HER2-overexpressing Metastatic Breast Cancer Research Articles

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.

Tumor Protection Following Vaccination With Low Doses of Lentivirally Transduced DCs Expressing the Self-antigen erbB2

Gene therapy strategies may accelerate the development of prophylactic immunotherapy against cancer. We synthesized a lentiviral (LV) vector encoding a kinase-deficient form of erbB2 (erbB2tr) to transduce murine dendritic cells (DCs) efficiently. Murine erbB2 models a clinically relevant tumor-associated self-antigen; its human homolog (HER-2/neu) is overexpressed in breast cancer and in 80% of metastatic prostate cancers. Following one infection, approximately 47% of DCs overexpressed erbB2tr. To determine whether low doses of transduced DCs could protect mice from prostate cancer cells, we performed prime/boost vaccinations with 2 x 10(3) or 2 x 10(5) erbB2tr-transduced DCs. Six weeks after vaccination, mice were simultaneously bilaterally challenged with the aggressive RM-1 prostate cancer cell line and an erbB2tr-expressing variant (RM-1-erbB2tr). Whereas control mice developed both tumors, all recipients of 2 x 10(5) erbB2tr-transduced DCs developed only wild-type RM-1 tumors. One-third of mice vaccinated with just 2 x 10(3) erbB2tr-transduced DCs also demonstrated erbB2tr-specific tumor protection. Protection against RM-1-erbB2tr tumors was associated with sustained levels of anti-erbB2tr antibody production and also correlated with erbB2tr-specific Th1 cytokine secretion. Depletion of CD4(+), CD8(+), or natural killer (NK) cells prior to tumor challenge underscored their role in mediating tumor protection. We conclude that administration of DCs expressing a self-antigen through efficient LV-based gene transfer activates cellular and humoral immunity, protecting host animals against specific tumor challenge.

Early detection of leptomeningeal metastasis in patients with metastatic breast carcinoma: validation of CA 15-3 measurement in cerebrospinal fluid

Fifteen per cent of metastatic breast cancer will develop symptomatic leptomeningeal metastases. The introduction of trastuzumab (Herceptin) therapy has improved the response rates of survival of patients with metastatic breast cancer overexpressing HER2. Although previous studies are retrospective and of limited number, involving small study groups and different types of patient management, several authors have reported a 30% incidence of leptomeningeal metastases in patients with metastatic breast cancer overexpressing HER2 who were treated with trastuzumab, while 70 to 80% of cases of the disease were controlled systemically. In order to improve control of the disease at the level of the central nervous system (CNS), routine detection of leptomeningeal metastases in high-risk patients could be offered. CA 15-3 in cerebrospinal fluid (CSF) detection might be useful in helping to diagnose CNS metastases, particularly where cytology results are negative--which applies to 30% of cases--because tumor markers are more sensitive in detecting the tumor process. Our study validate CA 15-3 measurement in CSF and reference values were given.

The acute effect of trastuzumab infusion on ECG parameters in metastatic breast cancer patients.

Although trastuzumab therapy is known to be associated with congestive heart failure, its arrhythmogenic potential has not been studied in detail. The purpose of this study was to determine the acute influence of trastuzumab infusion on electrocardiogram (ECG) parameters in patients with metastatic breast cancer. Twenty patients with HER2 overexpressing metastatic breast cancer and normal cardiac function were enrolled in this single-centre prospective study. Standard 12-lead ECG recordings were performed at baseline and after trastuzumab infusion (2 mg/kg given over 30 min). P-wave durations, QT and RR intervals were measured and QT dispersion (QTd) and P-wave dispersion (Pd) were calculated. In comparison with baseline, no statistically significant change in any ECG parameters, including QT and RR intervals, P wave durations, Pd and QTd, was observed after infusion of trastuzumab. In this study, no abnormality of atrial and ventricular depolarisation and repolarisation, indicated by Pd and QTd, was detected after infusion of trastuzumab. As Pd and QTd are both known to be associated with increased risk of serious arrhythmias and sudden death, it would appear that trastuzumab has no acute arrhythmogenic potential related to cardiac depolarisation and repolarisation.

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 ≥ 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.

