Targeted therapy for breast cancer has become a new treatment modality after the three traditional treatment modalities of surgery, radiotherapy and chemotherapy. Molecular targeted therapy for breast cancer refers to the treatment that targets oncogenes and their related expression products related to the occurrence and development of breast cancer. The biggest advantage is that it targets genes or gene products that are highly expressed in tumor cells but rarely or not expressed in normal cells, maximizing tumor cell killing and minimizing damage to normal cells. The most commonly used drug is trastuzumab.
1. Overview
Trastuzumab is a humanized monoclonal antibody that chimerizes the stable region (95%) of human IgG with the antigenic determinant cluster (5%) of a mouse-derived monoclonal antibody directed against the extracellular region of the HER-2 receptor. It is the first approved anti-HER-2 target drug, the target of action is the HER-2 gene regulation of the cell surface p185 glycoprotein.
2. Indications for trastuzumab-targeted therapy for breast cancer
1) Trastuzumab is recommended for patients with Her-2/neu gene overexpression breast cancer with primary tumor >1.0 cm; trastuzumab can be considered when the primary tumor is >0.5 cm but <1.0 cm.
2) Her-2/neu gene overexpression is defined as: 3+ by immunohistochemistry, or positive by fluorescence in situ hybridization (FISH), or positive by pigment in situ hybridization (CISH).
3) Patients with (++) Her-2 by immunohistochemistry deserve further FlSH or CISH to clarify whether there is gene amplification.
3. Relative contraindications to trastuzumab-targeted therapy for breast cancer
1) LVEF < 50% before treatment.
2) Ongoing chemotherapy with anthracyclines (doxorubicin, epirubicin, and pirarubicin) during the same period.
4. Pre-treatment interview
1) Good doctor-patient communication with the patient and family.
2) Preliminary results of ongoing clinical studies show that 1-year adjuvant trastuzumab treatment for breast cancer patients with Her-2/neu gene overexpression can reduce the recurrence rate of breast cancer.
3) Trastuzumab is a biologically targeted agent that has been clinically proven to have few adverse effects for more than 10 years, but one of the more serious adverse effects is that it increases the chance of congestive heart failure when combined with anthracyclines.
4) The high price of trastuzumab, the importance of Her-2/neu status confirmation and its testing cost.
5. Pre-treatment preparation
1) Precise Her-2/neu testing (see Annex 1 for details) to determine the presence or absence of Her-2/neu overexpression.
2) Cardiac function tests (cardiac ultrasound or isotope scan, with the former being more commonly used).
3) Sign the informed consent form for treatment-targeted therapy.
6. Method of use and precautions
1) Trastuzumab 6 mg/kg (first dose 8 mg/kg) every 3 weeks or 2 mg/kg (first dose 4 mg/kg) weekly regimen. The current tentative recommendation is 1 year of treatment, either concurrently with chemotherapy or sequentially after chemotherapy.
2) Observation for 4-8 h after the first treatment.
3) Caution should be exercised when used concurrently with anthracyclines, but it can be used in a sequential manner before and after. It can be used concurrently with non-anthracycline chemotherapy, endocrine therapy or radiotherapy.
4) LVEF should be monitored every 3 months; if LVEF falls below 50% during treatment, treatment should be suspended and LVEF results should be followed until it is above 50% before continuing the drug. Trastuzumab therapy should be discontinued if it does not recover, or if it continues to deteriorate or if symptoms of heart failure develop.
7. Principles of neoadjuvant chemotherapy treatment for breast cancer with trastuzumab
In the Buzdar neoadjuvant trial, trastuzumab in combination with paclitaxel in sequential CEF chemotherapy significantly improved the pCR rate compared to chemotherapy alone. In the Buzdar neoadjuvant trial, trastuzumab combined with paclitaxel sequential CEF chemotherapy resulted in a pCR rate of 65.2%, significantly higher than that of 26.3% in the chemotherapy alone group (P=0.016). The NOAH study showed that trastuzumab combined with AT/T/CMF regimen significantly increased the pCR rate in Her-2-positive locally advanced breast cancer (43% vs. 23% P=0.002). However, the available data on neoadjuvant therapy are relatively insufficient and clinical consideration of the regimen should be cautious, while the design of clinical study protocols should be more careful considering scientific and ethical principles. It is important to note that short-term trastuzumab used in combination with chemotherapy may achieve higher pCR, but not necessarily longer disease-free survival, and it is more difficult to determine the improvement of OS, so it cannot replace the subsequent long-term adjuvant therapy.
