Abstract
Environmental or lifestyle factors are likely to explain part of the heterogeneity in breast and ovarian cancer risk among BRCA1 and BRCA2 mutation carriers. We assessed parity as a risk modifier in 515 and 503 Spanish female carriers of mutations in BRCA1 and BRCA2, respectively. Hazard ratios (HR) and their corresponding 95% confidence intervals (CI) were estimated using weighted Cox proportional hazards regression, adjusted for year of birth and study centre. The results for ever being parous and number of live-births were very similar for carriers of mutations in both genes. For all mutation carriers combined, the estimated HR associated with ever having had a live-birth was 0.74 (95% confidence interval [CI] = 0.55–1.01, P = 0.06), and that associated with each live-birth was 0.87 (95%CI = 0.77–0.98, P = 0.02). The latter association was observed only in women aged 40 and above (HR = 0.81, 95%CI = 0.70–0.94, P = 0.004 vs. HR = 0.99, 95%CI = 0.83–1.18, P = 0.9 for women under age 40), and this trend was highly consistently observed for carriers of mutations in each gene. There was no evidence of an association between breast cancer risk and age at first birth for parous BRCA1 or BRCA2 mutation carriers (P-trend ≥ 0.3). The power to detect associations with ovarian cancer risk was much lower, especially for BRCA2 mutation carriers. Nevertheless, having a live-birth was associated with protection for BRCA1 mutation carriers (HR = 0.41, 95%CI = 0.18–0.94, P = 0.03), and a strong and consistent protective effect of age at first birth was observed for parous carriers of mutations in both genes (HR = 0.65, 95%CI = 0.52–0.83, P < 0.001). This is the third independent study to find that, as in the general population, parity appears to be associated with protection from breast cancer in women with mutations in BRCA1 and BRCA2. Parity appears to be protective for ovarian cancer in BRCA1 mutation carriers, but its role in BRCA2 mutation carriers remains unclear. Whether later age at first birth is also protective for ovarian cancer in mutation carriers requires further confirmation.
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References
Antoniou A, Pharoah PD, Narod S et al (2003) Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet 72(5):1117–1130. doi:10.1086/375033
Goldgar D, Venne V, Conner T et al (2007) BRCA phenocopies or ascertainment bias? J Med Genet 44(8):e86 (author reply e88)
Gronwald J, Cybulski C, Lubinski J et al (2007) Phenocopies in breast cancer 1 (BRCA1) families: implications for genetic counselling. J Med Genet 44(4):e76. doi:10.1136/jmg.2006.048462
Smith A, Moran A, Boyd MC et al (2007) Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening. J Med Genet 44(1):10–15. doi:10.1136/jmg.2006.043091
Milne RL, Osorio A, Ramón y Cajal T et al (2008) The average cumulative risks of breast and ovarian cancer for carriers of mutations in BRCA1 and BRCA2 attending genetic counselling units in Spain. Clin Cancer Res 14(9):2861–2869. doi:10.1158/1078-0432.CCR-07-4436
Tryggvadottir L, Sigvaldason H, Olafsdottir GH et al (2006) Population-based study of changing breast cancer risk in Icelandic BRCA2 mutation carriers, 1920–2000. J Natl Cancer Inst 98(2):116–122
King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646. doi:10.1126/science.1088759
Narod S, Lynch H, Conway T et al (1993) Increasing incidence of breast cancer in family with BRCA1 mutation. Lancet 341(8852):1101–1102. doi:10.1016/0140-6736(93)92468-9
Kelsey JL, Gammon MD, John EM (1993) Reproductive factors and breast cancer. Epidemiol Rev 15(1):36–47
Elmasry K, Gayther SA (2006) Ovarian cancer aetiology: facts and fiction. J Fam Plan Reprod Health Care 32(2):82–86. doi:10.1783/147118906776276297
Milne R, Chenevix-Trench G (2007) Breast cancer risk modifiers. In: Isaacs C, Rebbeck TR (eds) Hereditary breast cancer, 1st edn. Informa Healthcare, New York
Collaborative Group on Hormonal Factors in Breast Cancer (2002) Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 360(9328):187–195. doi:10.1016/S0140-6736(02)09454-0
Whittemore AS, Harris R, Itnyre J (1992) Characteristics relating to ovarian cancer risk: collaborative analysis of 12 US case-control studies. II. Invasive epithelial ovarian cancers in white women. Collaborative ovarian cancer group. Am J Epidemiol 136(10):1184–1203
Cullinane CA, Lubinski J, Neuhausen SL et al (2005) Effect of pregnancy as a risk factor for breast cancer in BRCA1/BRCA2 mutation carriers. Int J Cancer 117(6):988–991. doi:10.1002/ijc.21273