Cardiac safety of pegylated liposomal doxorubicin (PLD) in combination with trastuzumab (T) in patients with metastatic breast cancer (MBC): Results from a multicenter phase II study

1106 Background: Combination therapy of doxorubicin and trastuzumab is highly effective for Her2 positive MBC but characterized by frequent cardiac toxicity (CT). PLD can significantly reduce CT compared to conventional doxorubicin. Patients and Methods: 15 patients were enrolled in a phase II trial to evaluate cardiac safety of T (4 mg/Kg loading dose day 2, followed by weekly 2 mg/Kg) in combination with PLD (40 mg/m2 IV bolus day 1, q 28 d). 75% of pts. presented with more than 1 metastatic site and 40% for second line treatment. PLD was administered for 6 or 9 cycles, respectively, T until disease progression. To assess CT, all pts were evaluated with electrocardiogram (ECG) and echocardiograms (E) for Left Ventricular Ejection Fraction (LVEF) at baseline, every cycle during PLD and T, and every three months during T therapy alone. CT was defined as appearance of signs/ symptoms of congestive heart failure and/or an absolute decrease in LVEF > 10 units (below 50%) or decrease in LVEF > 15 units (above 50%). Results: Four pts. received 6 cycles, 4 pts. received 9 cycles of PLD, 4 pts discontinued treatment due to PD, 3 pts. due to toxicity. After a median follow up time of 15.4 months, 6 pts. (42.9%) demonstrated a clinical benefit and median OS was 16.2 months. Non cardiac side effects were mild with only 3 CTC Grade 3 events of 247 treatment cycles (1.2%). Three pts. developed minor ECG changes without pathological significance and 5 pts. had minor changes in their E with slight diastolic (n=3) or systolic (n=2) dysfunction. During follow-up, 3 pts. were diagnosed with pathological E findings, including 1 slight decrease of LVEF, one diffuse hypokinesia and one strong decrease in LVEF.The median LVEF in the study cohort was 66.1% at baseline, 62.7% after 6 cycles of therapy, 64.4% at the first follow up and did not change significantly until the 5 th examination. Conclusions: This study supports the combination of PLD and H in pts. with HER2 overexpressing metastatic breast cancer as a safe and feasible therapy. Due to the promising clinical response rates in this prognostically unfavorable group, this combination should be evaluated in larger studies as a potential regimen for adjuvant treatment of breast cancer. No significant financial relationships to disclose.

A multicenter phase II study of epirubicin (E) with low-dose herceptin (LD-H) as a first-line treatment in HER2 overexpressing metastatic breast cancer (MBC)

1060 Background: The combination of doxorubicin and herceptin (H) has been proven to be an effective regimen in metastatic breast cancer (MBC), although it was associated with an increased risk of cardiotoxicity. Methods: The aim of this study was to evaluate cardiac safety and efficacy of epirubicin (E) in combination with low-dose herceptin (LD-H) as first-line chemotherapy for women with HER-2 positive MBC. Forty-five patients were enrolled in a two-step, multicenter phase II study. In the first step, H was given at 2 mg/Kg loading dose on day 1, followed by 1 mg/Kg weekly; in the second step (≥ 12 objective responses/21pts), H dose was maintained at 1 mg/kg weekly. E was administered at 90 mg/m2 on day 1 every 3 weeks. After 6–8 courses, H was continued as a single agent for a maximum of 52 weeks. To assess cardiotoxicity, patients were evaluated for the left ventricular ejection fraction (LVEF) at baseline, every two cycles during E and LD-H, and every three months during LD-H alone. Cardiotoxicity was defined as signs or symptoms of congestive heart failure in = 10% of patients at an E dose of 720 mg/ m2 or in = 20% of patients at an E dose > 720 < 1,000 mg/m2. Results: Eight episodes of cardiotoxicity were observed (an asymptomatic decrease in LVEF =15% in 6 patients and an asymptomatic decline of LVEF at = 50% in 2 patients). Grade 3–4 neutropenia, alopecia and thrombocytopenia occurred in 25%, 45.5% and 6.8% of patients, respectively. Complete and partial responses were 2.4 and 61.9%, respectively, for an overall response rate of 64.3%. The median time to progression was 8.2 months (95% CI, 5.2–9.2 months) and the median overall survival was 32.8 months (95% CI, 17.1–48.6 months). Conclusions: E plus LD-H is an active treatment regimen for HER-2 positive MBC and demonstrates a very favourable safety profile, with manageable cardiotoxicity. No significant financial relationships to disclose.

