Skip to main content

Association between BRCA mutational status and survival in patients with breast cancer: a systematic review and meta-analysis

Abstract

Background

Studies evaluating role of BRCA mutations on the survival outcomes in breast cancer (BC) patients have given confounding results and hence, in this meta-analysis, we assessed the impact of BRCA mutations on survival in BC patients.

Methods

Studies comparing survival outcomes of BC patients having BRCA mutations against wildtype BRCA phenotype were retrieved from PubMed, EMBASE, and Cochrane Library. Overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), and breast cancer-specific survival (BCCS) were the outcomes. Hazard ratio (HR) with 95% confidence interval (CI) was used for analysis. Subgroup analysis was performed for survival based on triple negative breast cancer (TNBC) and follow-up durations. The meta-analysis was performed as per PRISMA guidelines.

Results

Altogether, 30 articles with 35,972 patients (mean age 45.6 years) were included. Patients with BRCA 1 mutation had significantly lower OS (HR [95% CI] 1.2 [1.08, 1.33]; P < 0.001), BRCA 2 mutation had significantly lower DFS (HR [95% CI] 1.35 [1.1, 1.67]; P = 0.0049) and BCSS (HR [95%CI] 1.46 [1.26, 1.7]; P < 0.0001), and TNBC patients with BRCA 1 mutation had significantly poor DFS (HR [95% CI] 1.65 [1.08, 2.54]; P = 0.0216). Based on follow-up duration, the OS in BRCA 1-mutated patients revealed significantly poorer outcomes in studies with ≤ 5 years (HR 1.48) and > 5 years (HR 1.14) of follow-up. In BRCA 2 -mutated patients, the OS was significantly poorer in studies with > 5 years of follow-up (HR 1.39, P < 0.05).

Conclusion

BC patients with BRCA 1 or BRCA 2 mutations had poor survival outcomes and hence screening patients with BC for BRCA mutations might help in strategizing their treatment and improving their survival.

This is a preview of subscription content, access via your institution.

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Data availability

All data generated or analyzed during this study are included in this article.

References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I et al (2018) Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68:394–424. https://doi.org/10.3322/caac.21492

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Murtaugh MA, Sweeney C, Giuliano AR et al (2008) Diet patterns and breast cancer risk in Hispanic and non-Hispanic white women: the Four-Corners Breast Cancer Study. Am J Clin Nutr 87:978–984. https://doi.org/10.1093/ajcn/87.4.978

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. 3.

    Aktipis CA, Ellis BJ, Nishimura KK, Hiatt RA (2015) Modern reproductive patterns associated with estrogen receptor positive but not negative breast cancer susceptibility. Evol Med Public Health 2015:52–74. https://doi.org/10.1093/emph/eou028

    Article  Google Scholar 

  4. 4.

    Rojas K, Stuckey A (2016) Breast cancer epidemiology and risk factors. Clin Obstet Gynecol 59(4):651–672. https://doi.org/10.1097/GRF.0000000000000239

    Article  Google Scholar 

  5. 5.

    Ruiz de Sabando A, Urrutia Lafuente E, García-Amigot F et al (2019) Genetic and clinical characterization of BRCA-associated hereditary breast and ovarian cancer in Navarra (Spain). BMC Cancer 19:1145. https://doi.org/10.1186/s12885-019-6277-x

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    BRCA: The Breast Cancer Gene. In: National Breast Cancer Foundation. https://www.nationalbreastcancer.org/what-is-brca. Accessed 26 Febr 2020

  7. 7.

    Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71. https://doi.org/10.1126/science.7545954

    Article  PubMed  CAS  Google Scholar 

  8. 8.

    Wooster R, Bignell G, Lancaster J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792. https://doi.org/10.1038/378789a0

    Article  PubMed  CAS  Google Scholar 

  9. 9.

    Easton DF, Ford D, Bishop DT (1995) Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56:265–271

    Article  CAS  Google Scholar 

  10. 10.

    Ford D, Easton DF, Stratton M et al (1998) Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet 62:676–689. https://doi.org/10.1086/301749

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. 11.

    Copson ER, Maishman TC, Tapper WJ et al (2018) Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study. Lancet Oncol 19:169–180. https://doi.org/10.1016/S1470-2045(17)30891-4

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Walsh T, Mandell JB, Norquist BM et al (2017) Genetic predisposition to breast cancer due to mutations other than BRCA1 and BRCA2 founder alleles among Ashkenazi Jewish women. JAMA Oncol 3:1647–1653. https://doi.org/10.1001/jamaoncol.2017.1996

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Liebens FP, Carly B, Pastijn A, Rozenberg S (2007) Management of BRCA1/2 associated breast cancer: a systematic qualitative review of the state of knowledge in 2006. Eur J Cancer 43:238–257. https://doi.org/10.1016/j.ejca.2006.07.019

    Article  PubMed  CAS  Google Scholar 

  14. 14.

