Trastuzumab and vinorelbine as highly effective and safe therapy for HER-2-overexpressing metastatic breast cancer. A single institution experience

AIMS AND BACKGROUND: Trastuzumab-based therapy has improved survival of women with human epidermal growth factor receptor 2 (HER2)-overexpressing metastatic breast cancer. STUDY DESIGN: From September 2002 to July 2006, 45 women with metastatic breast cancer HER2 3+, or 2+ and positive for HER2 gene amplification, were enrolled in the study and received a combination therapy with vinorelbine, 25 mg/m2 weeks 1 and 2, plus trastuzumab, 4 mg/kg loading dose and then 2 mg/kg weekly, in a three weeks cycle. Eligibility criteria included measurable disease and a baseline ejection fraction > or = 50%. Forty-two percent of the patients were not pretreated, whereas 58% had received a previous chemotherapy regimen for metastatic disease, including anthracyclines and/or taxanes (47%), and trastuzumab plus taxol (11%). RESULTS: We observed 14 (31%) complete responses and 21 (47%) partial responses, with an overall response rate of 78%. Stable disease > 6 months was assessed for 5 (11%) patients with a clinical benefit of 89%. Five (11%) patients progressed. With a median follow-up of 11 months, median time to progression was 9 months and median duration of response was 7.6 months for complete remissions and 4 months for partial remissions. Median survival was 29 months. CONCLUSIONS: In spite of a smaller dose intensity of vinorelbine than previously reported, the regimen evaluated was notably effective in terms of response rate, time to progression and survival, with very mild toxicity.     

Trastuzumab-based combinations in metastatic breast cancer: how to make a choice

Trastuzumab, a humanized monoclonal anti-human epidermal growth factor receptor-2 (HER2) antibody that has proven efficacy as monotherapy in HER2-overexpressing breast cancer, has a favorable toxicity profile characterized by infrequent infusion reactions and a slightly increased incidence of cardiac dysfunction. Regimens that combine trastuzumab with a cytotoxic agent can increase the overall response rate and prolong survival in patients with metastatic breast cancer. Trastuzumab has been investigated in combination with anthracyclines, taxanes, platinum salts, vinorelbine, gemcitabine, capecitabine, and combinations of these agents. Combining trastuzumab with these agents enhances the toxicity of treatment and can especially enhance the risk of cardiotoxicity. This article summarizes data on trastuzumab-based combinations with particular attention to the risk benefit ratio of these therapies. HER2 testing by immunohistochemistry or fluorescence in situ hybridization is discussed in the context of determining the optimal course of treatment for patients.     

Phase II study of weekly paclitaxel and trastuzumab in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer

Synergism between anti-HER2 monoclonal antibody (trastuzumab) and paclitaxel has been shown in vitro and in vivo. In previous experiences, weekly administration of trastuzumab and paclitaxel has shown significant activity in metastatic breast cancer. In this phase II study, we evaluated the activity and the toxicity of this weekly regimen in anthracycline- and taxane-pretreated patients with HER2-overexpressing metastatic breast cancer. Between November 1999 and July 2001, 25 patients were treated with trastuzumab (4 mg kg(-1) i.v. loading dose followed by 2 mg kg(-1) i.v. week(-1)) and paclitaxel (60-90 mg m(-2) h(-1) i.v. infusion week(-1)). The treatment was planned to continue until disease progression or prohibitive toxicity; in patients with responsive or stable disease, after 6 months of therapy, the decision to stop paclitaxel while continuing weekly trastuzumab was left to the physicians' judgement. At the median follow-up of 19.6 months (range 9.2-38.1), all patients are evaluable for response and toxicity. We obtained four (16%) complete responses (CR), 10 (40%) partial responses (PR), four (16%) stable diseases and seven (28%) disease progressions. The response rate (CR+PR) was 56% (95% CI, 36.5-75.5%). The median duration of response was 10.4 months (range 4.1-24.2+). Median time to progression was 8.6 months (range 2.5-24.2+). The toxicity was mild; five patients experienced fever and chills during the first infusion of trastuzumab (20%); leukopenia grade 2 was recorded in one patient (4%). Two patients (8%) came off study for grade 3 cardiotoxicity (after 9 and 17 weeks of treatment, respectively): both had already received anthracyclines and taxanes. Onycholysis grade 2 was observed in five patients (20%). These results confirm that weekly administration of trastuzumab and paclitaxel is active in anthracycline- and taxane-pretreated metastatic breast cancer patients HER2-overexpressing. Since cardiac disfunctions grade 3 were observed (8%), we recommend that cardiac function should be monitored in these patients.     

Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study

BACKGROUND: The optimal trastuzumab-based chemotherapy regimen for HER2-overexpressing, metastatic breast cancer is not known. The trastuzumab and vinorelbine or taxane (TRAVIOTA) study was a prospective, multicenter, randomized trial that was designed to compare these regimens. METHODS: Eligible patients had HER2-overexpressing, metastatic breast cancer and had received no prior chemotherapy for advanced disease. Patients were randomized 1:1 to receive either trastuzumab with weekly vinorelbine therapy or weekly taxane therapy (paclitaxel or docetaxel at the investigator's choice). Originally planned for 250 patients, the study was closed because of poor accrual with 81 evaluable patients, including 41 patients who received vinorelbine and 40 patients who received taxane. RESULTS: Response rates were 51% and 40% for the vinorelbine/trastuzumab arm and the taxane/trastuzumab arm, respectively (Fisher exact test; P = .37). The median time to disease progression was 8.5 months and 6.0 months for the vinorelbine- and taxane-based arms, respectively (log-rank test; P = .09). Treatment with either regimen generally was well tolerated, yielding comparable rates of neurologic and gastrointestinal toxicity. Vinorelbine-based treatment was associated with more anemia and neutropenia and with 2 episodes of cardiotoxicity. Taxane-based therapy was associated with more dermatologic toxicity, myalgias, and fluid retention. CONCLUSIONS: Both vinorelbine/trastuzumab and taxane/trastuzumab treatments were active as first-line therapy for HER2-positive, metastatic breast cancer and had comparable rates of efficacy and tolerability. The toxicities observed were the result of recognized side effects associated with each of the chemotherapy agents and schedules. These data can inform treatment decision making in this clinical setting.     

Vinorelbine plus trastuzumab combination as first-line therapy for HER 2-positive metastatic breast cancer patients: an international phase II trial

The aim of this international phase II trial was to determine the efficacy and safety profile of weekly vinorelbine plus trastuzumab as first-line chemotherapy for women with HER 2-overexpressing metastatic breast cancer. Sixty-nine patients with tumours overexpressing HER 2 received vinorelbine: 30 mg m-2 week-1 and trastuzumab: 4 mg kg-1 on day 1 as a loading dose followed by 2 mg kg-1 week-1 starting on day 8. Sixty-two patients were evaluable for response and 69 patients were evaluable for toxicity. The overall response rate was 62.9%. The median time to response was 8.4 weeks, the median duration of response was 17.5 months, the median progression-free survival was 9.9 months (95% CI, 5.6-12.1) and the one-year progression-free survival was 39.1%. The median survival for all patients was 23.7 months (95% CI, 18.4-32.6). This regimen was safe: grade 3-4 neutropenia were observed over 17.7% of courses in 83.8% of patients, with only two episodes of febrile neutropenia (0.1%) in two patients (2.9%). Only one patient discontinued treatment due to grade 3 symptomatic cardiac dysfunction that resolved with therapy. Vinorelbine plus trastuzumab is one of the most active treatment regimens for patients with HER 2-positive metastatic breast cancer and demonstrates a very favourable safety profile allowing prolonged treatment with long-term survival. This study has been presented in part at the following conferences: The San Antonio Breast Cancer Symposium, San Antonio, TX, USA, 2003; The American Society of Clinical Oncology, Orlando, FL, USA, 2005.     

