scholarly journals Overcoming endocrine resistance in hormone receptor–positive breast cancer

2018 ◽  
Vol 25 ◽  
pp. 18 ◽  
Author(s):  
A. AlFakeeh ◽  
C. Brezden-Masley
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Endocrine Therapy ◽  
Endocrine Resistance ◽  
Growth Factor Receptor ◽  
Signalling Pathways ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Endocrine therapy, a major modality in the treatment of hormone receptor (hr)–positive breast cancer (bca), has improved outcomes in metastatic and nonmetastatic disease. However, a limiting factor to the use of endocrine therapy in bca is resistance resulting from the development of escape pathways that promote the survival of cancer cells despite estrogen receptor (er)–targeted therapy. The resistance pathways involve extensive cross-talk between er and receptor tyrosine kinase growth factors [epidermal growth factor receptor, human epidermal growth factor receptor 2 (her2), and insulin-like growth factor 1 receptor] and their downstream signalling pathways—most notably pi3k/akt/mtor and mapk. In some cases, resistance develops as a result of genetic or epigenetic alterations in various components of the signalling pathways, such as overexpression of her2 and erα co-activators, aberrant expression of cell-cycle regulators, and PIK3CA mutations. By combining endocrine therapy with various molecularly targeted agents and signal transduction inhibitors, some success has been achieved in overcoming and modulating endocrine resistance in hr-positive bca. Established strategies include selective er downregulators, anti-her2 agents, mtor (mechanistic target of rapamycin) inhibitors, and inhibitors of cyclin-dependent kinases 4 and 6. Inhibitors of pi3ka are not currently a treatment option for women with hr-positive bca outside the context of clinical trial. Ongoing clinical trials are exploring more agents that could be combined with endocrine therapy, and biomarkers that would help to guide decision-making and maximize clinical efficacy. In this review article, we address current treatment strategies for endocrine resistance, and we highlight future therapeutic targets in the endocrine pathway of bca.

scholarly journals HER2-positive breast cancer and tyrosine kinase inhibitors: the time is now

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Ilana Schlam ◽  
Sandra M. Swain
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

AbstractHuman epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for 20–25% of all breast cancers. Multiple HER2-targeted therapies have been developed over the last few years, including the tyrosine kinase inhibitors (TKI) lapatinib, neratinib, tucatinib, and pyrotinib. These drugs target HER2 and other receptors of the epidermal growth factor receptor family, therefore each has unique efficacy and adverse event profile. HER2-directed TKIs have been studied in the early stage and advanced settings and have shown promising responses. There is increasing interest in utilizing these drugs in combination with chemotherapy and /or other HER2-directed agents in patients with central nervous system involvement, TKIs have shown to be effective in this setting for which treatment options have been previously limited and the prognosis remains poor. The aim of this review is to summarize currently approved TKIs for HER2+ breast, key clinical trials, and their use in current clinical practice.

scholarly journals Metastatic Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: Current Treatment Standards and Future Perspectives

Breast Care ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. 570-578
Author(s):  
Clemens Dormann
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Second Line ◽  
Current Standard ◽  
Epidermal Growth ◽  
Positive Breast Cancer

<b><i>Background:</i></b> The basis of improved systemic therapy for inoperable or metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is formed by HER2-targeting monoclonal antibodies. Dual HER2 blockade with pertuzumab and trastuzumab in combination with docetaxel in previously untreated patients, and trastuzumab emtansine (T-DM1, an antibody-drug conjugate [ADC] consisting of trastuzumab, a linker and a cytotoxic payload) after prior trastuzumab therapy have demonstrated progression-free survival (PFS) and overall survival (OS) superior to what was achieved with the previous treatment routine. Therefore, pertuzumab and trastuzumab with chemotherapy (preferably with a taxane) and T-DM1 are considered the current standard of care in the first- and second-line settings, respectively. For later lines of therapy, no uniformly recognized standard of care has been defined. Accepted options include treatment with trastuzumab beyond progression, in combination with a broad variety of single-agent chemotherapies used sequentially, or lapatinib (an HER2-targeting tyrosine kinase inhibitor [TKI]) in combination with either trastuzu­mab or capecitabine. However, most of these options have not been formally tested in patients receiving the current standard of care therapy for metastatic disease. <b><i>Summary:</i></b> In patients previously treated with today’s standard of care, including a significant subgroup with untreated or progressing brain metastases, the combination of tucatinib, a novel HER2-targeting TKI, with trastuzumab and capecitabine, demonstrates a clinically meaningful improvement in PFS and OS when compared to placebo with trastuzumab and capecitabine. Neratinib, another HER2 TKI, in combination with capecitabine, compared to lapatinib and capecitabine, as well as margetuximab, an HER2-directed monoclonal antibody with a fragment c (Fc) domain engineered to enhance immune activation, compared to trastuzumab, both combined with the investigator’s choice of chemotherapy, showed a statistically significantly longer PFS. However, not all patients in the respective trials had received pertuzumab and T-DM1 prior to enrollment and, so far, no improvement in OS has been demonstrated. After a median of 6 prior lines of therapy, trastuzumab deruxtecan (T-DXd), a novel ADC, showed a meaningful overall response and PFS. Although the safety profile was generally manageable, treatment-related interstitial lung disease (ILD) might pose a challenge in routine practice. Pyrotinib, another HER2 TKI, was evaluated in combination with capecitabine in patients after prior exposure to trastuzumab when pertuzumab and T-DM1 were not available. In this setting, PFS was better than with lapatinib and capecitabine. <b><i>Key Messages:</i></b> In 2020, pertuzumab and trastuzumab with taxane-based chemotherapy in the first line, and T-DM1 in the second line, remain the standard of care. Tucatinib, neratinib, margetuximab, and T-DXd expand the armamentarium for treatment beyond the second line. Pyrotinib might be another option, especially for patients, who do not have access to pertuzumab and T-DM1.

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