Review Article

Emerging Therapeutic Strategies in Breast Cancer

Authors: Kayla Cox, BS, Brandon Alford, BS, Hatem Soliman, MD

Abstract

The field of medical oncology is experiencing a period of rapid evolution owing to advances in the fields of genomics, tumor biology, and immunology. These disciplines have provided valuable insights into the heterogeneity between breast tumors, key oncogenic drivers, and the role of the immune system in the natural history of breast cancer. This knowledge is translating into many novel therapeutic strategies using personalized medicines, targeted drug delivery systems, and immunomodulatory agents in the treatment of both the early and metastatic stages of the disease. This review article attempts to cover the major developments in experimental therapeutics and how they relate to our understanding of breast cancer and its various biologic subtypes.

 

This content is limited to qualifying members.

Existing members, please login first

If you have an existing account please login now to access this article or view purchase options.

Purchase only this article ($25)

Create a free account, then purchase this article to download or access it online for 24 hours.

Purchase an SMJ online subscription ($75)

Create a free account, then purchase a subscription to get complete access to all articles for a full year.

Purchase a membership plan (fees vary)

Premium members can access all articles plus recieve many more benefits. View all membership plans and benefit packages.

References

1. Atta HM. Edwin Smith surgical papyrus: the oldest known surgical treatise. Am Surg 1999;65:1190-1192.
 
2. Breathnach CS. Rudolf Virchow (1821-1902) and Die Cellularpathologie (1858). J Ir Coll Physicians Surg 2002;31:43-46.
 
3. Duesberg PH, Vogt PK. Differences between the ribonucleic acids of transforming and nontransforming avian tumor viruses. Proc Natl Acad Sci U S A 1970;67:1673-1680.
 
4. Knudson AG Jr. Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A 1971;68:820-823.
 
5. Chazin VR, Kaleko M, Miller AD, et al. Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene 1992;7:1859-1866.
 
6. Dunn GP, Koebel CM, Schreiber RD. Interferons, immunity and cancer immunoediting. Nat Rev Immunol 2006;6:836-848.
 
7. Strebhardt K, Ullrich A. Paul Ehrlich's magic bullet concept: 100 years of progress. Nat Rev Cancer 2008;8:473-480.
 
8. Stockwell S. Classics in oncology. George Thomas Beatson, M.D. (1848-1933). CA Cancer J Clin 1983;33:105-121.
 
9. Jensen EV, Jordan VC. The estrogen receptor: a model for molecular medicine. Clin Cancer Res 2003;9:1980-1989.
 
10. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature 2000;406:747-752.
 
11. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol 2010;11:1135-1141.
 
12. Choi YJ, Anders L. Signaling through cyclin D-dependent kinases. Oncogene 2014;33:1890-1903.
 
13. Network Cancer Genome Atlas. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70.
 
14. Abraham RT, VanArsdale T, Shields DV, et al. Braking the cycle: Inhibition of the cyclin D-Cdk4/6 pathway in breast cancer. Cancer Res 2014;74.
 
15. Finn RS, Crown JP, Ettl J, et al. Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18. Breast Cancer Res 2016;18:67.
 
16. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 2016;17:425-439.
 
17. Hortobagyi GN, Stemmer SM, Burris HA, et al. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med 2016;375:1738-1748.
 
18. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH1: results from a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2-breast cancer, after chemotherapy for advanced disease. J Clin Oncol 2016;34.
 
19. Patnaik A, Rosen LS, Tolaney SM, et al. LY2835219, a novel cell cycle inhibitor selective for CDK4/6, in combination with fulvestrant for patients with hormone receptor positive (HR+) metastatic breast cancer. J Clin Oncol 2014;32.
 
20. Campbell RA, Bhat-Nakshatri P, Patel NM, et al. P hosphatidylinositol 3-kinase/AKT-mediated activation of estrogen receptor alpha: a new model for anti-estrogen resistance. J Biol Chem 2001;276:9817-9824.
 
21. Qian J, Chen Y, Meng T, et al. Molecular regulation of apoptotic machinery and lipid metabolism by mTORC1/mTORC2 dual inhibitors in preclinical models of HER2+/PIK3CAmut breast cancer. Oncotarget 2016;7:67071-67086.
 