Weekly Gemcitabine and Trastuzumab in the Treatment of Patients With HER2-Overexpressing Metastatic Breast Cancer

BackgroundThe use of trastuzumab in combination with either a taxane or vinorelbine has improved the efficacy of treatment for women with HER2-positive (HER+) breast cancer. We investigated the activity and toxicity of the gemcitabine/trastuzumab combination as first- or second-line treatment in women with HER2+ metastatic breast cancer (MBC).Patients and MethodsForty-one women with HER2+ MBC were treated with gemcitabine 1000 mg/m² intravenously (I.V.) days 1, 8, and 15 and trastuzumab 4-mg/kg I.V. loading dose and then 2 mg/kg weekly. Cycles were repeated every 28 days. Patients were evaluated after 8 weeks of treatment; responders/stable patients continued treatment until progression.ResultsPatients received a median of 28 weeks of treatment. Eleven of 37 evaluable patients (30%; 95% CI, 17%–46%) had major responses. The median progression-free survival (PFS) was 4 months (95% CI, 1.9–5.3 months), with a 1-year PFS of 17%. Four of 15 patients (27%) who had previously received trastuzumab for MBC had partial responses. The gemcitabine/trastuzumab combination was well tolerated.ConclusionThe combination of gemcitabine and trastuzumab is an active regimen but appears less active than trastuzumab in combination with either taxanes or vinorelbine. The role of gemcitabine/trastuzumab (versus gemcitabine alone) in women who have already received a trastuzumab-containing regimen for HER2+ MBC is not defined by this study.     

A prospective multicenter phase II study of oral and i.v. vinorelbine plus trastuzumab as first-line therapy in HER2-overexpressing metastatic breast cancer

BackgroundTo evaluate the efficacy and safety of oral and i.v. vinorelbine plus trastuzumab as first-line regimen in a patient-convenient application for human epidermal growth factor receptor 2 (HER2)-overexpressing patients with metastatic breast cancer.Patients and methodsForty-two women were enrolled in a multicenter study. The patients received i.v. vinorelbine at a dose of 25 mg/m² on day 1 followed by oral vinorelbine at a dose of 60 mg/m² on days 8 and 15 in a 3-week cycle. Standard dose trastuzumab was given at 3-week intervals.ResultsComplete response was observed in 7 patients (18.9%) and partial response in 19 patients (51.4%), for an overall response rate of 70.3% [95% confidence interval (CI) 53.0–84.1]. The disease control rate reached 91.9% (95% CI 78.1–98.3). The median time to progression was 9.3 months, while median overall survival reached 35.6 months. Hematological and non-hematological toxic effects were acceptable with grade 3–4 leukopenia of 14% and neutropenia of 38%; cardiac toxicity did not reach the level of clinical relevance.ConclusionThe combination of i.v. and oral vinorelbine plus trastuzumab demonstrates high activity and good tolerability in first-line treatment of HER2-overexpressing metastatic breast cancer. In addition, it offers convenience for the patients with only one i.v. treatment every 3 weeks.     

Phase I trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer

To determine the feasible dose and schedule for everolimus, an oral mTOR inhibitor, combined with vinorelbine and trastuzumab for patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib multicenter, Bayesian dose-escalation study, 50 patients received everolimus 5 mg/day, 20 mg/week, or 30 mg/week plus vinorelbine (25 mg/m² on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly). Endpoints included end-of-cycle-1 dose-limiting toxicity (DLT) rate (primary endpoint), safety, relative dose intensity, overall response rate (ORR), and pharmacokinetics. Grade 3/4 neutropenia was the most common end-of-cycle-1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg/day and 30 mg/week cohorts, respectively. Other end-of-cycle-1 DLTs included single cases of febrile neutropenia, grade 3 stomatitis with concomitant fatigue, grade 2 stomatitis, grade 3 anorexia, and grade 2 acneiform dermatitis, all in the 5-mg/day cohort. Based on the recorded DLTs and global safety, everolimus 5 mg/day and 30 mg/week were chosen as the optimal dose levels for the daily and weekly arms. Forty-seven patients were evaluable for efficacy. ORR was 19.1%, with a disease control rate of 83.0% and median progression-free survival of 30.7 weeks. No drug interaction was observed between everolimus and vinorelbine. Everolimus combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with HER2-overexpressing metastatic breast cancer that progressed on trastuzumab (NCT00426530).     

Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification.

PURPOSE: This phase II study evaluated weekly trastuzumab and paclitaxel therapy in women with HER2-normal and HER2-overexpressing metastatic breast cancer. Efficacy was correlated with immunohistochemical and fluorescent in situ hybridization (FISH) assay results. PATIENTS AND METHODS: Eligible patients had bidimensionally measurable metastatic breast cancer. Up to three prior chemotherapy regimens, including prior anthracycline and taxane therapy, were allowed. Trastuzumab 4 mg/kg and paclitaxel 90 mg/m2 were administered on week 1, with trastuzumab 2 mg/kg and paclitaxel 90 mg/m2 administered on subsequent weeks. HER2 status was evaluated using four different immunohistochemical assays and FISH. RESULTS: Patients received a median of 25 weekly infusions (range, one to 85 infusions). Median delivered paclitaxel dose-intensity was 82 mg/m2/wk (range, 52 to 90 mg/m2/wk). The intent-to-treat response rate for all 95 patients enrolled was 56.8% (95% confidence interval, 47% to 67%). A response rate of 61.4% (4.5% complete response, 56.8% partial response) was observed in 88 fully assessable patients. In patients with HER2-overexpressing tumors, overall response rates ranged from 67% to 81% compared with 41% to 46% in patients with HER2-normal expression (ranges reflect the different assay methods used to assess HER2 status). Differences in response rates between patients with HER2-overexpressing tumors and those with normal HER2 expression were statistically significant for all assay methods, with CB11 and TAB250 antibodies and FISH having the strongest significance. Therapy was generally well tolerated, although three patients had serious cardiac complications. CONCLUSION: Weekly trastuzumab and paclitaxel therapy is active in women with metastatic breast cancer. Therapy was relatively well tolerated; however, attention to cardiac function is necessary.     

Management of HER-2/neu-positive metastatic breast cancer

We reviewed therapies for the management of HER2-overexpressing metastatic breast cancer. HER2-overexpressing breast cancers have a distinctive molecular signal and distinctive clinical characteristics. They are associated with an adverse prognosis, relative resistance to certain types of therapies (i.e. tamoxifen), and responsiveness to anthracyclines and taxanes. Anti-HER2 therapies such as trastuzumab and lapatinib have revolutionised the treatment of breast cancer and can dramatically improve outcomes in women with HER2-overexpressing metastatic breast cancer. Response to these targeted agents is improved when used in combination with cytotoxic agents such as anthracyclines and taxanes. However, there is an approximate 13% (taxanes) to 27% (conventional anthracyclines) risk of cardiotoxicity with these combinations. The novel anthracycline, pegylated liposomal doxorubicin, shows efficacy similar to that of conventional doxorubicin and may offer significantly less cardiotoxicity; this should be confirmed in phase III clinical trials. Lapatinib is an oral small molecule targeting HER2 with promising antitumour activity in the metastatic setting and a potential for reduced cardiotoxicity as compared with trastuzumab. Neoadjuvant as well adjuvant trials involving lapatinib, trastuzumab or their combination have started recrutiment worldwide.     

