Role Of Trastuzumab Research Articles

The Role of Trastuzumab in Early Stage Breast Cancer: Current Data and Treatment Recommendations

Treatment of early stage breast cancer requires a multimodality approach in order to eradicate residual cancer and prevent recurrent disease. Targeting the pathways that promote or sustain cancer cell growth and invasion is critical to the effective treatment of breast and other cancers. Overexpression of the family of HER receptors have been associated with a variety of malignancies; the first and best studied is the association of overexpression of the HER2/neu receptor with a more aggressive breast cancer phenotype and poorer survival. A humanized antibody to HER2/neu, trastuzumab, is now FDA approved for the treatment of early stage, HER2/neu overexpressing breast cancer sequenced with chemotherapy including doxorubicin, cyclophosphamide, and paclitaxel. Additional international and national studies support the significant impact of trastuzumab on both disease free and overall survival in women with this aggressive form of breast cancer. Toxicity includes a low but clear risk of congestive heart failure, and the large phase III trials have helped to determine which patients are at higher risk for this complication. Non-anthracycline containing regimens are an alternative therapy associated with reduced cardiac toxicity. Trastuzumab therapy is now the standard of care for the treatment of early stage, HER2/neu positive breast cancer given in combination with one of several chemotherapy regimens. Ongoing questions include the appropriate duration of trastuzumab treatment as well as the optimal chemotherapy regimen and sequence. The next large phase III adjuvant trial for this subset of breast cancer is an international collaboration designed to evaluate the added or alternative benefit of an oral tyrosine kinase inhibitor targeting HER2/neu as well as the epidermal growth factor receptor (EGFR), lapatinib. Other trials are investigating differences in duration. Studies in the neoadjuvant setting should help to define markers of trastuzumab and lapatinib sensitivity and resistance. Preliminary data combining trastuzumab with the antiangiogenic antibody bevacizumab is encouraging; this combination will be tested in both early stage and late stage disease.

Role of trastuzumab in patients with brain metastases from Her2 positive breast cancer

To the Editor, We read with great interest the article by Bartsch et al. [1] in which they indicated that trastuzumab prolongs overall survival in patients with brain metastases from Her2 positive breast cancer. The authors presented some supportive data for the trastuzumab use in these patients. We want to add one more. Blood-brain-barrier (BBB) disruption can also be induced by radiation therapy. Radiotherapy with doses of 20–30 Gy with fraction size of 2 Gy may be used to increase the permeability of the BBB [2]. A Her2 level-dependent sensitization to radiation-induced apoptosis by trastuzumab in a panel of breast cancer cell lines has been observed [3]. Radiosensitization by trastuzumab was further demonstrated by a reduced clonogenic survival of breast cancer cells after radiation. Having given information above, we further suggest that trastuzumab should not be discarded in combination with radiotherapy as a treatment option in patients previously treated or during trastuzumabbased therapy for metastatic breast cancer.

Clinical role of trastuzumab in metastatic breast cancer: experience of a center

This article is part of the supplement: VII Madrid Breast Cancer Conference: Changes in the treatment of breast cancer

Potential use of humanized antibodies in the treatment of breast cancer

With the growing knowledge of key cellular pathways in tumor induction and evolution, targeted therapies make up an increasing proportion of new drugs entering clinical testing. In the treatment of breast cancer, humanized antibodies have become a major option. The humanized monoclonal antibody trastuzumab (Herceptin®; Genentech, Inc., CA, USA) for HER2-overexpressing, metastatic breast cancer, represents a successful agent associated with impressive survival benefits when combined with chemotherapy. Based on impressive results, trastuzumab will become a standard in the adjuvant treatment of HER2-overexpressing breast cancer. The role of trastuzumab in the neoadjuvant setting is promising, but must be further evaluated in large prospective, randomized trials. However, there is still a large proportion of patients overexpressing HER2 that do not respond to trastuzumab. Regarding this patient cohort, the optimal combination of trastuzumab with other agents needs further evaluation. In breast cancer lacking HER2 amplification, the role of the new antibody pertuzumab remains to be defined. The role of antibodies interfering with angiogenesis, tumor stroma or glycoproteins is of a preliminary nature and warrants further investigation. Here, an overview of humanized antibodies in human breast cancer is provided, with emphasis on the recent advances and future prospects in treating malignant breast cancer.

