Triple-Negative Breast Cancer: Frequency, Molecular Subtypes, and Therapeutic Options

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1 Eur J Surg Sci 2011;2(3):57-61 REVIEW Triple-Negative Breast Cancer: Frequency, Molecular Subtypes, and Therapeutic Options Bahri ÇAKABAY 1 1 Department of Surgical Oncology, Faculty of Medicine, University of Ankara, Ankara, Turkey ABSTRACT Triple-negative breast cancer is a subtype with poor outcome, no targeted therapy and high recurrence rates after adjuvant therapy. This review discusses the frequency, clinical expression, molecular subtypes, and therapeutic options of triple-negative breast cancer. Key words: Breast cancer, Triple-negative Received: November 16, 2011 Accepted: November 21, 2011 ÖZET Triple-Negative Meme Kanseri: Sıklık Moleküler Alt Tipler ve Tedavi Seçenekleri Triple-negative meme kanseri, kötü sonuçları olan, hedefe yönelik tedavisi olmayan ve adjuvant tedavi sonrası nüks oranı yüksek bir alt tiptir. Bu derlemede triple-negative meme kanserinin sıklığı, klinik ekspresyonu, moleküler alt tipleri ve tedavi seçenekleri tartışılmaktadır. Anahtar kelimeler: Meme kanseri, Triple-negative Geliş Tarihi: 16 Kasım 2011 Kabul Ediliş Tarihi: 21 Kasım 2011 INTRODUCTION Breast cancer is the most common malignancy in women. An estimated 1 million cases of breast cancer are diagnosed annually worldwide and patients die from the disease every year [1]. Multiple oncogenes, tumor suppressor genes, and sex steroid hormones and their receptors are involved in the genesis and development of breast cancer. Breast cancer is a heterogeneous malignancy that has many subtypes with different biological behaviors, clinicopathological features, and molecular characteristics. The treatment responses and prognosis of different subtypes of breast cancer also differ markedly. Implementation of mammography screening, improved adjuvant systemic treatment, and decreased hormone replacement therapy use have decreased both the incidence and mortality of breast cancer in developed countries over the past five years; worldwide, however, the incidence of breast cancer is increasing [2,3]. 57

2 Triple-Negative Breast Cancer: Frequency, Molecular Subtypes, and Therapeutic Options Triple-negative breast cancer (TNBC) is defined by the lack of protein expression of the estrogen receptor (ER) and progesterone receptor (PR) and the absence of HER2 protein overexpression. TNBC accounts for approximately 15% of breast cancers [4]. Although recently in the limelight and discussed frequently, TNBC is not a new type of breast cancer. TNBC is important for both researchers and clinicians because it has a poor disease-free and overall survival, no effective specific targeted therapy is readily available for TNBC, and TNBC cases cluster in premenopausal women. ClInIcal expression and molecular subtypes of TNBC Breast carcinomas can be divided into 18 different subtypes based on their histomorphological characteristics [5]. A large majority of breast tumors are designated as invasive ductal carcinoma no special type (NST) [6]. NST is defined as a tumor that does not exhibit sufficient morphological features to be categorized as one of the other subtypes [5-7]. The histological categorization of breast tumors fails to divide tumors into different disease entities with typespecific prognosis and treatment possibilities. The largest NST subtype has an inhomogeneous prognosis [6]. Gene expression profiling has been introduced into the clinical literature during the past decade as research suggests that assessing the expression of multiple genes in a tumor sample may reflect programs turned on by DNA alterations and predict tumor behavior. A new approach to characterizing breast tumors uses their molecular characteristics. The seminal work by Perou et al. and Sorlie et al. suggests a classification of breast cancer subtypes based on gene expression patterns they called molecular portraits of breast cancer [8,9]. Among the categories they defined were the luminal A and B tumor types (typically ER or PR positive), HER2 gene-amplified