Clinical trials of Herceptin(trastuzumab)

This report summarises the clinical efficacy and safety findings from clinical trials of the new anti-HER2 monoclonal antibody Herceptin(trastuzumab). Data from pivotal trials indicate that trastuzumab is active when added to chemotherapy in patients with advanced metastatic breast cancer. In particular, the combination significantly prolonged the median time to disease progression, increased the overall response rate, increased the duration of response, and improved median survival time by approximately 25% compared with chemotherapy alone. Furthermore, trastuzumab is active as a single agent in women with HER2-positive metastatic breast cancer, inducing durable objective tumour responses. In total, 15% of patients who had received extensive prior treatment for metastatic disease had an objective response. The median duration of response was 9.1 months following administration of single-agent trastuzumab. Notably, 2% of patients were free of disease progression at 6 months. The safety profile of trastuzumab either given alone or in combination was favourable.     

Use of trastuzumab beyond disease progression: observations from a retrospective review of case histories

HER2 overexpression is associated with poor breast cancer prognosis and is the target for the humanized monoclonal antibody trastuzumab. This novel agent, when administered until disease progression in combination with chemotherapy, extends the survival of women with HER2-positive metastatic breast cancer (MBC). However, the optimal duration of trastuzumab therapy remains to be confirmed. We conducted a retrospective case review study of women with HER2-positive MBC who continued to receive trastuzumab beyond disease progression. Objectives were to assess whether treatment beyond disease progression shows any evidence of efficacy and to evaluate the feasibility of this approach. One hundred five patients (median age, 47 years; range, 24-77 years) were identified in 13 centers. Women had received /=1 more trastuzumab regimen. Trastuzumab treatment beyond progression appears to be of value, producing responses and clinical benefit, and is well tolerated without significant cardiac toxicity. The feasibility of this approach warrants examination in prospective trials.     

Perspective of trastuzumab treatment

Trastuzumab (Herceptin) has many benefits for metastatic breast cancer patients with HER2 overexpression/amplification. Trastuzumab alone or trastuzumab in combination with chemotherapy regimens are standard treatment worldwide as first line therapy for metastatic breast cancer patients with HER2 overexpression/amplification. Furthermore, an international collaboration for adjuvant trastuzumab trials showed last year that trastuzumab treatment improves disease-free and overall survival after or in combination with adjuvant chemotherapy. However, there are many uncertain issues concerning trastuzumab adjuvant and metastatic treatment, such as treatment beyond disease progression (PD), combination with hormone therapy, duration of adjuvant treatment, and cardiac safety of long term treatment.     

曲妥珠单抗治疗后进展的转移性乳腺癌继续曲妥珠单抗治疗的疗效及安全性分析

目的：评价曲妥珠单抗治疗后进展的转移性乳腺癌患者继续行曲妥珠单抗治疗的疗效及安全性。方法回顾性分析曲妥珠单抗治疗过程中出现疾病进展,继续行曲妥珠单抗治疗,仅更换化疗方案的30例HER2阳性转移性乳腺癌患者的临床资料,并评价疗效及不良反应。结果30例HER2阳性转移性乳腺癌患者,均在复发转移阶段接受过曲妥珠单抗治疗,中位治疗时间6.0个月（95%CI为1.7~10.3个月）;30例患者在出现疾病进展后,均继续进行曲妥珠单抗治疗,仅更换联合的化疗方案。30例患者均可评价疗效,其中部分缓解（PR）7例（23.3%）,疾病稳定（SD）12例（40.0%）,疾病进展（PD）11例（36.7%）,无完全缓解（CR）患者。客观缓解率为23.3%,临床获益率为43.3%。总无进展生存期（PFS）为5.0个月（95%CI为3.0~7.0个月）。有临床获益的13例患者的PFS明显长于17例无临床获益者（9.0个月vs 3.0个月,P﹤0.001）。最常见的不良反应为血液学不良反应,考虑主要与化疗药物相关。结论对于曲妥珠单抗治疗过程中出现疾病进展的患者,继续使用曲妥珠单抗,更换化疗方案有较好的临床获益。     

