BRCA mutational status, initial disease presentation, and clinical outcome in high-grade serous advanced ovarian cancer: a multicenter study


      In the last decades, there have been several efforts to clarify the role of BRCA mutational status in women with advanced ovarian cancer, demonstrating its role in cancer development, as well as the prognostic significance of BRCA genotype.


      Our aim is to evaluate the correlation between BRCA mutational status and disease presentation in a large series of advanced high-grade serous ovarian cancer patients.

      Study Design

      This is a retrospective multicenter study including a consecutive series of newly diagnosed high-grade serous ovarian cancer patients with International Federation of Gynecology and Obstetrics stage IIIC-IV disease, at least 18 months of follow-up time, and tested for BRCA 1/2 germline mutation status. Disease presentation was analyzed using the following variables: laparoscopic predictive index value, incidence of bulky lymph nodes, and ovarian masses. Progression-free survival was defined as the months elapsed from initial diagnosis (staging laparoscopy) and recurrent disease or last follow-up.


      In all, 324 high-grade serous ovarian cancer patients received BRCA testing, and 273 fulfilled inclusion criteria. BRCA1/2 germline mutations were observed in 107 women (39.2%). No differences were documented according to BRCA mutation status in terms of International Federation of Gynecology and Obstetrics stage, CA125 levels, or presence of ascites. In patients with BRCA1/2 mutations we observed a higher incidence of peritoneal spread without ovarian mass (25.2% vs 13.9%; P value = .018) and of bulky lymph nodes (30.8% vs 17.5%; P value = .010) compared with women showing BRCA1/2 wild type genotype. Furthermore, women with BRCA1/2 mutations showed high peritoneal tumor load (laparoscopic predictive index value ≥8; 42.1% vs 27.1%; P value = .016) more frequently. Focusing on survival, no differences in term of median progression-free survival were observed among women treated with primary debulking surgery and neoadjuvant chemotherapy in the group of patients with BRCA1/2 mutations (P value = .268). On the other hand, in women showing BRCA wild type genotype, median progression-free survival after primary debulking surgery was 8 months longer compared with patients treated with neoadjuvant chemotherapy approach (26 vs 18 months; P value = .003).


      Women with BRCA1/2 mutations show at diagnosis higher peritoneal tumor load and increased frequency of bulky lymph nodes compared to patients without germline BRCA mutations. Primary debulking surgery seems to ensure a longer progression-free survival in women with BRCA wild type genotype compared to neoadjuvant chemotherapy. BRCA testing might be a reliable tool to personalize treatment in patients with high-grade serous ovarian cancer, thus giving novel points of discussion to the ongoing debate regarding the best initial treatment approach.

      Key words

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        • Miki Y.
        • Swensen J.
        • Shattuck-Eidens D.
        • et al.
        A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.
        Science. 1994; 266: 66-71
        • Wooster R.
        • Bignell G.
        • Lancaster J.
        • et al.
        Identification of the breast cancer susceptibility gene BRCA2.
        Nature. 1995; 378: 789-792
        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • et al.
        BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: a report from the Australian Ovarian Cancer Study Group.
        J Clin Oncol. 2012; 30: 2654-2663
        • Yang D.
        • Khan S.
        • Sun Y.
        • et al.
        Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer.
        JAMA. 2011; 306: 1557-1565
        • Vencken P.M.
        • Kriege M.
        • Hoogwerf D.
        • et al.
        Chemosensitivity and outcome of BRCA1- and BRCA2-associated ovarian cancer patients after first-line chemotherapy compared with sporadic ovarian cancer patients.
        Ann Oncol. 2011; 22: 1346-1352
        • Harter P.
        • Johnson T.
        • Berton-Rigaud D.
        • et al.
        BRCA1/2 mutations associated with progression-free survival in ovarian cancer patients in the AGO-OVAR 16 study.
        Gynecol Oncol. 2016; 140: 443-449
        • Mahdi H.
        • Gockley A.
        • Esselen K.
        • et al.
        Outcome of neoadjuvant chemotherapy in BRCA1/2 mutation positive women with advanced-stage müllerian cancer.
        Gynecol Oncol. 2015; 139: 407-412
        • Gorodnova T.V.
        • Sokolenko A.P.
        • Ivantsov A.O.
        • et al.
        High response rates to neoadjuvant platinum-based therapy in ovarian cancer patients carrying germ-line BRCA mutation.
        Cancer Lett. 2015; 369: 363-367
        • Gourley C.
        • Michie C.O.
        • Roxburgh P.
        • et al.
        Increased incidence of visceral metastases in Scottish patients with BRCA1/2-defective ovarian cancer: an extension of the ovarian BRCAness phenotype.
        J Clin Oncol. 2010; 28: 2505-2511
        • Hyman D.M.
        • Long K.C.
        • Tanner E.J.
        • et al.
        Outcomes of primary surgical cytoreduction in patients with BRCA-associated high-grade serous ovarian carcinoma.
        Gynecol Oncol. 2012; 126: 224-228
        • Wright A.A.
        • Bohlke K.
        • Armstrong D.K.
        • et al.
        Neoadjuvant chemotherapy for newly diagnosed, advanced ovarian cancer: Society of Gynecologic Oncology and American Society of Clinical Oncology Clinical Practice Guideline.
        J Clin Oncol. 2016; 34: 3460-3473
        • Vizzielli G.
        • Costantini B.
        • Tortorella L.
        • et al.
        Influence of intraperitoneal dissemination assessed by laparoscopy on prognosis of advanced ovarian cancer: an exploratory analysis of a single-institution experience.
        Ann Surg Oncol. 2014; 21: 3970-3977
        • Fagotti A.
        • Vizzielli G.
        • Fanfani F.
        • et al.
        Introduction of staging laparoscopy in the management of advanced epithelial ovarian, tubal and peritoneal cancer: impact on prognosis in a single institution experience.
        Gynecol Oncol. 2013; 131: 341-346
        • Petrillo M.
        • Vizzielli G.
        • Fanfani F.
        • et al.
        Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: proof of a concept.
        Gynecol Oncol. 2015; 139: 5-9
        • Aletti G.D.
        • Eisenhauer E.L.
        • Santillan A.
        • et al.
        Identification of patient groups at highest risk from traditional approach to ovarian cancer treatment.
        Gynecol Oncol. 2011; 120: 23-28
        • Minucci A.
        • Scambia G.
        • Santonocito C.
        • et al.
        Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review.
        Expert Rev Mol Diagn. 2015; 15: 1383-1403
        • Balabanski L.
        • Antov G.
        • Dimova I.
        • et al.
        Next-generation sequencing of and in breast cancer patients and control subjects.
        Mol Clin Oncol. 2014; 2: 435-439
        • Concolino P.
        • Costella A.
        • Minucci A.
        • et al.
        A preliminary quality control (QC) for next generation sequencing (NGS) library evaluation turns out to be a very useful tool for a rapid detection of BRCA1/2 deleterious mutations.
        Clin Chim Acta. 2014; 437: 72-77
        • Kaplan F.L.
        • Meier P.
        Non parametric estimation from incomplete observations.
        Am J Stat Assoc. 1958; 53: 457-481
        • Mantel N.
        Evaluation of survival data and two new rank order statistics arising in its consideration.
        Cancer Chemother Rep. 1966; 50: 163-170
        • Precision Medicine Initiative
        Available at:.
        (Accessed June 14, 2017)
        • Petrillo M.
        • Nero C.
        • Amadio G.
        • Gallo D.
        • Fagotti A.
        • Scambia G.
        Targeting the hallmarks of ovarian cancer: the big picture.
        Gynecol Oncol. 2016; 142: 176-183
        • Reyes M.C.
        • Arnold A.G.
        • Kauff N.D.
        • Levine D.A.
        • Soslow R.A.
        Invasion patterns of metastatic high-grade serous carcinoma of ovary or fallopian tube associated with BRCA deficiency.
        Mod Pathol. 2014; 27: 1405-1411
        • Soslow R.A.
        • Han G.
        • Park K.J.
        • et al.
        Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.
        Mod Pathol. 2012; 25: 625-636
        • Grabowski J.P.
        • Harter P.
        • Heitz F.
        • et al.
        Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase.
        Gynecol Oncol. 2016; 140: 457-462