High efficacy of gemcitabine and cisplatin plus trastuzumab in patients with HER2-overexpressing metastatic breast cancer: a phase II study

AimsEffective and tolerable regimens are sought specifically in women who have been pre-treated with anthracyclines and taxanes. Gemcitabine and cisplatin plus trastuzumab has shown synergistic activity in vitro, and provides a new mechanism of drug interaction. This multicentre phase II study aimed to evaluate the efficacy and tolerability of gemcitabine and cisplatin plus trastuzumab in previously treated patients with metastatic breast cancer (MBC).Materials and methodsPreviously treated patients with human epidermal growth factor receptor 2 (HER2) overexpressing MBC were enrolled in a multicentre phase II study (DAKO Hercep Test 3+). Treatment consisted of gemcitabine (750 mg/m²), cisplatin (30 mg/m²) given on days 1 and 8 every 3 weeks, and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly).ResultsTwenty patients were recruited, all of whom had previously received chemotherapy (12 pre-treated with taxanes, 18 pre-treated with anthracyclines seven pre-treated with taxanes and trastuzumab). A median of six cycles of the study treatment was delivered. There were eight partial responses, for an overall response rate of 40% (95% confidence interval 16.5–63.5%). The clinical benefit rate (complete response plus partial response plus stable disease) was 80% (95% CI 54.2–95.8%). The response rate in patients who had already received a trastuzumab-based regimen for MBC was 57.1% (95% CI 7.7–100%). Median time to progression was 10.2 months, and median overall survival was 18.8 months. Main toxicities were leukopenia (grade 3 in 55% of patients) and thrombocytopenia (grade 3 in 35% and grade 4 in 5% of patients). Non-haematological toxicity was rarely severe.ConclusionsCombination chemotherapy with gemcitabine and cisplatin plus trastuzumab is well tolerated and active in patients with HER2 overexpressing MBC, even after prior exposure to anthracyclines and taxanes.     

A phase II study of trastuzumab and capecitabine for patients with HER2-overexpressing metastatic breast cancer: Japan Breast Cancer Research Network (JBCRN) 00 Trial

Purpose To determine the response rate and toxicity profile of trastuzumab and capecitabine in women with HER2-overexpressing advanced breast cancer. Patients and methods A total of 59 patients from 6 participating centers in Japan entered onto the study of trastuzumab and capecitabine. Eighty six percent of women had received prior chemotherapy as part of adjuvant (21.4%) or metastatic treatment (48.2%), or both (16.1%), including substantial portions of patients who had previously received either CMF (7.1%), anthracyclines (28.6%), taxanes (25.0%), or both types (25.0%) of chemotherapy. Results Responses were observed in 28 of 56 patients (overall response rate, 50%). The response rate was 65.0% in patients treated with trastuzumab and capecitabine as first-line therapy for metastatic disease, and 62.5% among HER2 +3 positive patients, while high response rates were also seen in women treated with second- or third-line therapy. Patients receiving trastuzumab and capecitabine as first-line therapy had a longer TTP than did patients receiving this treatment as second- or third-line therapy (median TTP, 280 vs. 130 days, P < 0.05). Further, patients receiving trastuzumab and capecitabine as first-line therapy had longer OS than did patients receiving this treatment as second- or third-line therapy (median OS, 780 days vs. 480 weeks, P < 0.05). The treatment-related adverse events were hand–foot syndrome (30.4%), nausea (25%), diarrhea (10.7%), stomatitis (10.7%), fatigue (7.1%), and vomiting (5.4%). However, the majority were Grade 1–2 adverse events and only six patients experienced Grade 3 adverse events. Further Grade 1 cardiac toxicity was observed in one patient, while there were no cases of alopecia and treatment-related death. Conclusion Trastuzumab in combination with capecitabine is highly active in women with HER2-overexpressing metastatic breast cancer and is well tolerated.     