tumors, and a newly recognized class called basallike due to the expression of basal keratins. Basal tumors typically lack ER, PR, and HER2, and are often referred to as triple negative, although not all basallike tumors are triple negative. Overall, TNBCs share striking similarities with basal-like breast cancers (BBCs), and so a number of studies have considered them as the same. Approximately 20-25% of TNBCs are not basal-like on gene expression arrays [10,11]. Similarly, there are BBCs that are not triple-negative, and these also constitute approximately 20-25% of cases. Therefore, in clinical trials examining basal-like biology and using the triple-negative phenotype to identify patients, the potential for misclassification exists. Triple-negative disease encompasses more than one molecular subtype that shows a different prognosis and implies distinct therapeutic options. For example, non-basal-like TNBC does not behave like basal-like TNBC, as it has a better prognosis despite a reduced response to adjuvant chemotherapy [12-14]. Basal-like TNBC has a specific expression profile that distinguishes it from other breast tumors, including enhanced expression of Ki-67, vimentin, laminin, and p53, but reduced Bcl-2 expression, compared with other subtypes [15,16]. Several studies found that expression of the tumor suppressor PTEN was lost more frequently in basal-like TNBC than in non-basal-like TNBC [17-19]. Other genes that tend to be mutated more frequently in basal-like TNBC, as compared to other breast tumors, are the tumor suppressor retinoblastoma gene (RB1) and the KRAS oncogene, both well known to enhance tumor growth [19]. Besides mutations, other genetic changes differ among distinct subtypes, such as copy number alterations (CNAs). In more than 30% of the basal-like TNBC cases, two specific CNAs are found: gene amplification and chromosomal deletion [16,19]. In searching for the pathways that lead to the development of basal-like TNBC, several studies have found that BRCA1-related breast cancers are associated with the basal-like TNBC subtype, and the basal-like TNBC expression profiles resemble those of BRCA1- related breast cancers [20-22]. This resemblance gave rise to the idea that BRCA1 mutations play a role in the development of basal-like TNBC. Some studies have investigated epigenetic changes, such as DNA methylation, influencing the expression of BRCA1 in basal-like TNBC. However, DNA methylation does not seem to play a supportive role, given that BRCA1 methylation is similarly frequent in basal-like and non-basal-like TNBC [23,24]. Studies have linked basal-like TNBC to epidermal growth factor receptor (EGFR) expression [25]. This receptor, like HER2, is a potent stimulator of cell-growth-activating pathways and stimulates tumor growth when activated [26]. EGFR expression could be one of the causes of the poor disease outcome of basal-like TNBC. Since newly developed therapies target EGFR, an assessment of EGFR expression, as performed commonly for HER2, could have therapeutic relevance [27,28]. 58 Eur J Surg Sci 2011;2(3):57-61

3 Çakabay B. The claudin-low tumor subtype constitutes only approximately 5% of tumors, falls in the triple-negative spectrum, and has a significantly poorer outcome. This subtype is characterized by low expression of luminal markers and high expression of mesenchymal markers and is associated with a bad prognosis; it is also thought to be derived from stem cells [29]. TherapeutIc options: Future directions for TNBC Adjuvant therapeutic options for TNBC can be divided into two groups, cytotoxic agents and targeted therapies. Chemotherapy and antiangiogenic drugs known to be effective in triple-negative disease, as well as advances in chemotherapy, have benefited this patient group in particular. Currently, there is no effective strategy for selecting which patients would benefit the most from these agents. Potential approaches in triple-negative disease include more targeted chemotherapy, growth factor pathway approaches, and BRCA1-driven approaches. Cytotoxic therapies,e.g. combined