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Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis

Breast Cancer Research and Treatment volume 124, pages 441–451 (2010)Cite this article

Abstract

The incomplete penetrance of mutations in BRCA1 and BRCA2 suggests that some combination of environmental and genetic factors modifies the risk of breast cancer in mutation carriers. This study sought to identify possible interactions between established breast cancer risk factors and BRCA1 or BRCA2 mutations using a case-only study design. Breast cancer cases that had been tested for BRCA1 and BRCA2 mutations were identified from 11 collaborating centers. Comparisons of reproductive and lifestyle risk factors were made between women with breast cancer who were positive for BRCA1 mutations (n = 283), BRCA2 mutations (n = 204), or negative for both BRCA1 and BRCA2 mutations (n = 894). Interaction risk ratios (IRRs) were calculated using multinominal logistic regression models. Compared with non-carriers, statistically significant IRRs were observed for later age at menarche among BRCA2 mutation carriers, for a greater number of pregnancies among both BRCA1 and BRCA2 mutation carriers, and for alcohol use among BRCA1 mutation carriers. Our data suggest that the risk for breast cancer among BRCA1 or BRCA2 carriers may be modified by reproductive characteristics and alcohol use. However, our results should be interpreted cautiously given the overall inconsistency in the epidemiologic literature on modifiers of BRCA1 and BRCA2.

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References

  1. Fackenthal JD, Olopade OI (2007) Breast cancer risk associated with BRCA1 and BRCA2 in diverse populations. Nat Rev Cancer 7:937–948

    CAS  Article  PubMed  Google Scholar 

  2. Breast Cancer Linkage Consortium (1997) Pathology of familial breast cancer: differences between breast cancers in carriers of BRCA1 or BRCA2 mutations and sporadic cases. Lancet 349:1505–1510

    Article  Google Scholar 

  3. Atchley DP, Albarracin CT, Lopez A et al (2008) Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol 26:4282–4288

    Article  PubMed  Google Scholar 

  4. Reis-Filho JS, Tutt AN (2008) Triple negative tumours: a critical review. Histopathology 52:108–118

    CAS  Article  PubMed  Google Scholar 

  5. Bordeleau L, Panchal S, Goodwin P (2010) Prognosis of BRCA-associated breast cancer: a summary of evidence. Breast Cancer Res Treat 119:13–24

    CAS  Article  PubMed  Google Scholar 

  6. Narod SA, Dube MP, Klijn J et al (2002) Oral contraceptives and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 94:1773–1779

    CAS  PubMed  Google Scholar 

  7. Jernstrom H, Lerman C, Ghadirian P et al (1999) Pregnancy and risk of early breast cancer in carriers of BRCA1 and BRCA2. Lancet 354:1846–1850

    CAS  Article  PubMed  Google Scholar 

  8. 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 117:988–991

    CAS  Article  PubMed  Google Scholar 

  9. 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 98:535–544

    Article  PubMed  Google Scholar 

  10. Chang-Claude J, Andrieu N, Rookus M et al (2007) Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 16:740–746

    Article  PubMed  Google Scholar 

  11. 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 105:221–228

    Article  PubMed  Google Scholar 

  12. McGuire V, John EM, Felberg A et al (2006) No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages <50 years. Cancer Epidemiol Biomarkers Prev 15:1565–1567

    CAS  Article  PubMed  Google Scholar 

  13. Haile RW, Thomas DC, McGuire V et al (2006) BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev 15:1863–1870

    CAS  Article  PubMed  Google Scholar 

  14. Brohet RM, Goldgar DE, Easton DF et al (2007) Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 25:3831–3836

    Article  PubMed  Google Scholar 

  15. Jernstrom H, Lubinski J, Lynch HT et al (2004) Breast-feeding and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 96:1094–1098

    CAS  Article  PubMed  Google Scholar 

  16. Kotsopoulos J, Lubinski J, Lynch HT et al (2005) Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer Causes Control 16:667–674

    Article  PubMed  Google Scholar 

  17. Brunet JS, Ghadirian P, Rebbeck TR et al (1998) Effect of smoking on breast cancer in carriers of mutant BRCA1 or BRCA2 genes. J Natl Cancer Inst 90:761–766

    CAS  Article  PubMed  Google Scholar 

  18. Kotsopoulos J, Olopado OI, Ghadirian P et al (2005) Changes in body weight and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res 7:R833–R843

    CAS  Article  PubMed  Google Scholar 

  19. 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 95:105–109

    Article  PubMed  Google Scholar 

  20. Lee E, Ma H, McKean-Cowdin R et al (2008) Effect of reproductive factors and oral contraceptives on breast cancer risk in BRCA1/2 mutation carriers and noncarriers: results from a population-based study. Cancer Epidemiol Biomarkers Prev 17:3170–3178

    CAS  Article  PubMed  Google Scholar 

  21. Tryggvadottir L, Olafsdottir EJ, Gudlaugsdottir S et al (2003) BRCA2 mutation carriers, reproductive factors and breast cancer risk. Breast Cancer Res 5:R121–R128

