Solving the Puzzle of Treatment Resistance in Patients with HER2-Positive Metastatic Breast Cancer – New Approaches to HER Target Family Network
In the last twenty years, there has been remarkable progress in the development of therapies for human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), and now, systemic therapy is a key component of the metastatic BC management. Modern therapies for patients with HER2-positive metastatic BC include targeted anti-HER2 monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs), tyrosine kinase inhibitors (TKIs), and chemotherapy (CHT) (e.g., capecitabine). Consequently, various HER2-targeted agents, such as trastuzumab and pertuzumab (mAbs), trastuzumab emtansine (T-DM1) (an ADC), as well as lapatinib (a TKI) have been recommended as key components of the standard of care regimens for patients suffering from HER2-positive BC. This mini-review outlines possible mechanisms of resistance to common anti-HER2 treatments. In addition, this paper highlights novel HER2-targeted therapeutic strategies for the systemic treatment of patients with HER2-positive metastatic BC, including margetuximab (a novel mAb), trastuzumab deruxtecan (a high potency ADCs), and tucatinib (a selective TKI), based on the results of recent clinical trials. Furthermore, this article briefly comments on the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors and anti-HER3 approaches, in women with metastatic BC. This overview also addresses some possible advantages of immune checkpoint inhibitors and cyclin-dependent kinase (CDK) 4/6 inhibitors used in combination with anti-HER2 therapies for patients with HER2-positive metastatic BC, as well as some management issues, aiming at bridging the gap between the guidelines and the challenges of daily practice in individual women with HER2-positive metastatic BC.
1.Rimawi MF, Schiff R, Osborne CK. Targeting HER2 for the treatment of breast cancer. Annu Rev Med 2015;66:111–28. [CrossRef]
2. Larionov AA. Current therapies for human epidermal growth factor receptor 2-positive metastatic breast cancer patients. Front Oncol 2018;8:1–17. [CrossRef]
3. Rugo HS, Im SA, Wright GL, et al. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). Journal of Clinical Oncology 2019 37:15_suppl, 1000. [CrossRef]
4. Modi S, Saura C, Yamashita T, Park YH, Kim SB, Tamura K, Andre F. DESTINY-Breast01 Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer. N Engl J Med 2020;382:610–21. [CrossRef]
5. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med 2019.
6. Wilks ST. Potential of overcoming resistance to HER2-targeted therapies through the PI3K/Akt/mTOR pathway. Breast 2015;24:548–55. [CrossRef]
7. Mishra P, Patel H, Alanasi S. Yuan L, Garrett JT. HER3 signaling and targeted therapy in cancer. Oncol Rev 2018;355:45–62.
8. Pegram MD, Zong Y, Yam C, Goetz MP, Moulder SL. Innovative Strategies: Targeting Subtypes in Metastatic Breast Cancer. Am Soc Clin Oncol Educ Book 2018;38:65–77. [CrossRef]
9. Rinnerthaler G, Gampenrieder SP, Greil R. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer. Int J Mol Sci 2019;20:1–17. [CrossRef]
10. Tamura K, Tsuntani J, Takahashi S. et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a doseexpansion, phase 1 study. Lancet Oncol 2019;20:816–26.
11. Banerji U, van Herpen CML, Saura C, Thistlethwaite F, Lord S, Moreno V, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol 2019;20:1124–1135. [CrossRef]
12. Trail PA, Dubowchick GM, Lowinger TB. Antibody drug conjugates for treatment of breast cancer: novel targets and diverse approaches in ADC design. Pharmacol Ther 2018;181:126–42.
13. Kohrt HE, Houot R, Weiskopf K, et al. Stimulation of natural killer cells with a CD137-specific antibody enhances trastuzumab efficacy in xenotransplant models of breast cancer. J Clin Invest 2012;122:1066–75. [CrossRef]
14. Pegram MD. Tumor biology trumps anatomy in breast cancer brain metastases. Oncology (Williston Park) 2012;26:666–70.
15. Saura C, Oliveira M, Feng Y-H, Dai M-S, Hurvitz SA, Kim S-B. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019) 1002-1002. DOI: 10.1200/JCO.2019.37.15_suppl.1002. [CrossRef]
16. Guerrero-Zotano A, Mayer IA, Arteaga CL. P3K/AKT/mTOR: role in breast cancer progression, drug resistance, and treatment. Cancer Metastasis Rev 2016;35: 515–24. [CrossRef]
17. Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, 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;16:816–29.
18. André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G. 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;15:580–91. [CrossRef]
19. Gourd E. Pyrotinib shows activity in metastatic breast cancer. Lancet Oncol 2017;18: e643. [CrossRef]
20. Ma F, Ouyang Q, Li W, et al. Pyrotinib or Lapatinib Combined With Capecitabine in HER2-Positive Metastatic Breast Cancer With Prior Taxanes, Anthracyclines, and/or Trastuzumab: A Randomized, Phase II Study. J Clin Oncol 2019. [CrossRef]
21. Park YH, Lee KH, Sohn JH, et al. A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2- directed regimens: results of the NOV120101-203 trial. Int J Cancer 2018;143:3240–7. [CrossRef]
22. Chia S, Bedard PL, Hilton J, Amir E, Gelmon K, Goodwin R, et al. A Phase Ib Trial of Durvalumab in Combination with Trastuzumab in HER2-Positive Metastatic Breast Cancer (CCTG IND.229). Oncologist 2019;24:1439–45. [CrossRef]
23. Loi S, Giobbie-Hurder A, Gombos A, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2- positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b-2 trial. Lancet Oncol 2019;20:371–82. [CrossRef]
24. Emens LA, Esteva FJ, Beresford M, Saura C, De Laurentiis M, Kim S-B. Overall survival (OS) in KATE2, a phase II study of programmed death ligand 1 (PD-L1) inhibitor atezolizumab (atezo)+trastuzumab emtansine (T-DM1) vs placebo (pbo)+TDM1 in previously treated HER2+ advanced breast cancer (BC). Annals of Oncology 2019; Vol. 30 Supplement 5, Page v104.
25. Goel S, Wang Q, Watt AC, et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell 2016;29:255–69. [CrossRef]
26. Dickler MN, Tolaney SM, Rugo HS, et al. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res 2017;23:5218–24. [CrossRef]
27. Johnston S, Martin M, Di Leo A, et al. MONARCH 3 final PFS: A randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer 2019;5. [CrossRef]
28. Brandão M, Pondé NF, Poggio F, et al. Combination therapies for the treatment of HER2-positive breast cancer: current and future prospects. Expert Rev. Anticancer Ther 2018;18:629–49.
29. Tolaney SM, Wardley AM, Zambelli S, et al: MonarcHER: A randomized phase II study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-ofcare chemotherapy in women with HR+, HER2+ advanced breast cancer. ESMO Congress 2019. Abstract LBA23. Presented September 28,2019. [CrossRef]
30. Loibl S, Metzger O, Mandrekar SJ, Mundhenke C, Seiler S, Valagussa P, et al. PATINA: A Randomized, Open Label, Phase III Trial to Evaluate the Efficacy and Safety of Palbociclib + AntiHER2 Therapy + Endocrine Therapy (ET) vs. Anti-HER2 Therapy + ET after Induction Treatment for Hormone Receptor Positive (HR+)/HER2-Positive Metastatic Breast Cancer (MBC). Annals of Oncology 2018; 29 (suppl_8): viii90-viii121. [CrossRef]