes of newly diagnosed advanced EOC patients stratified by the WES-based test for maintenance PARPi therapy were satisfactory. In the future, a prospective study comprising patients with EOC who were prescribed PARPi guided by our test should be conducted. In Conclusion, The WES-based test provided comprehensive information on gene mutations and HRD scores. Based on these findings, the WES-based scarHRD test is a feasible option for HRD testing in patients with EOC and has potential for clinical application in the future. Abbreviations DDR DNA damage response DSBs Double-strand breaks EMA European Medicines Agency EOC Epithelial ovarian cancer FDA Food and Drug Administration FFPE Formalin-fixed, paraffin-embedded FIGO International Federation of Gynecology and Obstetrics GIS Genomic instability score HR Homologous recombination HRD Homologous recombination deficiency HRR Homologous recombination repair Indels Insertions and deletions LOH Loss of heterozygosity LST Large-scale state transition NGS Next-generation sequencing NHEJ Non-homologous end joining NPV Negative predictive value OS Overall survival PARP Poly (adenosine diphosphate-ribose) polymerase PARPi Poly (adenosine diphosphate-ribose) polymerase inhibitor PFS Progression-free survival PPV Positive predictive value SNP Single-nucleotide polymorphism SNVs Single-nucleotide variants SSBs Single-strand breaks TAI Telomere allelic imbalance WES Whole exome sequencing WGS Whole-genome sequencing Declarations Conflict of interests All authors declare that they have no conflict of interests. Funding This study was funded by Takeda Pharmaceuticals Taiwan, Ltd., which was not involved in the study design, collection, analysis, interpretation of data, or preparation of the manuscript. Availability of data and materials The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request. Contributions PL, YC, and WC designed this study. PL, KK, HH, WC, and YC collected and prepared patient tissues. PL, KK, HH, WH, and YC performed experiments. PL, KK, HH, WH, YC, and WC performed analyses and interpretations. PL, WC and YC wrote the manuscript. PL and YC prepared figures and tables, respectively. All authors contributed to the manuscript and approved the submitted version. Acknowledgements The authors thank the patients who participated in the study. We thank Chieh-Min Chen and Tzu-Ying Lin, who assisted with the study. 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Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 2014;16:211. Ray-Coquard I, Pautier P, Pignata S, Pérol D, González-Martín A, Berger R, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. New England Journal of Medicine 2019;381:2416-28. Coleman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J Med 2019;381:2403-15. Swisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017;18:75-87. Coleman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949-61. Davies H, Glodzik D, Morganella S, Yates LR, Staaf J, Zou X, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017;23:517-25. Zhao EY, Shen Y, Pleasance E, Kasaian K, Leelakumari S, Jones M, et al. Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer. Clin Cancer Res 2017;23:7521-30. Meienberg J, Zerjavic K, Keller I, Okoniewski M, Patrignani A, Ludin K, et al. New insights into the performance of human whole-exome capture platforms. Nucleic Acids Res 2015;43:e76. Barbitoff YA, Polev DE, Glotov AS, Serebryakova EA, Shcherbakova IV, Kiselev AM, et al. Systematic dissection of biases in whole-exome and whole-genome sequencing reveals major determinants of coding sequence coverage. Sci Rep 2020;10:2057. Clark MJ, Chen R, Lam HY, Karczewski KJ, Chen R, Euskirchen G, et al. Performance comparison of exome DNA sequencing technologies. Nat Biotechnol 2011;29:908-14. Seaby EG, Pengelly RJ, Ennis S. Exome sequencing explained: a practical guide to its clinical application. Brief Funct Genomics 2016;15:374-84. Takaya H, Nakai H, Takamatsu S, Mandai M, Matsumura N. Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma. Sci Rep 2020;10:2757. Daly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:77-102. Hennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD, 2nd, et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 2010;28:3570-6. Pennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 2014;20:764-75. Norquist BM, Brady MF, Harrell MI, Walsh T, Lee MK, Gulsuner S, et al. Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study. Clin Cancer Res 2018;24:777-83. Klek S, Heald B, Milinovich A, Ni Y, Abraham J, Mahdi H, et al. Genetic Counseling and Germline Testing in the Era of Tumor Sequencing: A Cohort Study. JNCI Cancer Spectr 2020;4:pkaa018. Tables Table 1. Characteristics of epithelial ovarian cancer patients in the training cohort Exercise group Number of patients 40 Age (years old) 56.5(39-75) Pretreatment CA-125 (U/ml) 889(153 - 7561) Histology: Serous carcinoma 40(100%) FIGO stage: Advanced 40(100%) Tumor grade: high 40(100%) Debulking surgery R0 13(32.5%) R1 27(67.5%) Platinum response Sensitive 23(57.5%) Resistant 17(42.5%) Recurrence Yes 31(77.5%) No 9(22.5%) Death Yes 21(52.5%) No 19(47.5%) Note: Data of age and CA-125 are presented as median (minimum-maximum), whereas those of other parameters are presented as number (percentage). CA-125, cancer antigen 125; FIGO, International Federation of Gynecology and Obstetrics. Table 2. Correlation of HRD status and clinical parameters of EOC patients in the training group HRD positive status Platinum response Recurrence Death Total Sensitive Resistant No Yes No Yes 40 23 17 9 31 19 21 WES-based scarHRD test Negative 9 1(4.3%) 8(47.1%) 0(0%) 9(29%) 3(15.8%) 6(28.6%) Positive 31 22(95.7%) 9(52.9%) 9(100%) 22(71%) 16(84.2%) 15(71.4%) p value* 0.002 0.090 0.457 Myriad MyChoice® CDx HRD test Negative 9 1(4.3%) 8(47.1%) 0(0%) 9 (29%) 4(21.1%) 5(23.8%) Positive 31 22(95.7%) 9(52.9%) 9(100%) 22(71%) 15(78.9%) 16(76.2%) p value* 0.002 0.090 1.000 Note : HRD, homologous recombination deficiency; WES, whole-exome sequencing. *Fisher's exact test. Table 3. Cox regression model for evaluating the risk factors for recurrence and death in EOC patients of training group (n=40). Recurrence Death Univariate Multivariate Univariate Multivariate n H.R. (95% C.I.) p H.R. (95% C.I.) p H.R. (95% C.I.) p H.R. (95% C.I.) p Debulking surgery R1 27 1 (reference) 1 (reference) 1 (reference) 1 (reference) R0 13 0.42(0.18-0.98) 0.045 0.48(0.20-1.16) 0.104 0.24(0.07-0.82) 0.023 0.26(0.07-0.90) 0.033 WES-based scarHRD test Negative 9 1 (reference) 1 (reference) 1 (reference) 1 (reference) Positive 31 0.29(0.12-0.68) 0.005 0.34(0.14-0.80) 0.014 0.40(0.14-1.12) 0.080 0.49(0.17-1.37) 0.170 Recurrence Death Univariate Multivariate Univariate Multivariate n H.R. (95% C.I.) p H.R. (95% C.I.) p H.R. (95% C.I.) p H.R. (95% C.I.) p Debulking surgery R1 27 1 (reference) 1 (reference) 1 (reference) 1 (reference) R0 13 0.42(0.18-0.98) 0.045 0.49(0.20-1.18) 0.112 0.24(0.07-0.82) 0.023 0.25(0.07-0.88) 0.031 Myriad MyChoice® CDx HRD test Negative 9 1 (reference) 1 (reference) 1 (reference) 1 (reference) Positive 31 0.28(0.12-0.66) 0.004 0.33 (0.14-0.79) 0.013 0.40(0.14-1.19) 0.099 0.48(0.16-1.43) 0.190 Table 4. Characteristics of epithelial ovarian cancer patients in the validation cohort Validation group WES-based scarHRD test Positive Negative Number of patients 12 11 Age (years old) 57.5(46-77) 64(28-74) Pretreatment CA-125 (U/ml) 1211 (375- 10000) 1206 (227-17750) Histology: Serous carcinoma 12(100%) 11(100%) FIGO stage: Advanced 12(100%) 11(100%) Tumor grade: high 12(100%) 11(100%) Debulking surgery R0 3(25%) 6(54.5%) R1 6(50%) 3(27.3%) R2 3(25%) 2(18.2%) Platinum response Sensitive 12(100%) 3(27.2%) Resistant 0(0%) 4(36.4%) N.A. 0(0%) 4(36.4%)* Patient numbers with PARPi 6(50%) 5(45.5%) PARPi interval (months) 17(9-22) 3(2-8) Recurrence Yes 8(66.7%) 5(45.5%) No 4(33.3%) 6(54.5%) Progression free survival (months) 14.5(8-24) 4(0-9) Note: Data of age, CA-125, PARPi interval and progression free survival are presented as median (minimum-maximum), whereas those of other parameters are presented as number (percentage). CA-125, cancer antigen 125; FIGO, International Federation of Gynecology and Obstetrics. *The follow-up interval after completing primary treatments in 4 patients was less than 6 months, and therefore it could not be categorized by platinum response. Additional Declarations No competing interests reported. Supplementary Files suppldata.pdf Supplementary Figure 1. Kaplan-Meier analysis of overall survival in training group of EOC. (A) OS of EOC patients stratified by surgical resection status. Note: EOC patients who underwent R0 resection had better OS than those who underwent R1 resection (p=0.013, log-rank test). (B) OS of EOC patients stratified by our WES-based scarHRD test. Note: No significant difference was noted in EOC patients with a positive or negative HRD status. (C) OS of EOC patients stratified by Myriad MyChoice® CDx test Note: No significant difference was noted in EOC patients with a positive or negative HRD status. Cite Share Download PDF Status: Published Journal Publication published 30 Jan, 2025 Read the published version in Journal of Ovarian Research → Version 1 posted Editorial decision: Revision requested 23 Oct, 2024 Reviewers agreed at journal 04 Sep, 2024 Reviews received at journal 03 Sep, 2024 Reviewers agreed at journal 31 Aug, 2024 Reviewers invited by journal 29 Aug, 2024 Editor assigned by journal 19 Jun, 2024 Submission checks completed at journal 19 Jun, 2024 First submitted to journal 18 Jun, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4601529","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":319989636,"identity":"59f7ca94-b88e-484e-928f-4b42e62685fd","order_by":0,"name":"Ying-Cheng Chiang","email":"","orcid":"","institution":"National Taiwan