Gronwald J, Byrski T, Huzarski T et al (2006) Influence of selected lifestyle factors on breast and ovarian cancer risk in BRCA1 mutation carriers from Poland. Breast Cancer Res Treat 95(2):105–109. doi:10.1007/s10549-005-9051-5
Jernstrom H, Lerman C, Ghadirian P et al (1999) Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 354(9193):1846–1850. doi:10.1016/S0140-6736(99)04336-6
Andrieu N, Goldgar DE, Easton DF et al (2006) Pregnancies, breast-feeding, and breast cancer risk in the international BRCA1/2 carrier cohort study (IBCCS). J Natl Cancer Inst 98(8):535–544
Antoniou AC, Shenton A, Maher ER et al (2006) Parity and breast cancer risk among BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 8(6):R72. doi:10.1186/bcr1630
Kotsopoulos J, Lubinski J, Lynch HT et al (2007) Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 105(2):221–228. doi:10.1007/s10549-006-9441-3
Rebbeck TR, Wang Y, Kantoff PW et al (2001) Modification of BRCA1- and BRCA2-associated breast cancer risk by AIB1 genotype and reproductive history. Cancer Res 61(14):5420–5424
McLaughlin JR, Risch HA, Lubinski J et al (2007) Reproductive risk factors for ovarian cancer in carriers of BRCA1 or BRCA2 mutations: a case-control study. Lancet Oncol 8(1):26–34. doi:10.1016/S1470-2045(06)70983-4
Antoniou AC, Rookus M, Andrieu N et al (2009) Reproductive and hormonal factors, and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: results from the International BRCA1/2 carrier cohort study. Cancer Epidemiol Biomarkers Prev 18(2):601–610. doi:10.1158/1055-9965.EPI-08-0546
Antoniou AC, Goldgar DE, Andrieu N et al (2005) A weighted cohort approach for analysing factors modifying disease risks in carriers of high-risk susceptibility genes. Genet Epidemiol 29(1):1–11. doi:10.1002/gepi.20074
StataCorp (2007) Stata Statistical Software: Release 10. StataCorp LP, College Station, TX, USA
Adami HO, Hsieh CC, Lambe M et al (1994) Parity, age at first childbirth, and risk of ovarian cancer. Lancet 344(8932):1250–1254. doi:10.1016/S0140-6736(94)90749-8
Riman T, Dickman PW, Nilsson S et al (2002) Risk factors for invasive epithelial ovarian cancer: results from a Swedish case-control study. Am J Epidemiol 156(4):363–373. doi:10.1093/aje/kwf048
Booth M, Beral V, Smith P (1989) Risk factors for ovarian cancer: a case-control study. Br J Cancer 60(4):592–598
Polychronopoulou A, Tzonou A, Hsieh CC et al (1993) Reproductive variables, tobacco, ethanol, coffee and somatometry as risk factors for ovarian cancer. Int J Cancer 55(3):402–407. doi:10.1002/ijc.2910550312
Acknowledgments
We thank the patients and families without whose generous participation this study would not have been possible. We also thank Alicia Barroso and Fernando Fernández who conducted the genetic testing at the Centro Nacional de Investigaciones Oncológicas; Guillermo Pita for information technology support; Marina Pollán and Fernando Artalejo from the Universidad Autónoma de Madrid; M. Carmen Alonso, Consol López and David Fisas from the Hospital de la Santa Creu i Sant Pau; Daniel Fortuny, Neus Gadea, and Orland Díez from Hospital Vall d’Hebron; Vicenta Garcés from the Hospital Clínico Universitario de Valencia, Pascual Bolufer from the Laboratorio de Biología Molecular, Hospital La Fe de Valencia; Dolores Salas and Dolores Cuevas from the Grupo de Cáncer Hereditario, Comunidad Valenciana. This work was partly supported by a grant from the Fondo de Investigación Sanitario [PI081120]. TC, MdH and ED-R were supported by the RTICC (RD06/0020/0021), Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation and a grant from the Fundación de Investigación Médica Mutua Madrileña (FMMA/06). The work at the Instituto Catalán de Oncología was supported by grants ISCIII-RETIC RD06/0020/1051 and 2005SGR00018. The Fundación Pública Galega de Medicina Xenómica -SERGAS component of this work was partially supported by grants from the Ministerio de Sanidad y Consumo (PI052275) and the Xunta de Galicia (PGIDIT06BTF910101PR) to AV. AB has a fellowship from the Instituto de Salud Carlos III. The work at the Instituto de Biologia y Genetica Molecular was partly supported by the Hereditary Cancer Prevention Programme of the Regional Government of Castilla y León, and grant PI06/1102 (Fondo de Investigación Sanitaria, Instituto de Salud Carlos III). The work at the Hospital de Cruces was funded by the grant BIO07/CA/006.
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Milne, R.L., Osorio, A., Ramón y Cajal, T. et al. Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119, 221–232 (2010). https://doi.org/10.1007/s10549-009-0394-1
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DOI: https://doi.org/10.1007/s10549-009-0394-1