A phase II study of three-weekly docetaxel and weekly trastuzumab in HER2-overexpressing advanced breast cancer

BACKGROUND: To test safety and activity of 3-weekly doses of docetaxel and a weekly dose of trastuzumab in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty-two women, median age 53 years (range 36-73 years), with HER2-overexpressing advanced breast cancer were enrolled in a study of docetaxel, 75 mg/m(2) q3w for 6 cycles, and trastuzumab, 4 mg/kg loading dose, 2 mg/kg weekly thereafter. Thirty-four patients (81%) had visceral metastatic involvement. Thirty-five patients had received prior chemotherapy as part of their treatment: adjuvant/neoadjuvant (26), metastatic (2) and both (7). Thirty-one patients had been previously exposed to an anthracycline and 11 to paclitaxel. Four patients had previously received high-dose chemotherapy followed by autologous stem cell transplant. RESULTS: 226 cycles (median 6, range 1-6) were administered. The median delivered dose intensity for docetaxel was 24 mg/m(2)/week (range 16-25 mg/m(2)/week). The intent to treat overall response rate was 67% (95% confidence interval, 52-79%). Median progression-free survival, time to treatment failure, and duration of response were 9, 8 and 12 months, respectively. Symptomatic cardiotoxicity (grade 3) occurred in 1 patient. The most common grade 3/4 toxicity was neutropenia (76% of the patients), although febrile neutropenia did not occur. CONCLUSIONS: Three-weekly doses of docetaxel and a weekly dose of trastuzumab is an active and safe combination in patients with HER2-overexpressing advanced breast cancer.     

Cardiac toxicity of trastuzumab-related regimens in HER2-overexpressing breast cancer

The pivotal trial by Slamon and colleagues of trastuzumab combined with chemotherapy in metastatic breast cancer showed a high incidence of congestive heart failure (CHF) among patients who had received trastuzumab and anthracycline-based therapy simultaneously. As a result, the development of nonanthracycline-based treatment options for patients with HER2-overexpressing breast cancer has garnered significant attention. This review discusses the cardiac toxic effects of trastuzumab and trastuzumab-related regimens and how their mechanisms of action and physiologic effects differ from cardiac toxicity typically associated with anthracycline use. An overview of cardiac safety data from selected trials of trastuzumab in combination with a taxane after anthracyclines for HER2-overexpressing early-stage breast cancer shows rates of symptomatic or severe CHF of < 4% and asymptomatic declines in left ventricular ejection fractions of > 10 points in < or = 30% of patients. For metastatic breast cancer, severe CHF has been reported in 2% of patients and ejection fraction declines in 6%-18% of patients. However, interstudy comparisons of chemotherapy-induced cardiac dysfunction are difficult because of the use of different definitions of cardiac dysfunction and different parameters for assessing cardiac safety. Recent data on cardiac safety of taxane/trastuzumab-based combination regimens demonstrate that the docetaxel/carboplatin/trastuzumab triple combination can offer clinical efficacy with a low risk of cardiac dysfunction in patients with HER2-overexpressing early-stage breast cancer as well as in patients with metastatic breast cancer.     

A phase II study of weekly vinorelbine and trastuzumab in patients with HER2-positive metastatic breast cancer

BACKGROUND: Trastuzumab combined with cytotoxic agents presents encouraging results in metastatic breast cancer (MBC), but cardiac toxicity limits some combinations. The synergism shown with trastuzumab and the favorable tolerability profile of vinorelbine provided the rationale for investigating this combination. PATIENTS AND METHODS: Patients with HER2-positive MBC who had received <2 lines of chemotherapy for metastatic disease were included. Vinorelbine (25 mg/m2 on day 2, then weekly on day 1) and trastuzumab (4 mg/kg on day 1, then 2 mg/kg weekly) were administered for a maximum of 6 cycles (1 cycle=3 weeks). RESULTS: A total of 52 patients were enrolled. The median age was 50 years (range, 26-79 years). Ninety percent of the patients had received adjuvant chemotherapy, 42% received a first line of chemotherapy for MBC, and 69% had disease at visceral sites. The overall response rate was 58% (95% CI, 43%-71%). The median time to progression and overall survival were 7 months (95% CI, 5-9 months) and 26 months (95% CI, 20-32 months), respectively. Grade 4 neutropenia was present in 3 courses; neutropenic fever was not reported. The main grade 3 nonhematologic toxicities were asthenia, neuropathy, diarrhea, alopecia, and nausea/vomiting. No patients experienced serious cardiac toxicity. CONCLUSION: These results confirm that weekly vinorelbine/trastuzumab is an active and safe regimen in patients with HER2-positive MBC with an unfavorable prognosis.     