University","correspondingAuthor":false,"prefix":"","firstName":"Ying-Cheng","middleName":"","lastName":"Chiang","suffix":""},{"id":319989638,"identity":"d519027f-8787-46b7-abca-1f6b0fccf322","order_by":1,"name":"Hsien-Neng Huang","email":"","orcid":"","institution":"National Taiwan University Hospital Hsin-Chu Branch","correspondingAuthor":false,"prefix":"","firstName":"Hsien-Neng","middleName":"","lastName":"Huang","suffix":""},{"id":319989639,"identity":"37f4f016-1d9e-42a7-a3d7-533bf530304f","order_by":2,"name":"Kuan-Ting Kuo","email":"","orcid":"","institution":"National Taiwan University","correspondingAuthor":false,"prefix":"","firstName":"Kuan-Ting","middleName":"","lastName":"Kuo","suffix":""},{"id":319989640,"identity":"ea8ca0af-eade-4da9-bf1d-5e1dafc5b0d2","order_by":3,"name":"Wuh-Liang Hwu","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wuh-Liang","middleName":"","lastName":"Hwu","suffix":""},{"id":319989641,"identity":"b7a2b7d2-ff0c-43f3-893c-ab6feafd1dac","order_by":4,"name":"Wen-Fang Cheng","email":"","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Wen-Fang","middleName":"","lastName":"Cheng","suffix":""},{"id":319989645,"identity":"9ff14225-487a-4d23-a803-9e9844541163","order_by":5,"name":"Po-Han Lin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYFACHiAukGBgY2Y+ABE4QJQWAwkGfna2BIjqAwyMDURoYWCQ7OcxIE6LOXvvwc8FBhZ5Bod5vj3+2MYgx3cjgf0xDx4tlj3nkqVnGEgUGxzm3W5wsI3BWPJGAmMzPi0GN3IMpHkMJBI3HObdJgHUkrgBpCUHvxbj3xAtPM9AWuqJ0WIGtmVmMw8bSEuCASEtlj1nzKxBWvqZ2cwkzpyTMJx55mHj7D94tJiz9xjf5qmoS2zjP/xMoqLMRp7vePKBjzPwOQyNLwHEBGISXcsoGAWjYBSMAkwAAN4fS8y8SsV4AAAAAElFTkSuQmCC","orcid":"","institution":"National Taiwan University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Po-Han","middleName":"","lastName":"Lin","suffix":""}],"badges":[],"createdAt":"2024-06-18 17:29:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4601529/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4601529/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s13048-024-01565-3","type":"published","date":"2025-01-30T15:57:15+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":60602805,"identity":"59938a00-5171-46ce-84d1-913d04c1c03e","added_by":"auto","created_at":"2024-07-18 16:18:01","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":51308,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe flowchart of the study.\u003c/strong\u003e In training group, the gene mutation and HRD status of 40 EOC patients was examined by our WES-based scarHRD test and Myriad MyChoice® CDx test. The correlation of clinical outcomes and HRD status were analyzed. In validation group, the gene mutation and HRD status of 23 EOC patients was defined by our WES-based scarHRD test. The correlation of clinical outcomes, especially the PARPi response, and HRD status were analyzed.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4601529/v1/bece407b5c177083dabc72e4.jpg"},{"id":60600508,"identity":"feffaf95-f641-4396-9e11-402a35ab0a59","added_by":"auto","created_at":"2024-07-18 16:02:01","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":238313,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe HRD scores, gene mutations and Kaplan-Meier analysis of progression free survival in training group of EOC. \u003c/strong\u003e(A) The HRD status.\u003cstrong\u003e \u003c/strong\u003e\u003cem\u003eNote: \u003c/em\u003eThe numbers indicate the HRD score from the two tests. The orange color indicates a positive HRD status obtained using our WES-based scarHRD test. The yellow color indicates a positive HRD status obtained using the Myriad MyChoice® CDx test. The red color indicates\u003cem\u003e BRCA1/2\u003c/em\u003e gene mutations. The green color indicates other DDR gene mutations. (B) Correlation between the WES-based scarHRD score and the Myriad MyChoice® CDx test score.\u003cem\u003e Note: \u003c/em\u003eWES-based scarHRD test score is highly correlated with the MyChoice® CDx test score. A MyChoice® CDx test score of 42 is equal to the WES-based scarHRD score of 50 obtained using the linear regression model. (C) PFS of EOC patients stratified bysurgical resection status.\u003cem\u003e Note:\u003c/em\u003e EOC patients who underwent R0 resection had better PFS than those who underwent R1 resection (p=0.032, log-rank test). (D) PFS of EOC patients stratified by our WES-based scarHRD test.\u003cem\u003e Note: \u003c/em\u003eEOC patients with a positive HRD status had better PFS than those with a negative HRD status (p=0.002, log-rank test). (E) PFS of EOC patients stratified by Myriad MyChoice® CDx test.\u003cem\u003e Note: \u003c/em\u003eEOC patients with a positive HRD status had better PFS than those with a negative HRD status (p=0.002, log-rank test).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4601529/v1/bd9fdbf8818ee9ff1ee50b2c.jpg"},{"id":60600509,"identity":"f0d9181e-dc7e-45df-886e-9ec1e6a7a7f5","added_by":"auto","created_at":"2024-07-18 16:02:01","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":182142,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe HRD status and clinical outcomes in validation group of EOC. \u003c/strong\u003eThe median intervals of PARPi in positive HRD EOC patients were longer than negative HRD patients. The median PFS of positive HRD EOC patients were longer than negative HRD patients. \u003cem\u003eNote: \u003c/em\u003eThe blue row indicated the interval of the patient taking PARPi. The orange row indicated progression free survival of the patient. The dark blue cross indicated the patient stopped taking PARPi. The light blue arrow indicated the patient keep PARPi. The red cross indicated cancer recurrence or persistent disease. The light red arrow indicated no evidence of cancer recurrence.\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4601529/v1/01f509bf6625108af3850e5e.jpg"},{"id":75352070,"identity":"9a51a6f6-6984-4505-9191-90e3fc50314b","added_by":"auto","created_at":"2025-02-03 16:13:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1401538,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4601529/v1/e8a7afef-9e46-4c35-907f-65c8332682b1.pdf"},{"id":60602011,"identity":"53f9b111-a7d2-4ee4-9d52-35e7a43a627d","added_by":"auto","created_at":"2024-07-18 16:10:01","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":305520,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1. Kaplan-Meier analysis of overall survival in training group of EOC.\u003c/strong\u003e (A) OS of EOC patients stratified by surgical resection status.\u003cem\u003e Note: \u003c/em\u003eEOC patients who underwent R0 resection had better OS than those who underwent R1 resection (p=0.013, log-rank test). (B) OS of EOC patients stratified by our WES-based scarHRD test.\u003cem\u003e Note: \u003c/em\u003eNo significant difference was noted in EOC patients with a positive or negative HRD status. (C) OS of EOC patients stratified by Myriad MyChoice® CDx test\u003cem\u003e Note: \u003c/em\u003eNo significant difference was noted in EOC patients with a positive or negative HRD status.\u003c/p\u003e","description":"","filename":"suppldata.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4601529/v1/ad99ab45f69c616dc7fe0bbf.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer","fulltext":[{"header":"Introduction","content":"\u003cp\u003eEpithelial ovarian cancer (EOC) is a major cause of cancer-related death in women [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Owing to the lack of specific symptoms and screening tools for identifying early-stage disease, most EOC patients are diagnosed at an advanced stage, where the disease would have spread beyond the pelvis, with a 5-year survival of less than 50% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Most advanced-stage EOC patients relapse after a good response to primary treatments, including debulking surgery and adjuvant platinum-based chemotherapy, and the response to salvage chemotherapy is generally unsatisfactory, leading to poor prognosis [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePrecision medicine is an evolving area in EOC that depends on the distinct genetic or molecular features of cancer, which are the targets of therapy. Maintenance PARPi therapy is a good example of an EOC [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Accumulation of DNA damage caused by replication errors, oxidative stress, ultraviolet light, radiation, or cytotoxic agents can lead to genomic instability. DNA damage response (DDR) pathways repair single-strand breaks (SSBs) or double-strand breaks (DSBs) in damaged DNA and DDR dysfunction is associated with carcinogenesis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Homologous recombination repair (HRR) is an error-proof DNA repair pathway involving several genes, such as \u003cem\u003eBRCA1/2\u003c/em\u003e, which restores the original sequence at the DSB sites [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Homologous recombination deficiency (HRD) is a condition in which when HRR is impaired, DSBs are repaired by error-prone pathways, such as non-homologous end joining (NHEJ), single-strand annealing, or microhomology-mediated end joining, which causes errors in the sequence of the repaired DNA [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Poly (adenosine diphosphate-ribose) polymerase (PARP) participates in SSBs repair by binding to DNA strand breaks. PARP inhibitor (PARPi) therapy is based on \u0026ldquo;synthetic lethality,\u0026rdquo; in which DSBs induced by PARPi are repaired by error-prone pathways, leading to genomic instability and subsequent apoptosis in HRD cancer cells [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe dilemma is that the most promising target drugs benefit only in a subpopulation, and it is important to select the right patients for targeted therapy. A cost-effective analysis suggested that PARPi should be reserved for EOC patients with positive HRD status [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. To stratify EOC patients for PARPi is currently based on the HRD status, and Myriad MyChoice\u0026reg; CDx test was one commercial test suggested by US Food and Drug Administration (FDA) and European Medicines Agency (EMA) [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. HRD is a highly sensitive biomarker to PARPi or platinum-based chemotherapy [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, the currently available FDA-approved HRD tests are not economical and feasible for real-world applications; establishing a method that most laboratories can perform is more consistent with clinical needs.