    Lee E-H, Park SK, Park B et al (2010) Effect of BRCA1/2 mutation on short-term and long-term breast cancer survival: a systematic review and meta-analysis. Breast Cancer Res Treat 122:11–25. https://doi.org/10.1007/s10549-010-0859-2

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Baretta Z, Mocellin S, Goldin E et al (2016) Effect of BRCA germline mutations on breast cancer prognosis. Medicine (Baltimore). https://doi.org/10.1097/MD.0000000000004975

    Article  Google Scholar 

  16. 16.

    Chen H, Wu J, Zhang Z et al (2018) Association between BRCA status and triple-negative breast cancer: a meta-analysis. Front Pharmacol. https://doi.org/10.3389/fphar.2018.00909

    Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Pogoda K, Niwińska A, Sarnowska E et al (2020) Effects of BRCA germline mutations on triple-negative breast cancer prognosis. J Oncol 2020:10. https://doi.org/10.1155/2020/8545643

    Article  CAS  Google Scholar 

  18. 18.

    Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLOS Med 6:e1000097. https://doi.org/10.1371/journal.pmed.1000097

    Article  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLOS Med 6:e1000100. https://doi.org/10.1371/journal.pmed.1000100

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Wells GA, Shea B, O’connell D et al (2015) The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

  21. 21.

    Bayraktar S, Gutierrez-Barrera AM, Lin H et al (2013) Outcome of metastatic breast cancer in selected women with or without deleterious BRCA mutations. Clin Exp Metastasis 30:631–642. https://doi.org/10.1007/s10585-013-9567-8

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Lang G-T, Shi J-X, Hu X et al (2017) The spectrum of BRCA mutations and characteristics of BRCA-associated breast cancers in China: screening of 2,991 patients and 1,043 controls by next-generation sequencing. Int J Cancer 141:129–142. https://doi.org/10.1002/ijc.30692

    Article  CAS  Google Scholar 

  23. 23.

    Wang C, Zhang J, Wang Y et al (2015) Prevalence of BRCA1 mutations and responses to neoadjuvant chemotherapy among BRCA1 carriers and non-carriers with triple-negative breast cancer. Ann Oncol 26:523–528. https://doi.org/10.1093/annonc/mdu559

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Tung N, Gaughan E, Hacker MR et al (2014) Outcome of triple negative breast cancer: comparison of sporadic and BRCA1-associated cancers. Breast Cancer Res Treat 146:175–182. https://doi.org/10.1007/s10549-014-2995-6

    Article  PubMed  CAS  Google Scholar 

  25. 25.

    Sambiasi D, Lambo R, Pilato B et al (2014) BRCA1/2 and clinical outcome in a monoinstitutional cohort of women with hereditary breast cancer. Oncol Rep 31:365–369. https://doi.org/10.3892/or.2013.2802

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Huzarski T, Byrski T, Gronwald J et al (2013) Ten-year survival in patients with BRCA1-negative and BRCA1-positive breast cancer. J Clin Oncol 31:3191–3196. https://doi.org/10.1200/JCO.2012.45.3571

    Article  PubMed  Google Scholar 

  27. 27.

    Tryggvadottir L, Olafsdottir EJ, Olafsdottir GH et al (2013) Tumour diploidy and survival in breast cancer patients with BRCA2 mutations. Breast Cancer Res Treat 140:375–384. https://doi.org/10.1007/s10549-013-2637-4

    Article  PubMed  CAS  Google Scholar 

  28. 28.

    Goodwin PJ, Phillips K-A, West DW et al (2012) Breast cancer prognosis in BRCA1 and BRCA2 mutation carriers: an International Prospective Breast Cancer Family Registry population-based cohort study. J Clin Oncol 30:19–26. https://doi.org/10.1200/JCO.2010.33.0068

    Article  PubMed  Google Scholar 

  29. 29.

    Arun B, Bayraktar S, Liu DD et al (2011) Response to neoadjuvant systemic therapy for breast cancer in BRCA mutation carriers and noncarriers: a single-institution experience. J Clin Oncol 29:3739–3746. https://doi.org/10.1200/JCO.2011.35.2682

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Bayraktar S, Gutierrez-Barrera AM, Liu D et al (2011) Outcome of triple-negative breast cancer in patients with or without deleterious BRCA mutations. Breast Cancer Res Treat 130:145–153. https://doi.org/10.1007/s10549-011-1711-z

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. 31.