A phase I-II study of combined blockade of the ErbB receptor network with trastuzumab and gefitinib in patients with HER2 (ErbB2)-overexpressing metastatic breast cancer

PURPOSE: To determine the safety, and efficacy of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in combination with trastuzumab in patients with metastatic HER2-positive metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with HER2-overexpressing breast cancer were treated with trastuzumab 2 mg/kg/week and gefitinib 250 to 500 mg/day. The primary end point of the study was to increase the proportion progression-free from 50% to 65% at 6 months in chemotherapy-naive patients and from 50% to 70% at 3 months in patients previously treated with chemotherapy in the metastatic setting. RESULTS: In the phase I study, all patients treated with gefitinib 500 mg/day developed grade 3 diarrhea. The phase II study was conducted using trastuzumab and gefitinib 250 mg/day. One patient achieved a complete response, 2 had a partial response, and 6 had stable disease for an overall response rate of 9% and a clinical benefit rate of 28% (9 of 32). Median time to progression (TTP) was 3 months (95% confidence interval, 2.3-4.1) in patients with no prior systemic therapy in the metastatic setting (n = 23). In patients treated with prior systemic therapy (n = 9), the median TTP of 5.3 months (95% confidence interval, 2.8-8.1). Overall median survival was 27 months. TTP was similar in EGFR-positive compared with EGFR-negative patients. CONCLUSIONS: Gefitinib 250 mg/day was the maximal dose that can be safely administered with weekly trastuzumab. Interim analysis of the efficacy suggested that the combination was unlikely to result in clinical benefit compared with trastuzumab alone. These results do not support the use of this combination in patients with HER2-positive breast cancer.     

Weekly paclitaxel plus trastuzumab in metastatic breast cancer pretreated with anthracyclines-a phase II multipractice study

ABSTRACT: BACKGROUND: The 3-weekly combination of trastuzumab and paclitaxel has been approved for the treatment of advanced breast cancer based on a large pivotal study. However, mono and combination chemotherapy trials suggest that weekly paclitaxel has a better therapeutic index, especially in the palliative setting. The present trial examined the efficacy and safety of weekly paclitaxel over a limited duration combined with continued trastuzumab in HER2+ patients. METHODS: Patients with histologically confirmed metastatic breast cancer overexpressing HER2 were eligible if pretreated with anthracycline in either the adjuvant or palliative setting. Treatment consisted of weekly trastuzumab (2 mg/kg/week for up to one year after a loading dose of 4 mg/kg in week 1) and paclitaxel (90 mg/m2, administered in weeks 1-6 and 8-13). RESULTS: Twenty-seven German centers enrolled 121 patients. The median number of metastatic sites was two (range 1-5); 38% of patients had received chemotherapy for advanced disease. After a median 42 weeks of trastuzumab treatment, limited by disease progression in roughly half the patients, a best objective response rate (complete response?+?partial response) of 76% was achieved, including complete remissions in 29%. 74% of patients lived without tumor progression at six months. Median progression-free and overall survival were 9.4 (95% confidence interval [CI]: 8.1-11.3) and 22 months (95% CI: 17-46). After alopecia, Common Toxicity Criteria grade ≥2 toxicity was predominantly hematological (leukopenia [31%] and anemia [41%]); however, thrombocytopenia occurred in only 5%. Neurotoxicity was remarkably low. Two cardiac events (grades 2 and 3) were presumed treatment-related. CONCLUSIONS: Weekly paclitaxel plus trastuzumab allows an increased dose density and offers an attractive and effective alternative to the conventional schedule. Limiting the duration of cytotoxic therapy to 3 months seems to be an option to reduce neurotoxicity without impairing long-term outcome.     