\u003c/p\u003e \u003cp\u003eA recent concept has shifted from single-nucleotide polymorphism (SNP) sequencing to whole-genome sequencing (WGS) or whole-exome sequencing (WES) [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Compared to SNP sequencing, WES provides more useful information about actionable genetic variants, microsatellite instability, and even tumor mutational burden for immune checkpoint blockade therapy. Some studies have demonstrated a very good correlation in HRD status between Myriad MyChoice\u0026reg; CDx testing and the WGS/WES method for breast cancer [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. However, the clinical significance of WES-based HRD analysis for EOC has not yet been validated.\u003c/p\u003e \u003cp\u003eIn this study, we used a training cohort to develop a WES-based HRD test for EOC patients and evaluated its concordance with the results of the Myriad MyChoice\u0026reg; CDx test in the HRD status. We also assessed the prognostic and predictive value of HRD, which was defined using a WES-based test in EOC patients. We then confirmed the performance of the HRD test in the validation cohort to demonstrate its ability to guide PARPi therapy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and specimens\u003c/h2\u003e \u003cp\u003e The study protocol was approved by the National Taiwan University Hospital Research Ethics Committee (201807116RINA), and the study was performed in accordance with the guidelines and regulations. As shown in Figs.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, 40 and 23 patients were included in the training and validation groups, respectively. Specimens were retrieved from formalin-fixed paraffin-embedded (FFPE) tissues obtained from the primary debulking surgery. After pathologists\u0026rsquo; review, FFPE specimens with a tumor purity of more than 20% were sliced at a thickness of 5\u0026ndash;10 \u0026micro;m and sent for experiments.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eClinical data were obtained from patients\u0026rsquo; medical records, including age, cancer stage, tumor grade, residual tumor size after debulking surgery, pathological reports, adjuvant treatments, and outcomes. All the patients underwent primary debulking surgery and adjuvant platinum-based chemotherapy. For debulking surgery, R0 resection was defined as no gross residual tumor following surgery, R1 resection as a maximal residual tumor size of \u0026lt;\u0026thinsp;1 cm following surgery, and R2 resection as a maximal residual tumor size\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;1 cm. Stage was defined based on the International Federation of Gynecology and Obstetrics (FIGO) criteria, and tumor grade was defined based on the International Union Against Cancer criteria [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Cancer recurrence was defined as biopsy-proven disease, abnormalities reported in imaging studies (including computed tomography or magnetic resonance imaging), or continuously elevated levels of cancer antigen 125 (CA-125; more than twice the upper normal limit) for at least two consecutive tests with a monthly interval. Patients were designated as \u0026ldquo;platinum-sensitive\u0026rdquo; when the tumor recurs beyond 6 months after completing primary treatment, and \u0026ldquo;platinum-resistant\u0026rdquo; when the tumor recurred within 6 months after completing primary treatment. Progression-free survival (PFS) was defined as the interval from the date of completion of the primary treatment to the date of confirmed recurrence, progression, or last follow-up. Overall survival (OS) was defined as the interval from the date of diagnosis to the date of EOC or the last follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eDNA extraction and library preparation\u003c/h2\u003e \u003cp\u003eGenomic DNA was isolated from FFPE specimens using a Quick-DNA FFPE extraction kit (Zymo Research, CA, USA), according to the manufacturer\u0026rsquo;s instructions. A total of 100-ng ng DNA per sample was used for library preparation. DNA fragmentation and library construction were performed using the KAPA HyperPlus Kit for next-generation sequencing (NGS) DNA Library Preparation. An exome library was generated using Roche KAPA HyperExome Probes (Roche, Basel, Switzerland).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eSequencing and bioinformatics\u003c/h2\u003e \u003cp\u003eThe samples were sequenced using Illumina NovaSeq with paired-end reads of 300 nucleotides, and the analysis algorithm was in accordance with our previous protocol [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Raw sequencing data were aligned with the reference human genome (December 2013, GRCh38) using Burrows-Wheeler Aligner software (version 0.5.9) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The SAM tools (version 0.1.18) were used for data conversion, sorting, and indexing [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We used the Genome Analysis Toolkit (GATK; version 4) Mutect2 for variant calling, including nonsynonymous variants, small insertion/deletions (indels), and variants of splicing boundaries [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. After variant calling, ANNOVAR was used for annotation of the genetic variants [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. ClinVar, dbSNP (version 150), Exome Sequencing Project 6500 (ESP6500), and 1000 Genomes variant datasets (ExAC and gnomAD) were used to filter common variants in the sequencing results. Pathogenic/likely pathogenic variants, which were defined by guidelines for the interpretation of sequencing variants, were considered deleterious and used for further analysis [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]; variants of uncertain significance were not enrolled. In the WES-based test, we focused on pathogenic variants of genes involved in DDR pathways, including \u003cem\u003eBRCA\u003c/em\u003e genes (Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e) [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eWES-based HRD test\u003c/h2\u003e \u003cp\u003eWe used scarHRD software to measure the HRD score, which is a combination of loss of heterozygosity (LOH)[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], the number of chromosomal regions with allelic imbalance extending to the telomere (TAI)[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and large-scale state transition (LST)[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The LOH score was defined as the number of LOH regions greater than 15 Mb in length. TAI refers to the unequal contribution of parental allele sequences extending to the end of the chromosome. LST is defined as a chromosomal break between adjacent regions, each of which is at least 10 Mb, and the distance between them is not larger than 3 Mb. The scarHRD is an R package program downloaded from the website (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://github.com/sztup/scarHRD\u003c/span\u003e\u003cspan address=\"https://github.com/sztup/scarHRD\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The positive HRD status of the specimen was defined under the following two conditions. First, deleterious variants of BRCA1 or BRCA2 were detected. Second, the HRD score of the specimen calculated using scarHRD software was \u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;50, which reflected the score of 42 of the Myriad MyChoice\u0026reg; CDx test by linear regression analysis (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eMyriad MyChoice\u0026reg; CDx test\u003c/h2\u003e \u003cp\u003eThe Myriad MyChoice\u0026reg; CDx test is an NGS-based diagnostic test that is conducted using DNA isolated from FFPE specimens. This test performed (1) qualitative detection of single-nucleotide variants (SNVs), insertions and deletions (indels), and large genomic rearrangement variants in protein-coding regions and intron/exon boundaries of \u003cem\u003eBRCA1\u003c/em\u003e/\u003cem\u003e2\u003c/em\u003e genes and (2) determination of the genomic instability score (GIS), which is an algorithmic measurement of LOH, TAI, and LST. Positive HRD status was defined as pathogenic or likely deleterious mutations in \u003cem\u003eBRCA1/2\u003c/em\u003e or GIS\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;42.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe chi-square test and Fisher\u0026rsquo;s exact test were used to calculate significant differences in the variables between the groups. The sensitivity and specificity of the WES-based scarHRD test were assessed using the Myriad MyChoice CDx test as a reference. The correlation between the HRD status and clinical outcomes was analyzed. PFS and OS were estimated using Kaplan-Meier analysis and log-rank tests. The HRD status on the risk of recurrence and death was evaluated using univariate and multivariate Cox proportional hazards regression models with corresponding 95% confidence intervals (CI). All p values were two-sided, and less than 0.05 were considered statistically significant.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eClinicopathologic characteristics of the\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;training cohort\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were 40 patients\u0026nbsp;with EOC in the training group,\u0026nbsp;and\u0026nbsp;their clinical characteristics are shown in\u0026nbsp;Table 1. The median age was 56.5 years old, and the median pretreatment CA-125 value was 889\u0026nbsp;U/ml.