Predictors of brain relapse in HER-2 positive metastatic breast cancer (MBC) patients (pts)

10508 Background: Brain relapse is a common occurrence in HER2-positive breast cancer pts. We assessed factors determining the risk of this event in a large unselected series of HER2-positive MBC pts. Methods: Study group included 233 consecutive HER2-positive (IH 3+ or FISH+) MBC pts (median age 53 years); 49% premenopausal, 49% postmenopausal and 2% with unknown menopausal status. Dominant site of disease included viscera (78%), soft tissue (11%) and bones (10%). Of the 206 pts (88%) with known steroid receptor status, ER+/PgR+, ER+/PgR-, ER-/PgR+, ER-/PgR- phenotypes included 58%, 15%, 5% and 21% of pts, respectively. Prior (neo)adjuvant chemotherapy, endocrine therapy or a combination thereof was administered in 40%, 6% and 35% of pts, respectively. Disease-free interval to the development of MBC ranged between 0 and 142 months (median 16 months). 184 pts (79%) received trastuzumab for MBC, usually in combination with chemotherapy. Statistical analysis included contingency tables, chi-square test, Kaplan-Meier survival analysis and Cox proportional hazard model. Results: Median follow-up from the development of MBC was 25 months (range 0.5–130 months). 54 pts (23%) developed brain metastases after a median of 13 months (range, 0 to 81 months). Cumulative risk of brain relapse was 11% (95% CI: 7–16%) and 24% (95% CI: 17–32%) at one and two years, respectively. Trastuzumab treatment was associated with insignificantly reduced risk of brain metastases (HR 0.63, 95% CI 0.29–1.39, p = 0.25). In the univariate analysis, premenopausal status was the only significant factor associated with increased risk of brain relapse (HR 2.56, 95% CI 1.28–5.00, p = 0.008). Conclusion: HER-2 positive MBC pts carry high risk of brain relapse, in particular prior to menopause. Protective role of trastuzumab warrants further research. [Table: see text]

Role of trastuzumab in adjuvant therapy for locally invasive breast cancer

The role of trastuzumab in adjuvant therapy for locally invasive breast cancer is discussed. Trastuzumab is a humanized monoclonal antibody that binds to the extracellular domain of human epidermal growth factor receptor-2 (HER2). Currently, trastuzumab is indicated for use in HER2-positive patients with metastatic breast cancer. Because trastuzumab specifically targets a receptor that is overexpressed in tumor cells, it is less likely to cause the cytotoxic adverse effects of traditional chemotherapy. Cardiotoxicity has been a major concern, however. Several trials were started to evaluate trastuzumab in the adjuvant setting in patients diagnosed with early-stage breast cancer. The interim results of these trials have shown a promising effect of adjuvant therapy with trastuzumab in improving overall survival, disease-free survival, relapse-free survival, and distant-disease-free survival. The use of trastuzumab as adjuvant therapy in patients with HER2-positive breast cancer can lead to increased survival. The appropriateness of trastuzumab therapy should be considered based on HER2 status, cost, and risk of toxicity.

A monoclonal antibody as an effective therapeutic agent in breast cancer: trastuzumab

Trastuzumab (Herceptin®; Genentech, Inc., CA, USA) is a humanised monoclonal antibody developed to target the HER-2/neu receptor, which is overexpressed in 20 – 25% of breast carcinomas. Clinical studies showed that trastuzumab is effective as single-agent therapy and that it has greater antitumour activity in combination with chemotherapy than chemotherapy alone in metastatic breast cancer. The indication for trastuzumab monotherapy and the combination with various chemotherapy agents is country-specific and is largely based on trials of efficacy and safety. Patients with a HER-2/neu overexpression level of 3+, determined by immunohistochemical assay or amplification using fluorescence in situ hybridisation, derive most clinical benefit from trastuzumab. Trastuzumab is generally well-tolerated. Cardiotoxicity is the main concern; thus, monitoring of cardiac function is recommended. Ongoing trials investigate the role of trastuzumab in the adjuvant and neoadjuvant settings.