Activity of trastuzumab (t) beyond disease progression in HER2 over-expressing metastatic breast cancer (MBC)

1066 Background: In HER-2 over-expressing MBC patients (pts), preclinical evidence suggests that T therapy should be continued until disease progression. On the other hand, the activity of T beyond disease progression is unknown. Methods: We retrospectively evaluated HER-2 over-expressing (score 3+ by IHC or 2+ and FISH amplified) unselected MBC pts treated at our institution with successive T-based cytotoxic therapies. Results: From 06/2001 to 06/2006 59 patients (57 female and 2 male) receiving at least 1 T-based regimen for advanced breast carcinoma were identified. Characteristics of patients at initiation of T were as follows: median age 51 years (32–73), pre-menopausal 28/57 (49%), HER-2 IHC 3+ 49/59 (83%), negative hormonal receptor status 34/59 (58%), visceral disease 45/59 (76%), adjuvant chemotherapy 47/59 (80%), chemo-naïve for MBC 30/59 (51%), median number of previous chemotherapy lines for MBC prior to T 1 (0–2). A total of 37, 16 and 9 patients received respectively a 2nd, 3rd and 4th T-based regimen. In the 1st T-based line there was an overall response rate (ORr) of 60% (clinical benefit-CB- 83%) while 2nd T-based line yielded an ORr of 29% (CB 62%). None of the 16 and 9 patients who received respectively a 3rd and 4th T-based line responded to treatment. At a median follow up of 26 months (range 7–78), median time to progression was 9.5 months (95%c.i. 8.2–10.9), 6.7 months (95%c.i. 3.9–9.4), 4.0 months (95%c.i. 2.4–6-0) and 4.5 months (95%c.i. 3.7–8.3) from 1st to 4th T-based line respectively. Overall survival (OS) was 37 months (95%c.i. 22.4–53.4). No significant difference was observed in OS between the 22 patients receiving only 1 T-based line and the 37 patients who underwent at least 2 T-containing regimens (28 months vs 38 months, p=0.85). Conclusions: In HER-2 positive MBC patients T beyond disease progression maintains activity in terms of CB, TTP and OS. Prospective randomized trials are warranted to draw definitive results. No significant financial relationships to disclose.

Phase II Study of Capecitabine Plus Trastuzumab in Human Epidermal Growth Factor Receptor 2–Overexpressing Metastatic Breast Cancer Pretreated With Anthracyclines or Taxanes

The oral fluoropyrimidine carbamate, capecitabine, is a highly active and well-tolerated treatment for metastatic breast cancer. In patients treated previously with anthracyclines and taxanes, capecitabine is an approved single-agent therapy. Trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor 2 (HER-2), is also highly active in HER-2-overexpressing breast cancer. We have conducted a phase II study to confirm activity and feasibility of capecitabine and trastuzumab in combination in HER-2-overexpressing advanced/metastatic breast cancer. Twenty-seven patients with HER-2-overexpressing metastatic breast cancer previously treated with anthracyclines and/or taxanes received oral capecitabine 1,250 mg/m(2) bid for 14 days followed by a 7-day rest period combined with intravenous trastuzumab 4 mg/kg body weight on day 1 (loading dose) followed by 2 mg/kg weekly. Capecitabine/trastuzumab treatment achieved objective responses in 12 patients (45%), including complete response in four patients (15%) and partial response in eight patients (30%). Disease was stabilized in an additional nine patients (33%). The median overall survival time was 28 months, and the median progression-free survival time was 6.7 months. The safety profile of the combination was favorable and predictable, with a low incidence of grade 3/4 adverse events. The most common adverse events were pain, hand-foot syndrome, and GI toxicities. Severe myelosuppression was rare and severe alopecia did not occur. These data confirm that the combination of capecitabine and trastuzumab is highly active in patients with HER-2-overexpressing anthracycline- and/or taxane-pretreated breast cancer, with only slight restrictions regarding quality of life.

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

To determine the response rate and toxicity profile of trastuzumab and capecitabine in women with HER2-overexpressing advanced breast cancer. 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. 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. Trastuzumab in combination with capecitabine is highly active in women with HER2-overexpressing metastatic breast cancer and is well tolerated.

Cell-penetrating peptides and antibodies: a new direction for optimizing radioimmunotherapy

Owing to their highly specific recognition of cognate antigens, antibodies have long been dream vehicles for targeted therapy and have recently been used to deliver radionuclides, drugs, toxins, and enzymes. Radioimmunotherapy (RIT) is an attractive therapeutic modality that combines the specificity of antibodies to antigens with the toxicity of the radionuclides. Radiolabeled antibodies like Bexxar and Zevalin have been approved by the FDA and are being used successfully to treat hematological malignancies in clinics. Moreover, because of their ability to inhibit the functional activity of the target antigen, some antibodies are also being used as unarmed therapeutics for solid tumors. Examples of these antibodies in clinics are: Avastin, an anti-VEGF monoclonal antibody that is used in the therapy of colorectal cancer, and Herceptin, an antiHer2 antibody approved for the therapy of Her2-overexpressing metastatic breast and other cancers. For solid tumors, however, radiolabeled antibody-based therapeutics have had limited success, primarily owing to slow uptake, poor penetration, and inadequate retention. Recent research efforts have centered on the strategies to overcome these limitations and optimize tumor uptake of armed antibodies.

