Adjuvant treatment of breast cancer The efficacy and safety of trastuzumab combined with chemotherapy in adjuvant treatment of breast cancer patients with HER2 overexpression were studied through the combined analysis of two randomized, open clinical trials [NSAPB B31 and NCCTGN9831]. In addition, the efficacy and safety of trastuzumab as adjuvant therapy were also studied in a randomized, open clinical trial (HERA (BO16348)) of 3386 patients. In clinical trials of NSAPB B31 and NCCTG N9831, breast tumor specimens must show HER2 overexpression (IHC test showed 3+) or gene amplification (FISH test was positive). HER2 examination was confirmed by the central laboratory (NCCTG N9831) or required to be completed in the reference laboratory (NSAPB B31) before random grouping. Patients with symptomatic history of active heart disease or uncontrollable hypertension (diastolic pressure ]1mmHg or systolic pressure ]2mmHg) with abnormal electrocardiogram, radiology or left ventricular ejection fraction were not included in the group. Patients were randomly (1: 1) given doxorubicin and cyclophosphamide followed by sequential paclitaxel (AC? Paclitaxel) or paclitaxel plus trastuzumab (AC paclitaxel plus trastuzumab). In two studies, patients received four treatments of 6 mg/m doxorubicin and 6 mg/m cyclophosphamide for 21 days. In NSAPB B31, paclitaxel was administered once a week (822mg/m) or once every three weeks (175mg/m) for 12 weeks. In NCCTG N9831, paclitaxel is administered according to weekly regimen. Tratuzumab was given at an initial loading dose of 4mg/kg on the day of initial treatment of paclitaxel, and then at a maintenance dose of 2mg/kg every week for 52 weeks. When congestive heart failure or persistent/recurrent left ventricular ejection fraction decreases, the treatment of trastuzumab should be permanently suspended (see dosage and administration). If radiotherapy is given, it should generally start after chemotherapy is completed. Patients with ER positive and/or PR positive can receive hormone therapy. The main end point of combined efficacy analysis is disease-free survival (DFS), which is defined as the time from randomization to recurrence, contralateral breast cancer, second primary tumor or death. A total of 3752 patients were analyzed for effectiveness. The data came from two groups of NSAPB B31 and two groups of NCCTG N9831. The average age of these patients is 49 years old (ranging from 22 to 8 years old, 6%] 65 years old), 84% are white, 7% are black, 4% are Hispanic and 4% are Asian/Pacific island residents. The disease features include 9% histologically invasive ductal carcinoma, 38% T1, 91% lymph node involvement, 27% moderate and 66% high-grade tumor, and 53 ％ER-positive and/or PR-positive tumor. 53% patients were randomly assigned to receive weekly paclitaxel treatment, and the rest patients received weekly paclitaxel treatment plan. In HERA (BO16348): Breast cancer samples need to show HER2 gene overexpression (IHC3+) or amplification (FISH) after detection in the central laboratory. Patients with negative lymph nodes must be in stage ≥ T1c before they can be selected. Patients with congestive heart failure or LVEF[55%, intractable arrhythmia, angina pectoris requiring drug treatment, clinically significant valvular disease, transmural myocardial infarction shown by ECG, and poor control of hypertension (systolic pressure] 18 mm Hg or diastolic pressure] 1 mm Hg) are not suitable for this study. In this study, patients who completed radical surgery and received at least 4 cycles of chemotherapy were randomly divided into 1:1 groups; No further treatment (n = 1693) or one-year trastuzumab treatment (n = 1693). Patients who have received local excision of breast cancer have also finished radiotherapy. ER-positive and/or PgR-positive breast cancer patients received hormone adjuvant therapy under the guidance of researchers. Tratuzumab was administered in an initial loading dose of 8 mg/kg followed by a maintenance dose of 6 mg/kg every 3 weeks, with a total course of 52 weeks. The main end point is the same as NSAPB B31 and NCCTG N9831, and the disease-free survival time is the same. In this study, 3386 patients in two treatment groups were randomly assigned: the median age was 49 years old (range: 21-8 years old), 83% patients were Caucasian, and 13% patients were Asian. The characteristics of breast cancer in these patients are: 94% patients are invasive ductal carcinoma, 5% patients are ER-positive and/or PgR-positive, 57% patients are lymph node-positive, 32% patients are lymph node-negative, and 11% patients are unable to determine their lymph node status because of the neoadjuvant chemotherapy. 