Combination of trastuzumab and vinorelbine in metastatic breast cancer

BACKGROUND: Since the clinical introduction of trastuzumab (Herceptin) for metastatic breast cancers that overexpress human epidermal growth factor receptor 2 (HER2), this anticancer agent has played an important role in breast cancer treatment. We examined the effects of trastuzumab and vinorelbine (Navelbine) as a second- or third-line therapy in 24 patients whose HER2-positive tumors did not respond to or relapsed after administration of trastuzumab alone or in combination with taxane. METHODS: Trastuzumab was administered at 2 mg/kg (loading dose 4 mg/kg) once weekly and vinorelbine at 25 mg/m(2) once weekly. The median treatment duration was 118.5 days (range, 22-351 days). RESULTS: The response rate was 42% (95% confidence interval (CI): 22%-63%). The adverse events of NCI-CTC grade 3 or above consisted of neutropenia in three patients; other adverse events, including vasculitis, generalized fatigue, anemia and thrombocytopenia, were grade 1 or 2. All adverse events were reversible after treatment withdrawal and were easily manageable. CONCLUSION: A combination of trastuzumab and vinorelbine can be safely administered on an outpatient basis, and is useful in the treatment of patients with HER2-overexpressing metastatic breast cancer.     

Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results

Trastuzumab/chemotherapy combinations have already shown superior results in metastatic breast cancer patients. The purpose of this study is to determine the clinical efficacy of neoadjuvant trastuzumab and docetaxel in women with locally advanced breast cancer, with or without metastatic disease. Treatment-naive women with HER2-overexpressing locally advanced breast cancer, with or without metastatic disease, were included. Patients received trastuzumab 4 mg/kg loading dose intravenously then 2 mg/kg weekly. On day 22, docetaxel 100 mg/m2 every 3 weeks for 4 cycles was added to weekly trastuzumab. Patients then underwent surgery and subsequent 4 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2) without trastuzumab. Weekly trastuzumab was resumed 1 month after completion of AC and continued for a year. Preliminary results from the first 22 patients with median follow-up of 15.5 months (range, 2-38 months) are reported. Of these, 9 patients (40.9%) had inflammatory breast cancer, and 6 patients (27.3%) had stage IV breast cancer. Seventeen of 22 patients (77.3%) had objective clinical response, with a clinical complete response in 9 patients (40.9%). Two patients (9.1%) had decline in cardiac function and 7 patients (31.8%) experienced neutropenia, with 2 deaths (9.1%) from neutropenic sepsis. Eight patients (36.4%) have relapsed, 3 with local skin recurrence (13.6%) and 5 with distant recurrence, of whom 1 had liver metastasis (4.5%) and 4 had brain metastasis (18.2%). Combined neoadjuvant trastuzumab and docetaxel induced high clinical response rates for HER2-overexpressing breast cancer, in particular for inflammatory breast cancer. A high rate of brain metastasis was noted, particularly in patients with baseline metastatic disease.     

Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer.