\u0026nbsp;All patients had advanced-stage (FIGO\u0026nbsp;stages III and IV) high-grade serous EOC. All patients underwent primary debulking surgery, with R0 resection in 13 and R1 resection in 27. All patients received adjuvant platinum-based and paclitaxel chemotherapy, and 23 (57.5%) patients were platinum-sensitive. The median follow-up\u0026nbsp;duration was 60 months. The Tumor recurred in 31 (77.5%) patients, and 21 (52.5%) patients died due to EOC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEstablish the of WES-based HRD\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe HRD scores and\u0026nbsp;deleterious gene mutations detected in these two tests\u0026nbsp;are shown\u0026nbsp;in Figure 2A. In\u0026nbsp;the\u0026nbsp;WES-based scarHRD test, the HRD scores of\u0026nbsp;40 patients ranged from 17 to 90. In the Myriad MyChoice CDx test, the HRD scores of 40 patients ranged from 3 to 84.\u0026nbsp;A linear regression model was applied to analyze the correlation between\u0026nbsp;the WES-based\u0026nbsp;scarHRD score and the Myriad MyChoice CDx HRD score (Figure 2B). The WES-based scarHRD score was strongly correlated with the Myriad MyChoice CDx\u0026nbsp;× HRD score (correlation coefficient (r): 0.82, p\u0026lt;0.001). Based on the regression model, we defined\u0026nbsp;positive HRD status as \u003cem\u003eBRCA\u003c/em\u003e gene mutation or a score of ≥50 in our\u0026nbsp;WES-based scarHRD test, which is equal to a score of 42 in the Myriad MyChoice® CDx test.\u003c/p\u003e\n\u003cp\u003eOverall, 32 patients had a positive HRD status (score \u003cu\u003e\u0026gt;\u003c/u\u003e50) in\u0026nbsp;the WES-based test and 30 patients had a positive HRD status\u0026nbsp;according to\u0026nbsp;the\u0026nbsp;Myriad MyChoice® CDx test\u0026nbsp;(score \u003cu\u003e\u0026gt;\u003c/u\u003e42). For DDR gene mutations,\u0026nbsp;\u003cem\u003eBRCA1\u003c/em\u003e mutation was noted in two patients, \u003cem\u003eBRCA2\u003c/em\u003e in two patients, \u003cem\u003eATM\u003c/em\u003e in one patient, \u003cem\u003eCHEK2\u003c/em\u003e in\u0026nbsp;one patient,\u003cem\u003e\u0026nbsp;RAD51C\u003c/em\u003e in\u0026nbsp;two patients, \u003cem\u003eFANCG\u003c/em\u003e in one patient,\u0026nbsp;and\u003cem\u003e\u0026nbsp;MSH6\u003c/em\u003e in one patient\u0026nbsp;(Supplementary Table S2). All patients with DDR mutations had a positive HRD status.\u0026nbsp;In addition, we confirmed that the sequencing outcome of \u003cem\u003eBRCA\u003c/em\u003e mutations in the cohort found by\u0026nbsp;the Myriad\u0026nbsp;MyChoice® CDx test was recapitulated in our WES-based test.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompared with the positive HRD status in the Myriad MyChoice® CDx test, the sensitivity, specificity,\u0026nbsp;positive predictive value\u0026nbsp;(PPV), and\u0026nbsp;negative predictive value\u0026nbsp;(NPV) of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively\u0026nbsp;(Supplementary Table S3).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrelation of HRD status to clinical outcomes in\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003ethe training group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn\u0026nbsp;WES-based test,\u0026nbsp;a higher percentage of patients with a platinum-sensitive response had a positive HRD status than that of patients with a platinum-resistant response (95.7% [22/23] vs. 52.9% [9/17], p=0.002, Fisher's exact test, Table 2). Similarly, a higher percentage of patients with a platinum-sensitive response had a positive HRD by\u0026nbsp;Myriad MyChoice® CDx\u0026nbsp;test than that of patients with a platinum-resistant response (95.7% [22/23]\u0026nbsp;versus 52.9%\u0026nbsp;[9/17], p=0.002, Fisher’s exact test, Table 2). There was no significant difference in the percentage of EOC patients with positive HRD status\u0026nbsp;as\u0026nbsp;defined by the two tests according to cancer recurrence and cancer-related death.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients\u0026nbsp;with EOC\u0026nbsp;who underwent\u0026nbsp;debulking surgery with R0 resection\u0026nbsp;had\u0026nbsp;a\u0026nbsp;longer PFS\u0026nbsp;(p=0.032, log-rank test; Figure 2C)\u0026nbsp;and OS (p=0.013, log-rank test;\u0026nbsp;Supplementary\u0026nbsp;Figure 1A)\u0026nbsp;than those who underwent R1 resection.\u0026nbsp;Patients with a positive HRD status, either by\u0026nbsp;the WES-based test or\u0026nbsp;the\u0026nbsp;Myriad MyChoice® CDx test,\u0026nbsp;had a longer PFS (both p=0.002, log-rank test; Figure 2D \u0026amp; 2E).\u0026nbsp;The predictive value of OS for the two HRD tests was\u0026nbsp;unsatisfactory\u0026nbsp;(Supplementary\u0026nbsp;Figure 1B, C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDebulking surgery with R0 resection (hazard ratio [HR] 0.42, 95% CI 0.18-0.98, p=0.045) and HRD positive status test (WES based HRD: HR 0.29, 95% CI 0.12-0.68; , Myriad MyChoice CDx test: HR 0.28, 95% CI 0.12-0.66) were associated with disease recurrence in univariate analysis.\u0026nbsp;The\u0026nbsp;multivariate Cox regression model showed that\u0026nbsp;a\u0026nbsp;positive HRD status, which was defined by either the WES-based test or the Myriad\u0026nbsp;MyChoice® CDx test, was an independent factor for disease progression\u0026nbsp;after adjustment for R0/R1 resection. However,\u0026nbsp;a positive HRD status\u0026nbsp;in both tests was associated with a better\u0026nbsp;OS\u0026nbsp;trend, which was not\u0026nbsp;statistically significant. The multivariate Cox regression model for the risk of cancer-related death revealed\u0026nbsp;that only debulking surgery with R0 resection was an independent risk factor\u0026nbsp;in\u0026nbsp;the multivariate analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEvaluation of WES-based scarHRD test\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;in validation group\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were 23 patients in the validation group, all of whom had advanced-stage high-grade serous EOC. The follow-up period was 24 months. The clinical characteristics are shown in Table 4. Twelve patients were positive for HRD status, as defined by the WES-based test. The median age was 57.5 years old in patients with a positive HRD status and 64 years in those with a negative HRD status. The median pretreatment CA-125 level was 1211 U/ml in patients with positive HRD and 1206 U/ml in those with negative HRD. All patients underwent primary debulking surgery, with R0 resection in three patients, R1 in six patients, and R2 in three patients with positive HRD. Among the negative HRD patients, R0 was observed in six patients, R1 in three patients, and R2 in two patients. All patients received adjuvant platinum-based and paclitaxel chemotherapy, and platinum-sensitive response was noted in 12 (100%) patients with positive HRD patients and three (27.2%) of negative HD patients. As shown in Figure 3, six positive and five negative HRD patients received maintenance PARPi. The median interval of PARPi was 17 months in patients with positive HRD and 3 months in those with negative HRD results. Eight patients with positive HRD and five with negative HRD had cancer recurrence, and the median PFS was 14.5 months in patients with positive HRD and 4 months in patients with negative HRD.\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eWe demonstrated a high degree of consistency in HRD assessment using the WES-based method and the Myriad MyChoice\u0026reg; CDx test. Patients with positive HRD status were associated with platinum sensitivity and better PFS than those without HRD. We then validated the performance of the WES-based HRD test in patients with advanced EOC for maintenance PARPi therapy, which showed satisfactory outcomes, suggesting that the WES-based HRD test is a useful tool for the treatment of patients with EOC.\u003c/p\u003e \u003cp\u003eThe WES-based scarHRD test provides an HRD score representing genomic instability to determine the HRD status of patients with EOC. \u0026ldquo;Genomic scars\u0026rdquo; represent a record that reflects the repair of DNA damage in response to harmful exposure through multiple pathways in cells [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Currently available methods for detecting \u0026ldquo;genomic scars\u0026rdquo; use SNP-based microarray or NGS to measure large-scale structural lesions in tumor specimens, including LOH, TAI, and LST [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The above three are characteristics of impaired DNA repair activity for DSBs, and the genomic instability score (GIS) combines them to represent the degree of HRD-related genomic instability. Myriad MyChoice\u0026reg; CDx (Myriad Genetics) and Foundation Focus CDx \u003cem\u003eBRCA\u003c/em\u003e LOH (Foundation Medicine) are Food and Drug Administration-approved diagnostic HRD tests. Positive HRD status in the Myriad MyChoice\u0026reg; CDx test was determined by \u003cem\u003eBRCA\u003c/em\u003e mutation or GIS\u0026thinsp;\u0026ge;\u0026thinsp;42 in PAOLA-1 [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e] and PRIMA [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], and by \u003cem\u003eBRCA\u003c/em\u003e mutation or GIS\u0026thinsp;\u0026ge;\u0026thinsp;33 in VELIA [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The cutoff value of GIS was determined retrospectively from exploratory analyses, and these PARPi trials were not prospectively designed to stratify patients by HRD tests. The Foundation HRD test includes \u003cem\u003eBRCA\u003c/em\u003e mutations and genomic LOH, calculated as the fraction of genomic regions with LOH by sequencing SNPs in tumor specimens. Moreover, 14% genomic LOH was considered a positive HRD status in the ARIEL2 trial [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], whereas 16% genomic LOH was considered the threshold in the ARIEL3 trial [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The compatibility between HRD defined by GIS and the percentage of genomic LOH also needs to be determined.