96%(155/198 cases) of patients with negative lymph nodes have high risk factors: among these 198 patients with negative lymph nodes, 49%(543 cases) are ER-negative and PgR-negative, and 47% (512 cases) are ER-positive and/or PgR-positive, and there is at least one of the following high risk factors: tumor diameter greater than 2 cm and pathological grade 2-3. Before randomization, 94% patients had received chemotherapy containing anthracycline antibiotics. See table 1 for the combined DFS analysis results of NSAPB B31 and NCCTG N9831 (see figure 3) and the DFS analysis results of NSAPB B31 and NCC TG N9831 and HERA (BO16348). In NSAPB B31 and NCCTG N9831, the number of patients in the following subgroups is small, and it is impossible to determine whether the curative effect of these subgroups is different from that of the total population: patients without lymph node metastasis, patients with low tumor pathological grade, and patients with special race/race (black, Spanish, Asia/Pacific island). In HERA (BO16348), the number of patients in the following subgroups is small, and it is impossible to determine whether the curative effect of these subgroups is different from that of the total population: patients with low tumor pathological grade, patients with special race/race (black, Spanish, Asia/Pacific island), or patients over 65 years old. Table 1 Therapeutic Effects of Tratuzumab on Breast Cancer after Adjuvant Therapy (NSAPB B31, NCCTG N9831 and HERA) In patients with NCCTG N9831 and HERA (BO16348), the effects of HER2 overexpression or gene amplification on DFS were explored. The analysis results are shown in Table 11. In NCCTG N9831, only IHC 3+/FISH+ subgroup had more events, accounting for 81% of the data. Because there are fewer events in other subgroups, it is impossible to draw a definite conclusion on the curative effect. In HERA(BO16348), there are enough events to prove that the unknown IHC 3+/FISH and the unknown FISH +/IHC have a significant impact on DFS. HERA(BO16348) included 122 patients from China (54 in the observation group and 68 in the one-year treatment group with trastuzumab). The average age of 122 patients with China is 46 years old (26-67 years old). The vast majority of patients (92%) had invasive ductal carcinoma as the pathological type of primary tumor. 5% of the patients were lymph node positive, 4% were lymph node negative, and 1% of the patients could not evaluate the lymph node status because of receiving neoadjuvant chemotherapy. Estrogen receptor positive patients accounted for 41%. 91% patients received anthracyclines in adjuvant therapy, and 26% patients received anthracyclines combined with taxanes in adjuvant therapy. In the DFS analysis of HERA (BO16348), the 2-year disease-free survival rates of the observation group and the one-year treatment group of China patients were 81.4% and 92.9% respectively, and the one-year treatment of trastuzumab reduced the risk of disease recurrence, metastasis or death (HR .29, 95% CI .8-1.8, p=.489). The clinical benefit trend of China patients after receiving trastuzumab adjuvant therapy is consistent with the overall curative effect of HERA (BO16348). See Table 12. Metastatic breast cancer In a randomized controlled clinical trial (H648g, n=469) and an open single drug clinical trial (H649g, n=222), the safety and effectiveness of trastuzumab combined with chemotherapy in metastatic breast cancer were studied. Both trials were aimed at patients with metastatic breast cancer whose HER2 protein was overexpressed. Immunohistochemical evaluation of central laboratory showed that patients with grade 2 or grade 3 overexpression of HER2 protein (grade ~ 3) in tumor tissues met the inclusion conditions. First-line treatment of metastatic breast cancer (H648g) H648g is a randomized, open and multicenter clinical trial, which was conducted in 469 women with metastatic breast cancer who did not receive chemotherapy. Tumor samples were tested by IHC (clinical research detection, CTA), and scored according to , 1+, 2+ and 3+, with 3+ being the strongest positive. Only 2+ or 3+ positive tumors meet the requirements (about 33% of the screeners). Patients were randomly treated with chemotherapy alone or combined with trastuzumab. Tratuzumab was given the first loading dose of 4mg/kg by intravenous infusion, and then the weekly maintenance dose of 2mg/kg was given. For patients who have received anthracycline drugs in adjuvant therapy, paclitaxel (175mg/m[sup]2[/sup], intravenous infusion for at least 3 hours, 21 days as a course of treatment, at least 6 courses of treatment) was used for chemotherapy; Other patients were treated