Understanding Molecular Process and Chemotherapeutics for the Management of Breast Cancer

Abhishek       Kumar; Neeraj       Masand; Vaishali    M.    Patil
Abstract

Breast cancer is the most common and highly heterogeneous neoplastic disease comprised of several subtypes with distinct molecular etiology and clinical behaviours. The mortality observed over the past few decades and the failure in eradicating the disease is due to the lack of specific etiology, molecular mechanisms involved in the initiation and progression of breast cancer. Understanding of the molecular classes of breast cancer may also lead to new biological insights and eventually to better therapies. The promising therapeutic targets and novel anti-cancer approaches emerging from these molecular targets that could be applied clinically in the near future are being highlighted. In addition, this review discusses some of the details of current molecular classification and available chemotherapeutics.
Keywords: Breast cancer, molecular mechanism, breast cancer types, therapeutic targets, carcinoma, chemotherapeutics.
Graphical Abstract

[1] 
Malvia S, Bagadi SA, Dubey US, Saxena S. Epidemiology of breast cancer in Indian women. Asia Pac J Clin Oncol  2017; 13(4): 289-95.
[http://dx.doi.org/10.1111/ajco.12661] [PMID: 28181405] 
[2] 
Turner NC, Reis-Filho JS. Tackling the diversity of triple-negative breast cancer. Clin Cancer Res  2013; 19(23): 6380-8.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0915] [PMID: 24298068] 
[3] 
Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol  2005; 23(29): 7350-60.
[http://dx.doi.org/10.1200/JCO.2005.03.3845] [PMID: 16145060] 
[4] 
Prat A, Parker JS, Karginova O, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res  2010; 12(5): R68.
[http://dx.doi.org/10.1186/bcr2635] [PMID: 20813035] 
[5] 
Mego M, Mani SA, Cristofanilli M. Molecular mechanisms of metastasis in breast cancer--clinical applications. Nat Rev Clin Oncol  2010; 7(12): 693-701.
[http://dx.doi.org/10.1038/nrclinonc.2010.171] [PMID: 20956980] 
[6] 
Neophytou C, Boutsikos P, Papageorgis P. Molecular mechanisms and emerging therapeutic targets of triple-negative breast cancer metastasis. Front Oncol  2018; 8: 31.
[http://dx.doi.org/10.3389/fonc.2018.00031] [PMID: 29520340] 
[7] 
Medeiros B, Allan AL. Molecular mechanisms of breast cancer metastasis to the lung: Clinical and experimental perspectives. Int J Mol Sci  2019; 20(9): 2272.
[http://dx.doi.org/10.3390/ijms20092272] [PMID: 31071959] 
[8] 
Eliyatkın N, Yalçın E, Zengel B, Aktaş S, Vardar E. Molecular classification of breast carcinoma: from traditional, old-fashioned way to a new age, and a new way. J Breast Health  2015; 11(2): 59-66.
[http://dx.doi.org/10.5152/tjbh.2015.1669] [PMID: 28331693] 
[9] 
Sinn HP, Kreipe H. A brief overview of the WHO classification of breast tumors. Breast Care (Basel)  2013; 8(2): 149-54.
[http://dx.doi.org/10.1159/000350774] [PMID: 24415964] 
[10] 
Klintman M, Buus R, Cheang MCU, Sheri A, Smith IE, Dowsett M. Changes in expression of genes representing key biologic processes after neoadjuvant chemotherapy in breast cancer, and prognostic implications in residual disease. Clin Cancer Res  2016; 22(10): 2405-16.
[http://dx.doi.org/10.1158/1078-0432.CCR-15-1488] [PMID: 27179111] 
[11] 
Sørlie 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(19): 10869-74.
[http://dx.doi.org/10.1073/pnas.191367098] [PMID: 11553815] 
[12] 
Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res  2007; 13(8): 2329-34.
[http://dx.doi.org/10.1158/1078-0432.CCR-06-1109] [PMID: 17438091] 
[13] 
Sorlie T, Tibshirani R, Parker J, et al. Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA  2003; 100(14): 8418-23.
