How does Herceptin work?
It has been established that Herceptin causes immune-mediated cytotoxicity, blocks proliferation and apoptosis of target cells, and has antiangiogenic activity. The principles of using Herceptin in the treatment of breast cancer, both as monotherapy and in combination with cytostatic drugs, are discussed in detail. Treatment with Herceptin may be effective for other types of tumors. Herceptin, unlike traditional chemotherapy drugs, affects only cancer cells with an increased content of HER2 receptors and therefore causes fewer side effects.
Duration of Herceptin therapy for HER2-positive breast cancer
International clinical studies show that the use of trastuzumab (Herceptin) in adjuvant therapy of patients with HER2-positive operable breast cancer (BC) significantly increases relapse-free and overall survival of patients.
When disseminated breast cancer progresses during treatment with a combination of trastuzumab and chemotherapy, Herceptin can be used as one of the components of subsequent drug therapy.
Studies are currently ongoing to examine the optimal duration of trastuzumab therapy in the adjuvant setting.
Table 1. Ligands to epidermal growth factor receptors
Table 2. Results of a clinical study of the efficacy of trastuzumab alone in disseminated HER2-positive breast cancer
Rice. 1. Mechanism of action of trastuzumab
Table 3. Efficacy of taxanes and their combination with trastuzumab in first-line treatment of HER2-positive breast cancer
Table 4. Trastuzumab: mechanisms of action and resistance [3]
Rice. 2. Experimental study of the feasibility of continuing the administration of trastuzumab after progression of HER2-positive breast cancer against the background of combination therapy including trastuzumab
Table 5. Drug combinations effective in HER2-positive breast cancer resistant to trastuzumab (summary data from randomized trials)
Table 6. Potential opportunities to overcome trastuzumab resistance
Table 7. International clinical trials evaluating the role of trastuzumab in the adjuvant treatment of HER2-positive operable breast cancer. Design. Characteristics of patients
Table 8. Role of trastuzumab in adjuvant therapy of HER2-positive operable breast cancer
Introduction
Breast cancer (BC) in approximately 25% of cases is characterized by increased expression of the HER2 protein due to amplification of the ErbB2 gene. From a biological point of view, such tumors are distinguished by an aggressive course, which is clinically manifested by a high frequency of disease relapses after treatment, a short relapse-free interval and a decrease in life expectancy. The HER2 protein belongs to the epidermal growth factor receptor (EGFR) family, consisting of 4 transmembrane tyrosine kinase (TK) receptors: HER1 (EGFR/ErbB1), HER2 (ErbB2/neu), HER3 (ErbB3) and HER4 (ErbB4).
In addition to the intracellular protein TK domain, all receptors have a transmembrane segment and an extracellular domain responsible for binding to the ligand. Currently, more than 10 ligands are known that bind to HER1, HER3 and HER4 (Table 1). The ligand binding to the extracellular domain induces conformational changes in the receptor, promoting its dimerization with other members of the EGFR family (homo- or hetero-), resulting in activation of the TK domain and autophosphorylation. As a result of autophosphorylation, each dimer can trigger various intracellular signaling pathways that transmit an activating signal to the cell nucleus, such as PI3K/Akt or Ras/Raf/MAPK and STATs, which play an important role in the processes of oncogenesis: growth, proliferation, survival, cell motility and apoptosis.
Ligands for HER2 have not yet been identified. It is believed to participate in the dimerization process as a coreceptor, forming heterodimers with other members of the EGFR family. In addition, HER2, having constitutive activity, can take part in ligand-independent homo- or heterodimerization. HER2 is believed to be the most common dimerization partner with all other receptors, including HER3. Unlike other EGFRs, the HER3 receptor does not have its own tyrosine kinase activity and requires heterodimerization to generate a signal.
In addition, it contains at least 6 domains for binding to the PI3K regulatory subunit: p85 and is the most potent activator of the PI3K pathway of all EGFRs. HER3 plays an important role in mediating the biological activities of HER2. Experimental evidence has emerged that breast cancer cell lines expressing both HER2 and HER3 receptors have a higher degree of Akt phosphorylation. According to some studies, HER3 overexpression is associated with poor prognosis and decreased survival of patients [1].
The main mechanism of HER2 protein overexpression is considered to be gene amplification. HER2 expression is known to promote carcinogenesis. Thus, experimental studies have shown that transfection of HER2 into mammary epithelial cells induces tumor transformation. However, to stimulate cell proliferation in breast cancer, the HER2 receptor requires HER3, which emphasizes the importance of the heterodimeric HER2/HER3 complex [2].