    Lee LJ, Alexander B, Schnitt SJ et al (2011) Clinical outcome of triple negative breast cancer in BRCA1 mutation carriers and noncarriers. Cancer 117:3093–3100. https://doi.org/10.1002/cncr.25911

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. 32.

    Budroni M, Cesaraccio R, Coviello V et al (2009) Role of BRCA2 mutation status on overall survival among breast cancer patients from Sardinia. BMC Cancer 9:62. https://doi.org/10.1186/1471-2407-9-62

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. 33.

    Rennert G, Bisland-Naggan S, Barnett-Griness O et al (2007) Clinical outcomes of breast cancer in carriers of BRCA1 and BRCA2 mutations. N Engl J Med 357:115–123. https://doi.org/10.1056/NEJMoa070608

    Article  PubMed  CAS  Google Scholar 

  34. 34.

    Brekelmans CTM, Tilanus-Linthorst MMA, Seynaeve C et al (2007) Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases. Eur J Cancer 43:867–876. https://doi.org/10.1016/j.ejca.2006.12.009

    Article  PubMed  CAS  Google Scholar 

  35. 35.

    Bonadona V, Dussart-Moser S, Voirin N et al (2007) Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review. Breast Cancer Res Treat 101:233–245. https://doi.org/10.1007/s10549-006-9288-7

    Article  PubMed  CAS  Google Scholar 

  36. 36.

    Brekelmans CTM, Seynaeve C, Menke-Pluymers M et al (2006) Survival and prognostic factors in BRCA1-associated breast cancer. Ann Oncol 17:391–400. https://doi.org/10.1093/annonc/mdj095

    Article  PubMed  CAS  Google Scholar 

  37. 37.

    Robson ME, Chappuis PO, Satagopan J et al (2004) A combined analysis of outcome following breast cancer: differences in survival based on BRCA1/BRCA2 mutation status and administration of adjuvant treatment. Breast Cancer Res 6:R8–R17. https://doi.org/10.1186/bcr658

    Article  PubMed  CAS  Google Scholar 

  38. 38.

    Verhoog LC, Brekelmans CT, Seynaeve C et al (1999) Survival in hereditary breast cancer associated with germline mutations of BRCA2. J Clin Oncol 17:3396–3402. https://doi.org/10.1200/JCO.1999.17.11.3396

    Article  PubMed  CAS  Google Scholar 

  39. 39.

    Verhoog LC, Brekelmans CT, Seynaeve C et al (1998) Survival and tumour characteristics of breast-cancer patients with germline mutations of BRCA1. Lancet 351:316–321. https://doi.org/10.1016/s0140-6736(97)07065-7

    Article  PubMed  CAS  Google Scholar 

  40. 40.

    Jóhannsson OT, Ranstam J, Borg A, Olsson H (1998) Survival of BRCA1 breast and ovarian cancer patients: a population-based study from southern Sweden. J Clin Oncol 16:397–404. https://doi.org/10.1200/JCO.1998.16.2.397

    Article  PubMed  Google Scholar 

  41. 41.

    Marcus JN, Watson P, Page DL et al (1996) Hereditary breast cancer: pathobiology, prognosis, and BRCA1 and BRCA2 gene linkage. Cancer 77:697–709. https://doi.org/10.1002/(sici)1097-0142(19960215)77:4%3c697::aid-cncr16%3e3.0.co;2-w

    Article  PubMed  CAS  Google Scholar 

  42. 42.

    Loman N, Johannsson O, Bendahl P et al (2000) Prognosis and clinical presentation of BRCA2-associated breast cancer. Eur J Cancer 36:1365–1373. https://doi.org/10.1016/s0959-8049(00)00098-8

    Article  PubMed  CAS  Google Scholar 

  43. 43.

    Deng M, Chen H-H, Zhu X et al (2019) Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer 145:1517–1528. https://doi.org/10.1002/ijc.32184

    Article  PubMed  CAS  Google Scholar 

  44. 44.

    Huszno J, Kołosza Z, Grzybowska E (2019) BRCA1 mutation in breast cancer patients: analysis of prognostic factors and survival. Oncol Lett 17:1986–1995. https://doi.org/10.3892/ol.2018.9770

    Article  PubMed  CAS  Google Scholar 

  45. 45.

    Wang YA, Jian J-W, Hung C-F et al (2018) Germline breast cancer susceptibility gene mutations and breast cancer outcomes. BMC Cancer 18:315. https://doi.org/10.1186/s12885-018-4229-5

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. 46.