[http://dx.doi.org/10.1073/pnas.0932692100] [PMID: 12829800] 
[14] 
Berry DA, Cirrincione C, Henderson IC, et al. Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA  2006; 295(14): 1658-67.
[http://dx.doi.org/10.1001/jama.295.14.1658] [PMID: 16609087] 
[15] 
Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res  2005; 11(16): 5678-85.
[http://dx.doi.org/10.1158/1078-0432.CCR-04-2421] [PMID: 16115903] 
[16] 
Sotiriou C, Neo SY, McShane LM, et al. Breast cancer classification and prognosis based on gene expression profiles from a population-based study. Proc Natl Acad Sci USA  2003; 100(18): 10393-8.
[http://dx.doi.org/10.1073/pnas.1732912100] [PMID: 12917485] 
[17] 
Burstein HJ, Winer EP. HER2 or not HER2: that is the question. J Clin Oncol  2005; 23(16): 3656-9.
[http://dx.doi.org/10.1200/JCO.2005.10.910] [PMID: 15738533] 
[18] 
Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature  2000; 406(6797): 747-52.
[http://dx.doi.org/10.1038/35021093] [PMID: 10963602] 
[19] 
Wuerstlein R, Harbeck N. Neoadjuvant therapy for HER2-positive breast cancer. Rev Recent Clin Trials  2017; 12(2): 81-92.
[http://dx.doi.org/10.2174/1574887112666170202165049] [PMID: 28164759] 
[20] 
Muggerud AA, Hallett M, Johnsen H, et al. Molecular diversity in ductal carcinoma in situ (DCIS) and early invasive breast cancer. Mol Oncol  2010; 4(4): 357-68.
[http://dx.doi.org/10.1016/j.molonc.2010.06.007] [PMID: 20663721] 
[21] 
Carey LA, Rugo HS, Marcom PK, et al. TBCRC 001: randomized phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer. J Clin Oncol  2012; 30(21): 2615-23.
[http://dx.doi.org/10.1200/JCO.2010.34.5579] [PMID: 22665533] 
[22] 
Shah SP, Roth A, Goya R, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature  2012; 486(7403): 395-9.
[http://dx.doi.org/10.1038/nature10933] [PMID: 22495314] 
[23] 
Gucalp A, Tolaney SM, Isakoff SJ, et al. Targeting the androgen receptor (AR) in women with AR+ ER-/PR-metastatic breast cancer (MBC). J Clin Oncol  2012; 30(15): 1006-6.
[http://dx.doi.org/10.1200/jco.2012.30.15_suppl.1006] 
[24] 
Masuda H, Baggerly KA, Wang Y, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res  2013; 19(19): 5533-40.
[http://dx.doi.org/10.1158/1078-0432.CCR-13-0799] [PMID: 23948975] 
[25] 
Mani SA, Guo W, Liao MJ, et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell  2008; 133(4): 704-15.
[http://dx.doi.org/10.1016/j.cell.2008.03.027] [PMID: 18485877] 
[26] 
Hackett AJ, Smith HS, Springer EL, et al. Two syngeneic cell lines from human breast tissue: the aneuploid mammary epithelial (Hs578T) and the diploid myoepithelial (Hs578Bst) cell lines. J Natl Cancer Inst  1977; 58(6): 1795-806.
[http://dx.doi.org/10.1093/jnci/58.6.1795] [PMID: 864756] 
[27] 
Gupta PB, Onder TT, Jiang G, et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell  2009; 138(4): 645-59.
[http://dx.doi.org/10.1016/j.cell.2009.06.034] [PMID: 19682730] 
[28] 
Creighton CJ, Li X, Landis M, et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA  2009; 106(33): 13820-5.
[http://dx.doi.org/10.1073/pnas.0905718106] [PMID: 19666588] 
[29] 
Li X, Lewis MT, Huang J, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst  2008; 100(9): 672-9.
[http://dx.doi.org/10.1093/jnci/djn123] [PMID: 18445819] 
[30] 
Imyanitov EN, Hanson KP. Mechanisms of breast cancer. Drug Discov Today Dis Mech  2004; 1(2): 235-45.