\u003c/p\u003e \u003cp\u003eRecently, the concept of HRD testing has shifted from SNP-based methods to WGS or WES methods. For example, HRDetect, a WGS-based assay, could predict \u003cem\u003eBRCA\u003c/em\u003e deficiency with sensitivity of 98.7% and nearly 100% in 560 breast cancer cases and 73 ovarian cancer cases, respectively, in the validation cohort [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. However, the ability of HRDetect to predict the PARPi response in EOC has not been confirmed [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. WGS analyzes the whole genome, whereas WES analyzes all coding regions, which comprise 1%-2% of the genome [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The original data provided by WGS are quite larger than those provided by WES; therefore, WGS is more time-consuming and expensive than WES [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Thus, WES is more affordable in clinical practice if WES-based HRD is accurate. The scarHRD is an open-source R program that can be freely downloaded, and WGS or WES data can be used to calculate GIS. The results of our WES-based scarHRD test correlated well with those of the Myriad HRD test, and the WES-based scarHRD test provided a significant predictive value for clinical outcomes. These findings suggest that the WES-based HRD test is suitable for guiding precision oncology research. The cutoff value for HRD in our WES-based scarHRD test was 50, which was different from that of 42 for the Myriad MyChoice\u0026reg; CDx test. The use of different methods and a baseline reference to measure the HRD score may generate different thresholds to define a positive HRD status [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. The linear regression model revealed a highly positive correlation between WES-based scarHRD and Myriad HRD scores. Thus, we defined the threshold of our WES-based scarHRD score according to the results of the linear regression analysis when the Myriad HRD score was equal to 42. The positive HRD status defined by our test had satisfactory sensitivity, specificity, and PPV/NPV compared to the HRD status determined by the Myriad MyChoice\u0026reg; CDx test. EOC patients with a positive HRD status according to the WES-based test showed a sensitive response to platinum chemotherapy, favorable PARPi maintenance interval, and better PFS. All evidence demonstrated that the clinical utility of our WES-based scarHRD test to guide PARPi is encouraging.\u003c/p\u003e \u003cp\u003eThe WES-based test provides information about DDR gene mutations, including BRCA and non-BRCA DDR genes, such as \u003cem\u003eATM\u003c/em\u003e, \u003cem\u003eBRCA1/2\u003c/em\u003e, \u003cem\u003eBRIP1\u003c/em\u003e, \u003cem\u003eMLH1\u003c/em\u003e, \u003cem\u003eMSH2\u003c/em\u003e, \u003cem\u003eMSH6\u003c/em\u003e, \u003cem\u003ePALB2\u003c/em\u003e, \u003cem\u003eRAD51C\u003c/em\u003e, and \u003cem\u003eRAD51D\u003c/em\u003e, as recommended by the National Comprehensive Cancer Network guidelines for EOC [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. The percentage of \u003cem\u003eBRCA1/2\u003c/em\u003e somatic mutations in serous EOC in this study was 7.9% (5/63), consistent with the findings of previous literature [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. Approximately 11\u0026ndash;18% of high-grade serous EOC patients have a germline \u003cem\u003eBRCA\u003c/em\u003e mutation and another 6\u0026ndash;7% of patients with somatic \u003cem\u003eBRCA\u003c/em\u003e mutations can be identified from tumor specimens [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. In addition to \u003cem\u003eBRCA\u003c/em\u003e mutated EOC patients who receive the greatest benefit from PARPi therapy, patients with non-\u003cem\u003eBRCA\u003c/em\u003e HR gene mutations such as \u003cem\u003eATM\u003c/em\u003e, \u003cem\u003eBRIP1\u003c/em\u003e, \u003cem\u003ePALB2\u003c/em\u003e, \u003cem\u003eRAD51C\u003c/em\u003e, \u003cem\u003eRAD51D\u003c/em\u003e also derive a survival benefit [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. Furthermore, these genes are cancer-predisposing genes, and somatic sequencing of pathogenic variants of the above genes may imply a potential germline origin[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e]. Genetic counseling and cancer prevention are suggested if genetic testing confirms germline origin. Thus, WES is helpful in providing comprehensive management for patients with EOC.\u003c/p\u003e \u003cp\u003eThe present study had some limitations. First, the number of cases was small, and it is necessary to recruit more participants to confirm the value of WES-based HRD testing further. Second, no prospective randomized trial-designed clinical response to PARPi was observed in this cohort. In the training cohort, we used platinum sensitivity as the clinical surrogate marker to develop our WES-based scarHRD test because platinum sensitivity has been used as an indicator for obtaining GIS [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Our WES-based test showed good predictability for platinum response and progression-free survival (PFS). In the validation cohort, the outcomes of newly diagnosed advanced EOC patients stratified by the WES-based test for maintenance PARPi therapy were satisfactory. In the future, a prospective study comprising patients with EOC who were prescribed PARPi guided by our test should be conducted.\u003c/p\u003e \u003cp\u003eIn Conclusion, The WES-based test provided comprehensive information on gene mutations and HRD scores. Based on these findings, the WES-based scarHRD test is a feasible option for HRD testing in patients with EOC and has potential for clinical application in the future.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDDR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDNA damage response\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eDSBs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDouble-strand breaks\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEMA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEuropean Medicines Agency\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eEOC\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eEpithelial ovarian cancer\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFDA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFood and Drug Administration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFFPE\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFormalin-fixed, paraffin-embedded\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eFIGO\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInternational Federation of Gynecology and Obstetrics\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eGIS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eGenomic instability score\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHomologous recombination\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHomologous recombination deficiency\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHRR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eHomologous recombination repair\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIndels\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eInsertions and deletions\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLOH\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLoss of heterozygosity\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eLST\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLarge-scale state transition\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNext-generation sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNHEJ\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNon-homologous end joining\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eNPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNegative predictive value\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eOS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eOverall survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePARP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePoly (adenosine diphosphate-ribose) polymerase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePARPi\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePoly (adenosine diphosphate-ribose) polymerase inhibitor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePFS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eProgression-free survival\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePPV\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePositive predictive value\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSNP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSingle-nucleotide polymorphism\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSNVs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSingle-nucleotide variants\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSSBs\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSingle-strand breaks\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTAI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eTelomere allelic imbalance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWES\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhole exome sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eWGS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eWhole-genome sequencing\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare that they have no conflict of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Takeda Pharmaceuticals Taiwan, Ltd.,\u0026nbsp;which was not involved in\u0026nbsp;the study design,\u0026nbsp;collection, analysis, interpretation of data, or\u0026nbsp;preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analyzed during the current study are available from the corresponding author\u0026nbsp;upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePL, YC, and WC\u0026nbsp;designed this study. PL, KK, HH, WC, and YC collected and prepared patient tissues. PL, KK, HH, WH,\u0026nbsp;and YC performed experiments. PL, KK, HH, WH, YC, and WC performed analyses and interpretations. PL, WC and YC wrote the manuscript. PL and YC prepared figures and tables, respectively. All authors\u0026nbsp;contributed to the\u0026nbsp;manuscript and approved the submitted version.