Therefore, trastuzumab is recommended as postoperative adjuvant for patients who have been treated with trastuzumab in preoperative neoadjuvant therapy for a total duration of 1 year.
Trastuzumab is recommended for postoperative adjuvant therapy for Her-2 positive breast cancer patients who have not used trastuzumab in preoperative neoadjuvant therapy.
8. Principles of adjuvant chemotherapy for breast cancer with trastuzumab
Clinical studies have shown that the use of trastuzumab for postoperative adjuvant treatment of Her-2-positive early-stage breast cancer significantly reduces recurrence and death. Therefore, both the NCCN and the Chinese cNCCN clinical practice guidelines for breast cancer include trastuzumab adjuvant therapy.
1) Adjuvant trastuzumab for Her-2 positive breast cancer
① AC-TH: Doxorubicin (or epirubicin) in combination with cyclophosphamide for 1/21 d x 4 cycles, followed by 4 cycles of paclitaxel or doxorubicin, along with weekly trastuzumab therapy of 2 mg/kg (first dose 4 mg/kg) or once every 3 weeks 6 mg/kg (first dose 8 mg/kg) for 1 year.
② Patients who are not suitable for anthracyclines can be treated with TCH: doxorubicin 75 mg/m2 and carboplatin AUC 6 every 21 d for 6 cycles, along with trastuzumab weekly therapy, and trastuzumab 6 mg/kg once every 3 weeks to 1 year after the end of chemotherapy.
(iii) 1 year of treatment with trastuzumab alone after standard chemotherapy, trastuzumab 6 mg/kg, (first dose 8 mg/kg), every 3 weeks regimen, for 1 year.
④ The 4-year follow-up results of the HERA study showed that patients with Her-2-positive breast cancer who were not initially treated with trastuzumab after surgery could also benefit from delayed adjuvant trastuzumab, and therefore patients who had finished adjuvant chemotherapy but remained disease-free could be treated with trastuzumab for 1 year.
2) Currently, the appropriate dosing period for adjuvant trastuzumab in Her-2-positive breast cancer is 1 year, because the latest follow-up results from Finher did not demonstrate that a short course of 9 weeks of trastuzumab treatment improves prognosis, so the 9-week regimen of trastuzumab adjuvant therapy is not recommended at this time, and there is no evidence to date that 2 years of adjuvant therapy is more effective.
9. Principles of relapsed metastatic breast cancer with trastuzumab-relief chemotherapy treatment
1) For Her-2 positive advanced recurrent metastatic breast cancer, the first choice of treatment should be trastuzumab-containing based therapy, with the patient’s hormone receptor status and previous (neo)adjuvant therapy being used as the basis for selecting a treatment regimen to maximize the patient’s benefit.
2) Trastuzumab monotherapy for Her-2 positive metastatic breast cancer has shown some efficacy, but more clinical studies have shown that trastuzumab is more effective in combination with chemotherapeutic agents. trastuzumab in combination with paclitaxel published in the New England Journal of Medicine (NEJM) by Slamon et al. and trastuzumab in combination with doxorubicin published in the Journal of Clinical Oncology (JCO) by Marty et al. The results of the pivotal phase III clinical study, published in the Journal of Clinical Oncology (JCO), established trastuzumab in combination with paclitaxel as the first-line treatment for Her-2-positive advanced breast cancer. Therefore, trastuzumab in combination with paclitaxel or doxorubicin can be the first-line option for Her-2 positive breast cancer that has failed anthracycline chemotherapy.
3) Trastuzumab can be combined with other chemotherapeutic agents such as vincristine, platinum, capecitabine and gemcitabine for Her-2 positive breast cancer that failed paclitaxel treatment.