Recherche des métastases cérébrales dans les cancers du sein métastatiques traités par Herceptin ® : une place pour la biologie ?

Between 10 and 15% of metastatic breast cancers will develop symptomatic brain metastases. The introduction of trastuzumab (Herceptin ®) therapy has improved the response rates and survival of patients with metastatic breast cancer overexpressing HER2+. Although previous studies are retrospective and limited in number, involving small study groups and different types of patient management, several authors have reported a 30% incidence of brain metastases in patients with metastatic breast cancer overexpressing HER2 who were treated with trastuzumab, while 70 to 80% of cases of the disease were controlled systemically. In order to improve control of the disease at the level of the central nervous system, routine detection of brain metastases in high-risk patients could be offered. Tumor marker assays might be useful in helping to diagnose central nervous system metastases, particularly where cytology results are negative — which applies to 30% of cases — because such assays are more sensitive in detecting the tumor process.

P101 A multicenter phase II study of Epirubicin with low-dose Herceptin as a first line treatment in HER-2 overexpressing metastatic breast cancer

P101 A multicenter phase II study of Epirubicin with low-dose Herceptin as a first line treatment in HER-2 overexpressing metastatic breast cancer

Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC)

Aim Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. Methods Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. Results (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T + CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2 → p-MAPKs. Conclusions p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials.

Ratio of trastuzumab levels in serum and cerebrospinal fluid is altered in HER2-positive breast cancer patients with brain metastases and impairment of blood–brain barrier

Patients receiving trastuzumab for HER2-overexpressing metastatic breast cancer seem to suffer from an increased risk of brain metastases, even in cases with responsive disease. To evaluate whether trastuzumab is able to penetrate the blood-brain barrier, we measured trastuzumab levels in the serum and in cerebrospinal fluid of metastatic breast cancer patients with brain metastases receiving trastuzumab for HER2-overexpressing metastatic breast cancer. In a pilot study, metastatic breast cancer patients with brain metastases and HER2-overexpressing tumors (HercepTest; Dako, Copenhagen, Denmark) were included. At different time points, trastuzumab levels in the serum and cerebrospinal fluid were measured using a newly developed immunoenzymatic test for trastuzumab. Six out of eight patients were evaluable for determination of trastuzumab level in the serum and cerebrospinal fluid. Before radiotherapy, median trastuzumab level in the serum was 52 054 ng/ml compared with 124 ng/ml in cerebrospinal fluid (ratio 420 : 1). After completion of radiotherapy, median trastuzumab level was 20 185 ng/ml in the serum and 226 ng/ml in cerebrospinal fluid, respectively (ratio 76 : 1). With concomitant meningeal carcinomatosis, trastuzumab level in the serum after radiotherapy was 17 431 and 356 ng/ml in cerebrospinal fluid (ratio 49 : 1). For the first time, we present clinical evidence that trastuzumab levels in cerebrospinal fluid are increased under conditions of an impaired blood-brain barrier such as meningeal carcinomatosis or radiotherapy. This evidence supports the concept of continuing trastuzumab therapy in patients with brain metastases treated by radiotherapy. Monitoring of trastuzumab levels in the serum and cerebrospinal fluid may enable individualized therapy strategies in metastatic breast cancer patients with brain metastases, and lead to a better understanding of trastuzumab pharmacokinetics in the cerebrospinal fluid and serum.

Efficacy and safety of combined trastuzumab and paclitaxel therapy as a second-line treatment in women with metastatic Breast Cancer: A single institutional experience

In breast cancer, HER-2 overexpression suggests s poor prognosis. Trastuzumab is a humanized monoclonal antibody with specificity to the HER-2 protein. We evaluated the safety and efficacy of combined trastuzumab and paclitaxel therapy in women with metastatic breast cancer. Combination chemotherapy was given to patients with HER-2 overexpressing metastatic breast cancer. All patients had previously received one or more chemotherapy treatments. Patients received a loading trastuzumab dose of 4 mg/kg intravenously (i.v.), followed by 2 mg/kg maintenance dose at weekly intervals. A paclitaxel dose of 80 mg/m(2) was administered on the same day as the trastuzumab infusion. A total of 53 patients were examined. Seventy percent received two or more prior chemotherapy treatments for metastatic breast cancer, and 66.0% of patients had two or more metastatic sites. The overall response rate to our approach was 37.7%. Median time to progression was 12.0 months. Grade 3/4 neutropenia was seen in only 11.3% of patients. Peripheral neuropathy occurred in 65.1% of patients after seven treatments, requiring us to change to biweekly paclitaxel administration in 16 patients. Most of them were able to continue the treatment. Other toxicities were mild and tolerable. Combined trastuzumab and paclitaxel therapy, administered as second-line or later treatment, produced lasting objective responses and was well tolerated by women with HER-2 overexpressing metastatic breast cancer. A major obstacle to continuing treatment was peripheral neuropathy. However, modifying the interval to every 2 weeks enabled us to continue the treatment. This combination chemotherapy was safely performed in our outpatient clinic.

