I. Relationship between Her2 and tumors
The HER2 receptor (also known as c-erbB-2, HER2/neu) gene is located on human chromosome 17q21 and encodes a transmembrane glycoprotein with a molecular weight of 185 kD and tyrosine kinase activity, p180, which is a member of the EGFR family. The Her2 monomer is inactive and the Her2 heterodimer reduces endocytic degradation of EGFR, leading to overexpression of EGFR in the cell membrane, resulting in overproliferation and phenotypic malignant transformation.
It is only expressed at low levels in very few tissues after adulthood. However, it is overexpressed in a variety of human tumors, such as breast, ovarian, and endometrial cancers, and suggests a poor prognosis. It has been found that 30% of breast cancer patients have HER2 gene overexpression. These patients have high tumor malignancy, early onset of recurrence and metastasis, poor prognosis, and resistance to certain chemotherapeutic agents such as CMF regimen and endocrine therapy.
How to detect Her2
IHC3+ is HER2+ and IHC0 and 1+ are HER2-. IHC2+ is indeterminate and requires further HER2 detection by ISH to detect gene amplification status. strong and intact cell membrane staining.
The FISH technique hybridizes to DNA target sequences in the nucleus by means of fluorescently labeled DNA probes. Current probes for HER2 gene status detection are dual probes containing both the HER2 gene and the sequence of the chromosome 17 mitogen (CEPl7) where the gene is located or single probes containing only the HER2 gene.
(1) HER2+ when HER2/CEP17 ratio ≥ 2,0; HER2+ also when HER2/CEP17 ratio < 2,0 but mean her2 copy number/cell ≥ 6,0.
(2) HER2- when HER2/CEPl7 ratio was <2,0 and mean her2 copy number/cell was <4,0.
(3) HER2ISH results were inconclusive when HER2/CEP17 ratio was <2, 0 and mean her2 copy number/cell was <6, 0 but >4, 0. For cases with indeterminate ISH results. The signal in 20 more nuclei need to be counted or recounted by another analyst.
III. Principles of biologically targeted therapy for breast cancer
(1) Biologically targeted therapeutic agents
A. Trastuzumab: Anti-Her2 monoclonal antibody, which blocks the growth of cancer cells by attaching itself to Her2 to prevent the human epidermal growth factor from attaching to Her2, Herceptin can also stimulate the body’s own immune cells to destroy cancer cells.
B. Patuximab, Pertuzumab, Perjeta: a monoclonal antibody. By binding HER2, it blocks the heterodimerization of HER2 with other HER receptors, thus slowing down the growth of the tumor.
C. Lapatinib, Lapatinib: an orally administered small molecule epidermal growth factor tyrosine kinase inhibitor.
D. Trastuzumabemtansine (T-DM1): is a novel antibody drug that is coupled with trastuzumab and DM1, a small molecule microtubule inhibitor, to produce a synergistic anti-cancer effect.
(2) Expert recommendations for the treatment of HER-2-positive breast cancer
During the American Society of Clinical Oncology in 2014, the expert panel presented the preferred expert recommendations namely the American Society of Clinical Oncology Clinical Practice Guidelines: Systemic Therapy for HER-2-positive Advanced Breast Cancer. In this guideline, the following consensus was proposed.
1. Her-2 targeted therapy-based combination therapy is recommended as first-line treatment (trastuzumab, pertuzumab combined with paclitaxel-based chemotherapy).
2, If disease progression occurs after the treatment period, T-DM1 monotherapy is recommended as second-line therapy to improve patient prognosis. Lapatinib in combination with gemcitabine can be applied to treat Her-2-positive breast cancer that is not treated with anthracycline, paclitaxel and trastuzumab.
3. Third-line treatment can be applied either with T-DM1 (not previously applied) or with pertuzumab (not previously used).
4. Targeted therapy combined with chemotherapy or targeted therapy combined with endocrine therapy is recommended for Her-2-positive patients with hormone receptor-positive disease (endocrine therapy alone can be applied in certain patients).
(3) Current status of treatment for Chinese patients with Her-2-positive breast cancer
Foreign guidelines recommend chemotherapy plus combination targeting, but since the drugs recommended in the guidelines, such as pertuzumab and T-DM1, are not yet available in China, in clinical work, clinicians need to combine the reality and actively explore combination chemotherapy plus single targeting to develop an individualized treatment plan for HER-2-positive MBC patients under the framework of the guidelines.
A. Adjuvant endocrine therapy combined with chemotherapy and trastuzumab targeted therapy is recommended for patients with primary tumor >1cm, positive lymph nodes, positive hormone receptors and Her-2 positive breast cancer.
B. Adjuvant chemotherapy combined with trastuzumab targeted therapy is recommended for patients with primary tumor >1cm, positive lymph nodes, hormone receptor negative and Her-2 positive breast cancer.
C. Combination chemotherapy regimen
Early-stage breast cancer and locally advanced breast cancer
Preferred regimen.
AC → TH (doxorubicin/cyclophosphamide → paclitaxel + trastuzumab) regimen
Intensive AC→Intensive paclitaxel+trastuzumab regimen
TCH (docetaxel/carboplatin/trastuzumab) regimen
Other regimens
AC→docetaxel+trastuzumab regimen
Docetaxel/cyclophosphamide + trastuzumab regimen
Paclitaxel + trastuzumab
Recurrent or stage IV tumors
Preferred regimen.
Paclitaxel±carboplatin+trastuzumab-containing regimen
Docetaxel + trastuzumab regimen
Vincristine + trastuzumab regimen
Capecitabine + trastuzumab regimen
Preferred regimen for patients who have relapsed or stage IV on trastuzumab
Lapatinib in combination with capecitabine
Capecitabine + trastuzumab regimen
Lapatinib + trastuzumab regimen
In case of bone metastasis can be combined with osteoprotective drugs. If 3 consecutive chemotherapy regimens are ineffective or ECOG physical status score >3, chemotherapy will no longer be considered and palliative treatment will be used instead.
D. Trastuzumab application dose
8mg/kg for the first dose of 3-week therapy, followed by 6mg/kg every 3 weeks
The first dose of one-week therapy was 4mg/kg, followed by 2mg/kg every week.
Total 52 weeks.
E. Precautions for trastuzumab application
Trastuzumab can cause left ventricular insufficiency p arrhythmia p hypertension p symptomatic heart failure p cardiomyopathy p and cardiogenic death, and also cause symptomatic left ventricular ejection fraction (LVEF) reduction. And the absolute incidence of symptomatic cardiac insufficiency is highest when trastuzumab is used in combination with anthracyclines.
Therefore, concomitant trastuzumab and anthracycline chemotherapy should be avoided and left ventricular ejection fraction (LVEF) should be measured before starting treatment and LVEF should be monitored closely and frequently during treatment.
Trastuzumab treatment should be stopped for at least 4 weeks and LVEF should be tested every 4 weeks if the following conditions occur:
(1) LVEF decreases ≥16% in absolute terms from pre-treatment values.
(2) LVEF is below the normal range of the test center and LVEF has decreased by ≥10% in absolute terms from the pre-treatment value.
(3) Trastuzumab may be resumed if LVEF returns to the normal range within 4-8 weeks or if there is an absolute decrease in LVEF of ≤15% from pretreatment 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.