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      , PhD a , * , , MSc b , * , , PhD c , , PhD a , , MB a , d , , Prof, PhD e , , MD a , , BSc b , , BSc b , , Prof, PhD f , , Prof, MD g , , Prof, MD h , , Prof, PhD i , , Prof, PhD i , , PhD i , , Prof, BM j , , Prof, MD k , , Prof, PhD l , , Prof, MB m , , MD n , , Prof, DM o , , MB d , , MSc b , , Prof, MD a , d , * ,
      The Lancet. Oncology
      Lancet Pub. Group

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          Summary

          Background

          Retrospective studies provide conflicting interpretations of the effect of inherited genetic factors on the prognosis of patients with breast cancer. The primary aim of this study was to determine the effect of a germline BRCA1 or BRCA2 mutation on breast cancer outcomes in patients with young-onset breast cancer.

          Methods

          We did a prospective cohort study of female patients recruited from 127 hospitals in the UK aged 40 years or younger at first diagnosis (by histological confirmation) of invasive breast cancer. Patients with a previous invasive malignancy (except non-melanomatous skin cancer) were excluded. Patients were identified within 12 months of initial diagnosis. BRCA1 and BRCA2 mutations were identified using blood DNA collected at recruitment. Clinicopathological data, and data regarding treatment and long-term outcomes, including date and site of disease recurrence, were collected from routine medical records at 6 months, 12 months, and then annually until death or loss to follow-up. The primary outcome was overall survival for all BRCA1 or BRCA2 mutation carriers ( BRCA-positive) versus all non-carriers ( BRCA-negative) at 2 years, 5 years, and 10 years after diagnosis. A prespecified subgroup analysis of overall survival was done in patients with triple-negative breast cancer. Recruitment was completed in 2008, and long-term follow-up is continuing.

          Findings

          Between Jan 24, 2000, and Jan 24, 2008, we recruited 2733 women. Genotyping detected a pathogenic BRCA mutation in 338 (12%) patients (201 with BRCA1, 137 with BRCA2). After a median follow-up of 8·2 years (IQR 6·0–9·9), 651 (96%) of 678 deaths were due to breast cancer. There was no significant difference in overall survival between BRCA-positive and BRCA-negative patients in multivariable analyses at any timepoint (at 2 years: 97·0% [95% CI 94·5–98·4] vs 96·6% [95·8–97·3]; at 5 years: 83·8% [79·3–87·5] vs 85·0% [83·5–86·4]; at 10 years: 73·4% [67·4–78·5] vs 70·1% [67·7–72·3]; hazard ratio [HR] 0·96 [95% CI 0·76–1·22]; p=0·76). Of 558 patients with triple-negative breast cancer, BRCA mutation carriers had better overall survival than non-carriers at 2 years (95% [95% CI 89–97] vs 91% [88–94]; HR 0·59 [95% CI 0·35–0·99]; p=0·047) but not 5 years (81% [73–87] vs 74% [70–78]; HR 1·13 [0·70–1·84]; p=0·62) or 10 years (72% [62–80] vs 69% [63–74]; HR 2·12 [0·82–5·49]; p= 0·12).

          Interpretation

          Patients with young-onset breast cancer who carry a BRCA mutation have similar survival as non-carriers. However, BRCA mutation carriers with triple-negative breast cancer might have a survival advantage during the first few years after diagnosis compared with non-carriers. Decisions about timing of additional surgery aimed at reducing future second primary-cancer risks should take into account patient prognosis associated with the first malignancy and patient preferences.

          Funding

          Cancer Research UK, the UK National Cancer Research Network, the Wessex Cancer Trust, Breast Cancer Now, and the PPP Healthcare Medical Trust Grant.

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          Most cited references22

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

          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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            Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases

            (2000)
            Estimates of the contribution of BRCA1 and BRCA2 to breast cancer incidence in outbred populations have been based on studies that are either small or have selected for cases diagnosed at an early age. Only one of these has reported an estimate of the breast cancer risk associated with a mutation in these genes, and there is no published ovarian cancer risk estimate derived from a population-based case series. We screened a population-based series of breast cancer cases diagnosed before the age of 55 for mutations in BRCA1 and BRCA2. Pedigree information from the mutation carriers was used to estimate penetrance and the proportion of familial risk of breast cancer due to BRCA1 and BRCA2. We identified eight (0.7%)BRCA1 and 16 (1.3%)BRCA2 mutation carriers in 1220 breast cancer cases (actual sample size 1435 adjusted for 15% polymerase chain reaction failure rate). Mutation prevalence was substantially higher in cases diagnosed before 35 years-of-age and with increasing number of relatives affected with breast or ovarian cancer. However, most mutation carriers were diagnosed in the older age groups, and a minority reported a first-degree relative with breast cancer. Breast cancer penetrance by age 80 was estimated to be 48% (95% CI 7–82%) for BRCA1 mutation carriers and 74% (7–94%) for BRCA2 mutation carriers. Ovarian cancer penetrance for BRCA1 and BRCA2 combined was 22% (6–65%) by age 80. 17% of the familial risk of breast cancer was attributable to BRCA1 and BRCA2. At birth, the estimated prevalence of BRCA1 mutation carriers was 0.07% or 0.09% depending on the penetrance function used for the calculation. For BRCA2 the birth prevalence estimates were 0.14% and 0.22%. Mutations in the genes BRCA1 and BRCA2 are rare in the population and account for a small fraction of all breast cancer in the UK. They account for less than one fifth of the familial risk of breast cancer. Eligibility criteria for BRCA1 and BRCA2 mutation testing based on family history and age of onset will identify only a small proportion of mutation carriers. © 2000 CancerResearch Campaign
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              Pathologic complete response rates in young women with BRCA1-positive breast cancers after neoadjuvant chemotherapy.

              To estimate the rate of pathologic complete response (pCR) to neoadjuvant chemotherapy in BRCA1 mutation carriers according to chemotherapy regimen. From a registry of 6,903 patients, we identified 102 women who carried a BRCA1 founder mutation and who had been treated for breast cancer with neoadjuvant chemotherapy. Pathologic complete response was evaluated using standard criteria. Twenty-four (24%) of the 102 BRCA1 mutation carriers experienced a pCR. The response rate varied widely with treatment: a pCR was observed in one (7%) of 14 women treated with cyclophosphamide, methotrexate, and fluorouracil (CMF); in two (8%) of 25 women treated with doxorubicin and docetaxel (AT); in 11 (22%) of 51 women treated with doxorubicin and cyclophosphamide (AC) or fluorouracil, doxorubicin, and cyclophosphamide (FAC), and in 10 (83%) of 12 women treated with cisplatin. A low rate of pCR was observed in women with breast cancer and a BRCA1 mutation who were treated with AT or CMF. A high rate of pCR was seen after treatment with cisplatin. An intermediate rate of PCR was associated with AC or FAC. The relative benefits of AC and platinum therapy need to be confirmed through follow-up of this and other cohorts.
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                Author and article information

                Contributors
                Journal
                Lancet Oncol
                Lancet Oncol
                The Lancet. Oncology
                Lancet Pub. Group
                1470-2045
                1474-5488
                1 February 2018
                February 2018
                : 19
                : 2
                : 169-180
                Affiliations
                [a ]Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK
                [b ]Southampton Clinical Trials Unit, University of Southampton, Southampton, UK
                [c ]Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton, UK
                [d ]University Hospital Southampton NHS Foundation Trust, Southampton, UK
                [e ]Centre for Statistics in Medicine, Nuffield Department of Orthopaedics, Rheumatology & Musculoskeletal Sciences, University of Oxford, Oxford, UK
                [f ]Tumour Biology Department, Institute of Cancer, Barts and The London School of Medicine & Dentistry, London, UK
                [g ]Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, University of Manchester MAHSC, St Mary's Hospital, Manchester, UK
                [h ]University of Texas MD Anderson Cancer Center, Houston, TX, USA
                [i ]Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
                [j ]Department of Pathology, University of Leeds, Faculty of Medicine, Leeds, UK
                [k ]Discipline of Molecular & Cellular Pathology, Faculty of Medicine, University of Queensland, The Royal Brisbane & Women's Hospital, Brisbane, QLD, Australia
                [l ]Institute of Cancer Research, London, UK
                [m ]Department of Radiology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK
                [n ]Guy's & St Thomas' Hospital, London, UK
                [o ]St George's Hospital, University of London, London, UK
                Author notes
                [* ]Correspondence to: Prof Diana M Eccles, Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UKCorrespondence to: Prof Diana M Eccles, Cancer Sciences Academic UnitFaculty of MedicineUniversity of Southampton and University Hospital Southampton NHS Foundation TrustSouthamptonSO16 6YDUK d.m.eccles@ 123456soton.ac.uk
                [*]

                Joint first authors

                [†]

                Corresponding author

                Article
                S1470-2045(17)30891-4
                10.1016/S1470-2045(17)30891-4
                5805863
                29337092
                222f4183-e84c-4089-a42d-e7f6a039c30a
                © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Oncology & Radiotherapy
                Oncology & Radiotherapy

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