Abstract:

The present study is a review of literature that covers an aspect of role of BRCA1 gene mutation in breast cancer metastasis, risk of recurrence influenced by stage at initial presentation, the underlying biology of the tumor, time of relapse after diagnosis of the primary tumor, reasons for metastasis, various biological markers discovered up till date, discussion of several mathematical models, with a focus on how they have been used to predict the initiation time of metastatic growth, and standard choice of treatment best suited for triple negative breast cancer metastasis.

Breast cancer starts as a local disease, but it could metastasize to the lymph nodes and distant organs. As by definition, Metastatic breast cancer, also known as Advanced or Stage IV breast cancer, is the stage in breast cancer progression in which malignant cells from the primary tumor successfully create new tumors in distant organs.  According to the Research studies, women who have BRCA1 mutations are at higher risk for triple negative breast cancer. The prognosis of women with triple negative breast cancers (ER-negative, PR-negative and HER2-neu –negative) is poor as compared to women with other subtypes of breast cancer. TNBC relapses more frequently than hormone receptor-positive subtypes and is often associated with poor outcomes.

Patients and oncologists always have a dilemma on how to cope with this aggressive disease. For patients, the diagnosis of breast cancer is fearsome; so when they know additionally that they suffer from TNBC—a subtype with poor outcomes—this situation is often more stressful. TNBC patients have a unique pattern of relapse, which occurs mostly in the first 3 years following diagnosis. Although metastatic breast cancer is not curable, meaningful improvements in survival have been seen, coincident with the introduction of newer systemic therapies.

Keywords: TNBC (Triple Negative Breast Cancer), Metastasis, tumor, ER-negative, PR-negative, HER2-neu negative, BRCA1 mutations, Overall Survival, Lungs, Mathematical Models, Recurrence, Chemokines, Chemotherapy.

References:

[1]. Amorotti, G.F., Chiodoni, C., & Shen, F. (2014). Suppression of Invasion and Metastasis of Triple-Negative Breast Cancer Lines by Pharmacological or Genetic Inhibition of Slug Activity. Neoplasia, 16(12), 1047–1058. doi: 10.1016/j.neo.2014.10.006.

[2]. Anders, C.K., & Carey, L.A. (2009). Biology, Metastatic Patterns and treatment of patients with Triple-Negative Breast Cancer. Clin Breast Cancer, 9(2): S73–S81. doi:  10.3816/CBC.2009.s.008. (PMCID: PMC2919761).

[3]. Anderson, A., Choy, C., & Neman, J., et al. (2013). Metastatic breast cancer to the brain: A clinical primer for Translational Investigation. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; Retrieved from: http://www.ncbi.nlm.nih.gov/books/NBK154381/ .

[4]. Andy J. Minn, A.J., Gupta, G.P., & Siegel, P.M. et al. (2005). Genes that mediate breast cancer metastasis to lung. Nature, 436, 518-524. doi: 10.1038/nature03799.

[5]. Boyle, P. (2012). Triple-negative breast cancer: epidemiological considerations and recommendations. Annals of Oncology, 23 (6): vi7–vi12. doi:10.1093/annonc/mds187.

[6]. Breast cancer. org. Metastatic or Distant Recurrence Symptoms. Retrieved from: http://www.breastcancer.org/symptoms/types/recur_metast/where_recur/metastic

[7]. Chuang, H.Y., Lee, E., & Liu, Y.T. (2007). Network-based classification of breast cancer metastasis. Molecular Systems Biology, 3: 140. doi: 10.1038/msb4100180.

[8]. Clare, S.E., Nakhlis, F., Carl, & Panetta, J.C. (2000). Molecular biology of breast metastasis: The use of mathematical models to determine relapse and to predict response to chemotherapy in breast cancer. Breast Cancer Res, 2(6): 430–435. doi:  10.1186/bcr90.

[9]. Deng, C.X. (2006). BRCA1: cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Research, 34 (5): 1416-1426.doi: 10.1093/nar/gkl010.

[10]. Dent, R., Hanna, W.M., Trudeau, M. (2009).Pattern of metastatic spread in triple negative breast cancer. Breast Cancer Research and Treatment, 115(2), 423-428.