[http://dx.doi.org/10.1016/j.ddmec.2004.09.002] 
[31] 
Ye Y, Qiu TH, Kavanaugh C, Green JE. Molecular mechanisms of breast cancer progression: lessons from mouse mammary cancer models and gene expression profiling. Breast Dis  2004; 19(1): 69-82.
[http://dx.doi.org/10.3233/BD-2004-19109] [PMID: 15687699] 
[32] 
Felty Q, Singh KP, Roy D. Estrogen-induced G1/S transition of G0-arrested estrogen-dependent breast cancer cells is regulated by mitochondrial oxidant signaling. Oncogene  2005; 24(31): 4883-93.
[http://dx.doi.org/10.1038/sj.onc.1208667] [PMID: 15897899] 
[33] 
Oberley TD, Allen RG, Schultz JL, Lauchner LJ. Antioxidant enzymes and steroid-induced proliferation of kidney tubular cells. Free Radic Biol Med  1991; 10(1): 79-83.
[http://dx.doi.org/10.1016/0891-5849(91)90024-W] [PMID: 2050299] 
[34] 
Patel MM, Bhat HK. Differential oxidant potential of carcinogenic and weakly carcinogenic estrogens: Involvement of metabolic activation and cytochrome P450. J Biochem Mol Toxicol  2004; 18(1): 37-42.
[http://dx.doi.org/10.1002/jbt.20005] [PMID: 14994278] 
[35] 
Bhat HK, Calaf G, Hei TK, Loya T, Vadgama JV. Critical role of oxidative stress in estrogen-induced carcinogenesis. Proc Natl Acad Sci USA  2003; 100(7): 3913-8.
[http://dx.doi.org/10.1073/pnas.0437929100] [PMID: 12655060] 
[36] 
Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact  2006; 160(1): 1-40.
[http://dx.doi.org/10.1016/j.cbi.2005.12.009] [PMID: 16430879] 
[37] 
Levin ER. Bidirectional signaling between the estrogen receptor and the epidermal growth factor receptor. Mol Endocrinol  2003; 17(3): 309-17.
[http://dx.doi.org/10.1210/me.2002-0368] [PMID: 12554774] 
[38] 
Kirkegaard T, Witton CJ, McGlynn LM, et al. AKT activation predicts outcome in breast cancer patients treated with tamoxifen. J Pathol  2005; 207: 139-46.
[http://dx.doi.org/10.1002/path.1829] 
[39] 
Knowlden JM, Hutcheson IR, Jones HE, et al. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology  2003; 144(3): 1032-44.
[http://dx.doi.org/10.1210/en.2002-220620] [PMID: 12586780] 
[40] 
Nabha SM, Glaros S, Hong M, et al. Upregulation of PKC-δ contributes to antiestrogen resistance in mammary tumor cells. Oncogene  2005; 24(19): 3166-76.
[http://dx.doi.org/10.1038/sj.onc.1208502] [PMID: 15735693] 
[41] 
Gee JM, Robertson JF, Gutteridge E, et al. Epidermal growth factor receptor/HER2/insulin-like growth factor receptor signalling and oestrogen receptor activity in clinical breast cancer. Endocr Relat Cancer  2005; 12(Suppl. 1): S99-S111.
[http://dx.doi.org/10.1677/erc.1.01005] [PMID: 16113104] 
[42] 
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(12): 1913-27.
[http://dx.doi.org/10.1093/annonc/mdp492] [PMID: 19901010] 
[43] 
Karihtala P, Soini Y. Reactive oxygen species and antioxidant mechanisms in human tissues and their relation to malignancies. APMIS  2007; 115(2): 81-103.
[http://dx.doi.org/10.1111/j.1600-0463.2007.apm_514.x] [PMID: 17295675] 
[44] 
Karihtala P, Puistola U. Hypoxia and oxidative stress in the pathogenesis of gynecological cancers and in therapeutical options. Curr Cancer Ther Rev  2011; 7(1): 37-55.
[http://dx.doi.org/10.2174/157339411794474128] 
[45] 
Rabilloud T, Heller M, Gasnier F, et al. Proteomics analysis of cellular response to oxidative stress. Evidence for in vivo overoxidation of peroxiredoxins at their active site. J Biol Chem  2002; 277(22): 19396-401.