Trastuzumab (Herceptin) in the treatment of breast cancer with HER2 overexpression

HER2 is a 185 kDa transmembrane receptor with tyrosine kinase activity encoded by the HER2/neu gene. HER2 is overexpressed in 25%–30% of breast cancer and confers an agressive clinic course. Trastuzumab (Herceptin) is a monoclonal antibody directed against HER2 receptor that has a favorable toxicity profile and produces responses as a single agent in women with metastatic breast cancer with HER2 overexpression. A multicenter phase III trial in HER2 positive metastatic breast cancer, compared first line chemotherapy with adriamycin/cyclophosphamide or paclitaxel alone or the same chemotherapy plus trastuzumab. Response rate, duration of response and time to progression, were better with the combination. Remarkably, overall survival was significantly improved in patients with trastuzumab and chemotherapy. These studies led to the approval of trastuzumab for HER2 positive metastatic breast cancer. Ongoing trials are analyzing new combinations of trastuzumab and chemotherapy or hormonal therapy. The role of trastuzumab in adjuvant and neoadjuvant therapy is also under investigation.      

Spotlight on Trastuzumab in Metastatic Breast Cancer Overexpressing HER2

Trastuzumab is a humanized monoclonal antibody developed to target the HER2 receptor which is over-expressed by some cancer cells, including 25 to 30% of breast cancers. Binding with high affinity to the extracellular domain of HER2, trastuzumab inhibits the proliferation of tumor cells that overexpress HER2. A large well designed multicenter study found that the addition of trastuzumab to either an anthracycline plus cyclophosphamide or to paclitaxel, as first-line therapy for metastatic breast cancer overexpressing the HER2 receptor, significantly increased time to disease progression, rate of objective response, duration of response and survival compared with chemotherapy alone. Single-agent trastuzumab was associated with an objective response in 15% of extensively pretreated patients with metastatic breast cancer overexpressing HER2, and 26% of previously untreated patients. Patients with a HER2 overexpression level of 3+ using immunohistochemical assay, or a positive HER2 result using fluorescence in situ hybridisation, benefit more from trastuzumab therapy than those with tumors overexpressing at a level of 2+. Trastuzumab has demonstrated synergistic action with several chemotherapy agents preclinically but the optimal combination clinically is yet to be determined. Trastuzumab is generally well tolerated by most patients; the most significant adverse effects being acute fever and/or chills and the potential to cause cardiac dysfunction. Serious adverse events, including anaphylaxis and death, have occurred in 0.25% of patients. Symptomatic or asymptomatic cardiac dysfunction occurred in 27% of patients receiving an anthracycline and cyclophosphamide combined with trastuzumab. Thus, combination therapy with anthracyclines is not recommended. Symptomatic or asymptomatic cardiac dysfunction occurred in 13% of patients receiving trastuzumab plus paclitaxel and in 4.7% of patients receiving trastuzumab alone. In conclusion, intravenous trastuzumab is effective as a single-agent, and in combination with chemotherapy it significantly improves the median time to disease progression and survival time in patients with metastatic breast cancer overexpressing the HER2 receptor compared with chemotherapy alone. Cardiotoxicity is the main concern with therapy; particularly in patients with pre-existing cardiac dysfunction, the elderly and in combination with, or following, anthracyclines. Trastuzumab is indicated for use with paclitaxel as first-line therapy or as a single agent in second- or third-line treatment regimens for patients with metastatic breast cancer overexpressing HER2. Investigation is ongoing to ascertain the optimal combination regimen containing trastuzumab and antineoplastic agents. In addition, current research is focusing on the optimal timing, sequencing and duration of therapy as well as administration in the neoadjuvant and adjuvant setting.     

Combining the anti-HER2 antibody trastuzumab with taxanes in breast cancer: results and trial considerations

Overexpression of the p185/HER2 protein is seen in 20%-25% of primary breast cancers and is associated with poor prognosis. Recent phase II and III clinical trials demonstrate that trastuzumab is active against breast tumors, both as a single agent and in combination with chemotherapy. In patients with HER2-overexpressing metastatic breast cancer, use of trastuzumab in combination with chemotherapy is associated with a 20% reduction in relative risk of death and an increase in median survival from 20.3 to 25.1 months compared to chemotherapy alone. Side effects include fever and chills and an unexpected increase in doxorubicin/trastuzumab-associated cardiomyopathy. Clinical development is now focused on trastuzumab in combination with chemotherapy regimens that do not contain an anthracycline. Trastuzumab in combination with docetaxel is synergistic in vitro. Data from ongoing clinical trials are consistent with this finding. Preliminary data from 3 phase II studies suggest a 44%-63% response rate when the combination is used first or second line in HER2-overexpressing metastatic breast cancer. The combination of docetaxel with trastuzumab is well tolerated and has not been associated with significant cardiotoxicity. Given in vitro evidence that platinum salts act synergistically with trastuzumab and docetaxel, and phase II data suggesting clinical efficacy and good tolerability, the combination of platinum salt plus trastuzumab and docetaxel is now being assessed in adjuvant trials     

