Genetic Susceptibility to Triple‐Negative Breast Cancers

Michelle W Wong‐Brown, University of Newcastle, Newcastle, Australia
Rodney J Scott, University of Newcastle, Newcastle, Australia

Published online: May 2014

DOI: 10.1002/9780470015902.a0025352

Abstract

Triple‐negative breast cancer (TNBC) is a histological classification of breast cancer, where there is no expression of either the oestrogen or the progesterone receptor and no amplification of the HER2 receptor. TNBC is an important breast cancer subtype as it is aggressive in nature and has a poorer disease prognosis, mainly due to a paucity of targeted therapies. Studies in recent years have tried to elucidate the genetic aetiology of TNBC to better understand the disease and to predict response to treatments based on their genetic profile. TNBC has been shown to be very similar to BRCA1 mutation‐associated breast tumours, where it is estimated that approximately 20% of TNBC patients harbour germline BRCA (especially BRCA1) mutations. The contribution of germline mutations in other breast cancer susceptibility genes to TNBC still remains to be determined. Several common and novel breast cancer susceptibility loci have also been specifically linked to TNBC. These findings support the argument that genetic testing should be offered to patients based on the triple‐negative phenotype of their breast tumours.

Key Concepts:

  • TNBC is an important area of study due to the aggressive nature of this tumour subtype and the difficulties in disease treatment.

  • Women with TNBC have a poorer prognosis due to lack of endocrine therapies.

  • TNBC has histopathological characteristics similar to BRCA1‐ and BRCA2‐associated tumours, and could have similar molecular aetiology.

  • Germline mutations in BRCA1 and BRCA2 have been associated with up to 20% of TNBC cohorts unselected for family history of the disease.

  • The contribution of germline mutations in other breast cancer susceptibility genes to TNBC remains to be determined.

  • Several known breast cancer susceptibility loci have been shown to be specifically associated with TNBC.

  • Patients with TNBC could benefit from genetic screening of both BRCA genes based solely on the phenotype of their breast tumour.

Keywords: triple‐negative breast cancer; genetic; BRCA1 and BRCA2; germline mutations; mutation prevalence; genetic testing; targeted therapies

Figure 1.

Pathway diagram showing a small part on the DNA repair pathway involving BRCA1, BRCA2, CHEK2, ATM, BACH1 and PALB2 (encoded by BRCA1, BRCA2, CHEK2, ATM, BRIP1 and PALB2, respectively). These genes have been investigated in determining their mutation prevalence in TNBC.

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References

Andre F, Job B, Dessen P et al. (2009) Molecular characterization of breast cancer with high‐resolution oligonucleotide comparative genomic hybridization array. Clinical Cancer Research 15(2): 441–451.

Antoniou AC, Wang X, Fredericksen ZS et al. (2010) A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor‐negative breast cancer in the general population. Nature Genetics 42(10): 885–892.

Atchley DP, Albarracin CT, Lopez A et al. (2008) Clinical and pathologic characteristics of patients with BRCA‐positive and BRCA‐negative breast cancer. Journal of Clinical Oncology 26(26): 4282–4288.

Balmaña J, Diez O, Rubio IT and Cardoso F (2011) BRCA in breast cancer: ESMO Clinical Practice Guidelines. Annals of Oncology 22(suppl. 6): vi31–vi34.

Broeks A, Schmidt MK, Sherman ME et al. (2011) Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium. Human Molecular Genetics 20(16): 3289–3303.

Byrski T, Dent R, Blecharz P et al. (2012) Results of a phase II open‐label, non‐randomized trial of cisplatin chemotherapy in patients with BRCA1‐positive metastatic breast cancer. Breast Cancer Research 14(4): R110.

Carey LA (2010) Targeted chemotherapy? Platinum in BRCA1‐dysfunctional breast cancer. Journal of Clinical Oncology 28(3): 361–363.

Carey L, Winer E, Viale G, Cameron D and Gianni L (2010) Triple‐negative breast cancer: disease entity or title of convenience? Nature Reviews Clinical Oncology 7(12): 683–692.

Comen E, Davids M, Kirchhoff T et al. (2011) Relative contributions of BRCA1 and BRCA2 mutations to ‘triple‐negative’ breast cancer in Ashkenazi Women. Breast Cancer Research and Treatment 129(1): 185–190.

Couch FJ, Wang X, McGuffog L et al. (2013) Genome‐wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk. PLoS Genetics 9(3): e1003212.

Daniel M, Peek GW and Tollefsbol TO (2012) Regulation of the human catalytic subunit of telomerase (hTERT). Gene 498(2): 135–146.

Feng L, Huang J and Chen J (2009) MERIT40 facilitates BRCA1 localization and DNA damage repair. Genes & Development 23(6): 719–728.

Fong PC, Boss DS, Yap TA et al. (2009) Inhibition of poly(ADP‐ribose) polymerase in tumors from BRCA mutation carriers. New England Journal of Medicine 361(2): 123–134.

