Research Article| Volume 165, ISSUE 3, P437-445, June 2022

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Germline BRCA variants, lifestyle and ovarian cancer survival


      • It is unknown whether associations between lifestyle factors and ovarian cancer survival differ by BRCA variant status.
      • The adverse effects of smoking on ovarian cancer survival may be stronger for women with a BRCA variant than those without.
      • There was no differential association in survival by BRCA variant status for physical activity, BMI or alcohol intake.



      Women with ovarian cancer who have a pathogenic germline variant in BRCA1 or BRCA2 (BRCA) have been shown to have better 5-year survival after diagnosis than women who are BRCA-wildtype (non-carriers). Modifiable lifestyle factors, including smoking, physical activity and body mass index (BMI) have previously been associated with ovarian cancer survival; however, it is unknown whether these associations differ by germline BRCA status.


      We investigated measures of lifestyle prior to diagnosis in two cohorts of Australian women with invasive epithelial ovarian cancer, using Cox proportional hazards regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).


      In the combined studies (n = 1923), there was little association between physical activity, BMI or alcohol intake and survival, and no difference by BRCA status. However, the association between current smoking status before diagnosis and poorer survival was stronger for BRCA variant carriers (HR 1.98; 95% CI 1.20–3.27) than non-carriers (HR 1.18; 95% CI 0.96–1.46; p-interaction 0.02). We saw a similar differential association with smoking when we pooled results from two additional cohorts from the USA and UK (n = 2120). Combining the results from all four studies gave a pooled-HR of 1.94 (95% CI 1.28–2.94) for current smoking among BRCA variant carriers compared to 1.08 (0.90–1.29) for non-carriers.


      Our results suggest that the adverse effect of smoking on survival may be stronger for women with a BRCA variant than those without. Thus, while smoking cessation may improve outcomes for all women with ovarian cancer, it might provide a greater benefit for BRCA variant carriers.



