Results Data were available for 1694 women randomly assigned to two years of treatment with trastuzumab, 1694 women assigned to one year of trastuzumab, and 1693 women assigned to observation. We report here the results only of treatment with trastuzumab for one year or observation. At the first planned interim analysis (median follow-up of one year), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P. Her2/ neu (hereafter referred to as HER2) belongs to a family of four transmembrane receptor tyrosine kinases that mediate the growth, differentiation, and survival of cells.

Overexpression of the HER2 protein, amplification of the HER2 gene, or both occur in approximately 15 to 25 percent of breast cancers, and are associated with aggressive behavior in the tumor. Trastuzumab (Herceptin, Roche), a humanized monoclonal antibody against the extracellular domain of HER2, has been shown to benefit patients with HER2-positive metastatic breast cancer when administered weekly or every three weeks, alone or in combination with chemotherapy. Trastuzumab is not associated with the adverse events that typically occur with chemotherapy, such as alopecia, myelosuppression, and severe nausea and vomiting.

Shank is the cult-classic revival of the sidescrolling beat-em-up. Play as Shank in an over-the-top grindhouse game, packed to the rim with enemies, bosses, combos, and more by the award-winning team at Klei Entertainment. The 2D sidescroller beat-em-up is finally on Steamplay, now with improved. You are here. Home»Fixes»PC»Shank»Shank v1.0 All No-DVD [Reloaded]. Shank v1.0 All No-DVD [Reloaded]. Install Fonts Windows 10. Image gallery (0) Add an image Contribute fixes. Total votes: 49. March 11, 2011 - 9:31am. Shank v1.0 All No-DVD [Reloaded].

With the exception of hypersensitivity, which has been seen mainly and occasionally with the first infusion, cardiotoxicity (principally congestive heart failure) is the most important adverse effect of trastuzumab. Cardiotoxicity has been reported in 1.4 percent of women who received the drug as a single agent for metastatic disease. The adverse effect of the interaction between trastuzumab and anthracyclines on the heart and the lesser adverse effect of the interaction between trastuzumab and taxanes are concerns in the design and conduct of studies of adjuvant therapy, given the established activity and central role of anthracyclines and taxanes in the treatment of breast cancer.

For this reason, investigations of trastuzumab in the adjuvant setting require careful cardiac monitoring and stopping rules specified for cardiotoxicity. Our group investigated whether the administration of trastuzumab was effective as adjuvant treatment for HER2-positive breast cancer if used after completion of the primary treatment (e.g., surgery, radiotherapy, and chemotherapy given preoperatively [neoadjuvant], postoperatively [adjuvant], or both). The administration of trastuzumab after chemotherapy permits the application of our findings to the wide variety of chemotherapy regimens used throughout the world. In our trial, one group of women received trastuzumab for one year and another group received the drug for two years. We included these two groups for three reasons: a major peak in the rate of relapse occurs 18 to 24 months after surgery, effective treatment of HER2-positive breast cancer may require prolonged attenuation of HER2 activity, and tamoxifen, which is an effective targeted therapy for breast cancer, is most beneficial when given for longer than one year. We report a comparison of the results obtained with observation or with one year of trastuzumab after primary treatment of breast cancer.

Eligibility Criteria Eligible patients had histologically confirmed, completely excised invasive breast cancer with HER2 overexpression or HER2 amplification as assessed in the participating institution and verified in the central laboratory of the trial (Kassel, Germany). A result on immunohistochemical analysis (IHC) at the central laboratory (Herceptest, Dako) of 3+ (IHC 3+), in a range from 0 to 3+ with higher values indicating increased overexpression, was required for confirmation of the status of tumors assessed at the participating institution as IHC 3+, and a positive result on fluorescence in situ hybridization (FISH) for HER2 amplification (PathVision, Vysis) at the central laboratory was required for tumors that were assessed in the participating institution as IHC 2+ or FISH-positive. The hormone-receptor status of the tumor was determined and the tumor tissue was accessible for central review. Eligible patients had node-positive disease (irrespective of pathological tumor size) or node-negative disease (including only a negative sentinel node) if on pathological examination the tumor size was larger than 1 cm. Adjuvant chemotherapy, neoadjuvant chemotherapy, or both, selected from a list of approved regimens consisting of at least four cycles (described in detail in, available with the full text of this article at www.nejm.org), was completed before randomization.