Activation of insulin-like growth factor 1 receptors (IGF-1R) is also associated with the development and progression of breast cancer. IGF-1R is also a tyrosine kinase receptor, binding to IGF-1 and IGF-2, it regulates cell proliferation and survival. There is evidence of crosstalk between the signaling pathways activated by the EGFR family and the IGF-1R. Thus, in breast cancer cells resistant to trastuzumab, heterodimerization between IGF-1R and HER2 was detected, which may be one of the reasons for resistance [1].
The introduction into clinical practice of trastuzumab (Herceptin), a humanized monoclonal antibody against the extracellular domain of the HER2 protein, has dramatically affected the survival of patients with HER2-positive breast cancer, significantly improving both immediate and long-term treatment results.
Trastuzumab. Mechanism of antitumor action
Trastuzumab has a complex mechanism of antitumor action, which is due to the blockade of intracellular signal transduction pathways triggered by HER2, as well as stimulation of the antitumor immune response (Fig. 1) [3]. As a result of clinical studies, the following effects of trastuzumab have been proven:
- promotes HER2 internalization and degradation;
- suppresses proliferation and restores the ability of tumor cells to apoptosis due to blockade of the PI3K/Akt signaling pathway, which also determines the synergy of trastuzumab with chemotherapy;
- inhibits HER2-regulated angiogenesis;
- prevents the formation of HER2p95, a transcribed active form of the HER2 receptor, which is characterized by the absence of an extracellular domain in the presence of tyrosine kinase activity, thus inhibiting tumor development;
- induces an antitumor immune response due to the activation of antibody-dependent cellular cytotoxicity. The structure of trastuzumab, which is an immunoglobulin of the G1 subclass, contains an Fc domain. It is recognized by effector cells of the immune system that express the Fcγ receptor. Due to the binding of natural killer cells to the Fc domain of trastuzumab, tumor cell lysis occurs.
Efficacy of trastuzumab treatment in disseminated HER2-positive breast cancer
Clinical studies have shown that in disseminated HER2-positive breast cancer, trastuzumab monotherapy is effective both in the first and subsequent lines of treatment (Table 2). Table 3 presents the results of randomized trials that compared the effectiveness of taxanes and their combination with trastuzumab in the first line treatment of HER2-positive breast cancer. Compared with standard chemotherapy (CT) (Table 3) and trastuzumab monotherapy (Table 2), the use of a combination of trastuzumab with cytostatics significantly increases the effectiveness of the first-line treatment of HER2-positive breast cancer.
Subsequent clinical studies showed that trastuzumab was well tolerated and effective in combination with vinorelbine, platinum derivatives, capecitabine, gemcitabine, and aromatase inhibitors [9]. The addition of carboplatin [10] or capecitabine [11] to the combination of trastuzumab with docetaxel did not increase the effectiveness of treatment, with the exception of a significant increase in the median time to disease progression from 12.8 to 17.9 months. when using a three-drug regimen with capecitabine. The addition of paclitaxel to the combination of Herceptin with carboplatin increased the rate of achieving an objective effect from 36 to 52% (p = 0.04), the median time to disease progression from 7.1 to 10.7 months. (p = 0.03) without increasing the median life expectancy (32.2 and 35.7 months, p = 0.73) of patients [12].
Currently, Herceptin is the standard of care for both adjuvant and first-line therapy for HER2-positive breast cancer.
Trastuzumab is usually prescribed until the disease progresses, which inevitably occurs due to the development of tumor drug resistance. The mechanisms of resistance development are presented in Table 4. The question of further therapeutic tactics for HER2-positive breast cancer is very relevant, especially in the treatment of metastatic forms. Duration of treatment with trastuzumab for advanced breast cancer
Does it make sense to continue Herceptin after disease progression has been documented? This issue was investigated in an experiment on transplantable tumors of HER2-positive breast cancer (Fig. 2). After the development of tumor resistance to Herceptin, the maximum suppression of tumor growth was caused by the combination of Herceptin with paclitaxel; paclitaxel alone was significantly less effective [13]. Experimental data were confirmed in a small clinical trial GBG-26/BIG03-06, devoted to a comparative study of the effectiveness of capecitabine alone or in combination with Herceptin in disseminated HER2-positive breast cancer, resistant to first-line therapy with Herceptin in combination with chemotherapy [14].