Future options with trastuzumab for primary systemic and adjuvant therapy

HER2 positivity can be detected early in breast cancer development and is associated with a poor outcome. Primary systemic therapy with trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) in combination with taxanes and other cytotoxic agents has been studied in phase II clinical trials in women with HER2-positive breast cancer. These combinations have achieved pathologic complete response rates of 12% to 42% and clinical complete response rates of 30% to 67%. These results compare favorably with those of primary systemic therapy using standard combinations in patients with unselected (HER2-positive or -negative) breast cancer. Consequently, larger studies are in progress in which trastuzumab is administered before surgery in combination with chemotherapy. Trastuzumab is continued as monotherapy afterward to complete 1 year of treatment or until disease progression. These studies aim to provide further proof of the clinical benefits associated with trastuzumab as primary systemic therapy. They will also investigate the molecular determinants of sensitivity and resistance. In addition, four major randomized trials, in more than 13,500 patients, are investigating the impact of adding trastuzumab to standard adjuvant therapy. Planned interim cardiac safety analyses have been passed without concerns. Recruitment to these studies has either recently been completed or continues as planned. Together, this extensive program, which includes analysis of predictive molecular and pathologic makers, will establish the efficacy, safety, and role of trastuzumab in early breast cancer.

HER2/neu gene amplification and protein overexpression in G3 pT2 transitional cell carcinoma of the bladder: a role for anti-HER2 therapy?

HER2/neu is an oncogene encoding a type 1 tyrosine kinase growth factor receptor. Polysomy 17, gene amplification and HER2/neu protein overexpression are associated with a poor prognosis in transitional cell carcinomas (TCC) of the bladder. Due to the application of different laboratory techniques, the exact incidence of HER/neu abnormalities remains uncertain in TCC. Standardised laboratory techniques are therefore important in the determination of the HER2/neu status if an assessment of the potential value of anti-HER2/neu treatments in the clinical management of patients with TCC is to be made. In this study, 75 TCCs with evidence of detrusor muscle invasion at first clinical presentation were included. Gene amplification, polysomy 17 and HER2 copy number were assessed using fluorescence in situ hybridisation (FISH), with separate probes for chromosome 17 and HER2/neu. Protein overexpression was assessed using immunohistochemistry (IHC), with the CB11 antibody and a scoring system evaluating only membranous staining as positive. The mean patient age was 69.5 years (range 42–93 years) and the median survival was 15 months (range 1–156 months). Polysomy 17 occurred in 97%, increased HER/neu copy number in 92% and HER2/neu gene amplification in 7%. Protein overexpression occurred in 57% of cases. Polysomy 17 and HER2/neu protein overexpression are common in G3 pT2 TCCs of the bladder. However, gene amplification is uncommon. Mechanisms other than gene amplification may be responsible for protein overexpression in this tumour type. Evidence from breast cancer suggests that only tumours with HER2/neu gene amplification respond to the anti-HER2/neu therapy trastuzumab (Herceptin™). If this were true for bladder cancer, only 4/75 (5%) of G3 pT2 TCCs would be suitable for treatment. The role of trastuzumab in these tumours remains untested at present.

Role of Her-2/neu overexpression and clinical determinants of early mortality in glioblastoma multiforme.

Her-2/neu or c-erbB-2, a 185-kD protein is an important prognostic indicator/target for therapy in metastatic breast carcinoma. Recent reports have also identified a role for Her-2/neu overexpression in other solid tumors. We performed a retrospective analysis to evaluate the prevalence and prognostic role of Her-2/neu overexpression in patients with glioblastoma multiforme (GBM). Data collection (chart review) included demographic information, symptoms at presentation, histologic grade, survival time, and treatment offered. Testing for Her-2/neu overexpression was performed on paraffin-embedded archival tumor tissue using immunohistochemistry (IHC) (Hercep test). An IHC score of 2+ or greater was considered overexpression. An experienced pathologist who was blinded from the clinical history performed all the IHC testing. Between 1990 and 2001, 149 subjects (68 females, 81 males) with a biopsy-proven diagnosis of GBM were identified. Age range was 26 to 79 years (mean: 64 years) and overall mean survival was 12 months. Her-2/neu overexpression was detected in 23 patients (15.4%). Interestingly, the median survival for patients whose pathologic specimens revealed Her-2/neu overexpression was 4 months compared to those who lacked overexpression, in whom survival was 8 months. After adjusting for age, performance status, smoking history, and treatment, logistic regression analysis (with a survival of <3 months as the dependent variable) revealed that Her-2/neu overexpression significantly (p < 0.01) increased the odds of early mortality (<3 months). The results of our large study indicate that Her-2/neu overexpression may be a poor prognostic marker in patients with GBM. In addition, in a proportion of subjects (15.4%), Her-2/neu may be a potential target for tumor-specific monoclonal antibody therapy. The role of trastuzumab (alone or in combination with conventional therapy) needs to be evaluated.