with anthracycline plus cyclophosphamide (AC: 6 mg/m [sup] 2 or 75 mg/m [sup] 2 [/sup] of epirubicin+6 mg/m[sup]2[/sup] of cyclophosphamide, with 21 days as one course of treatment and 6 courses of treatment). In this trial, 65% of patients randomly assigned to receive single chemotherapy were treated with trastuzumab as the disease progressed, as part of an independent extended study. According to the conclusion of the Independent Review Committee, compared with patients who only received chemotherapy, patients who randomly received trastuzumab and chemotherapy significantly prolonged the median disease progression time, increased the overall remission rate (ORR) and prolonged the median remission duration. Patients who randomly received trastuzumab and chemotherapy also had a longer median survival time (see Table 13). These therapeutic effects can be seen in both patients receiving trastuzumab plus paclitaxel and patients receiving trastuzumab plus AC, but the effect is better in the combination of paclitaxel. Table 13 H648g: First-line therapeutic effect of metastatic breast cancer According to the data of H648g, the benefit of clinical efficacy is mainly limited to patients with the highest level of HER2 protein overexpression (3+) (see Table 14). In a multicenter, open single-group clinical trial (H649g), a single-drug trial of trastuzumab was conducted in patients with metastatic breast cancer with overexpression of HER2, who had previously received chemotherapy for metastatic diseases once or twice. Of the 222 patients, 66% had received adjuvant chemotherapy, 68% had received two chemotherapy schemes to treat metastatic diseases, and 25% had received pre-myeloablative and hematopoietic reconstruction treatment. The patient received intravenous infusion of tratuzumab at the first loading dose of 4mg/kg, followed by intravenous infusion at the maintenance dose of 2mg/kg once a week. The ORR (Complete Remission+Partial Remission) is 14%, of which the complete remission rate is 2% and the partial remission rate is 12%. Complete remission is only seen in patients whose tumor metastasis is limited to skin and lymph nodes. The overall remission rate of patients with CTA 3+ and CTA 2+ was 18% and 6%, respectively. Metastatic gastric cancer In a randomized (1:1), controlled and open multicenter phase III clinical trial (ToGA trial), the safety and efficacy of trastuzumab combined with capecitabine or 5-FU and cisplatin in the treatment of metastatic gastric cancer patients with HER2 overexpression were compared. The patients who participated in the trial were metastatic gastric adenocarcinoma or gastric esophageal junction adenocarcinoma that had not been treated before. The primary endpoint was overall survival. A total of 594 patients were enrolled, and 314 patients (53%) were enrolled from Asian countries. In the second interim analysis of the plan, the results were statistically improved, and the study was terminated early. At the time of analysis, *** 351 patients who were randomly assigned died: 184 patients in the control group (62.2%) and 167 patients in the experimental group (56.%). Most of the deaths are related to patients' cancer diseases. Randomly stratified according to the following parameters: disease degree (metastasis and local advanced stage), primary site (stomach vs. gastroesophageal junction), measurable tumor focus (yes vs. no), physical condition of ECOG (,1 vs. 2) and fluorouracil (capecitabine vs. 5- fluorouracil). All patients are HER2 gene amplification (FISH+) or HER2 overexpression (IHC 3+), and patients are also required to have appropriate cardiac function (such as LVEF] 5%). In the treatment group containing trastuzumab, the initial dose of trastuzumab was 8 mg/kg and the subsequent dose was 6mg/kg, once every 3 weeks until the disease progressed. In the two study groups, starting from the first day, cisplatin was gIVen iv at a dose of 8mg/m2 for 2 hours, once every 3 weeks for ***6 cycles. In the two study groups, capecitabine was given orally at a dose of 1mg/m[sup]2[/sup] twice a day (with a total daily dose of 2mg/m2) for 14 days, 21 days per cycle, *** 6 cycles. Another alternative treatment is continuous intravenous infusion (CIV )5- of 5-fluorouracil at a dose of 8 mg/m2/ day once every 3 weeks for 6 cycles. The median age of the study population is 6 years old (range: 21 ~ 83 years old); 76% are men; 53% are Asians, 38% are Caucasians, 5% are Spanish, and 5% are other races/races; 91% ECOG PS is or 1; 82% suffered from primary gastric cancer, and 18% suffered from primary adenocarcinoma of the gastroesophageal junction. Of these patients, 23% had undergone gastrectomy.