4) The results of the study showed that trastuzumab combined with anastrozole in first-line treatment of Her-2 concurrent ER/PR-positive advanced breast cancer was significantly better than anastrozole alone in terms of progression-free survival, clinical benefit rate and time to disease progression. Therefore, patients with Her-2 and hormone receptor-positive postmenopausal metastatic breast cancer can be treated with trastuzumab in combination with an aromatase inhibitor.
5) Treatment strategy after disease progression with trastuzumab
① Continue trastuzumab and replace with other chemotherapy drugs
With conventional cytotoxic drug therapy, disease progression means a change in treatment regimen is required. However, due to its different mechanism of action, trastuzumab does not necessarily need to be discontinued when a patient has been treated effectively and subsequently develops disease progression.
Preclinical studies have shown that continued trastuzumab inhibition of Her-2 expression helps control breast cancer cell growth, while discontinuation of trastuzumab results in accelerated tumor growth. The results of the GBG26/BIG03-05 randomized clinical trial of trastuzumab for the treatment of disease progressive metastatic Her-2-positive breast cancer, randomized to capecitabine alone and capecitabine in combination with trastuzumab, showed that continued treatment with trastuzumab after disease progression still resulted in a longer time free of disease progression.
Therefore, after disease progression with trastuzumab combination chemotherapy for Her-2-positive breast cancer, trastuzumab can be retained and replaced with other combination chemotherapy regimens.
② Switch to other targeted therapies
Clinical studies have demonstrated that lapatinib + capecitabine has a longer time to disease progression than capecitabine alone in breast cancer that has failed trastuzumab treatment, so patients with Her-2 positive disease progression after trastuzumab regimen can also choose lapatinib + capecitabine.
③ A regimen of trastuzumab + other targeted therapeutic agents (lapatinib) that are non-cytotoxic may also be considered.
10. Cardiotoxicity of trastuzumab
Trastuzumab in combination with chemotherapeutic agents, especially anthracyclines, may increase myocardial damage, and heart failure may occur in severe cases. Although the number of cardiotoxic events in the NSABPB-31, N9831 and HERA trials was low and recoverable, the clinical studies enrolled cases that were screened for safety of cardiac function after chemotherapy.
In clinical practice, it is recommended that trastuzumab be initiated after baseline assessment of past history, physical examination, electrocardiogram, and echocardiogram LVEF, and that cardiac function should be monitored every 3 months during its use. Monitoring should be more frequent (e.g., every 6 to 8 weeks) if the patient has asymptomatic cardiac insufficiency, and trastuzumab therapy should be discontinued for at least 4 weeks and LVEF should be tested every 4 weeks if.
1) LVEF decreases ≥16% in absolute terms from pre-treatment values.
2) LVEF falls below the normal range of the test center and LVEF decreases by ≥10% in absolute terms from the pretreatment value.
3) Resumption of trastuzumab if LVEF returns to the normal range within 4 to 8 weeks or if LVEF decreases by ≤15% in absolute terms from pre-treatment values.
4) Trastuzumab should be permanently discontinued if LVEF continues to decline (>8 weeks) or if trastuzumab therapy is discontinued more than 3 times due to cardiomyopathy.
Annex 1 Her-2 test and outcome determination criteria.
1, Her-2 positivity can be defined as a standard immunohistochemistry (IHC) ++++, or a positive fluorescence in situ hybridization (FISH) assay.
2, if the patient’s immunohistochemistry test shows Her-2 (+++), it can be directly judged as Her-2 positive; if immunohistochemistry test Her-2
(++), FISH should be performed again for clarification. If the standard laboratory immunohistochemistry test result Her-2 (+) or Her-2 (-), it is judged as Her-2 negative.
3. Her-2 positivity can also be determined by FISH testing. The FISH test performed in a qualified laboratory with a ratio >2.2 can be judged as Her-2 positive; <1.8 is a Her-2 negative patient; if the result obtained is a threshold value of 1.8 to 2.2, it should be combined with immunohistochemistry results.
4, if the patient’s disease development does not conform to the characteristics of Her-2 negative patients, the clinic believes that it is possible to be Her-2 positive, or relapsed metastatic patients in the course of treatment in order to strive for treatment opportunities, it is recommended to conduct Her-2 re-testing, which can be done with the primary tumor specimen, but it is more advocated to re-biopsy the relapsed lesion, the method can be used IHC or FISH.