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors thank the patients who participated in the study. We thank Chieh-Min Chen and Tzu-Ying Lin, who assisted with the study. The PI thanks the Department of Medical Genetics of the National Taiwan University Hospital for the NGS platform and the National Applied Research Laboratories for providing access to a high-performance computer for NGS data analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSiegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin 2022;72:7-33.\u003c/li\u003e\n\u003cli\u003eChiang YC, Chen CA, Chiang CJ, Hsu TH, Lin MC, You SL, et al. Trends in incidence and survival outcome of epithelial ovarian cancer: 30-year national population-based registry in Taiwan. J Gynecol Oncol 2013;24:342-51.\u003c/li\u003e\n\u003cli\u003eDavis A, Tinker AV, Friedlander M. \u0026quot;Platinum resistant\u0026quot; ovarian cancer: what is it, who to treat and how to measure benefit? Gynecol Oncol 2014;133:624-31.\u003c/li\u003e\n\u003cli\u003eLindemann K, Gao B, Mapagu C, Fereday S, Emmanuel C, Alsop K, et al. Response rates to second-line platinum-based therapy in ovarian cancer patients challenge the clinical definition of platinum resistance. Gynecol Oncol 2018;150:239-46.\u003c/li\u003e\n\u003cli\u003eGonz\u0026aacute;lez-Mart\u0026iacute;n A, Pothuri B, Vergote I, DePont Christensen R, Graybill W, Mirza MR, et al. Niraparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2019;381:2391-402.\u003c/li\u003e\n\u003cli\u003eMoore K, Colombo N, Scambia G, Kim BG, Oaknin A, Friedlander M, et al. Maintenance Olaparib in Patients with Newly Diagnosed Advanced Ovarian Cancer. N Engl J Med 2018;379:2495-505.\u003c/li\u003e\n\u003cli\u003eMiller RE, Leary A, Scott CL, Serra V, Lord CJ, Bowtell D, et al. ESMO recommendations on predictive biomarker testing for homologous recombination deficiency and PARP inhibitor benefit in ovarian cancer. Ann Oncol 2020;31:1606-22.\u003c/li\u003e\n\u003cli\u003ePili\u0026eacute; PG, Tang C, Mills GB, Yap TA. State-of-the-art strategies for targeting the DNA damage response in cancer. Nat Rev Clin Oncol 2019;16:81-104.\u003c/li\u003e\n\u003cli\u003eDottino JA, Moss HA, Lu KH, Secord AA, Havrilesky LJ. U.S. Food and Drug Administration-Approved Poly (ADP-Ribose) Polymerase Inhibitor Maintenance Therapy for Recurrent Ovarian Cancer: A Cost-Effectiveness Analysis. Obstet Gynecol 2019;133:795-802.\u003c/li\u003e\n\u003cli\u003eGonzalez R, Havrilesky LJ, Myers ER, Secord AA, Dottino JA, Berchuck A, et al. Cost-effectiveness analysis comparing \u0026quot;PARP inhibitors-for-all\u0026quot; to the biomarker-directed use of PARP inhibitor maintenance therapy for newly diagnosed advanced stage ovarian cancer. Gynecol Oncol 2020;159:483-90.\u003c/li\u003e\n\u003cli\u003eAbkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 2012;107:1776-82.\u003c/li\u003e\n\u003cli\u003eChiang YC, Lin PH, Cheng WF. Homologous Recombination Deficiency Assays in Epithelial Ovarian Cancer: Current Status and Future Direction. Front Oncol 2021;11:675972.\u003c/li\u003e\n\u003cli\u003eSztupinszki Z, Diossy M, Krzystanek M, Reiniger L, Csabai I, Favero F, et al. Migrating the SNP array-based homologous recombination deficiency measures to next generation sequencing data of breast cancer. npj Breast Cancer 2018;4:16.\u003c/li\u003e\n\u003cli\u003eChopra N, Tovey H, Pearson A, Cutts R, Toms C, Proszek P, et al. Homologous recombination DNA repair deficiency and PARP inhibition activity in primary triple negative breast cancer. Nat Commun 2020;11:2662.\u003c/li\u003e\n\u003cli\u003ePrat J. Staging classification for cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2014;124:1-5.\u003c/li\u003e\n\u003cli\u003eLin PH, Chen M, Tsai LW, Lo C, Yen TC, Huang TY, et al. Using next-generation sequencing to redefine BRCAness in triple-negative breast cancer. Cancer Sci 2020;111:1375-84.\u003c/li\u003e\n\u003cli\u003eWang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res 2010;38:e164.\u003c/li\u003e\n\u003cli\u003eRichards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405-24.\u003c/li\u003e\n\u003cli\u003eChiang YC, Lin PH, Lu TP, Kuo KT, Tai YJ, Hsu HC, et al. A DNA Damage Response Gene Panel for Different Histologic Types of Epithelial Ovarian Carcinomas and Their Outcomes. Biomedicines 2021;9.\u003c/li\u003e\n\u003cli\u003eBirkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2012;2:366-75.\u003c/li\u003e\n\u003cli\u003ePopova T, Mani\u0026eacute; E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 2012;72:5454-62.\u003c/li\u003e\n\u003cli\u003eSztupinszki Z, Diossy M, Krzystanek M, Reiniger L, Csabai I, Favero F, et al. Migrating the SNP array-based homologous recombination deficiency measures to next generation sequencing data of breast cancer. NPJ Breast Cancer 2018;4:16.\u003c/li\u003e\n\u003cli\u003eLord CJ and Ashworth A. The DNA damage response and cancer therapy. Nature 2012;481:287-94.\u003c/li\u003e\n\u003cli\u003eWatkins JA, Irshad S, Grigoriadis A, Tutt AN. Genomic scars as biomarkers of homologous recombination deficiency and drug response in breast and ovarian cancers. Breast Cancer Res 2014;16:211.\u003c/li\u003e\n\u003cli\u003eRay-Coquard I, Pautier P, Pignata S, P\u0026eacute;rol D, Gonz\u0026aacute;lez-Mart\u0026iacute;n A, Berger R, et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. New England Journal of Medicine 2019;381:2416-28.\u003c/li\u003e\n\u003cli\u003eColeman RL, Fleming GF, Brady MF, Swisher EM, Steffensen KD, Friedlander M, et al. Veliparib with First-Line Chemotherapy and as Maintenance Therapy in Ovarian Cancer. N Engl J Med 2019;381:2403-15.\u003c/li\u003e\n\u003cli\u003eSwisher EM, Lin KK, Oza AM, Scott CL, Giordano H, Sun J, et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol 2017;18:75-87.\u003c/li\u003e\n\u003cli\u003eColeman RL, Oza AM, Lorusso D, Aghajanian C, Oaknin A, Dean A, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2017;390:1949-61.\u003c/li\u003e\n\u003cli\u003eDavies H, Glodzik D, Morganella S, Yates LR, Staaf J, Zou X, et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 2017;23:517-25.\u003c/li\u003e\n\u003cli\u003eZhao EY, Shen Y, Pleasance E, Kasaian K, Leelakumari S, Jones M, et al. Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer. Clin Cancer Res 2017;23:7521-30.\u003c/li\u003e\n\u003cli\u003eMeienberg J, Zerjavic K, Keller I, Okoniewski M, Patrignani A, Ludin K, et al. New insights into the performance of human whole-exome capture platforms. Nucleic Acids Res 2015;43:e76.\u003c/li\u003e\n\u003cli\u003eBarbitoff YA, Polev DE, Glotov AS, Serebryakova EA, Shcherbakova IV, Kiselev AM, et al. Systematic dissection of biases in whole-exome and whole-genome sequencing reveals major determinants of coding sequence coverage. Sci Rep 2020;10:2057.\u003c/li\u003e\n\u003cli\u003eClark MJ, Chen R, Lam HY, Karczewski KJ, Chen R, Euskirchen G, et al. Performance comparison of exome DNA sequencing technologies. Nat Biotechnol 2011;29:908-14.\u003c/li\u003e\n\u003cli\u003eSeaby EG, Pengelly RJ, Ennis S. Exome sequencing explained: a practical guide to its clinical application. Brief Funct Genomics 2016;15:374-84.\u003c/li\u003e\n\u003cli\u003eTakaya H, Nakai H, Takamatsu S, Mandai M, Matsumura N. Homologous recombination deficiency status-based classification of high-grade serous ovarian carcinoma. Sci Rep 2020;10:2757.\u003c/li\u003e\n\u003cli\u003eDaly MB, Pal T, Berry MP, Buys SS, Dickson P, Domchek SM, et al. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 2021;19:77-102.\u003c/li\u003e\n\u003cli\u003eHennessy BT, Timms KM, Carey MS, Gutin A, Meyer LA, Flake DD, 2nd, et al. Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer. J Clin Oncol 2010;28:3570-6.\u003c/li\u003e\n\u003cli\u003ePennington KP, Walsh T, Harrell MI, Lee MK, Pennil CC, Rendi MH, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas. Clin Cancer Res 2014;20:764-75.\u003c/li\u003e\n\u003cli\u003eNorquist BM, Brady MF, Harrell MI, Walsh T, Lee MK, Gulsuner S, et al. Mutations in Homologous Recombination Genes and Outcomes in Ovarian Carcinoma Patients in GOG 218: An NRG Oncology/Gynecologic Oncology Group Study. Clin Cancer Res 2018;24:777-83.\u003c/li\u003e\n\u003cli\u003eKlek S, Heald B, Milinovich A, Ni Y, Abraham J, Mahdi H, et al. Genetic Counseling and Germline Testing in the Era of Tumor Sequencing: A Cohort Study. JNCI Cancer Spectr 2020;4:pkaa018.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Characteristics of epithelial ovarian cancer patients in the training cohort\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"378\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eExercise group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eAge (years old)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e56.5(39-75)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003ePretreatment CA-125 (U/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e889(153 - 7561)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eHistology: Serous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e40(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eFIGO stage: Advanced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e40(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eTumor grade: high\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e40(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eDebulking surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e13(32.