    CAS  Article  PubMed  Google Scholar 

  22. Milne RL, Knight JA, John EM et al (2005) Oral contraceptive use and risk of early-onset breast cancer in carriers and noncarriers of BRCA1 and BRCA2 mutations. Cancer Epidemiol Biomarkers Prev 14:350–356

    CAS  Article  PubMed  Google Scholar 

  23. Ursin G, Henderson BE, Haile RW et al (1997) Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? Cancer Res 57:3678–3681

    CAS  PubMed  Google Scholar 

  24. Piegorsch WW, Weinberg CR, Taylor JA (1994) Non-hierarchical logistic models and case-only designs for assessing susceptibility in population-based case–control studies. Stat Med 13:153–162

    CAS  Article  PubMed  Google Scholar 

  25. Schmidt S, Schaid DJ (1999) Potential misinterpretation of the case-only study to assess gene–environment interaction. Am J Epidemiol 150:878–885

    CAS  PubMed  Google Scholar 

  26. Chen S, Parmigiani G (2007) Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol 25:1329–1333

    Article  PubMed  Google Scholar 

  27. Tai YC, Domchek S, Parmigiani G et al (2007) Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst 99:1811–1814

    CAS  Article  PubMed  Google Scholar 

  28. Frank TS, Deffenbaugh AM, Reid JE et al (2002) Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10, 000 individuals. J Clin Oncol 20:1480–1490

    CAS  Article  PubMed  Google Scholar 

  29. Milne RL, Osorio A, Ramon y Cajal T et al (2009) Parity and the risk of breast and ovarian cancer in BRCA1 and BRCA2 mutation carriers. Breast Cancer Res Treat 119:221–232

    Article  PubMed  Google Scholar 

  30. 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 61:5420–5424

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was funded by the following grants and contracts from the National Cancer Institute, National Institutes of Health: P50-CA068438 Specialized Program of Research Excellence (SPORE) in breast cancer, Duke University Medical Center; Cancer Genetics Network (U01 CA78284 and HHSN261200744000C), Massachusetts General Hospital.

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Affiliations

  1. Cancer Prevention Detection and Control Research Program, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, 27705, USA

    Patricia G. Moorman, Frances Wang & Joellen M. Schildkraut

  2. Department of Statistical Science, Duke University, Durham, NC, 27705, USA

    Edwin S. Iversen

  3. Division of Oncology, Department of Medicine, Duke University Medical Center, Durham, NC, 27705, USA

    P. Kelly Marcom

  4. Department of Surgery, Duke University Medical Center, Durham, NC, 27705, USA

    Jeffrey R. Marks

  5. Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA

    Eunjung Lee & Giske Ursin

  6. Department of Nutrition, University of Oslo, Oslo, Norway

    Giske Ursin

  7. Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA

    Timothy R. Rebbeck

  8. Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA

    Timothy R. Rebbeck & Susan M. Domchek

  9. Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA

    Susan M. Domchek

  10. Breast Medical Oncology and Clinical Cancer Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA

    Banu Arun

  11. School of Medicine, University of North Carolina-Chapel Hill, Chapel Hill, NC, USA

    Lisa Susswein

  12. Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA

    Claudine Isaacs

  13. Department of Medical Oncology and Population Sciences, Dana Farber Cancer Institute, Boston, MA, USA

    Judy E. Garber

  14. Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA

    Kala Visvanathan

  15. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Kala Visvanathan & Constance A. Griffin

  16. Department of Pediatrics, University of South Florida, Tampa, FL, USA

    Rebecca Sutphen

  17. Moffitt Cancer Center, Tampa, FL, USA

    Jennifer Brzosowicz

  18. Division of Molecular Medicine & Genetics, University of Michigan, Ann Arbor, MI, USA

    Stephen Gruber

  19. Harvard School of Public Health and Harvard Medical School, Boston, MA, USA

    Dianne M. Finkelstein

Authors
  1. Patricia G. Moorman
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  2. Edwin S. Iversen
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  3. P. Kelly Marcom
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  4. Jeffrey R. Marks
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  5. Frances Wang
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  6. Eunjung Lee
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  7. Giske Ursin
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  8. Timothy R. Rebbeck
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  9. Susan M. Domchek
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  10. Banu Arun
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  11. Lisa Susswein
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  12. Claudine Isaacs
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  13. Judy E. Garber
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  14. Kala Visvanathan
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  15. Constance A. Griffin
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  16. Rebecca Sutphen
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  17. Jennifer Brzosowicz
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  18. Stephen Gruber
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  19. Dianne M. Finkelstein
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  20. Joellen M. Schildkraut
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Consortia

Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab)

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Correspondence to Patricia G. Moorman.

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Moorman, P.G., Iversen, E.S., Marcom, P.K. et al. Evaluation of established breast cancer risk factors as modifiers of BRCA1 or BRCA2: a multi-center case-only analysis. Breast Cancer Res Treat 124, 441–451 (2010). https://doi.org/10.1007/s10549-010-0842-y

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  • DOI: https://doi.org/10.1007/s10549-010-0842-y

Keywords

  • Breast cancer
  • BRCA1
  • BRCA2
  • Mutations
  • Modifiers