Adjuvant endocrine therapy, primarily tamoxifen, was given after chemotherapy to women with hormone-receptor–positive disease unless contraindicated. During the course of the trial, an amendment to the protocol allowed aromatase inhibitors to be used instead of, or in sequence with, tamoxifen. Patients were required to have adequate baseline hepatic, renal, and bone marrow function.

Patients were required to use adequate non–hormone-based contraceptive measures, if indicated. Patients were excluded if they had distant metastases, a previous invasive breast carcinoma, or a neoplasm not involving the breast, except for curatively treated basal-cell or squamous-cell carcinoma of the skin or in situ carcinoma of the cervix. Patients with clinical stage T4 tumors, including inflammatory breast cancers or involvement of supraclavicular nodes, were not eligible. F5n Drivers For Windows 7.

Suspicious internal mammary nodes were an exclusion criterion, unless they were subjected to radiotherapy. Prior mediastinal irradiation (except internal mammary-node irradiation for the present breast cancer) and cumulative doses of anthracycline exceeding 360 mg per square meter of body-surface area for doxorubicin, or 720 mg per square meter for epirubicin or stem-cell support for chemotherapy were also exclusion criteria. Only patients who, after completion of all chemotherapy and radiotherapy, had a normal left ventricular ejection fraction (LVEF) (≥55 percent as measured on echocardiography or multiple gated acquisition [MUGA] scanning) were eligible. Cardiac exclusion criteria included a history of documented congestive heart failure, coronary artery disease with previous Q-wave myocardial infarction, angina pectoris requiring medication, uncontrolled hypertension, clinically significant valvular disease, and unstable arrhythmias. Administration of Trastuzumab Trastuzumab was administered intravenously over a 90-minute period at all doses. Patients were closely observed for at least six hours after the start of the first dose of 8 mg per kilogram of body weight of trastuzumab.

The second and all subsequent maintenance doses were 6 mg per kilogram given every three weeks. Actual body weight was used to calculate the dose. If the administration of trastuzumab was delayed by more than seven days, treatment was restarted at the level of the initial dose of 8 mg per kilogram, which was followed by the usual maintenance dose (6 mg per kilogram every three weeks). If nonhematologic grade 3 or 4 toxic effects occurred, trastuzumab was temporarily withheld until recovery to grade 2 or lower; it was discontinued if the recovery took more than five weeks, if the severe side effect recurred on readministration of trastuzumab, or if symptomatic congestive heart failure and an LVEF of 45 percent or less developed or an LVEF of less than 50 percent with an absolute reduction of at least 10 percent from baseline developed. In patients without symptoms of congestive heart failure, the same criteria for left ventricular function were used to withhold treatment.

Trastuzumab was discontinued if, in asymptomatic patients, left ventricular function did not return to a level above the criteria for withholding treatment after the therapy was stopped for three weeks. Follow-up Procedures All patients adhered to the same schedule of follow-up visits, which required the recording of symptoms, side effects (graded according to the National Cancer Institute Common Toxicity Criteria [NCI-CTC] version 2.0), and findings on clinical examination every three months for the first two years, with hematologic and chemistry studies performed every six months. These assessments are scheduled to occur annually for year 3 to year 10. Annual chest radiography is required to year 5 and annual mammography to year 10.

Cardiac Monitoring Cardiac monitoring in the trastuzumab group and the observation group included responses to a cardiac questionnaire, physical examination, 12-lead electrocardiogram, and an assessment of LVEF by echocardiography or MUGA scanning at baseline and 3, 6, 12, 18, 24, 30, 36, and 60 months after randomization. Cardiac events are described in Table 2 Adverse Events, with a Special Focus on Cardiotoxicity, among Patients Included in the Safety Analysis.. A core laboratory reviewed the echocardiograms, and data management and clinical science staff reviewed the MUGA scan results of the first 900 patients who were followed for six months. Three prespecified interim cardiac safety analyses were performed after 300, 600, and 900 patients had been enrolled and treated for at least six months.

An absolute difference of more than 4 percentage points in the incidence of severe congestive heart failure or cardiac death between the trastuzumab group and the observation group would have triggered a recommendation by the independent data-monitoring committee to stop or modify the trial. Statistical Analysis Enrollment of 4482 patients was planned to detect a 23 percent relative reduction in the risk of a disease-free–survival event with 80 percent power, with the use of a two-sided significance level of 2.5 percent for each comparison: two years of trastuzumab versus observation and one year of trastuzumab versus observation. A total of 951 disease-free–survival events were required for the final analysis. One interim efficacy analysis was planned after 475 events, with a specified significance level of P≤0.001 required, with the use of a sequential plan according to the O'Brien–Fleming boundary as implemented by Lan and DeMets.