曲妥珠单抗治疗141例人表皮生长因子受体2阳性乳腺癌的回顾性分析

目的 总结曲妥珠单抗在人表皮生长因子受体2(Her-2)阳性乳腺癌患者新辅助、辅助和复发转移治疗中的临床应用经验,评价其与化疗联用的疗效.方法 对2004年1月至2008年12月门诊应用曲妥珠单抗治疗的141乳腺癌患者进行回顾性分析.随访时间为3～319个月.分析患者的无病生存时间(DFS),比较患者辅助、复发转移一线及二线使用曲妥珠单抗治疗的总生存时间(OS)、治疗失败时间(TTF)和临床有效率的差异.结果 与曲妥珠单抗治疗联用的新辅助化疗中,紫杉醇联合卡铂方案占66.7%;辅助治疗中,蒽环类和蒽环类序贯紫杉类方案占53.9%.复发转移的患者治疗后中位DFS为17个月.复发转移的患者经一线曲妥珠单抗联合化疗治疗后,临床总有效 率为84.5%,中位TTF为24个月;二线治疗有效率为44.4%,中位TTF为5个月.两者比较,差异有统计学意义(P=0.002).结论 紫杉醇和卡铂化疗联合曲妥珠单抗,值得在新辅助治疗中推广,紫杉类和蒽环类联合或序贯靶向治疗仍是辅助治疗的标准方案.转移性乳腺癌一线应用曲妥珠单抗联合化疗比二线治疗的临床有效率更高,在继续应用曲妥珠单抗的基础上改用化疗方案,可提高治疗有效率,减少治疗失败的概率.     

Herceptin, a monoclonal humanized antibody anti-HER2: a major therapeutic progress in breast cancers overexpressing this oncogene?]

HER2 is overexpressed in about 25% to 30% of breast cancers and associated with poor prognosis, resistance to hormonotherapy and lack of sensitivity to CMF-based adjuvant chemotherapy. Herceptin (trastuzumab), a humanized monoclonal antibody, administered as a single agent, produces objective responses in phase II trials in patients with metastatic breast cancers overexpressing HER2. It has shown a substantial benefit in a phase III trial which compares a standard first line chemotherapy (doxorubicin and cyclophosphamide or taxol alone) to the same chemotherapy with Herceptin in metastatic breast cancer. The Herceptin arm had significantly higher response rate (+ 53%), an improvement in the median duration of response (+ 57%) as well as in time to progression (+ 65%) compared to chemotherapy alone.     

Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients

Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.     

Results From the First Multicenter,Open-label,Phase IIIb Study Investigating the Combination of Pertuzumab With Subcutaneous Trastuzumab and a Taxane in Patients With HER2-positive Metastatic Breast Cancer (SAPPHIRE)

