We retrospectively reviewed the medical records of 326 patients with pathologically confirmed ovarian cancer who from 2006 to 2018 received NAC at the Yonsei Cancer Center, Seoul, South Korea. The patient inclusion criteria included (1) histopathologically confirmed FIGO Stage III or IV high-grade ovarian carcinoma; (2) patients who underwent IDS after NAC; and (3) patients who received three cycles of NAC before IDS.
The exclusion criteria were as follows: Patients still receiving chemotherapy at the time of data analysis (N = 19); patients who had not received IDS after NAC (N = 15); patients for whom data was missing (N = 31); and, lastly, patients who had not undergone a germline BRCA test (N = 92). After this review, 169 patients met our criteria. Of these, 122 patients had the wild-type BRCA genotype, and 47 had BRCA1 or BRCA2 mutations (Fig. 1).
Most patients received taxane (paclitaxel, docetaxel) and platinum (carboplatin) combination chemotherapy and some patients received paclitaxel, carboplatin and bevacizumab combination chemotherapy. Other treatments such as radiation or endocrine therapy were not performed before surgery. Determination of which patients required NAC was based on initial imaging studies that showed high tumor dissemination that was assumed to have occurred under the following conditions : (1) patients had a poor performance status and high operative risk because of medical comorbidities, or (2) optimal debulking surgery (residual disease measuring 1 cm or less) was unsuitable because of a high tumor burden [predictive index value (PIV) ≥ 8]. For diagnostic laparoscopy, the degree of tumor burden was determined with the PIV . For IDS, all patients underwent surgery with the intent to achieve complete resection with no residual tumor. Standard surgical procedures included the following: sampling of free fluid or peritoneal washings for cytology; thorough inspection of the abdomen and pelvis, including the upper abdominal viscera, diaphragm, and retroperitoneal spaces; and hysterectomy, bilateral oophorectomy and omentectomy, pelvic/para-aortic lymph node dissection, and appendectomy. Radical surgery included any of following: bowel surgery, cholecystectomy, diaphragm peritonectomy/resection, distal pancreatectomy video-assisted thoracoscopic surgery, splenectomy, liver resection, supraclavicular fossa resection, ureter resection, and others. Subsequently, additional cycles of adjuvant chemotherapy were administered to complete a total of six cycles at the discretion of the treating physician. Surgical complexity was classified as low, intermediate, or high .
The resected tissues were formalin-fixed and paraffin-embedded according to standard procedures and stained with hematoxylin and eosin (H&E) in the Department of Pathology, Severance Hospital, Yonsei University College of Medicine. All available H&E-stained slides obtained from IDS tissues were reviewed by three experienced gynecologic pathologists who independently scored each slide according to the three-tiered CRS system proposed by Böhm et al.  CRS 1 indicated minimal or zero tumor response. CRS 2 indicated appreciable tumor response amid a viable tumor easily identifiable in the omentum. CRS 3 indicated complete or near-complete response with zero or very little residual tumor up to a maximum size of 2 mm.
From the whole blood samples, genomic DNA was extracted according to the protocol provided by the manufacturer (QIAamp DNA Blood Mini Kit, QIAGEN, USA). To assess the germline mutations in BRCA1 and BRCA2, the entire coding region and intron-exon boundaries of two genes were amplified using polymerase chain reaction (PCR) amplification. We identified all variants using Sanger sequencing on a 3730 DNA Analyzer with the BigDye Terminator v3.1 Cycle Sequencing Kit (Applied Biosystems, Foster City, CA, USA). Sequencing data were aligned against appropriate reference sequences (accession numbers NM_007294 and NM_000059, respectively) and analyzed using the Sequencher 5.3 software (Gene Codes Corp., Ann Arbor, MI, USA). Variations were described following the nomenclature system of the Human Genome Variation Society (http://www.hgvs.org/mutnomen) and the conventional nomenclature system from the Breast Cancer Information Core (BIC; http://research.nhgri.nih.gov/bic/). Pathogenicity interpretation of the variants were performed according to 2015 American College of Medical Genetics and Genomics guideline by professional medical geneticists, using evidences of variant type assessment, population allele frequency, prediction algorithm results, and database search such as Human Gene Mutation Database, ClinVar, and BIC.
Descriptive data are reported as the median (range) or frequency (percentage). Categorical variables were compared with the chi-square or continuous variables with the Student's t-test or Mann-Whitney U test for parametric/non-parametric variables, respectively. Responses were assessed according to the Response Evaluation Criteria in Solid Tumors criteria, version 1.1. We defined PFS as the time from the date of diagnosis to disease progression or death; overall survival (OS) was measured from the date of diagnosis to death or to the date of the last follow-up. Survival analysis was performed using the Kaplan-Meier method with a log-rank test. For all analyses, the significance level was set at 0.05. The statistical analyses were performed with the SPSS statistical software (version 21.0; IBM Corp., Armonk, NY).