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.
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.
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).
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.
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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
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
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
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
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
BRCA: The Breast Cancer Gene. In: National Breast Cancer Foundation. https://www.nationalbreastcancer.org/what-is-brca. Accessed 26 Febr 2020
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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.19188.8.131.5296
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
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.19184.108.40.2067
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
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
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
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
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
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
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
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
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
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
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
Foulkes WD (2008) Inherited susceptibility to common cancers. N Engl J Med 359:2143–2153. https://doi.org/10.1056/NEJMra0802968
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
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
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
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
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
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
The authors acknowledge Dr. Kaushik Subramanian, Indegene pvt Ltd, Bangalore, India, for the medical writing assistance.
The study was funded by AstraZeneca.
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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
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