IntroductionThe primary objective of this study was to assess the safety and tolerability of combination pertuzumab, subcutaneous trastuzumab (Herceptin), and investigator’s choice of taxane chemotherapy in previously untreated patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Efficacy was a secondary objective.Patients and MethodsThis study was an open-label, non-randomized study of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who had no previous systemic non-hormonal anti-cancer therapy for metastatic disease. The primary endpoints included adverse events (AE), serious AEs, and cardiac AEs. Secondary endpoints included overall response rate, progression-free survival, and overall survival. Patients were treated with pertuzumab and subcutaneous trastuzumab in 3-weekly cycles with taxane chemotherapy until disease progression, unacceptable toxicity, or withdrawal of consent and followed for a minimum of 24 months from initiation of study treatment.ResultsFifty patients were enrolled and included in the analysis. All patients experienced at least 1 AE, with diarrhea, fatigue, peripheral neuropathy, alopecia, rash, and nausea the most common. Three patients experienced at least 1 grade 3 event of suspected cardiac origin (cardiac failure, cardiomyopathy, hypertension). Six patients withdrew from therapy owing to AEs (cardiac failure, drug hypersensitivity, decreased left ventricular ejection fraction, syncope, and bullous dermatitis). Taxane chemotherapy comprised nab-paclitaxel (74.0% of patients), docetaxel (28.0%), or paclitaxel (4.0%). The overall response rate was 73.3% (95% confidence interval, 58.1%-85.4%), the median progression-free survival was 17.0 months (95% confidence interval, 12.5-31.2 months), and the median overall survival was not reached.ConclusionsSubcutaneous trastuzumab in this combination has an acceptable safety and tolerability profile, including cardiac safety profile. Safety and efficacy appear similar to previous studies of intravenous trastuzumab in this combination.     

Carboplatin in combination therapy for metastatic breast cancer

BACKGROUND: Anthracycline-based regimens have a limited role in patients with metastatic breast cancer due to cumulative cardiotoxicity and their common use in adjuvant chemotherapy. New nonanthracycline regimens are, therefore, needed for metastatic disease. Single-agent carboplatin is active in patients with previously untreated metastatic breast cancer, producing response rates of 20%-35%. Preclinical studies have demonstrated synergistic antitumor efficacy of carboplatin and trastuzumab in HER2(+) models. METHODS: Phase II and III clinical trial data of combination therapy with carboplatin (Paraplatin; Bristol-Myers Squibb; Princeton, NJ), a taxane, and/or trastuzumab (Herceptin; Genentech, Inc.; South San Francisco, CA) in metastatic breast cancer were identified from multiple sources, including: A) clinical trial data published in peer-reviewed journals within the last 5 years; B) preliminary clinical trial data from abstracts recently presented at national meetings; and C) phase III protocols currently evaluating carboplatin-based combination regimens. RESULTS: In several phase II studies, combination carboplatin and paclitaxel (Taxol; Bristol-Myers Squibb) therapy was active and reasonably well tolerated in the first-line treatment of metastatic breast cancer, producing objective response rates of 53%-62%-substantially higher rates than those seen in other phase II trials of either drug alone. Similar phase II data for carboplatin with docetaxel (Taxotere; Aventis; Bridgewater, NJ) have been reported, and recent phase III data suggest that adding carboplatin to a paclitaxel/trastuzumab regimen produces superior efficacy than paclitaxel/trastuzumab alone for patients with HER2(+) metastatic disease. Drug scheduling plays an important role in the therapeutic ratio of this combination treatment. CONCLUSIONS: Incorporation of carboplatin as a standard agent in first-line treatment of metastatic breast cancer has support from several recent studies. Preliminary results of combination carboplatin/taxane therapy with trastuzumab in metastatic disease are encouraging, and other carboplatin combinations are also being investigated in other phase II and III trials in patients selected based on the HER2 status of their cancer. Results are eagerly awaited.     

A phase II study of paclitaxel/cisplatin combination in patients with metastatic breast cancer refractory to anthracycline-based chemotherapy