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eR1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e27(67.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003ePlatinum response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eSensitive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e23(57.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eResistant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e17(42.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e31(77.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e9(22.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e21(52.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"59.78835978835979%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"40.21164021164021%\" valign=\"top\"\u003e\n \u003cp\u003e19(47.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote:\u0026nbsp;\u003c/em\u003eData of age and CA-125 are presented as median (minimum-maximum), whereas those of other parameters are presented as number (percentage). CA-125, cancer antigen 125; FIGO, International Federation of Gynecology and Obstetrics.\u003c/p\u003e\n\u003cp\u003eTable 2. Correlation of HRD status and clinical parameters of EOC patients in the training group\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"625\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.80191693290735%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eHRD positive status\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.399361022364218%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003ePlatinum response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.399361022364218%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.399361022364218%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.91653290529695%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003eSensitive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003eResistant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"23.91653290529695%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003e40\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"bottom\"\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.597110754414125%\" colspan=\"3\"\u003e\n \u003cp\u003eWES-based scarHRD test\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.643659711075442%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.272873194221509%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"top\"\u003e\n \u003cp\u003e1(4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e8(47.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e9(29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e3(15.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e6(28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.643659711075442%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.272873194221509%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\" valign=\"top\"\u003e\n \u003cp\u003e22(95.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e9(52.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e9(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e22(71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e16(84.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e15(71.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.643659711075442%\"\u003e\n \u003cp\u003ep value*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.272873194221509%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e0.457\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.597110754414125%\" colspan=\"3\"\u003e\n \u003cp\u003eMyriad MyChoice\u0026reg; CDx HRD test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.643659711075442%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.272873194221509%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e1(4.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e8(47.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e9 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e4(21.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e5(23.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.643659711075442%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.272873194221509%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e22(95.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e9(52.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e9(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e22(71%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e15(78.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e16(76.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"13.643659711075442%\"\u003e\n \u003cp\u003ep value*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"10.272873194221509%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e0.090\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.680577849117174%\"\u003e\n \u003cp\u003e1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote\u003c/em\u003e:\u0026nbsp;HRD, homologous recombination deficiency; WES, whole-exome sequencing.\u003c/p\u003e\n\u003cp\u003e*Fisher\u0026apos;s exact test.\u003c/p\u003e\n\u003cp\u003eTable 3.\u0026nbsp;Cox regression model for evaluating the risk factors for recurrence and death in EOC patients of training group (n=40).\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"1153\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.3755420641804%\" colspan=\"5\"\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.3755420641804%\" colspan=\"4\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.1875%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.079861111111111%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32638888888889%\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.378472222222222%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.809027777777779%\" colspan=\"2\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.809027777777779%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.10763888888889%\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.597222222222222%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.10763888888889%\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.597222222222222%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eDebulking surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eR1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e0.42(0.18-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e0.48(0.20-1.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e0.104\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e0.24(0.07-0.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e0.26(0.07-0.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e0.033\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eWES-based scarHRD test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e0.29(0.12-0.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e0.34(0.14-0.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e0.40(0.14-1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e0.49(0.17-1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e0.170\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.3755420641804%\" colspan=\"5\"\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"39.3755420641804%\" colspan=\"4\"\u003e\n \u003cp\u003eDeath\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.1875%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.079861111111111%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.32638888888889%\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.378472222222222%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.809027777777779%\" colspan=\"2\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"9.809027777777779%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.10763888888889%\"\u003e\n \u003cp\u003eUnivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.597222222222222%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.10763888888889%\"\u003e\n \u003cp\u003eMultivariate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.597222222222222%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003en\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003eH.R. (95% C.I.)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003ep\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eDebulking surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eR1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\" valign=\"top\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\" valign=\"top\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\" valign=\"top\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\" valign=\"top\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\" valign=\"top\"\u003e\n \u003cp\u003e0.42(0.18-0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\" valign=\"top\"\u003e\n \u003cp\u003e0.045\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e0.49(0.20-1.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e0.112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\" valign=\"top\"\u003e\n \u003cp\u003e0.24(0.07-0.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\" valign=\"top\"\u003e\n \u003cp\u003e0.023\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e0.25(0.07-0.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e0.031\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"33.564614050303554%\" colspan=\"3\"\u003e\n \u003cp\u003eMyriad MyChoice\u0026reg; CDx HRD test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e1 (reference)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"17.172593235039027%\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"4.076322636600174%\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"12.315698178664354%\"\u003e\n \u003cp\u003e0.28(0.12-0.