Fostira F, Tsitlaidou M, Papadimitriou C et al. (2012) Prevalence of BRCA1 mutations among 403 women with triple‐negative breast cancer: implications for genetic screening selection criteria: a Hellenic Cooperative Oncology Group Study. Breast Cancer Research and Treatment 134(1): 353–362.

Foulkes WD, Smith IE and Reis‐Filho JS (2010) Triple‐negative breast cancer. New England Journal of Medicine 363(20): 1938–1948.

Garcia‐Closas M, Couch FJ, Lindstrom S et al. (2013) Genome‐wide association studies identify four ER negative‐specific breast cancer risk loci. Nature Genetics 45(4): 392–398, 398e1–398e2.

Gonzalez‐Angulo AM, Timms KM, Liu S et al. (2011) Incidence and outcome of BRCA mutations in unselected patients with triple receptor‐negative breast cancer. Clinical Cancer Research 17(5): 1082–1089.

Greenup R, Buchanan A, Lorizio W et al. (2013) Prevalence of BRCA mutations among women with triple‐negative breast cancer (TNBC) in a genetic counseling cohort. Annals of Surgical Oncology 20(10): 3254–3258.

Haiman CA, Chen GK, Vachon CM et al. (2011) A common variant at the TERT‐CLPTM1L locus is associated with estrogen receptor‐negative breast cancer. Nature Genetics 43(12): 1210–1214.

Hartman AR, Kaldate RR, Sailer LM et al. (2012) Prevalence of BRCA mutations in an unselected population of triple‐negative breast cancer. Cancer 118(11): 2787–2795.

Hicks C, Kumar R, Pannuti A et al. (2013) An integrative genomics approach for associating GWAS information with triple‐negative breast cancer. Journal of Cancer Informatics 12: 1–20.

Hu X, Stern HM, Ge L et al. (2009) Genetic alterations and oncogenic pathways associated with breast cancer subtypes. Molecular Cancer Research 7(4): 511–522.

Isakoff SJ (2010) Triple‐negative breast cancer: role of specific chemotherapy agents. Cancer Journal 16(1): 53–61.

Jaspers JE, Rottenberg S and Jonkers J (2009) Therapeutic options for triple‐negative breast cancers with defective homologous recombination. Biochimica et Biophysica Acta 1796(2): 266–280.

Kreike B, van Kouwenhove M, Horlings H et al. (2007) Gene expression profiling and histopathological characterization of triple‐negative/basal‐like breast carcinomas. Breast Cancer Research 9(5): R65.

Kuusisto KM, Bebel A, Vihinen M, Schleutker J and Sallinen SL (2011) Screening for BRCA1, BRCA2, CHEK2, PALB2, BRIP1, RAD50, and CDH1 mutations in high‐risk Finnish BRCA1/2‐founder mutation‐negative breast and/or ovarian cancer individuals. Breast Cancer Research 13(1): R20.

Lakhani SR, Van De Vijver MJ, Jacquemier J et al. (2002) The pathology of familial breast cancer: predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER‐2, and p53 in patients with mutations in BRCA1 and BRCA2. Journal of Clinical Oncology 20(9): 2310–2318.

Lee AJ, Cunningham AP, Kuchenbaecker KB et al. (2014) BOADICEA breast cancer risk prediction model: updates to cancer incidences, tumour pathology and web interface. British Journal of Cancer 110(2): 535–545.

Liedtke C, Mazouni C, Hess KR et al. (2008) Response to neoadjuvant therapy and long‐term survival in patients with triple‐negative breast cancer. Journal of Clinical Oncology 26(8): 1275–1281.

Lips EH, Mulder L, Oonk A et al. (2013) Triple‐negative breast cancer: BRCAness and concordance of clinical features with BRCA1‐mutation carriers. British Journal of Cancer 108(10): 2172–2177.

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 Epidemiology, Biomarkers & Prevention 21(1): 134–147.

Meyer P, Landgraf K, Hogel B, Eiermann W and Ataseven B (2012) BRCA2 mutations and triple‐negative breast cancer. PLoS One 7(5): e38361.

Nathanson KL, Wooster R and Weber BL (2001) Breast cancer genetics: what we know and what we need. Nature Medicine 7(5): 552–556.

National Comprehensive Cancer Network (2013) NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®). Genetic/Familial high‐risk assessment: breast and ovarian. Version 3.2013. Accessed 24 September 2013.

O'Shaughnessy J, Osborne C, Pippen JE et al. (2011) Iniparib plus chemotherapy in metastatic triple‐negative breast cancer. New England Journal of Medicine 364(3): 205–214.

Pern F, Bogdanova N, Schurmann P et al. (2012) Mutation analysis of BRCA1, BRCA2, PALB2 and BRD7 in a hospital‐based series of German patients with triple‐negative breast cancer. PLoS One 7(10): e47993.

Prat A, Parker JS, Karginova O et al. (2010) Phenotypic and molecular characterization of the claudin‐low intrinsic subtype of breast cancer. Breast Cancer Research 12(5): R68.