treatment with anthracyclines or taxanes, achieved good tumour regression rates in the neoadjuvant setting, but also showed considerable recurrence during the first five years after therapy. Patients with triple-negative, basal-like breast cancer (TNBBC) have increased pathologic complete response (pcr) rates compared to non- TNBC patients, especially to taxanes and anthracycline agents [30]. In spite of the better response to chemotherapy, the prognosis of TNBC is still worse than that of other breast cancer subtypes, due to a higher likelihood of relapse in patients with residual disease [11,12,30]. Another group of cytotoxic agents showing good results in TNBBC are the platinum-containing agents, such as cisplatin and carboplatin [31]. Study of Sirohi et al. reported a clinical response rate of 88% in TNBBC after neo-adjuvant treatment with platinum containing cytotoxic agents, compared to 55% clinical complete response rate in other breast tumours [32]. However, the overall five-year survival was still worse for TNBBC compared to tumours of other subtypes. Many antiangiogenic treatments have been introduced or are currently under development, and may hold promise for patients with TNBC. There are much data on bevacizumab in breast cancer. Although specific clinical subsets that benefited were not well characterized in further analyses, it was determined that patients with triple-negative disease benefited as much as, if not more than, the average [33]. This was also demonstrated in some subset analyses of tyrosine kinase inhibitor approaches, including vascular endothelial growth factor receptor inhibition. The basal cluster includes EGFR, which has been of interest in preclinical studies for several years. EGFR is present and expressed on tissue microarrays from basal-like tumors, and TNBC cell lines show EGFR-dependent growth and proliferation. EGFR is considered a sensible target in TNBC. Cetuximab, which is an anti-egfr monoclonal antibody, has been added to chemotherapy for TNBC [34]. Poly (ADP-ribose) polymerase (PARP) inhibition is another therapeutically valuable mechanism in patients with triple negative disease. PARP inhibition involves synthetic lethality, meaning cell death by targeting more than one pathway, when impairment of one pathway alone is not lethal [35]. In a normal cell subject to certain types of DNA damage there are several mechanisms available to repair the damage, including homologous recombination, which is BRCA1-dependent, and base excision repair, highlighted because it is a PARP-dependent function. Conclusıon In developed countries, there has been a remarkable reduction in mortality from breast cancer, but almost all of that benefit has occurred in the ER- and HER-2-subsets. TNBC is a unique subgroup, with a specific molecular profile, aggressive behavior, a relative lack of effective therapies, and a poor prognosis. Targeted therapies, like PARP inhibitors and EGFRtargeting agents, are additional promising therapeutic options. RE FE REN CES 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2009; 59: Glass AG, Lacey JV Jr, Carreon JD, et al. Breast cancer incidence, : combined roles of menopausal hormone therapy, screening mammography, and estrogen receptor status. J Natl Cancer Inst 2007; 99: Gluz O, Liedtke C, Gottschalk N, Pusztai L, Nitz U, Harbeck N. Triple-negative breast cancer-current status and future directions. Ann Oncol 2009; 20: Epub 2009 Nov Kaplan HG, Malmgren JA, Atwood MK. Impact of triple negative phenotype on breast cancer prognosis. Poster Eur J Surg Sci 2011;2(3):