[11]. Dent, R., Trudeau, M., & Pritchard, K.I., et al. (2007). Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res, 13, 4429. doi: 10.1158/1078-0432.CCR-06-3045.

[12]. Dolle, J.M., et al. (2009). Risk factors for triple negative breast cancer in women under the age of 45 years.  Cancer Epidemiology Biomarkers & Prevention. American Association for Cancer Research, 18(4), 1157-66. (PMID: 19336554).

[13]. Fantozzi, A., & Christofori, G. (2006). Mouse models of breast cancer metastasis. Breast Cancer Research, 8, 212. doi: 10.1186/bcr1530.

[14]. Ford, D., Easton, D.F., & Stratton, M., et al. (1998). Genetic heterogeneity and Penetrance Analysis of the BRCA1 and BRCA2 genes in Breast Cancer families. The American Society of Human Genetics, 62(3), 676–689. doi: 10.1086/301749.

[15]. Gluz, O., et al. (2009). Triple negative breast cancer--current status and future directions. (2009). Annals of Oncology, 20(12), 1913-27. (PMID: 19901010).

[16]. Gupta, G.P., & Massagué, J. (2006). Cancer Metastasis: Building a Framework. Cell, 127(4), 679–695. doi:10.1016/j.cell.2006.11.001.

[17]. Gupta, G.P., Nguyen, D.X., & Chiang, A.C. (2007). Mediators of vascular remodeling co-opted for sequential steps in lung metastasis. Nature, 446, 765-770. doi: 10.1038/nature05760.

[18]. Hedenfalk, I., Duggan, D., & Chen, Y., et al. (2001). Gene-expression profiles in hereditary breast cancer. N Engl J Med, 344, 539-548. doi: 10.1056/NEJM200102223440801.

[19]. Inman, S. (2014). Eribulin Improves Survival in Metastatic Triple-Negative Breast Cancer. Retrieved from: http://www.onclive.com/web-exclusives/Eribulin-Improves-Survival-in-HER2-Negative-Metastatic-Breast-Cancer.

[20]. Isakoff, S.J. (2010).Triple-negative breast cancer: role of specific chemotherapy agents.  Cancer Journal, 16(1), 53-61 (PMID: 20164691).

[21]. Ismail-Khan, R., & Bui, M.M. (2010). A review of triple-negative breast cancer. Cancer Control, 17(3), 173-176.

[22]. Karsten, U., & Goletz, S. (2013). What makes cancer stem cell markers different?. Springer Plus, 2, 301. doi: 10.1186/2193-1801-2-301.

[23]. Kassam, F., Enright, K., & Dent, R., et al. (2009). Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer, 9(1), 29-33. doi: 10.3816/CBC.2009.n.005.

[24]. Kennecke, H., Yerushalmi, R., & Woods, R., et al. (2010). Metastatic Behavior of Breast Cancer Subtypes. American Society of Clinical Oncology, 28(20), 3271-3277. doi: 10.1200/JCO.2009.25.9820.

[25]. Korsching, E., Jeffrey, S.S., & Meinerz, W., et al. Basal carcinoma of the breast revisited: an old entity with new interpretations. Journal of Clinical Pathology, 61(5), 553-60. (PMID: 18326009).

[26]. Maksimenko, J., Irmejs, A., & Millasevica, M.N., et al. (2014). Prognostic role of BRCA1 mutation in patients with triple-negative breast cancer. Oncol Lett, 7(1), 278–284. doi: 10.3892/ol.2013.1684.

[27]. Marcus, J.N., Watson, P., & Page, D.L., et al. (1996). Hereditary breast cancer: Pathobiology, Prognosis and BRCA1 & BRCA2 Gene linkage. Cancer, 15; 77(4), 697-709.

[28]. National Cancer Institute. A story of discovery: HER2’s Genetic link to Breast Cancer Spurs Development of New treatments. Retrieved from: http://www.cancer.gov/research/progress/discovery/HER2#.

[29]. Nguyen, D.X., & Massagué, J. (2007). Genetic determinants of cancer metastasis. Nature Reviews Genetics, 8, 341-352. doi: 10.1038/nrg2101.