AIMS AND BACKGROUND: To investigate the safety and efficacy of a paclitaxel and cisplatin regimen in a selected group of metastatic breast cancer patients with primary or acquired chemo-resistance to anthracycline-based chemotherapy. PATIENTS AND METHODS: Thirty-eight consecutive women with metastatic breast cancer (PS < or =2) were entered in this phase II trial; all patients had been previously treated for metastatic disease with chemotherapy containing anthracyclines and had shown a progression of the disease during drug administration or after a clinical response lasting less than 6 months. Fifteen patients had received 2 or more chemotherapeutic regimens for advanced disease; 31 patients had > or =2 sites of metastatic disease. Paclitaxel (135 mg/m2) was administered iv by a 3-hr infusion followed by iv infusion of cisplatin (75 mg/m2) on day 1, every 3 weeks for 6 cycles. After the completion of the planned chemotherapy administration, 9 responsive patients continued to receive paclitaxel alone (175 mg/m2) iv, on day 1, every 3 weeks, until disease progression or unacceptable toxicity. RESULTS: A partial clinical response was recorded in 17 cases (45%; 95% CI, 30-64%). The median duration of overall response was 8 months; for the 9 responsive patients who continued treatment with paclitaxel alone, 4 had maintained the partial clinical response at the median follow-up of 24 months from the onset of therapy. The median time to progression was 6 months and median overall survival 8 months. Neurotoxicity was the most frequent adverse effect and caused treatment discontinuation in 5 cases for grade 3-4 paresthesia and/or an arthralgia/myalgia syndrome. Grade 3-4 neutropenia occurred in 16 patients (44%). CONCLUSIONS: Paclitaxel/cisplatin is an active regimen for the treatment of patients with metastatic breast cancer refractory to anthracycline-based chemotherapy. However, the cumulative neurotoxicity should limit the efficacy of prolonged paclitaxel monotherapy in responsive patients.     

A review of the use of trastuzumab (Herceptin) plus vinorelbine in metastatic breast cancer.

The combination of trastuzumab (Herceptin) and vinorelbine (Navelbine) in the treatment of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is valuable for several reasons. There is proven synergism of these agents in preclinical models, both agents are well tolerated and there is minimal overlapping toxicity. This article reviews clinical experience with trastuzumab and vinorelbine from phase II/III trials including >450 assessable patients. Results across the trials show objective response rates for the combination in the range of 44%-86% (51%-86% as first-line treatment) and a median duration of response of 10-17.5 months. Approximately 50% of patients experience grade 3/4 neutropenia, which is of short duration and manageable. Symptomatic cardiac events are infrequent (seven episodes of grade 3 toxicity across all trials). Overall, trastuzumab-vinorelbine combination therapy offers patients with HER2-positive MBC, an effective and well-tolerated treatment that is suitable for prolonged duration of use.     

Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel.

PURPOSE: This phase II study evaluated the pharmacokinetics and safety of trastuzumab and paclitaxel given every 3 weeks to women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. PATIENTS AND METHODS: Thirty-two patients received a loading dose of trastuzumab 8 mg/kg intravenously (day 1) and paclitaxel 175 mg/m2 (day 0). Thereafter, trastuzumab 6 mg/kg was administered on the same day as paclitaxel 175 mg/m2 every 3 weeks for seven cycles. In responding patients, trastuzumab monotherapy every 3 weeks was then continued until disease progression or patient withdrawal. RESULTS: Trastuzumab trough levels were more than 20 mug/mL by the end of cycle 1. The half-life of trastuzumab was estimated to be 18 to 27 days, although this may be an underestimate. The combination of paclitaxel and trastuzumab was generally well tolerated, with no unexpected toxicities and no pharmacokinetic interaction. The most common adverse events were myalgia, paresthesias, alopecia, arthralgia, and fatigue. Events associated with trastuzumab included infusion-related reactions and cardiac dysfunction. Ten patients had a > or = 15% decrease in ejection fraction, but only one had symptomatic heart failure. The investigator-assessed objective response rate was 59% (four complete and 15 partial responses) and seven patients (22%) had stable disease. The median duration of response was 10.5 months and median time to progression was 12.2 months. CONCLUSION: Additional investigation of trastuzumab administered every 3 weeks is warranted. In combination with paclitaxel, it is generally well tolerated. Plasma trastuzumab trough levels and clinical response rates compare favorably with those achieved with the standard weekly trastuzumab regimen plus chemotherapy. The presence of trastuzumab does not alter exposure to paclitaxel.     