The study included 156 patients, 78 of whom, after randomization, were assigned to therapy with Xeloda in the standard regimen (X), the other 78 - with Xeloda while continuing the administration of Herceptin (X + H). The primary objective of the study was to compare time to disease progression. The combination of Xeloda with Herceptin compared with Xeloda monotherapy resulted in an increase in the median time to disease progression from 5.6 to 8.2 months. (HR = 0.69; 95% CI 0.48–0.97; two-sided log-rank p = 0.0338), increasing the rate of achieving an objective effect from 27.0 to 48.1% (OR = 2.50; p = 0.0115) and tumor growth control, including the rate of objective response and disease stabilization lasting more than 24 weeks, from 54.1 to 75.3% (p = 0.0068). The median overall survival of patients during treatment with capecitabine and Herceptin was 25.5 months, and against capecitabine alone – 20.4 months. (p = 0.257).
Another randomized phase III trial, EGF 104-900, which included 296 patients with HER2-positive breast cancer resistant to Herceptin, was devoted to studying the effectiveness of “maximal” HER2 blockade [15, 16]. The choice of treatment was carried out by randomization, after which patients received either the tyrosine kinase inhibitor of HER1 and HER2 receptors lapatinib at a standard dose of 1500 mg/day, or lapatinib 1000 mg/day while continuing weekly trastuzumab. The main objective of the study was to compare progression-free survival of patients. According to the study results, the combination of two targeted drugs is significantly more effective than lapatinib monotherapy. The median progression-free survival of patients receiving lapatinib while continuing trastuzumab was 12.0 weeks, and 8.1 weeks in patients receiving lapatinib monotherapy (HR = 0.73; 95% CI 0.57–0.93; p = 0.008), objective effect – 10 and 7%, median overall survival – 52 and 39 weeks, respectively, although the difference was not statistically significant.
Thus, the results of both clinical studies indicate that after progression occurs during treatment with trastuzumab in combination with chemotherapy, it is advisable to maintain Herceptin as one of the components of subsequent drug therapy. In this case, a cytostatic drug that the patient has not previously received, or one of the targeted drugs, can be used in combination with Herceptin.
Until now, the combination of lapatinib with Xeloda was most often prescribed for the treatment of HER2-positive breast cancer resistant to trastuzumab. The basis for this choice was data from the randomized trial EGF100151, the main purpose of which was to compare the time to disease progression when treated with capecitabine alone or in combination with lapatinib [17]. The median time to disease progression was significant (p
Thus, if resistance to trastuzumab develops in patients with HER2-positive breast cancer, at least 3 combination regimens with similar efficacy can be used to continue treatment (Table 5), depending on the availability of a particular drug. Preclinical results suggest that lapatinib treatment of HER2-positive breast cancer restores the sensitivity of tumor cell HER2 receptors to trastuzumab. On this basis, Italian scientists are studying the feasibility of re-prescribing trastuzumab after progression of HER2-positive breast cancer in the second line of treatment with lapatinib and capecitabine. Currently, out of 179 patients, 69 have been evaluated, 51 of them (74%) had visceral metastases, and 16 (23%) had brain metastases. All patients had previously received treatment that included both trastuzumab and lapatinib.
As a result of repeated treatment with trastuzumab, 1 (2%) patient achieved complete regression of the disease, 18 (29%) - partial, 10 (14%) showed stabilization of the disease for 6 months or more, 47% of patients - clinical improvement . The median duration of effect was 8.1 months. With a median follow-up of 13 months. The median survival of patients without disease progression was 4.9 months, the median overall survival was 19.4 months. The median overall survival was significantly higher in patients who had clinical improvement (not achieved) than in patients without it (13.4 months, p = 0.002). Brain metastases were associated with lower median patient survival (17.3 vs. 23.3 months, p = 0.021). According to the authors, re-administration of trastuzumab allows for clinical improvement in 47% of patients with HER2-positive breast cancer, resistant to previous therapy with trastuzumab and lapatinib, and helps to increase life expectancy [18]. Further progress in overcoming trastuzumab resistance may be associated with the development and study of targeted therapy drugs (Table 6).