[http://dx.doi.org/10.1074/jbc.M106585200] [PMID: 11904290] 
[46] 
Lau A, Villeneuve NF, Sun Z, Wong PK, Zhang DD. Dual roles of Nrf2 in cancer. Pharmacol Res  2008; 58(5-6): 262-70.
[http://dx.doi.org/10.1016/j.phrs.2008.09.003] [PMID: 18838122] 
[47] 
Hunter KW, Crawford NP, Alsarraj J. Mechanisms of metastasis. Breast Cancer Res  2008; 10(1)(Suppl. 1): S2.
[http://dx.doi.org/10.1186/bcr1988] [PMID: 19091006] 
[48] 
Wick W, Petersen I, Schmutzler RK, et al. Evidence for a novel tumor suppressor gene on chromosome 15 associated with progression to a metastatic stage in breast cancer. Oncogene  1996; 12(5): 973-8.
[PMID: 8649814] 
[49] 
Sekita N, Suzuki H, Ichikawa T, et al. Epigenetic regulation of the KAI1 metastasis suppressor gene in human prostate cancer cell lines. Jpn J Cancer Res  2001; 92(9): 947-51.
[http://dx.doi.org/10.1111/j.1349-7006.2001.tb01185.x] [PMID: 11572762] 
[50] 
Ried T, Heselmeyer-Haddad K, Blegen H, Schröck E, Auer G. Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: a phenotype/genotype correlation. Genes Chromosomes Cancer  1999; 25(3): 195-204.
[http://dx.doi.org/10.1002/(SICI)1098-2264(199907)25:3<195:AID-GCC1>3.0.CO;2-8] [PMID: 10379865] 
[51] 
Fidler IJ, Gersten DM, Hart IR. The biology of cancer invasion and metastasis. Adv Cancer Res  1978; 28: 149-250.
[http://dx.doi.org/10.1016/S0065-230X(08)60648-X] [PMID: 360795] 
[52] 
Mitchell K, Svenson KB, Longmate WM, et al. Suppression of integrin α3β1 in breast cancer cells reduces cyclooxygenase-2 gene expression and inhibits tumorigenesis, invasion, and cross-talk to endothelial cells. Cancer Res  2010; 70(15): 6359-67.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-4283] [PMID: 20631072] 
[53] 
Comijn J, Berx G, Vermassen P, et al. The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Mol Cell  2001; 7(6): 1267-78.
[http://dx.doi.org/10.1016/S1097-2765(01)00260-X] [PMID: 11430829] 
[54] 
Eger A, Aigner K, Sonderegger S, et al. DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene  2005; 24(14): 2375-85.
[http://dx.doi.org/10.1038/sj.onc.1208429 PMID: 15674322] 
[55] 
Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res  2002; 62(6): 1613-8.
[PMID: 11912130] 
[56] 
Yang J, Mani SA, Donaher JL, et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell  2004; 117(7): 927-39.
[http://dx.doi.org/10.1016/j.cell.2004.06.006] [PMID: 15210113] 
[57] 
Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3′ kinase/AKT pathways. Oncogene  2005; 24(50): 7443-54.
[http://dx.doi.org/10.1038/sj.onc.1209091 PMID: 16288291] 
[58] 
Blick T, Widodo E, Hugo H, et al. Epithelial mesenchymal transition traits in human breast cancer cell lines. Clin Exp Metastasis  2008; 25(6): 629-42.
[http://dx.doi.org/10.1007/s10585-008-9170-6] [PMID: 18461285] 
[59] 
McSherry EA, Donatello S, Hopkins AM, McDonnell S. Molecular basis of invasion in breast cancer. Cell Mol Life Sci  2007; 64(24): 3201-18.
[http://dx.doi.org/10.1007/s00018-007-7388-0] [PMID: 17957337] 
[60] 
Scully OJ, Bay BH, Yip G, Yu Y. Breast cancer metastasis. Cancer Genomics Proteomics  2012; 9(5): 311-20.
[PMID: 22990110] 
[61] 
Zheng T, Wang A, Hu D, Wang Y. Molecular mechanisms of breast cancer metastasis by gene expression profile analysis. Mol Med Rep  2017; 16(4): 4671-7.