[30]. Peshkin, B.N., Alabek, M.L., & Isaacs, C. (2010). BRCA1/2 Mutations and Triple Negative Breast Cancers. Breast Dis, 32. doi:  10.3233/BD-2010-0306. (PMCID: PMC3870050).

[31]. Pestalozzi, B.C. (2009). Brain metastasis and subtypes of breast cancer. Annals of Oncology, 20 (5), 803-805. doi: 10.1093/annonc/mdp246.

[32]. Phuah, S.Y., Looi, L.M., & Hassan, N., et al. (2012).Triple-Negative Breast Cancer and PTEN (Phosphate and Tensin Homologue) loss are predictors of BRCA1 Germline Mutations in women with Early-onset and familial Breast Cancer, but not in women with isolated late-onset breast cancer. Breast Cancer Research, 14, R142. doi: 10.1186/bcr3347.

[33]. Pogoda, K., Niwińska, A., & Murawska, M., et al. (2013). Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Medical Oncology, 30, 388. doi: 10.1007/s12032-012-0388-4.

[34]. Rakha, E.A., Reis-Filho, J.S., & Ellis, I.O. (2008). Basal-like breast cancer: a critical review. Journal of Clinical Oncology, 26(15), 2568-81 (PMID: 18487574).

[35]. Rhee, J., Han, S.W., & Oh, D.Y., et al. (2008). The clinicopathologic characteristics and prognostic significance of triple negativity in node-negative breast cancer. BMC Cancer, 8, 307. doi: 10.1186/1471-2407-8-307 (PMID: 18947390).

[36]. Schott, F.A., Hayes, D.F., & Vora, S.R. (2015). Systemic treatment of metastatic breast cancer in women: Chemotherapy. Retrieved from: http://www.uptodate.com/contents/systemic-treatment-of-metastatic-breast-cancer-in-women-chemotherapy 

[37]. Scully, O.J., Bay, B.H., & Yip, G., et al. (2012). Breast cancer metastasis. Cancer Genomics and Proteomics, 9(5), 311-320.

[38]. Seal, M.D., & Chia, S.K. (2010). What is the difference between triple negative and basal breast cancers?.  Cancer Journal: The Journal of Principles & Practice of Oncology, 16(1), 12-6. (PMID: 20164685).

[39]. Sirohi, B., Arnedos, M., & Popat. S., et al. (2008).Platinum-based chemotherapy in triple-negative breast cancer. Annals of Oncology, 19(11), 1847-52. (PMID: 18567607).

[40]. Smid, M., Wang, Y., & Zhang, Yi., et al. (2008). Subtypes of Breast Cancer Show Preferential Site of Relapse. Cancer Research, 68, 3108; doi: 10.1158/0008-5472.

[41]. Talmadge, J.E., & Fidler, I.J. (2010). AACR Centennial Series: The Biology of Cancer Metastasis: Historical Perspective. Cancer Res, 70, 5649. doi: 10.1158/0008-5472.CAN-10-1040.

[42]. Tseng, L.M., Hsu, N.C., & Chen, S.C., et al. (2013). Distant metastasis in triple-negative breast cancer. Neoplasma, 60(3), 290-4. doi: 10.4149/neo_2013_038. (PMID: 23373998).

[43]. Weigel, B., Peterse, J.L., & Veer, L.J.V. (2005). Breast cancer metastasis: markers and models. Nature Reviews Cancer, 5, 591-602. doi: 10.1038/nrc1670.

[44]. Weill Cornell Medical College. (2013, January 14). Aggressive breast cancer's metastatic path revealed. ScienceDaily. Retrieved October 29, 2015 from www.sciencedaily.com/releases/2013/01/130114124930.htm

[45]. Zhang, X.H.F., Giuliano, M., & Trivedi, M.V., et al. (2013). Metastasis Dormancy in Estrogen Receptors- Positive Breast Cancer. Clinical Cancer Research, 19, 6389. doi: 10.1158/1078-043.

[46]. Zhou, W., et al. (2010). Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study. BMC Cancer, 10, 653 (PMID: 21118480).