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"7.372072853425846%\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.96357328707719%\" colspan=\"2\"\u003e\n \u003cp\u003e0.33\u0026nbsp;(0.14-0.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.72419774501301%\"\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e0.40(0.14-1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e0.099\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.096270598438855%\"\u003e\n \u003cp\u003e0.48(0.16-1.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"6.591500433651344%\"\u003e\n \u003cp\u003e0.190\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4. Characteristics of epithelial ovarian cancer patients in the validation cohort\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"538\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eValidation group\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eWES-based scarHRD test\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003ePositive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003eNegative\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eNumber of patients\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eAge (years old)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e57.5(46-77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e64(28-74)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003ePretreatment CA-125 (U/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e1211\u003c/p\u003e\n \u003cp\u003e(375- 10000)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e1206\u003c/p\u003e\n \u003cp\u003e(227-17750)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eHistology: Serous carcinoma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e12(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e11(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eFIGO stage: Advanced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e12(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e11(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eTumor grade: high\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e12(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e11(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eDebulking surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eR0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e3(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e6(54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eR1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e6(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e3(27.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eR2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e3(25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e2(18.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003ePlatinum response\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eSensitive\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e12(100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e3(27.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eResistant\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e4(36.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eN.A.\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e0(0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e4(36.4%)*\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003ePatient numbers with PARPi\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e6(50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e5(45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003ePARPi interval (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e17(9-22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e3(2-8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eRecurrence\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e8(66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e5(45.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e4(33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e6(54.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"49.07063197026022%\" valign=\"top\"\u003e\n \u003cp\u003eProgression free survival (months)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e14.5(8-24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.46468401486989%\" valign=\"top\"\u003e\n \u003cp\u003e4(0-9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cem\u003eNote:\u0026nbsp;\u003c/em\u003eData of age, CA-125, PARPi interval and progression free survival are presented as median (minimum-maximum), whereas those of other parameters are presented as number (percentage). CA-125, cancer antigen 125; FIGO, International Federation of Gynecology and Obstetrics.\u003c/p\u003e\n\u003cp\u003e*The follow-up interval after completing primary treatments in 4 patients was less than 6 months, and therefore it could not be categorized by platinum response. \u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Epithelial ovarian cancer, Homologous recombination deficiency test, Whole-exome sequencing, scarHRD","lastPublishedDoi":"10.21203/rs.3.rs-4601529/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4601529/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe homologous recombination deficiency (HRD) test is an important tool for identifying patients with epithelial ovarian cancer (EOC) benefit from the treatment with poly(adenosine diphosphate-ribose) polymerase inhibitor (PARPi). Using whole exome sequencing (WES)-based platform can provide information of gene mutations and HRD score; however, the clinical value of WES-based HRD test was less validated in EOC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe enrolled 40 patients with EOC in the training cohort and 23 in the validation cohort. The WES-based HRD score was calculated using the scarHRD software. We first evaluated the concordance of the HRD status defined by the Myriad MyChoice CDx and then assessed the value of HRD on clinical prognosis in patients with EOC.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe HRD score defined by the WES-based test was positively correlated with that of the Myriad MyChoice\u0026reg; CDx test (r\u0026thinsp;=\u0026thinsp;0.82, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) in the training cohort. In compared to HRD status of Myriad test, the sensitivity, specificity, positive predictive value, and negative predictive value of the WES-based HRD test were 93.5% (29/31), 77.8% (7/9), 93.5% (29/31), and 77.8% (7/9), respectively. Patients with positive HRD status defined by WES-based scarHRD test and Myriad MyChoice\u0026reg; CDx test were both highly associated with platinum sensitive response (both Fisher's exact test, p\u0026thinsp;=\u0026thinsp;0.002) as well as the superior progression-free survival (both log-rank p\u0026thinsp;=\u0026thinsp;0.002). The multi-variate Cox regression model incorporated with optimal debulking surgery showed that the recurrence risk was decreased in the patients with positive HRD status, either defined by Myriad MyChoice\u0026reg; CDx test (Hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.14\u0026ndash;0.79, p\u0026thinsp;=\u0026thinsp;0.013) or WES-based test Myriad MyChoice\u0026reg; CDx test (HR 0.34, 95% CI 0.14\u0026ndash;0.80, p\u0026thinsp;=\u0026thinsp;0.014). Nine patients had mutations in the genes involved in HR DNA repair, and all of them were positive for HRD. In the validation group, 23 patients were defined as positive HRD by WES-based testing. Six positive HRD patients and 5 negative HRD patients received maintenance PARPi. The median responsive interval of PARPi was 17 months in positive HRD patients and 3 months in negative HRD patients.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe WES-based test is a feasible option for determining the HRD status in EOC patients.\u003c/p\u003e","manuscriptTitle":"Whole exome sequencing-based homologous recombination deficiency test for epithelial ovarian cancer","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-07-18 16:01:56","doi":"10.21203/rs.3.rs-4601529/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-10-23T23:32:28+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"90736606470010297860203777405030954242","date":"2024-09-04T16:58:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-03T07:20:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"312755858173966101518197270411724407064","date":"2024-08-31T08:31:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-08-29T19:05:13+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-06-20T00:55:18+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-06-19T11:49:09+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Ovarian Research","date":"2024-06-18T17:28:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-ovarian-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jovr","sideBox":"Learn more about [Journal of Ovarian Research](http://ovarianresearch.biomedcentral.com)","snPcode":"13048","submissionUrl":"https://submission.nature.com/new-submission/13048/3","title":"Journal of Ovarian Research","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c3f6bacd-db4e-4efa-b807-302f92863ded","owner":[],"postedDate":"July 18th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-03T16:10:54+00:00","versionOfRecord":{"articleIdentity":"rs-4601529","link":"https://doi.org/10.1186/s13048-024-01565-3","journal":{"identity":"journal-of-ovarian-research","isVorOnly":false,"title":"Journal of Ovarian Research"},"publishedOn":"2025-01-30 15:57:15","publishedOnDateReadable":"January 30th, 2025"},"versionCreatedAt":"2024-07-18 16:01:56","video":"","vorDoi":"10.1186/s13048-024-01565-3","vorDoiUrl":"https://doi.org/10.1186/s13048-024-01565-3","workflowStages":[]},"version":"v1","identity":"rs-4601529","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4601529","identity":"rs-4601529","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}