4 Triple-Negative Breast Cancer: Frequency, Molecular Subtypes, and Therapeutic Options presented at: 29 th Annual San Antonio Breast Cancer Symposium; December 14-17, 2006; San Antonio, TX. 5. Tavassoli FA, Devilee P. World Health Organisation Classification of Tumours. Pathology and Genetics of Tumours of the Breast and Female Genital Organs IARC Press, Lyon. 6. Weigelt B, Horlings HM, Kreike B, Hayes MM, Hauptmann M, Wessels LF, et al. Refinement of breast cancer classification by molecular characterization of histological special types. J Pathol. 2008; 216: Page DL. Special types of invasive breast cancer, with clinical implications. Am J Surg Pathol 2003; 27: Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000; 406: Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001; 98: Carey LA, Perou CM, Livasy CA, Dressler LG, Cowan D, Conway K, et al. Race, breast cancer subtypes, and survival in the Carolina Breast Cancer Study. JAMA 2006; 295: Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 2007; 13: Rouzier R, Perou CM, Symmans WF et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 2005; 11: Rody A, Karn T, Solbach C, et al. The erbb2 cluster of the intrinsic gene set predicts tumor response of breast cancer patients receiving neoadjuvant chemotherapy with docetaxel, doxorubicin and cyclophosphamide within the GEPARTRIO trial. Breas 2007; 16: Tischkowitz M, Brunet JS, Begin LR, et al. Use of immunohistochemical markers can refine prognosis in triple negative breast cancer. BMC Cancer 2007; 7: Rodriguez-Pinilla SM, Sarrio D, Honrado E, et al. Vimentin and laminin expression is associated with basal-like phenotype in both sporadic and BRCA1-associated breast carcinomas. J Clin Pathol 2007; 60: Han W, Jung EM, Cho J, et al. DNA copy number alterations and expression of relevant genes in triple-negative breast cancer. Genes Chromosomes Cancer 2008; 47: Perren A, Weng LP, Boag AH, et al. Immunohistochemical evidence of loss of PTEN expression in primary ductal adenocarcinomas of the breast. Am J Pathol 1999; 155: Saal LH, Gruvberger-Saal SK, Persson C, et al. Recurrent gross mutations of the PTEN tumor suppressor gene in breast cancers with deficient DSB repair. Nat Genet 2008; 40: Hu X, Stern HM, Ge L, et al. Genetic alterations and oncogenic pathways associated with breast cancer subtypes. Mol Cancer Res 2009; 7: Foulkes WD, Stefansson IM, Chappuis PO, et al.germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst 2003; 95: Lakhani SR, Reis-Filho JS, Fulford L, et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 2005; 11: Diaz LK, Cryns VL, Symmans WF, Sneige N. Triple negative breast carcinoma and the basal phenotype: from expression profiling to clinical practice. Adv Anat Pathol 2007; 14: Turner NC, Reis-Filho JS, Russell AM, et al. BRCA1 dysfunction in sporadic basal-like breast cancer. Oncogene 2007; 26: Matros E, Wang ZC, Lodeiro G, Miron A, Iglehart JD, Richardson AL. BRCA1 promoter methylation in sporadic breast tumors: relationship to gene expression profiles. Breast Cancer Res Treat 2005; 91: Nielsen TO, Hsu FD, Jensen K, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 2004; 10: Burgess AW. EGFR family: structure physiology signalling and therapeutic targets. Growth Factors 2008; 26: Stratford AL, Habibi G, Astanehe A, et al. Epidermal growth factor receptor (EGFR) is transcriptionally induced by the Y-box binding protein-1 (YB-1) and can be inhibited with Iressa in basal-like breast cancer, providing a potential target for therapy. Breast Cancer Res 2007; 9: R Hoadley KA, Weigman VJ, Fan C, et al. EGFR associated expression profiles vary with breast tumor subtype. BMC Genomics 2007; 8: Prat A, Perou CM. Mammary development meets cancer genomics. Nat Med 2009, 15: Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res 2007; 13: Eur J Surg Sci 2011;2(3):57-61

5 Çakabay B. 31. Tan AR, Swain SM. Therapeutic strategies for triplenegative breast cancer. Cancer J 2008; 14: Sirohi B, Arnedos M, Popat S, Ashley S, Nerurkar A, Walsh G, et al. Platinum-based chemotherapy in triplenegative breast cancer. Ann Oncol 19: Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med 2007; 357: Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer. J Clin Oncol 2008; 26(Suppl 15): Abstract Address for Correspondence Bahri ÇAKABAY, MD Department of Surgical Oncology Faculty of Medicine University of Ankara Ibn-i Sina Hospital Ankara-Turkey surgeonbahri@gmail.com 35. Comen EA, Robson M. Inhibition of poly(adp)-ribose polymerase as a therapeutic strategy for breast cancer. Oncology (Williston Park) 2010; 24: Eur J Surg Sci 2011;2(3):