      AOCS (Australian Ovarian Cancer Study), BMI (body mass index), CI (confidence interval), FIGO (International Federation of Obstetricians and Gynecologists), MAYO (Mayo Clinic Case-Only Ovarian Cancer Study/Mayo Clinic Ovarian Cancer Case Control Study), METhrs (metabolic equivalent hours), OCAC (Ovarian Cancer Association Consortium), OPAL (Ovarian cancer Prognosis and Lifestyle), PA (physical activity), pHR (pooled hazard ratio), SEARCH (Study of Epidemiology and Risk Factors in Cancer Heredity study)
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        • Sung H.
        • Ferlay J.
        • Siegel R.L.
        • Laversanne M.
        • Soerjomataram I.
        • Jemal A.
        • et al.
        Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J. Clin. 2021; 71: 209-249
        • Arnold M.R.M.
        • Lam F.
        • Bray F.
        • Ervik M.
        • Soerjomataram I.
        ICBP SURVMARK-2 Online Tool: International Cancer Survival Benchmarking Lyon.
        International Agency for Research on Cancer, France2019 (Available from)
        • Toss A.
        • Tomasello C.
        • Razzaboni E.
        • Contu G.
        • Grandi G.
        • Cagnacci A.
        • et al.
        Hereditary ovarian cancer: not only BRCA 1 and 2 genes.
        Biomed. Res. Int. 2015; 2015341723
        • Alsop K.
        • Fereday S.
        • Meldrum C.
        • deFazio A.
        • Emmanuel C.
        • George J.
        • 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.
        Journal of clinical oncology. 2012; 30: 2654-2663
        • Candido-dos-Reis F.J.
        • Song H.
        • Goode E.L.
        • Cunningham J.M.
        • Fridley B.L.
        • Larson M.C.
        • et al.
        Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer.
        Clinical cancer research. 2015; 21: 652-657
        • Kotsopoulos J.
        • Rosen B.
        • Fan I.
        • Moody J.
        • McLaughlin J.R.
        • Risch H.
        • et al.
        Ten-year survival after epithelial ovarian cancer is not associated with BRCA mutation status.
        Gynecol. Oncol. 2016; 140: 42-47
        • Wang Y.
        • Ren F.
        • Song Z.
        • Wang X.
        • Zhang C.
        • Ouyang L.
        PARP inhibitors in patients with newly diagnosed advanced ovarian cancer: a Meta-analysis of randomized clinical trials.
        Front. Oncol. 2020; 10: 1204
        • Anuradha S.
        • Webb P.M.
        • Blomfield P.
        • Brand A.H.
        • Friedlander M.
        • Leung Y.
        • et al.
        Survival of Australian women with invasive epithelial ovarian cancer: a population-based study.
        Med. J. Aust. 2014; 201: 283-288
        • Kim S.J.
        • Rosen B.
        • Fan I.
        • Ivanova A.
        • McLaughlin J.R.
        • Risch H.
        • et al.
        Epidemiologic factors that predict long-term survival following a diagnosis of epithelial ovarian cancer.
        Br. J. Cancer. 2017; 116: 964-971
        • Ørskov M.
        • Iachina M.
        • Guldberg R.
        • Mogensen O.
        • Mertz Nørgård B.
        Predictors of mortality within 1 year after primary ovarian cancer surgery: a nationwide cohort study.
        BMJ Open. 2016; 6e010123
        • Cannioto R.
        • LaMonte M.
        • Kelemen L.
        • Risch H.
        • Eng K.
        • Minlikeeva A.
        • et al.
        Recreational physical inactivity and mortality in women with invasive epithelial ovarian cancer: evidence from the Ovarian Cancer Association Consortium.
        Br. J. Cancer. 2016; 115: 95-101
        • Nagle C.M.
        • Dixon S.C.
        • Jensen A.
        • Kjaer S.K.
        • Modugno F.
        • deFazio A.
        • et al.
        Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium.
        Br. J. Cancer. 2015; 113: 817-826
        • Præstegaard C.
        • Jensen A.
        • Jensen S.M.
        • Nielsen T.S.S.
        • Webb P.M.
        • Nagle C.M.
        • et al.
        Cigarette smoking is associated with adverse survival among women with ovarian cancer: results from a pooled analysis of 19 studies.
        Int. J. Cancer. 2017; 140: 2422-2435
        • Gudmundsdottir K.
        • Ashworth A.
        The roles of BRCA1 and BRCA2 and associated proteins in the maintenance of genomic stability.
        Oncogene. 2006; 25: 5864-5874
        • Beesley V.L.
        • Smith D.D.
        • Nagle C.M.
        • Friedlander M.
        • Grant P.
        • DeFazio A.
        • et al.
        Coping strategies, trajectories, and their associations with patient-reported outcomes among women with ovarian cancer.
        Support Care Cancer. 2018; 26: 4133-4142
        • Merritt M.A.
        • Green A.C.
        • Nagle C.M.
        • Webb P.M.
        Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer.
        Int. J. Cancer. 2008; 122: 170-176
        • Arts-de Jong M.
        • de Bock G.H.
        • van Asperen C.J.
        • Mourits M.J.E.
        • de Hullu J.A.
        • Kets C.M.
        Germline BRCA1/2 mutation testing is indicated in every patient with epithelial ovarian cancer: a systematic review.
        Eur. J. Cancer. 2016; 61: 137-145
        • Ovarian Cancer Australia
        Traceback Research Project.
        (Available from)
        • Landrum M.J.
        • Lee J.M.
        • Benson M.
        • Brown G.R.
        • Chao C.
        • Chitipiralla S.
        • et al.
        ClinVar: improving access to variant interpretations and supporting evidence.
        Nucleic Acids Res. 2018; 46: D1062-d7