    Sun J, Meng H, Yao L et al (2017) Germline mutations in cancer susceptibility genes in a large series of unselected breast cancer patients. Clin Cancer Res 23:6113–6119. https://doi.org/10.1158/1078-0432.CCR-16-3227

    Article  PubMed  CAS  Google Scholar 

  47. 47.

    Schmidt MK, van den Broek AJ, Tollenaar RAEM et al (2017) Breast cancer survival of BRCA1/BRCA2 mutation carriers in a hospital-based cohort of young women. J Natl Cancer Inst. https://doi.org/10.1093/jnci/djw329

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Kim MC, Choi JE, Lee SJ, Bae YK (2016) Coexistent loss of the expressions of BRCA1 and p53 predicts poor prognosis in triple-negative breast cancer. Ann Surg Oncol 23:3524–3530. https://doi.org/10.1245/s10434-016-5307-z

    Article  PubMed  Google Scholar 

  49. 49.

    Zhong X, Dong Z, Dong H et al (2016) Prevalence and prognostic role of BRCA1/2 variants in unselected Chinese breast cancer patients. PLoS One 11:e0156789. https://doi.org/10.1371/journal.pone.0156789

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. 50.

    Schlacher K, Christ N, Siaud N et al (2011) Double-strand break repair-independent role for BRCA2 in blocking stalled replication fork degradation by MRE11. Cell 145:529–542. https://doi.org/10.1016/j.cell.2011.03.041

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. 51.

    Roy R, Chun J, Powell SN (2011) BRCA1 and BRCA2: different roles in a common pathway of genome protection. Nat Rev Cancer 12:68–78. https://doi.org/10.1038/nrc3181

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. 52.

    Foulkes WD (2008) Inherited susceptibility to common cancers. N Engl J Med 359:2143–2153. https://doi.org/10.1056/NEJMra0802968

    Article  PubMed  CAS  Google Scholar 

  53. 53.

    Mavaddat N, Barrowdale D, Andrulis IL et al (2012) Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: results from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Cancer Epidemiol Biomark Prev 21:134–147. https://doi.org/10.1158/1055-9965.EPI-11-0775

    Article  CAS  Google Scholar 

  54. 54.

    Aleskandarany M, Caracappa D, Nolan CC et al (2015) DNA damage response markers are differentially expressed in BRCA-mutated breast cancers. Breast Cancer Res Treat 150:81–90. https://doi.org/10.1007/s10549-015-3306-6

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. 55.

    Steward L, Conant L, Gao F, Margenthaler JA (2014) Predictive factors and patterns of recurrence in patients with triple negative breast cancer. Ann Surg Oncol 21:2165–2171. https://doi.org/10.1245/s10434-014-3546-4

    Article  PubMed  Google Scholar 

  56. 56.

    Richman J, Dowsett M (2019) Beyond 5 years: enduring risk of recurrence in oestrogen receptor-positive breast cancer. Nat Rev Clin Oncol 16:296–311. https://doi.org/10.1038/s41571-018-0145-5

    Article  PubMed  CAS  Google Scholar 

  57. 57.

    Fasching PA, Hu C, Hart S et al (2019) Germline BRCA1and BRCA2 mutations in patients with HER2-negative metastatic breast cancer (mBC) treated with first-line chemotherapy: data from the German PRAEGNANT registry. JCO 37:1048–1048. https://doi.org/10.1200/JCO.2019.37.15_suppl.1048

    Article  Google Scholar 

  58. 58.

    McLaurin K, Dalvi T, Collins JM et al (2019) A real-world evidence study of CDK4/6 inhibitor treatment patterns and outcomes in metastatic breast cancer by gBRCA mutation status. JCO 37:1563–1563. https://doi.org/10.1200/JCO.2019.37.15_suppl.1563

    Article  Google Scholar 

Download references

Acknowledgements

The authors acknowledge Dr. Kaushik Subramanian, Indegene pvt Ltd, Bangalore, India, for the medical writing assistance.

Funding

The study was funded by AstraZeneca.

Author information

Affiliations

Authors

Contributions

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; gave final approval of the version to be published; and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Shu Wang.

Ethics declarations

Conflict of interest

All authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants performed by any of the authors.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Liu, M., Xie, F., Liu, M. et al. Association between BRCA mutational status and survival in patients with breast cancer: a systematic review and meta-analysis. Breast Cancer Res Treat 186, 591–605 (2021). https://doi.org/10.1007/s10549-021-06104-y

Download citation

Keywords

  • BRCA
  • Breast cancer
  • Survival
  • Prognosis