[http://dx.doi.org/10.3892/mmr.2017.7157] [PMID: 28791367] 
[62] 
Patel JD, Krilov L, Adams S, et al. Clinical cancer advances 2013: Annual report on progress against cancer from the American society of clinical oncology. J Clin Oncol  2014; 32(2): 129-60.
[http://dx.doi.org/10.1200/JCO.2013.53.7076] [PMID: 24327669] 
[63] 
Coiffier B, Lepage E, Briere J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med  2002; 346(4): 235-42.
[http://dx.doi.org/10.1056/NEJMoa011795] [PMID: 11807147] 
[64] 
Richardson PG, Sonneveld P, Schuster MW, et al. Assessment of Proteasome Inhibition for Extending Remissions (APEX) investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med  2005; 352(24): 2487-98.
[http://dx.doi.org/10.1056/NEJMoa043445] [PMID: 15958804] 
[65] 
Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol  2009; 27(22): 3584-90.
[http://dx.doi.org/10.1200/JCO.2008.20.1293] [PMID: 19487381] 
[66] 
Savage P, Mahmoud S. Development and economic trends in cancer therapeutic drugs: a 5-year update 2010-2014. Br J Cancer  2015; 112(6): 1037-41.
[http://dx.doi.org/10.1038/bjc.2015.56] [PMID: 25668005] 
[67] 
Cancer gov. Drugs approved for breast cancer.Available from:. https://www.cancer.gov/about-cancer/treatment/drugs/breast[August 18, 2019];
[68] 
Waks AG, Winer EP. Breast cancer treatment. JAMA  2019; 321(3): 316.
[http://dx.doi.org/10.1001/jama.2018.20751] [PMID: 30667503] 
[69] 
Davies C, Godwin J, Gray R, et al. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet  2011; 378(9793): 771-84.
[http://dx.doi.org/10.1016/S0140-6736(11)60993-8] [PMID: 21802721] 
[70] 
Davies C, Pan H, Godwin J, et al. Adjuvant tamoxifen: Longer Against Shorter (ATLAS) collaborative group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet  2013; 381(9869): 805-16.
[http://dx.doi.org/10.1016/S0140-6736(12)61963-1] [PMID: 23219286] 
[71] 
Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med  2016; 375(3): 209-19.
[http://dx.doi.org/10.1056/NEJMoa1604700] [PMID: 27264120] 
[72] 
Rugo HS, Barve A, Watter CF, et al. Heritage: a phase III safety and efficacy trial of the proposed trastuzumab biosimilar MYL-1401O versus Herceptin. J Clin Oncol  2016; 34(Suppl. 1): S41. [ASCO abstract LBA503
[http://dx.doi.org/10.1200/JCO.2016.34.18_suppl.LBA503] 
[73] 
Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther  2013; 30(10): 870-84.
[http://dx.doi.org/10.1007/s12325-013-0060-1] [PMID: 24158787] 
[74] 
Hurvitz SA, Andre F, Jiang Z, et al. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol  2015; 16(7): 816-29.
[http://dx.doi.org/10.1016/S1470-2045(15)00051-0] [PMID: 26092818] 
[75] 
Piccart M, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol  2014; 25(12): 2357-62.
[http://dx.doi.org/10.1093/annonc/mdu456] [PMID: 25231953] 
[76] 
André F, O’Regan R, Ozguroglu M, et al. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol  2014; 15(6): 580-91.
[http://dx.doi.org/10.1016/S1470-2045(14)70138-X] [PMID: 24742739] 
[77] 
Baselga J, Im SA, Iwata H, et al.  PIK3CA status in circulating tumour DNA predicts efficacy of buparlisib  plus fulvestrant in postmenopausal women with endocrine resistant HER+/HER2- advanced breast cancer: First results from the randomized, phase III BELLE-2 trial. San Antonio Breast Cancer Symposium. Abstract S6-01. Presented December 11,  
[78] 
Knudsen E, Cox D, Franco J, et al. Targeting CDK4/6 in HER2 positive breast cancer: therapeutic effect, markers, and combination strategies. Ann Oncol  2014; 25(Suppl. 1): i21-2.