PURPOSE: To assess pathologic complete response (pCR), clinical response, feasibility, safety, and potential predictors of response to preoperative trastuzumab plus vinorelbine in patients with operable, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. EXPERIMENTAL DESIGN: Forty-eight patients received preoperative trastuzumab and vinorelbine weekly for 12 weeks. Single and multigene biomarker studies were done in an attempt to identify predictors of response. RESULTS: Eight of 40 (20%) patients achieved pCR (95% confidence interval, 9-36%). Of 9 additional patients recruited for protocol-defined toxicity analysis, 8 were evaluable; 42 of 48 (88%) patients had clinical response (16 patients, clinical complete response; 26 patients, clinical partial response). T(1) tumors more frequently exhibited clinical complete response (P = 0.05) and showed a trend to exhibit pCR (P = 0.07). Five (13%) patients experienced grade 1 cardiac dysfunction during preoperative treatment. Neither HER2 nor estrogen receptor status changed significantly after exposure to trastuzumab and vinorelbine. RNA profiling identified three top-level clusters by unsupervised analysis. Tumors with extremes of response [pCR (n = 3) versus nonresponse (n = 3)] fell into separate groups by hierarchical clustering. No predictive genes were identified in pCR tumors. Nonresponding tumors were more likely to be T(4) stage (P = 0.02) and express basal markers (P < 0.00001), growth factors, and growth factor receptors. Insulin-like growth factor-I receptor membrane expression was associated with a lower response rate (50% versus 97%; P = 0.001). CONCLUSIONS: Preoperative trastuzumab plus vinorelbine is active and well tolerated in patients with HER2-positive, operable, stage II/III breast cancer. HER2-overexpressing tumors with a basal-like phenotype, or with expression of insulin-like growth factor-I receptor and other proteins involved in growth factor pathways, are more likely to be resistant to this regimen.     

Feasibility and cardiac safety of pegylated liposomal doxorubicin plus trastuzumab in heavily pretreated patients with recurrent HER2-overexpressing metastatic breast cancer

BACKGROUND: Few studies have evaluated concomitant pegylated liposomal doxorubicin (PLD) plus trastuzumab as therapy for HER2-overexpressing metastatic breast cancer (MBC). This open-label, prospective, phase II trial assessed the safety and efficacy of this regimen, with cardiac tolerance as the principal focus. PATIENTS AND METHODS: Women with HER2-overexpressing recurrent MBC, baseline left ventricular ejection fraction >or= 55%, and no history of serious cardiac illness were eligible; preexisting cardiac risk factors, including previous anthracyclines and previous trastuzumab for MBC, were allowed. Patients received weekly trastuzumab and every-3-week PLD until progression, prohibitive toxicity, or patient refusal. Left ventricular ejection fraction was assessed during and after therapy. Grade 3/4 congestive heart failure (CHF) was monitored for premature closure. RESULTS: The trial closed after 2.5 years for slow accrual. Twelve patients were enrolled: 7 had received adjuvant anthracyclines; 9 had received previous MBC treatment, of whom 7 had received trastuzumab in combination with chemotherapy. Patients received a mean of 4.8 cycles of PLD; 8 patients experienced stable disease; 4 patients experienced progression. Mean left ventricular ejection fraction levels did not change substantially: 60.4%, 57%, 60.3%, and 56.8% at baseline, after cycle 2, after cycle 4, and after completion of treatment, respectively. No patients experienced grade 4 CHF. One patient discontinued treatment after grade 3 CHF. Three patients experienced grade 2 left ventricular dysfunction, of whom 2 discontinued treatment. Cardiac function improved in all 4 patients after going off study. Other adverse events were generally mild (grade 1/2) and infrequent. CONCLUSION: Pegylated liposomal doxorubicin plus trastuzumab might be an option for heavily pretreated patients with recurrent HER2-overexpressing MBC.     

Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study

We conducted a pilot phase II trial of trastuzumab administered concurrently with docetaxel in women with HER2-overexpressing advanced breast cancer. Twenty-five women with HER2-positive (3+ by immunohistochemistry = 16, 2+ = 9) metastatic breast cancer received docetaxel (75 mg/m every 3 weeks for 6 cycles) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-three patients (92%) had visceral metastatic involvement. Twenty-three patients had received prior chemotherapy as part of adjuvant (18), metastatic (2), and both (3) treatment. The number of cycles administered was 121 (median 6, range 1-6). Symptomatic cardiotoxicity (GIII) occurred in one patient. The most common grade GIII/IV toxicity was neutropenia (80% of the cycles), although febrile neutropenia did not occur. No other GIII/IV toxicities were observed. Response rate was 70% (1 complete response and 15 partial responses) in 23 evaluable patients. The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity.