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      Ovarian cancer in BRCA1 and BRCA2 gene mutation carriers: analysis of prognostic factors and survival

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          Abstract

          Objectives

          To compare clinical–pathological characteristics and outcome between sporadic ovarian cancer and ovarian cancer in patents with hereditary breast and ovarian cancer syndrome (HBOC).

          Methods

          Twenty-four patients with ovarian cancer treated between 2000 and 2009 who tested positive for BRCA1/2 mutation (BRCA+) and a control group of 64 age-matched patients with no family history of breast/ovarian cancer (controls) were enrolled. Clinical–pathological characteristics, surgical outcome, overall (OS), and progression-free survival (PFS) were compared between the two groups.

          Results

          The high-grade serous histotype was more represented in BRCA+ than in controls (70.8% versus 53.1%) (p > 0.05). BRCA+ cancers were more frequently diagnosed at stage II than controls (20.83% versus 4.69%) (p = 0.024). Radical primary surgery was performed in 70% of women in both groups, with no difference in debulking results. In patients undergoing surgery after neoadjuvant chemotherapy, in all BRCA+ patients, optimal cytoreduction was achieved (versus 70% of the controls). PFS was significantly longer for BRCA+ patients compared to controls (60 months versus 22 months; p = 0.039). No significant difference was observed in OS between BRCA+ patients and controls.

          Conclusions

          At a median follow-up time of 46 months, BRCA+ patients have a better prognosis than controls in terms of PFS. Higher chemosensitivity of BRCA+ tumours was observed.

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          Most cited references20

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          Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.

          Kelly L Bolton, Georgia Chenevix-Trench, Cindy S.L. Goh … (2012)
          Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Five-year overall mortality. The 5-year overall survival was 36% (95% CI, 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P < .001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P < .001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P < .001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P < .001). The BRCA1 HR estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.
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            "BRCAness" syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations.

            Richard M Gore, Elizabeth Bancroft, Stan B. Kaye … (2008)
            We evaluated the clinical impact of germ-line BRCA1/2 mutations in patients with epithelial ovarian cancer (EOC) on responses to first and subsequent lines of chemotherapy, treatment-free interval (TFI) between each line of therapy, and overall survival (OS). Twenty-two EOC patients with germ-line BRCA1 or BRCA2 mutations (BRCA-positive) were selected from our database and matched (1:2) with 44 nonhereditary EOC controls (defined by no associated personal history of breast cancer and no family history of breast and ovarian cancer or an uninformative BRCA mutation test) for stage, histologic subtype, age, and year of diagnosis. All patients received primary platinum-based chemotherapy. Statistical comparisons included responses after first-, second-, and third-line treatment (chi(2)/Fisher's exact test) and median OS (Kaplan-Meier method/log-rank test). Compared with controls, BRCA-positive patients had higher overall (95.5% v 59.1%; P = .002) and complete response rates (81.8% v 43.2%; P = .004) to first line treatment, higher responses to second and third line platinum-based chemotherapy (second line, 91.7% v 40.9% [P = .004]; third line, 100% v 14.3% [P = .005]) and longer TFIs. A significant improvement in median OS in BRCA-positive patients compared with controls was observed from both time of diagnosis (8.4 v 2.9 years; P < .002) and time of first relapse (5 v 1.6 years; P < .001). BRCA status, stage, and length of first response were independent prognostic factors from time of first relapse. BRCA-positive EOC patients have better outcomes than nonhereditary EOC patients. There exists a clinical syndrome of BRCAness that includes serous histology, high response rates to first and subsequent lines of platinum-based treatment, longer TFIs between relapses, and improved OS.
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              Improved survival in women with BRCA-associated ovarian carcinoma.

              Ilana Cass, Rae Baldwin, Taz Varkey … (2003)
              The objective of this study was to determine the clinical characteristics, treatment response, and frequency of p53 overexpression in Ashkenazi Jewish women with hereditary ovarian carcinoma. Seventy-one Jewish women with epithelial ovarian carcinoma (EOC) were tested for the three BRCA founder mutations using single-strand conformation polymorphism analysis, heteroduplex analysis, and protein truncation testing. Clinical and histopathologic data were reviewed retrospectively. In vitro chemoresistance was analyzed in 32 patients. Mutations of p53 were studied using immunohistochemical detection of p53 overexpression. Thirty-four of 71 Jewish patients with EOC (48%) had germline BRCA mutations (BRCA heterozygotes), including 22 BRCA1 mutations and 12 BRCA2 mutations. BRCA heterozygotes were younger compared with Jewish patients who had EOC without mutations (sporadic carcinoma; 50 years vs. 59 years, respectively; P = 0.01). BRCA1 heterozygotes were younger compared with BRCA2 heterozygotes (48 years vs. 57 years, respectively; P = 0.01). Histopathologic tumor features were similar; however, tumors with low malignant potential were seen only in women with sporadic carcinoma. Both groups had equivalent rates of surgical cytoreduction and similar median follow-up (72 months). BRCA heterozygotes had higher response rates to primary therapy compared with patients who had sporadic disease (P = 0.01). In vitro chemoresistance predicted tumor response to platinum chemotherapy correctly in BRCA heterozygotes (P = 0.0096). BRCA heterozygotes with advance-stage disease had improved survival compared with patients who had advanced stage sporadic carcinoma (91 months vs. 54 months, respectively; P = 0.046) and had a longer disease free interval (49 months vs. 19 months, respectively; P = 0.16). p53 overexpression was common in BRCA heterozygotes (80%). BRCA1 heterozygotes developed EOC at a younger age compared with BRCA2 heterozygotes and women who had sporadic ovarian carcinoma. BRCA heterozygotes had a better response to platinum chemotherapy compared with women who had sporadic disease, which may have contributed to their improved prognosis. Copyright 2003 American Cancer Society.DOI 10.1002/cncr.11310
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                Author and article information

                Journal
                Journal ID (nlm-ta): Ecancermedicalscience
                Journal ID (iso-abbrev): Ecancermedicalscience
                Journal ID (publisher-id): ecancermedicalscience
                Title: ecancermedicalscience
                Publisher: Cancer Intelligence
                ISSN (Electronic): 1754-6605
                Publication date Collection: 2016
                Publication date (Electronic): 03 May 2016
                Volume: 10
                Electronic Location Identifier: 639
                Affiliations
                [1 ]Unit of Obstetrics and Gynaecology, Mauriziano Umberto I Hospital, Largo Turati, 62, 10128, Turin, Italy
                [2 ]Gynecological Oncology Unit, Candiolo Cancer Institute FPO, IRCCS, Km 3,95, SP142, 10060 Candiolo (TO), Italy
                [3 ]Obstetrics and Gynaecology I, Sant’Anna Hospital, AOU Città della Salute e della Scienza di Torino, Corso Spezia, 60, 10126, Turin, Italy
                [4 ]AOU Città della Salute e della Scienza, Department of Medical Sciences, Corso Bramante, 88-10126, Turin, Italy
                [5 ]AOU Città della Salute e della Scienza, SC Genetica Medica U, Via Santena, 19-10126, Turin, Italy
                Author notes
                Correspondence to: Nicoletta Biglia. nicoletta.biglia@ 123456unito.it
                Article
                Publisher ID: can-10-639
                DOI: 10.3332/ecancer.2016.639
                PMC ID: 4898941
                PubMed ID: 27350785
                SO-VID: f33f8bf0-549d-479c-b708-eab2d1282a3d
                Copyright © © the authors; licensee ecancermedicalscience.
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 28 October 2015
                Categories
                Subject: Clinical Study

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: ovarian cancer,hereditary breast and ovarian cancer syndrome,brca1,brca2,gene mutations,prognosis
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: ovarian cancer, hereditary breast and ovarian cancer syndrome, brca1, brca2, gene mutations, prognosis

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