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 A Novel Prognostic Nomogram for the 2-year Survival in Human Epidermal Growth Factor Receptor 2 Positive Breast Cancer Patients

2021 ◽  
Author(s):  
Mengdi Chen ◽  
Jiayi Wu ◽  
Deyue Liu ◽  
Weilin Chen ◽  
Weiguo Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Seer Database ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Abstract Background: Targeted therapies have largely improved prognosis of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Yet, disease can still progress rapidly for some patients in the first two years after diagnosis. Our study aimed to establish a nomogram model to predict the 2-year breast cancer-specific survival (BCSS) in early HER2-positive breast cancer patients. Methods: A total of 32,481 HER2-positive patients derived from Surveillance, Epidemiology, and End Results (SEER) database were included in the construction of nomogram. Concordance index (C-index) and calibration curve were used to evaluate the discrimination ability and predictive accuracy. We tested the model in 804 patients from Shanghai Jiao Tong University Breast Cancer Data Base (SJTU-BCDB). Results: Age, estrogen receptor (ER) status, progesterone receptor (PR) status, histologic type, T stage and N stage were selected to construct the nomogram according to multivariable analysis. The 2-year BCSS rate was 95% and 60% for patients at low risk (<8 points) and high risk (>13 points) respectively. The C-index of model derived from SEER database is 0.81 (95%CI 0.79-0.83). Sensitivity analysis was performed in patients after breast surgeries with the C-index of 0.81 (95%CI, 0.79-0.83). Validation in 804 patients from SJTU-BCDB showed respective C-index of 0.77 (95%CI, 0.62-0.92) in total population, 0.67 (95%CI 0.44-0.90) and 0.90 (95%CI 0.81-0.90) in patients who received anti-HER2 therapy or not. Discussion: The novel nomogram can predict the 2-year survival outcome in HER2-positive patients independent of receiving anti-HER2 therapy or not and allow clinicians to adjust therapeutic strategies for patients with higher risk.

scholarly journals Tyrosine Kinase Inhibitors in the Combination Therapy of HER2 Positive Breast Cancer

2020 ◽  
Vol 19 ◽  
pp. 153303382096214
Author(s):  
Xue Yang ◽  
Dapeng Wu ◽  
Shengli Yuan
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) accounts for about 20% to 30% of all BC subtypes and is characterized by invasive disease and poor prognosis. With the emergence of anti-HER2 target drugs, HER2-positive BC patient outcomes have changed dramatically. However, treatment failure is mostly due to drug resistance and the special treatment needs of different subgroups. Small molecule tyrosine kinase inhibitors can inhibit multiple targets of the human epidermal growth factor receptor family and activate PI3K/AKT, MAPK, PLC γ, ERK1/2, JAK/STAT, and other pathways affecting the expression of MDM2, mTOR, p27, and other transcription factors. This can help regulate the differentiation, apoptosis, migration, growth, and adhesion of normal cells and reverse drug resistance to a certain extent. These inhibitors can cross the blood-brain barrier and be administered orally. They have a good synergistic effect with effective drugs such as trastuzumab, pertuzumab, t-dm1, and cyclin-dependent kinase 4 and 6 inhibitors. These advantages have resulted in small-molecule tyrosine kinase inhibitors attracting attention. The new small-molecule tyrosine kinase inhibitor was investigated in multi-target anti-HER2 therapy, showed a good effect in preclinical and clinical trials, and to some extent, improved the prognosis of HER2-positive BC patients. Its use could lead to a de-escalation of treatment in some patients, possibly preventing unnecessary procedures along with the associated side effects and costs.

Understanding the Mechanisms Behind Trastuzumab Therapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer

2009 ◽  
Vol 27 (34) ◽  
pp. 5838-5847 ◽  
Author(s):  
Neil L. Spector ◽  
Kimberly L. Blackwell
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Clinical Benefit ◽  
Growth Factor Receptor ◽  
Mechanisms Of Action ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
Positive Breast Cancer

PurposeTargeted therapy with the humanized monoclonal antibody trastuzumab has become a mainstay for human epidermal growth factor receptor 2 (HER2) –positive breast cancer (BC). The mechanisms of action of trastuzumab have not been fully elucidated, and data available to date are reviewed here. The impact of the mechanisms of action on clinical benefit also is discussed.MethodsAn extensive literature review of trastuzumab and proposed mechanisms of action was performed.ResultsAt least five potential extracellular and intracellular antitumor mechanisms of trastuzumab have been identified in the preclinical setting. These include activation of antibody-dependent cellular cytotoxicity, inhibition of extracellular domain cleavage, abrogation of intracellular signaling, reduction of angiogenesis, and decreased DNA repair. These effects lead to tumor cell stasis and/or death. Clinical benefit from trastuzumab-based therapy in both early and advanced BC has been demonstrated. The benefit of trastuzumab use beyond progression has also been shown, which indicates the need for continuous suppression of the HER2 pathway. Targeting both HER2, with various approaches, and other pathways may enhance the clinical benefit observed with trastuzumab and overcome potential resistance. Novel combinations include pertuzumab (a HER2 dimerization inhibitor), lapatinib (a HER1/HER2 tyrosine kinase inhibitor), bevacizumab (an antiangiogenic agent), tanespimycin (a heat shock protein inhibitor), antiestrogen therapies, and an antibody-drug conjugate (trastuzumab-DM1).ConclusionTrastuzumab is the foundation of care for patients with HER2-positive BC. Emerging data from studies of other targeted agents may provide alternative treatment combinations to maximize the clinical benefit from trastuzumab and prevent or delay resistance. The continued development of trastuzumab highlights promising treatment approaches for the future.

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