        • Thompson B.A.
        • Spurdle A.B.
        • Plazzer J.P.
        • Greenblatt M.S.
        • Akagi K.
        • Al-Mulla F.
        • et al.
        Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
        Nat. Genet. 2014; 46: 107-115
        • Parsons M.T.
        • Tudini E.
        • Li H.
        • Hahnen E.
        • Wappenschmidt B.
        • Feliubadaló L.
        • et al.
        Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: an ENIGMA resource to support clinical variant classification.
        Hum. Mutat. 2019; 40: 1557-1578
        • Sundararajan V.
        • Henderson T.
        • Perry C.
        • Muggivan A.
        • Quan H.
        • Ghali W.A.
        New ICD-10 version of the Charlson comorbidity index predicted in-hospital mortality.
        J. Clin. Epidemiol. 2004; 57: 1288-1294
        • World Health Organisation
        Physical status: the use and interpretation of anthropometry.
        in: Report of a WHO Expert Committee. 1995 (Report No: 0512–3054)
        • Australian Institute of Health and Welfare
        The Active Australia Survey: A Guide and Manual for Implementation, Analysis and Reporting.
        AIHW, Canberra2003
        • Olsen C.M.
        • Bain C.J.
        • Jordan S.J.
        • Nagle C.M.
        • Green A.C.
        • Whiteman D.C.
        • et al.
        Recreational physical activity and epithelial ovarian cancer: a case-control study, systematic review, and meta-analysis.
        Cancer Epidemiol. Biomark. Prev. 2007; 16: 2321-2330
        • Ibiebele T.I.
        • Parekh S.
        • Mallitt K.-a.
        • Hughes M.C.
        • O’Rourke P.K.
        • Webb P.M.
        Reproducibility of food and nutrient intake estimates using a semi-quantitative FFQ in Australian adults.
        Public Health Nutr. 2009; 12: 2359-2365
        • Marks G.C.
        • Hughes M.C.
        • van der Pols J.C.
        The effect of personal characteristics on the validity of nutrient intake estimates using a food-frequency questionnaire.
        Public Health Nutr. 2006; 9: 394-402
        • Mcnaughton S.A.
        • Marks G.C.
        • Gaffney P.
        • Williams G.
        • Green A.
        Validation of a food-frequency questionnaire assessment of carotenoid and vitamin E intake using weighed food records and plasma biomarkers: the method of triads model.
        Eur. J. Clin. Nutr. 2004; 59: 211
        • StataCorp
        Stata Statistical Software: Release 15.
        StataCorp LLC, College Station, TX2017
        • Goode E.L.
        • Chenevix-Trench G.
        • Hartmann L.C.
        • Fridley B.L.
        • Kalli K.R.
        • Vierkant R.A.
        • et al.
        Assessment of hepatocyte growth factor in ovarian cancer mortality.
        Cancer Epidemiology Biomarkers Prevention. 2011; 20: 1638
        • Song H.
        • Ramus S.J.
        • Quaye L.
        • DiCioccio R.A.
        • Tyrer J.
        • Lomas E.
        • et al.
        Common variants in mismatch repair genes and risk of invasive ovarian cancer.
        Carcinogenesis. 2006; 27: 2235-2242
        • Kelemen L.E.
        • Sellers T.A.
        • Schildkraut J.M.
        • Cunningham J.M.
        • Vierkant R.A.
        • Pankratz V.S.
        • et al.
        Genetic variation in the one-carbon transfer pathway and ovarian cancer risk.
        Cancer Res. 2008; 68: 2498-2506
        • Faber M.T.
        • Kjær S.K.
        • Dehlendorff C.
        • Chang-Claude J.
        • Andersen K.K.
        • Høgdall E.
        • et al.
        Cigarette smoking and risk of ovarian cancer: a pooled analysis of 21 case-control studies.
        Cancer causes & control: CCC. 2013; 24: 989-1004
        • Ko K.P.
        • Kim S.J.
        • Huzarski T.
        • Gronwald J.
        • Lubinski J.
        • Lynch H.T.
        • et al.
        The association between smoking and cancer incidence in BRCA1 and BRCA2 mutation carriers.
        Int. J. Cancer. 2018; 142: 2263-2272
        • Stämpfli M.R.
        • Anderson G.P.
        How cigarette smoke skews immune responses to promote infection, lung disease and cancer.
        Nat. Rev. Immunol. 2009; 9: 377-384
        • National Centre for Chronic Disease Prevention and Health Promotion (US) Office of Smoking and Health
        The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General.
        Centers for Disease Control and Prevention (US), Atlanta (GA)2014
        • O’Malley M.
        • King A.N.
        • Conte M.
        • Ellingrod V.L.
        • Ramnath N.
        Effects of cigarette smoking on metabolism and effectiveness of systemic therapy for lung cancer.
        Journal of thoracic oncology. 2014; 9: 917-926
        • Cacciamani G.E.
        • Ghodoussipour S.
        • Mari A.
        • Gill K.S.
        • Desai M.
        • Artibani W.
        • et al.
        Association between smoking exposure, neoadjuvant chemotherapy response and survival outcomes following radical cystectomy: systematic review and Meta-analysis.
        J. Urol. 2020; 204: 649-660
        • George J.
        • Alsop K.
        • Etemadmoghadam D.
        • Hondow H.
        • Mikeska T.
        • Dobrovic A.
        • et al.
        Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations.
        Clinical cancer research. 2013; 19: 3474-3484
        • Soslow R.A.
        • Han G.
        • Park K.J.
        • Garg K.
        • Olvera N.
        • Spriggs D.R.
        • et al.
        Morphologic patterns associated with BRCA1 and BRCA2 genotype in ovarian carcinoma.
        Modern Pathology. 2012; 25: 625-636