HER2-Positive Breast Cancer

Breast cancer is a leading cause of malignancy-related death in women. The prognosis for patients with breast cancer is determined by well established pathologic features associated with poor outcome such as histological grade, tumor size, and node involvement. The proto-oncogene HER2/neu or its protein receptor HER2 is amplified/overexpressed in nearly 25–30% of breast tumors. It is now recognized that breast tumors that overexpress the HER2 receptor are associated with poor prognosis and outcome. The discovery of monoclonal antibodies targeted against the transmembrane protein p185^HER2/neu of HER2/neu represents a new tool for the treatment of breast cancer patients with tumors that overexpress this receptor. Trastuzumab is a recombinant humanized monoclonal antibody against the HER2 receptor that has been shown to be very active in both preclinical and clinical trials. In metastatic disease, the addition of trastuzumab to current chemotherapy has proven to be beneficial compared with chemotherapy alone. Clinical trials with different trastuzumab combination chemotherapies in metastatic settings are ongoing. In addition, trastuzumab therapy is now being tested beyond advanced disease; several trials in America and Europe are designed to add trastuzumab to adjuvant chemotherapy for patients with early nonmetastatic breast cancer. The efficacy and safety of trastuzumab in clinical trials are reviewed in this report.     

Phase II study of trastuzumab plus gemcitabine in chemotherapy-pretreated patients with metastatic breast cancer

We evaluated the efficacy and toxicity of trastuzumab plus gemcitabine in patients with HER2-positive metastatic breast cancer (MBC). Sixty-four patients were enrolled, the majority of whom (95%) had been treated with an anthracycline and a taxane before study enrollment. Eligible women were treated with gemcitabine (1200 mg/m(2) weekly for 2 weeks with the third week off on a 21-day cycle) plus weekly doses of trastuzumab (4-mg/kg loading dose; 2 mg/kg thereafter) until disease progression. The median patient age was 55 years, and the median number of previously administered (including adjuvant) chemotherapy regimens was 3. Twenty-two patients were scored as 2+ for HER2 expression by immunohistochemistry; 39 patients scored 3+. Three patients were assessed as HER2-negative on central pathology review and were ineligible for evaluation. Fifty-nine of the 61 patients remained evaluable for response. The objective response rates were 38% in the intent-to-treat population (23 of 61) and 44% among the 39 patients with HER2 3+ expression. The median response duration was 5.8 months, median overall survival was 14.7 months, and median time to disease progression was 5.8 months. Trastuzumab plus gemcitabine was well tolerated. No cases of clinical congestive heart failure occurred. Grade 3/4 toxicities included asthenia in 4 patients, fever in 4, neutropenia in 18, dyspnea in 6, abdominal or back pain in 3, and edema and nausea in 1 patient each. The combination of trastuzumab plus gemcitabine appears to be well tolerated and effective for patients with HER2-positive MBC previously treated with chemotherapy.     

Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression.

PURPOSE: In a pivotal phase III trial, the addition of trastuzumab to chemotherapy significantly improved response rate, time to disease progression, and overall survival in women with HER2 overexpressing metastatic breast cancer. We conducted an extension study to this trial to obtain additional safety information and to provide trastuzumab following disease progression. PATIENTS AND METHODS: A total of 247 patients with documented disease progression received weekly intravenous trastuzumab in the extension study. Concurrent therapies were administered at the discretion of the treating physician. Patient groups were based on initial study treatment: chemotherapy alone (group 1, n=154) or chemotherapy plus trastuzumab (group 2, n=93). RESULTS: Sixty-eight percent of group 1 and 76% of group 2 received chemotherapy plus trastuzumab in the extension trial; the remainder received trastuzumab alone or combined with palliative radiotherapy or hormonal therapy. Seventy-six percent of group 1 and 55% of group 2 experienced at least one adverse event, similar to effects observed in the pivotal trial. Symptomatic or asymptomatic cardiac dysfunction occurred in 9% of group 1 and 2% of group 2 patients. Overall objective response rates were 14% in group 1 and 11% in group 2; median durations of response exceeded 6 months in both groups. CONCLUSION: Our results suggest that prolonged use of trastuzumab therapy is safe and well tolerated. Longer durations of therapy did not appear to increase the risk of cardiac dysfunction. Patients progressing on trastuzumab-containing therapy demonstrate some response to a second trastuzumab-containing regimen. The independent contribution of trastuzumab in this setting merits further study.