[http://dx.doi.org/10.1093/annonc/mdu069.1] 
[79] 
Turner NC, Ro J, André F, et al. PALOMA3 study group. palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med  2015; 373(3): 209-19.
[http://dx.doi.org/10.1056/NEJMoa1505270] [PMID: 26030518] 
[80] 
Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol  2015; 16(1): 25-35.
[http://dx.doi.org/10.1016/S1470-2045(14)71159-3] [PMID: 25524798] 
[81] 
Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1: Results from a phase IIstudy of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy,  in patients with HR+/HER2- breast cancer, after chemotherapy for advanced disease. ASCO Annual Meeting. Abstract 510. Presented June 3, 2016.. 
[82] 
Perez EA, Romond EH, Suman VJ, et al. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol  2014; 32(33): 3744-52.
[http://dx.doi.org/10.1200/JCO.2014.55.5730] [PMID: 25332249] 
[83] 
Giordano SH, Temin S, Kirshner JJ, et al. American Society of Clinical Oncology. Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol  2014; 32(19): 2078-99.
[http://dx.doi.org/10.1200/JCO.2013.54.0948] [PMID: 24799465] 
[84] 
Swain SM, Baselga J, Kim SB, et al. CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med  2015; 372(8): 724-34.
[http://dx.doi.org/10.1056/NEJMoa1413513] [PMID: 25693012] 
[85] 
Krop IE, Kim SB, González-Martín A, et al. TH3RESA study collaborators. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol  2014; 15(7): 689-99.
[http://dx.doi.org/10.1016/S1470-2045(14)70178-0] [PMID: 24793816] 
[86] 
Chan A, Delaloge S, Holmes FA, et al. ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol  2016; 17(3): 367-77.
[http://dx.doi.org/10.1016/S1470-2045(15)00551-3] [PMID: 26874901] 
[87] 
Schnipper LE, Davidson NE, Wollins DS, et al. American society of clinical oncology. American society of clinical oncology statement: A conceptual framework to assess the value of cancer treatment options. J Clin Oncol  2015; 33(23): 2563-77.
[http://dx.doi.org/10.1200/JCO.2015.61.6706] [PMID: 26101248] 
[88] 
Durkee BY, Qian Y, Pollom EL, et al. Cost-effectiveness of pertuzumab in human epidermal growth factor receptor 2-positive metastatic breast cancer. J Clin Oncol  2016; 34(9): 902-9.
[http://dx.doi.org/10.1200/JCO.2015.62.9105] [PMID: 26351332] 
[89] 
Thill M. New frontiers in oncology: biosimilar monoclonal antibodies for the treatment of breast cancer. Expert Rev Anticancer Ther  2015; 15(3): 331-8.
[http://dx.doi.org/10.1586/14737140.2015.993318] [PMID: 25539719] 
[90] 
Rugo HS, Rumble RB, Burstein HJ. Endocrine therapy for hormone receptor positive metastatic breast cancer: American society of clinical oncology guideline summary. J Oncol Pract  2016; 12(6): 583-7.
[http://dx.doi.org/10.1200/JOP.2016.012914] 
[91] 
Dirix LY, Takacs I, Nikolinakos P, et al. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumour trial. San Antonio Breast Cancer Symposium. Abstract S1-04. Presented December 9, 
[92] 
Rugo HS, Delord J-P. . Preliminary efficacy and safety of pembrolizumab (MK-3475) in patients with PDL1- positive estrogen receptor positive/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. San Antonio Breast Cancer Symposium. Abstract S5-1 07. Presented December 11, 
[93] 
Sparano JA, Gray RJ, Makower DF, et al. Prospective validation of a 21-gene expression assay in breast cancer. N Engl J Med  2015; 373(21): 2005-14.
[http://dx.doi.org/10.1056/NEJMoa1510764] [PMID: 26412349] 
[94] 
Harris LN, Ismaila N, McShane LM, et al. American Society of Clinical Oncology. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American society of clinical oncology clinical practice guideline. J Clin Oncol  2016; 34(10): 1134-50.
[http://dx.doi.org/10.1200/JCO.2015.65.2289] [PMID: 26858339] 
[95] 
Cardoso F, van’t Veer LJ, Bogaerts J, et al. MINDACT investigators. 70-gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med  2016; 375(8): 717-29.
[http://dx.doi.org/10.1056/NEJMoa1602253] [PMID: 27557300] 
[96] 
 Hopkins medicine. Biologic targeted therapy for breast cancer: johns hopkins breast center. biologic targeted therapy for breast cancer: johns hopkins breast center. Available from:  https://www.hopkinsmedicine. org/breast_center/treatments_services/medical_oncology/biologic_targeted_therapy.html [August 18, 2019]
[97] 
Tong CWS, Wu M, Cho WCS, To KKW. Recent advances in the treatment of breast cancer. Front Oncol  2018; 8: 227.
[http://dx.doi.org/10.3389/fonc.2018.00227] [PMID: 29963498] 
[98] 
Meropol NJ, Schrag D, Smith TJ, et al. American Society of Clinical Oncology. American Society of Clinical Oncology guidance statement: the cost of cancer care. J Clin Oncol  2009; 27(23): 3868-74.
[http://dx.doi.org/10.1200/JCO.2009.23.1183] [PMID: 19581533] 
[99] 
Sullivan R, Peppercorn J, Sikora K, et al. Delivering affordable cancer care in high-income countries. Lancet Oncol  2011; 12(10): 933-80.
[http://dx.doi.org/10.1016/S1470-2045(11)70141-3] [PMID: 21958503] 
[100] 
Experts in Chronic Myeloid Leukemia. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood  2013; 121(22): 4439-42.
[http://dx.doi.org/10.1182/blood-2013-03-490003] [PMID: 23620577] 
[101] 
de Souza JA, Yap BJ, Hlubocky FJ, et al. The development of a financial toxicity patient-reported outcome in cancer: The COST measure. Cancer  2014; 120(20): 3245-53.
[http://dx.doi.org/10.1002/cncr.28814] [PMID: 24954526] 
[102] 
Reporting KN, Toxicity GF. J Clin Oncol  2014; 29: 3337-8.
[103] 
Chun KH, Park JH, Fan S. Predicting and overcoming chemotherapeutic resistance in breast cancer. Adv Exp Med Biol  2017; 1026: 59-104.
[http://dx.doi.org/10.1007/978-981-10-6020-5_4] [PMID: 29282680] 
[104] 
Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med  2011; 62: 233-47.
[http://dx.doi.org/10.1146/annurev-med-070909-182917] [PMID: 20887199] 
[105] 
Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer  2002; 2(2): 101-12.
[http://dx.doi.org/10.1038/nrc721] [PMID: 12635173] 
[106] 
Haque MM, Desai KV. Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol (Lausanne)  2019; 10: 573.
[http://dx.doi.org/10.3389/fendo.2019.00573] [PMID: 31496995] 
[107] 
Ernst B, Anderson KS. Immunotherapy for the treatment of breast cancer. Curr Oncol Rep  2015; 17(2): 5.
[http://dx.doi.org/10.1007/s11912-014-0426-9] [PMID: 25677118] 
[108] 
Mittendorf EA, Peoples GE. Injecting hope - A review of breast cancer vaccine. Oncology (Williston Park)  2016; 30(5): 475-481, 485.
[PMID: 27188680] 
[109] 
Soliman H. Developing an effective breast cancer vaccine. Cancer Contr  2010; 17(3): 183-90.
[http://dx.doi.org/10.1177/107327481001700307] [PMID: 20664516] 
[110] 
Behravan J, Razazan A, Behravan G. Towards breast cancer vaccines, progress and challenges. Curr Drug Discov Technol  2019; 16(3): 251-8.
[http://dx.doi.org/10.2174/1570163815666180502164652] [PMID: 29732989] 
[111] 
García-Aranda M, Redondo M. Immunotherapy: A challenge of breast cancer treatment. Cancers (Basel)  2019; 11(12): 1822.
[http://dx.doi.org/10.3390/cancers11121822] [PMID: 31756919] 
Cite As
Current Chemical Biology

Understanding Molecular Process and Chemotherapeutics for the Management of Breast Cancer

Abstract

Graphical Abstract