Purrington KS, Slager S, Eccles D et al. (2014) Genome‐wide association study identifies 25 known breast cancer susceptibility loci as risk factors for triple negative breast cancer. Carcinogenesis. doi: 10.1093/carcin/bgt404.

Robertson L, Hanson H, Seal S et al. (2012) BRCA1 testing should be offered to individuals with triple‐negative breast cancer diagnosed below 50 years. British Journal of Cancer 106(6): 1234–1238.

Rummel S, Varner E, Shriver CD and Ellsworth RE (2013) Evaluation of BRCA1 mutations in an unselected patient population with triple‐negative breast cancer. Breast Cancer Research and Treatment 137(1): 119–125.

Shah SP, Roth A, Goya R et al. (2012) The clonal and mutational evolution spectrum of primary triple‐negative breast cancers. Nature 486(7403): 395–399.

Silver DP, Richardson AL, Eklund AC et al. (2010) Efficacy of neoadjuvant Cisplatin in triple‐negative breast cancer. Journal of Clinical Oncology 28(7): 1145–1153.

Sørlie T, Tibshirani R, Parker J et al. (2003) Repeated observation of breast tumor subtypes in independent gene expression data sets. Proceedings of the National Academy of Sciences of the USA 100(14): 8418–8423.

Stevens KN, Fredericksen Z, Vachon CM et al. (2012) 19p13.1 is a triple‐negative‐specific breast cancer susceptibility locus. Cancer Research 72(7): 1795–1803.

Stevens KN, Vachon CM and Couch FJ (2013) Genetic susceptibility to triple‐negative breast cancer. Cancer Research 73(7): 2025–2030.

Stevens KN, Vachon CM, Lee AM et al. (2011) Common breast cancer susceptibility loci are associated with triple‐negative breast cancer. Cancer Research 71(19): 6240–6249.

The Cancer Genome Atlas Network (2012) Comprehensive molecular portraits of human breast tumours. Nature 490(7418): 61–70.

Tilch E, Seidens T, Cocciardi S et al. (2014) Mutations in EGFR, BRAF and RAS are rare in triple‐negative and basal‐like breast cancers from Caucasian women. Breast Cancer Research and Treatment 143(2): 385–392.

Tun N, Villani G, Ong K et al. (2014) Risk of having BRCA1 mutation in high‐risk women with triple‐negative breast cancer: a meta‐analysis. Clinical Genetics 85(1): 43–48.

Turner NC, Reis‐Filho JS, Russell AM et al. (2007) BRCA1 dysfunction in sporadic basal‐like breast cancer. Oncogene 26(14): 2126–2132.

Wong‐Brown MW, Avery‐Kiejda KA, Bowden NA and Scott RJ (2014) Low prevalence of germline PALB2 mutations in Australian triple‐negative breast cancer. International Journal of Cancer 134(2): 301–305.

Xiong S, Pant V, Suh YA et al. (2010) Spontaneous tumorigenesis in mice overexpressing the p53‐negative regulator Mdm4. Cancer Research 70(18): 7148–7154.

Young SR, Pilarski RT, Donenberg T et al. (2009) The prevalence of BRCA1 mutations among young women with triple‐negative breast cancer. BMC Cancer 9: 86.

Further Reading

Bauer KR, Brown M, Cress RD et al. (2007) Descriptive analysis of estrogen receptor (ER)‐negative, progesterone receptor (PR)‐negative, and HER2‐negative invasive breast cancer, the so‐called triple‐negative phenotype: a population‐based study from the California cancer Registry. Cancer 109(9): 1721–1728.

Carey LA, Perou CM, Livasy CA et al. (2006) Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. Journal of the American Medical Association 295(21): 2492–2502.

Dent R, Trudeau M, Pritchard KI et al. (2007) Triple‐negative breast cancer: clinical features and patterns of recurrence. Clinical Cancer Research 13(15 Pt 1): 4429–4434.

Kriege M, Jager A, Hooning MJ et al. (2012) The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer 118(4): 899–907.

Perou CM, Sørlie T, Eisen MB et al. (2000) Molecular portraits of human breast tumours. Nature 406(6797): 747–752.

Rakha EA, El‐Sayed ME, Green AR et al. (2007) Prognostic markers in triple‐negative breast cancer. Cancer 109(1): 25–32.

Weigelt B, Baehner FL and Reis‐Filho JS (2010) The contribution of gene expression profiling to breast cancer classification, prognostication and prediction: a retrospective of the last decade. Journal of Pathology 220(2): 263–280.

Related Sub-Topics:

Cancer Genetics | Molecular Genetics of Common and Complex Disease | Gene Expression Profiling of Genetic Disease | Cell Biology of Cancer
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Article Title: Genetic Susceptibility to Triple‐Negative Breast Cancers
 
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Wong‐Brown, Michelle W, and Scott, Rodney J(May 2014) Genetic Susceptibility to Triple‐Negative Breast Cancers. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025352]