The independent data-monitoring committee reviewed data on patient enrollment, deaths, compliance, and safety every six months and conducted the interim cardiac safety and efficacy reviews as preplanned. The efficacy analyses were conducted according to the intention-to-treat principle. Chi-square tests for categorical data and log-rank tests for time-to-event end points provided two-sided P values. Kaplan–Meier curves are presented. Cox proportional-hazards regression analysis was used to estimate hazard ratios and 95 percent confidence intervals. Interim Efficacy Analysis The 475 disease-free-survival events needed for the interim efficacy analysis were recorded in the database on March 29, 2005, and the database was locked on April 8, 2005; results were reviewed by the independent data-monitoring committee on April 25, 2005.

The independent data-monitoring committee recommended release of the results because improvements in disease-free survival were highly significant, crossing the sequential boundary for both one year and two years of trastuzumab, as compared with observation. After a median follow-up period of 1 year (range, 0 to 36 months), the independent data-monitoring committee released detailed information only for the groups assigned to 1 year of treatment with trastuzumab or observation. These groups are the focus of this report; evaluation of the group assigned to two years of treatment with trastuzumab is ongoing. Study Population Between December 2001 and March 2005, 5081 women for whom information was available for analysis were enrolled in the study. Of these, 1694 women were assigned to the trastuzumab group receiving the drug for one year and 1693 women were assigned to the observation group ( ).

HER2-positive status as assessed by the central laboratory was IHC 3+ without FISH testing among 67 percent of the patients. Lists baseline characteristics of the patients, tumors, and primary treatment. The baseline characteristics of the two groups were well balanced ( ). The median age was 49 years, one third of the patients had node-negative disease, and 48 percent of the patients had hormone-receptor–negative tumors. Chemotherapy was anthracycline-based in 94 percent of patients; 26 percent received a taxane, 76 percent received radiotherapy, and tamoxifen was the predominant endocrine therapy. The median time between diagnosis of breast cancer and the initiation of trastuzumab was 8.4 months (interquartile range, 7.1 to 9.6 months). There were major eligibility violations in 11 patients (8 patients in the trastuzumab group and 3 patients in the observation group): LVEF less than 55 (4 patients), status of HER2-positive not centrally confirmed (3 patients), microinvasive breast cancer (3 patients), and metastatic disease (1 patient).

In addition, 39 patients in the trastuzumab group and 52 patients in the observation group had node-negative disease with tumors 1 cm in diameter or less. Adverse Effects and Cardiac Safety Twenty patients assigned to one year of trastuzumab did not receive treatment, and three patients assigned to observation received trastuzumab. These 23 patients are included in the alternative group for the safety analyses ( and ). Shows a higher incidence of NCI-CTC grade 3 or 4 adverse events and serious adverse events in the trastuzumab group than in the observation group. There were six fatal adverse events in the trastuzumab group and three in the observation group ( ). There was one cardiac death in the observation group, and nine patients (0.54 percent) in the trastuzumab group had severe congestive heart failure (as defined in ). Symptomatic congestive heart failure, including the nine severe cases (as defined in ), occurred in 1.7 percent of patients in the trastuzumab group and 0.06 percent of patients in the observation group; a decrease in LVEF (as defined in ) was noted on at least one assessment among 7.1 percent of patients in the trastuzumab group and among 2.2 percent of those in the observation group.

Efficacy A total of 127 disease-free–survival events were reported in the trastuzumab group and 220 in the observation group ( Table 3 Efficacy End-Point Events (Intention-to-Treat Groups). The unadjusted hazard ratio for the risk of an event in the trastuzumab group, as compared with the observation group, was 0.54 (95 percent confidence interval, 0.43 to 0.67; P. Discussion This study shows that trastuzumab can benefit women with HER2-positive breast cancer when given after completion of adjuvant chemotherapy.