22. Nicholson KM, Anderson NG. The protein kinase B/Akt signalling pathway in human malignancy. Cell Signal 2002;14:381-395.
 
23. deGraffenried LA, Friedrichs WE, Russell DH, et al. Inhibition of mTOR activity restores tamoxifen response in breast cancer cells with aberrant Akt activity. Clin Cancer Res 2004;10:8059-8067.
 
24. Lui A, New J, Ogony J, et al. Everolimus downregulates estrogen receptor and induces autophagy in aromatase inhibitor-resistant breast cancer cells. BMC Cancer 2016;16:487.
 
25. Beck JT, Hortobagyi GN, Campone M, et al. Everolimus plus exemestane as first-line therapy in HR + , HER2 − advanced breast cancer in BOLERO-2. Breast Cancer Res Treat 2014;143:459-467.
 
26. Huang K, Fingar DC. Growing knowledge of the mTOR signaling network. Semin Cell Dev Biol 2014;36:79-90.
 
27. Guichard SM, Curwen J, Bihani T, et al. AZD2014, an inhibitor of mTORC1 and mTORC2, is highly effective in ER+ breast cancer when administered using intermittent or continuous schedules. Mol Cancer Ther 2015;14:2508-2518.
 
28. Wakeling AE, Dukes M, Bowler J. A potent specific pure antiestrogen with clinical potential. Cancer Res 1991;51:3867-3873.
 
29. Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr Relat Cancer 2000;7:17-28.
 
30. Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol 2016;2:1310-1315.
 
31. Toy W, Weir H, Razavi P, et al. Activating ESR1 mutations differentially affect the efficacy of ER antagonists. Cancer Discov 2017;7:277-287.
 
32. Casa AJ, Hochbaum D, Sreekumar S, et al. The estrogen receptor alpha nuclear localization sequence is critical for fulvestrant-induced degradation of the receptor. Mol Cell Endocrinol 2015;415:76-86.
 
33. Mishra AK, Abrahamsson A, Dabrosin C. Fulvestrant inhibits growth of triple negative breast cancer and synergizes with tamoxifen in ERα positive breast cancer by up-regulation of ERβ. Oncotarget 2016;7:56876-56888.
 
34. Garner F, Shomali M, Paquin D, et al. RAD1901: a novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs 2015;26:948-956.
 
35. Lai A, Kahraman M, Govek S, et al. Identification of GDC-0810 (ARN-810), an orally bioavailable selective estrogen receptor degrader (SERD) that demonstrates robust activity in tamoxifen-resistant breast cancer xenografts. J Med Chem 2015;58:4888-4904.
 
36. Gonzalez-Angulo AM, Timms KM, Liu S, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 2011;17:1082-1089.
 
37. Turner N, Tutt A, Ashworth A. Hallmarks of"BRCAness"in sporadic cancers. Nat Rev Cancer 2004;4:814-819.
 
38. Birgisdottir V, Stefansson OA, Bodvarsdottir SK, et al. Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer. Breast Cancer Res 2006;8:R38.
 
39. McCabe N, Turner NC, Lord CJ, et al. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 2006;66:8109-8115.
 
40. De Vos M, Schreiber V, Dantzer F. The diverse roles and clinical relevance of PARPs in DNA damage repair: current state of the art. Biochem Pharmacol 2012;84:137-146.
 
41. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005;434:917-921.
 
42. Bryant HE, Schultz N, Thomas HD, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005;434:913-917.
 
43. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376:235-244.
 
44. Rodler ET, Gralow J, Kurland BF, et al. Phase I: Veliparib with cisplatin (CP) and vinorelbine (VNR) in advanced triple-negative breast cancer (TNBC) and/or BRCA mutation-associated breast cancer. http://ascopubs.org/doi/abs/10.1200/jco.2014.32.15_suppl.2569. Accessed August 3, 2017.
 
45. Isakoff SJ, Puhalla S, Domchek SM, et al. A randomized Phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: design and rationale. Future Oncol 2017;13:307-320.
 
46. Tutt AJN, Kaufman B, Gelber R, et al. OlympiA: A randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm). http://ascopubs.org/doi/abs/10.1200/jco.2015.33.15_suppl.tps1109. Accessed August 3, 2017.
 