Trastuzumab in adjuvant therapy of HER2-positive operable breast cancer
Six large international randomized controlled trials were devoted to assessing the role of trastuzumab in the adjuvant therapy of operable HER2-positive breast cancer: HERA (the Herceptin Adjuvant trial) [19], NSABP B-31 (the National Surgical Adjuvant Breast and Bowel Project B-31 trial) [20], NCCTG N9831 (the North Central Cancer Treatment Group N9831 trial) [20, 21], BCIRG-006 (the Breast Cancer International Research Group 006 trial) [22], FinHer (the Finland Herceptin trial) [23], PACS-04 (the Protocol Adjuvant dans le Cancer du Sein trial) [24]. In total, these studies included more than 14,000 women and assessed the feasibility of adding trastuzumab to various chemotherapy regimens in different sequences (Table 7).
In four of the international clinical trials mentioned above, it was shown that the addition of trastuzumab to chemotherapy leads to a significant increase in relapse-free survival, and in three trials, in addition to an increase in DFS, it led to a significant increase in overall survival (Table 8). The data obtained from these studies, as well as the results of a meta-analysis based on individual data from patients included in the studies, confirm the positive effect of Herceptin on the effectiveness of adjuvant therapy. According to the results of a meta-analysis, the inclusion of Herceptin in adjuvant therapy leads to a significant reduction in mortality (p
Conclusion
In most studies that form the basis of current recommendations, the duration of trastuzumab was 1 year. A longer period of trastuzumab administration (2 years) is being studied in the HERA trial, the results of which have not yet been published. The FinHer study used a shorter Herceptin course of 9 weeks. The results of a two-year follow-up of patients showed that the addition of Herceptin to adjuvant chemotherapy contributed to a significant increase in 2-year disease-free survival with a tendency to increase overall life expectancy. However, 5-year follow-up results showed that a 9-week course of trastuzumab does not lead to a significant increase in disease-free and overall survival of patients [26]. Currently, studies are ongoing to study the optimal duration of administration of trastuzumab as part of adjuvant therapy, the results of which may change our understanding of the rational duration of Herceptin administration. Today, the optimal duration of Herceptin administration as part of adjuvant therapy is considered to be 1 year.
Indications for use of Herceptin:
Metastatic breast cancer with tumor overexpression of HER2:
- as monotherapy, after one or more chemotherapy regimens;
- in combination with paclitaxel or docetaxel, in the absence of previous chemotherapy (first line of therapy);
- in combination with aromatase inhibitors for positive hormonal receptors (estrogen and/or progesterone) in postmenopausal women.
Early stages of breast cancer with tumor overexpression of HER2:
- in the form of adjuvant therapy after surgery, completion of chemotherapy (neoadjuvant or adjuvant) and radiation therapy;
- in combination with paclitaxel or docetaxel after adjuvant chemotherapy with doxorubicin and cyclophosphamide;
- in combination with adjuvant chemotherapy consisting of docetaxel and carboplatin;
- in combination with neoadjuvant chemotherapy and subsequent adjuvant monotherapy with Herceptin for locally advanced (including inflammatory form) disease or in cases where the tumor size exceeds 2 cm in diameter.
Pharmacokinetics
The administration of Herceptin in the form of short intravenous infusions once a week with a dosage of 10–500 mg is characterized by nonlinear pharmacokinetics. As the dose increases, a decrease in clearance is observed.
The half-life of the drug is 28–38 days. If Herceptin is discontinued, the withdrawal period lasts 27 weeks.
Mode of application
Testing for HER2 expression by the tumor is performed before starting therapy. The drug Herceptin is administered exclusively intravenously; Under no circumstances should the drug be administered intravenously. The medicine is compatible with infusion bags made of PVC, polyethylene, polypropylene.
According to the instructions for the Herceptin drug, the solution is prepared under strict aseptic conditions. Draw the solvent into a syringe and use it to dissolve the contents of the bottle with lyophilisate. Rock the bottle to dissolve the powder as quickly as possible. The prepared solution is stable for 28 days at a temperature of 2–8 °C. Cannot be frozen.
Due to the risk of protein aggregation, Herceptin is incompatible with dextrose solution (5%). According to the instructions, the drug should also not be mixed or diluted with other medications. A special solvent (bacteriostatic water for injection) is supplied with the medication.
Sterile water for injection that does not contain preservatives can also be used as a solvent. In this case, the solution remains stable only for 24 hours!
Side effects
Chills, nausea, fever, pain, vomiting, cough, tremor, shortness of breath, dizziness, skin rash, hypertension, weakness, arterial hypotension, bronchospasm, wheezing in the lungs, tachycardia, respiratory distress syndrome.