The development and clinical use of trastuzumab (Herceptin).

HER-2 is a member of the c-erbB family of receptor tyrosine kinases and is overexpressed by 20-30% of human breast cancers. HER-2 overexpression is an independent adverse prognostic factor and may also predict for response to both chemotherapy and endocrine agents. Trastuzumab is a humanised monoclonal antibody that binds with high affinity to the extracellular domain of HER-2. In HER-2-overexpressing preclinical models trastuzumab has been shown to have a marked antiproliferative effect and demonstrates synergy with a number of cytotoxic drugs. Several phase II and phase III clinical trials have now been performed in patients with advanced breast cancer that overexpress HER-2. Trastuzumab was initially shown to be active and well tolerated as a single agent in heavily pretreated women. Subsequently, studies of first-line treatment for metastatic breast cancer have demonstrated an improvement in survival for trastuzumab when used in combination with either paclitaxel or an anthracycline-cyclophosphamide regimen compared with chemotherapy alone. Unexpectedly, the combination of trastuzumab and the anthracycline-containing regimen was associated with a significant incidence of cardiac dysfunction. The benefit of trastuzumab is generally confined to patients whose tumours have gene amplification as detected by fluorescence in situ hybridisation (FISH) and this is tightly associated with immunohistochemical (IHC) staining at the highest (3+) level. A small number of patients have IHC 2+ tumours together with FISH evidence of gene amplification and may also derive benefit from treatment. Trastuzumab has also been shown to be effective when used as first-line monotherapy for advanced breast cancer. Trials to date have employed trastuzumab in a weekly schedule, but there is emerging evidence that a three-weekly regimen may be as effective. Trastuzumab has shown encouraging activity when used with other agents including docetaxel and vinorelbine. The combination of trastuzumab, docetaxel, and platinum salts also appears to be very active. The role of trastuzumab as adjuvant therapy for early breast cancer is being tested in a number of large randomised trials.

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.

Future directions in the adjuvant treatment of breast cancer: The role of trastuzumab

Current evidence shows that adjuvant cytotoxic or hormonal therapy increases the disease-free and overall survival of patients. The analysis by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) showed that anthracycline/cyclophosphamide (AC)-containing regimens are more effective than those without AC, providing an 11% greater reduction in the risk of death compared with non-AC-containing regimens. In addition, paclitaxel and docetaxel have significant anti-tumor activity in previously treated patients and sequential treatment with paclitaxel may further reduce the risk of recurrence and improve survival. Tamoxifen is effective in reducing the risk of recurrence and death in patients with estrogen receptor (ER)-positive tumors. The addition of tamoxifen to combination chemotherapy in patients with ER-positive tumors further reduces the risk of recurrence and improves survival. Debate on the effectiveness of tamoxifen in HER2-positive patients is currently underway. A number of trials are in progress or planned to investigate the use of the anti-HER2 monoclonal antibody trastuzumab (Herceptin) in the adjuvant setting. These include a National Surgical Adjuvant Breast and Bowel Project (NSABP) adjuvant trial (AC --> paclitaxel vs. AC --> paclitaxel + trastuzumab) and an Intergroup study (AC --> paclitaxel vs. AC --> paclitaxel + trastuzumab vs. AC --> paclitaxel --> trastuzumab). Results from these trials will determine whether this novel therapy has a survival benefit in early breast cancer.

Taxanes for Breast Cancer: An Evidence-Based Review of Randomized Phase II and Phase III Trials

The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early- or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n=1) or phase III (n=17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m 2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m 2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m 2 every 3 weeks) was given following 4 cycles of conventional doxorubicincyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/ne u, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.