47. Dwadasi S, Tong Y, Walsh T, et al. Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple-negative breast cancer (TNBC): Hoosier Oncology Group BRE09-146. http://ascopubs.org/doi/abs/10.1200/jco.2014.32.15_suppl.1019. Accessed August 3, 2017.
 
48. Rugo HS, Olopade O, DeMichele A, et al. Veliparib/carboplatin plus standard neoadjuvant therapy for high-risk breast cancer: first efficacy results from the I-SPY 2 TRIAL. Cancer Res 2013;73(24 Suppl):S5-02.
 
49. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646-674.
 
50. McArthur HL, Diab A, Page DB, et al. A pilot study of preoperative single-dose ipilimumab and/or cryoablation in women with early-stage breast cancer with comprehensive immune profiling. Clin Cancer Res 2016;22:5729-5737.
 
51. Ratcliffe MJ, Sharpe A, Midha A, et al. Abstract LB-094: A comparative study of PD-L1 diagnostic assays and the classification of patients as PD-L1 positive and PD-L1 negative. Cancer Res 2016;76(14 Suppl):LB-094-LB-094.
 
52. Nanda R, Chow LQ, Dees EC, et al. P Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib KEYNOTE-012 study. J Clin Oncol 2016;34:2460-2467.
 
53. Emens LA, Braiteh FS, Cassier P, et al. Abstract 2859: inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Cancer Res 2015;75(15 Suppl):2859.
 
54. Adams S, Diamond J, Hamilton E, et al. Safety and clinical activity of atezolizumab (anti-PD-L1) in combination with nab-paclitaxel in patients with triple-negative breast cancer. Paper presented at: San Antonio Breast Cancer Symposium December 10, 2015. Abstr no. 850477.
 
55. Emens LA, Adams S, Loi A, et al. IMpassion130: a Phase III randomized trial of atezolizumab with nab-paclitaxel for first-line treatment of patients with metastatic triple-negative breast cancer (mTNBC). J Clin Oncol 2016;34.
 
56. Roth M, Barris DM, Piperdi S, et al. Targeting glycoprotein NMB with antibody-drug conjugate, glembatumumab vedotin, for the treatment of osteosarcoma. Pediatr Blood Cancer 2016;63:32-38.
 
57. Rose AA, Grosset AA, Dong Z, et al. Glycoprotein nonmetastatic B is an independent prognostic indicator of recurrence and a novel therapeutic target in breast cancer. Clin Cancer Res 2010;16:2147-2156.
 
58. Yardley DA, Weaver R, Melisko ME, et al. EMERGE: a randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB-expressing breast cancer. J Clin Oncol 2015;33:1609-1619.
 
59. Sussman D, Smith LM, Anderson ME, et al. SGN-LIV1A: a novel antibody-drug conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Mol Cancer Ther 2014;13:2991-3000.
 
60. Somlo G, Lau S, Frankel P, et al. Basal-, luminal-, and HER2-molecular subtype, and the MammaPrint 70-gene signature as predictors of response to neoadjuvant chemotherapy (NCT) with docetaxel, doxorubicin, cyclophosphamide (TAC), or AC and nab-paclitaxel and carboplatin+/− trastuzumab in patients (Pts) with stage II-III andinflammatory breast cancer (BC). Cancer Res 2009;69:600 s.
 
61. Verma S, Miles D, Gianni L, et al. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012;367:1783-1791.
 
62. Barrios CH, Cella D, Martin M, et al. Patient-reported outcomes (PROs) from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/− pertuzumab (P) vs trastuzumab plus taxane (HT) for HER2-positive advanced breast cancer. J Clin Oncol. 2016;34.
 
63. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 2005;5:341-354.
 
64. Olayioye MA, Graus-Porta D, Beerli RR, et al. ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol Cell Biol 1998;18:5042-5051.
 
65. Johnston SR, Leary A. Lapatinib: a novel EGFR/HER2 tyrosine kinase inhibitor for cancer. Drugs Today (Barc) 2006;42:441-453.
 
66. Park JW, Liu MC, Yee D, et al. Adaptive randomization of neratinib in early breast cancer. N Engl J Med 2016;375:11-22.
 
67. Chan A, Delaloge S, Holmes FA, et al. 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;17:367-377.