As compared with observation after primary therapy (including surgery with or without radiotherapy and neoadjuvant or adjuvant chemotherapy), trastuzumab given after primary therapy reduced the rate of recurrence, particularly distant recurrence, by approximately 50 percent. This degree of benefit in early breast cancer is the largest to be reported since the introduction of tamoxifen in hormone-receptor–positive disease. This trial is the culmination of a collaboration between basic research scientists and clinical investigators over the past two decades.

The interpretation of our results must take into account the very short follow-up period — a median of 12 months and a maximum of 36 months. However, the pattern of early, and largely distant, relapse found among patients with HER2-positive breast cancer, and the clinically and statistically significant reduction in the risk of relapse achieved with trastuzumab, justified release of the results of the interim efficacy analysis. We acknowledge that we have only an incomplete picture of the risks associated with trastuzumab.

The risk of cardiotoxicity is currently low in our trial, but this could change with longer follow-up. Another concern is that longer follow-up may show that trastuzumab is not effective in reducing the incidence of disease recurrence in the central nervous system. Brain metastases developed in approximately one third of the women receiving trastuzumab as treatment for advanced breast cancer, despite control of systemic disease.

It is not clear whether such central nervous system metastases reflect aggressive disease or poor penetration of trastuzumab into the brain. Will the benefit of adjuvant trastuzumab accrue to all women who have HER2-positive breast cancer who are treated outside clinical trials? Women with small (≤1 cm in diameter), node-negative invasive tumors were not eligible for this trial.

Although at a median of one year of follow-up, trastuzumab improved the disease-free survival in all subgroups ( ), further follow-up may show that the magnitudes of absolute benefit differ across subgroups. For example, almost 60 percent of the disease-free–survival events observed so far occurred in the hormone-receptor–negative cohort (48 percent of the patients), but we cannot rule out the possibility that in the future disease-free–survival events may occur disproportionately more often among patients in the subgroup with hormone-receptor–positive tumors. By design, women with cardiac risk factors and an LVEF of less than 55 percent after completion of chemotherapy with or without radiotherapy were excluded from the study, and our data are not applicable to the treatment of such women. In our study, HER2 overexpression or HER2 amplification had to be confirmed by a central laboratory before randomization, thereby reducing the risk of false positive results. It is our view that adjuvant trastuzumab should be considered only if the HER2-positive status of the tumor has been determined by a high-volume laboratory with quality-control procedures. The results of the HERA trial should be widely applicable to women with HER2-positive breast cancer for the following reasons: different types of neoadjuvant or adjuvant chemotherapy were allowed before the initiation of trastuzumab; the schedule of administration of one dose every three weeks, which was shown in the metastatic setting to have efficacy, side effects, and pharmacokinetics similar to those of the weekly schedule, was used; and patients with node-negative disease were included.

It appears that trastuzumab is effective regardless of the type of chemotherapeutic regimens received before treatment with trastuzumab and the extent of nodal involvement. We do not know if introducing trastuzumab early in the course of adjuvant systemic therapy, concomitantly with chemotherapy, could further improve the outcome. The question of timing is likely to remain unanswered, because early administration of trastuzumab, as studied in ongoing trials, requires the drug to be used concurrently with specific chemotherapy regimens that are hypothesized to enhance the effectiveness of trastuzumab. The results of this trial indicate that one year of adjuvant trastuzumab should be considered a standard option on completion of locoregional therapy and neoadjuvant or adjuvant chemotherapy for women who fulfill the study eligibility criteria used in the HERA trial.

References • 1 Yarden Y, Sliwkowski M. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127-137 • 2 Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004;4:361-370 • 3 Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177-182 • 4 Slamon DJ, Godolphin W, Jones LA, et al.

Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-712 • 5 Vogel CL, Cobleigh MA, Tripathy D, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719-726 • 6 Baselga J, Carbonell X, Castaneda-Soto NJ, et al. Phase II study of efficacy, safety, and pharmacokinetics of trastuzumab monotherapy administered on a 3-weekly schedule. J Clin Oncol 20-2171 • 7 Slamon DJ, Leyland-Jones B, Shak S, et al. Concurrent administration of anti-HER2 monoclonal antibody and first-line chemotherapy for HER2-overexpressing metastatic breast cancer.

A phase III, multinational, randomized controlled trial. N Engl J Med 2001;344:783-792 • 8 Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 Study Group.

J Clin Oncol 20-4274 • 9 Bell R. What can we learn from Herceptin trials in metastatic breast cancer? Oncology 2002;63:Suppl 1:39-46.