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.

Cardiac dysfunction associated with trastuzumab

The HER2/neu gene is amplified in ∼ 25% of breast cancers, leading to HER2 protein overexpression and shortened overall survival and time to relapse. Trastuzumab is a humanised, monoclonal antibody against HER2, which improves survival for women with metastatic HER2-overexpressing breast cancer and reduces the risk of recurrence in women with early stage HER2-overexpressing breast cancer. Cardiac toxicity was an unexpected finding in the pivotal Phase III trial leading to the approval of trastuzumab, and prospective cardiac monitoring has, therefore, been incorporated into more recent clinical trials of trastuzumab. This article reviews the cardiac toxicity findings in key trastuzumab clinical trials and clinical characteristics of trastuzumab-associated cardiac toxicity.

Overcoming Trastuzumab Resistance in HER2-Overexpressing Breast Cancer Cells by Using a Novel Celecoxib-Derived Phosphoinositide-Dependent Kinase-1 Inhibitor

Although trastuzumab has been successfully used in patients with HER2-overexpressing metastatic breast cancer, resistance is a common problem that ultimately culminates in treatment failure. In light of the importance of Akt signaling in trastuzumab's antitumor action, we hypothesized that concurrent inhibition of Akt could enhance trastuzumab sensitivity and moreover reverse the resistant phenotype in HER2-positive breast cancer cells. Based on our finding that celecoxib mediates antitumor effects through the inhibition of phosphoinositide-dependent kinase-1 (PDK-1)/Akt signaling independently of cyclooxygenase-2 (COX-2), we used celecoxib as a scaffold to develop a COX-2-inactive PDK-1 inhibitor, 2-amino-N-[4-[5-(2-phenanthrenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-acetamide (OSU-03012). Here, we investigated the effect of OSU-03012 on trastuzumab-mediated apoptosis in four breast cancer cell lines with different HER2 expression and trastuzumab-resistance status, including MDA-MB-231, BT474, SKBR3, and insulin-like growth factor-I receptor-overexpressing SKBR3 (SKBR3/IGF-IR). Effects of trastuzumab and OSU-03012, individually or in combination, on cell viability and changes in pertinent biomarkers including HER2 expression, phosphorylation of Akt, p27(kip1), and the PDK-1 substrate p70(S6K) were assessed. OSU-03012 alone was able to trigger apoptosis in all cell lines with equal potency (IC(50) = 3-4 microM), suggesting no cross-resistance with trastuzumab. Medium dose-effect analysis indicates that OSU-03012 potentiated trastuzumab's antiproliferative effect in HER2-positive cells, especially in SKBR3/IGF-IR cells, through the down-regulation of PDK-1/Akt signaling. This synergy, however, was not observed in HER2-negative MDA-MB-231 cells. This combination treatment represents a novel strategy to increase the efficacy of trastuzumab and to overcome trastuzumab resistance in the treatment of HER2-positive breast cancer.

Trastuzumab in combination with gemcitabine and vinorelbine as second-line therapy for HER-2/neu overexpressing metastatic breast cancer

The aim of this study was to evaluate the safety and efficacy of combined treatment with trastuzumab (T), gemcitabine (gem) and vinorelbine (vin) as second-line therapy for HER-2 overexpressing metastatic breast cancer, pretreated with anthracyclines and/or taxanes and/or trastuzumab. Eligible patients had HER-2/neu-positive disease (IHC 2+ or 3+), performance status (PS) <or=2 and normal L-VEF. Patients were treated with weekly T (4 mg/kg on day 0, then 2 mg/kg), in combination with gem (800 mg/m(2)) and vin (25 mg/m(2)) on days 1 and 8, every 21 days. Patients were restaged every 3 cycles. A total of 30 patients (median age, 58 years; range, 41-74) were enrolled in the study. Fifteen patients were HER-2 3+ and 26 (86.7%) presented >or=2 metastatic sites. Of the patients, 7 (23.3%) had received trastuzumab as first-line therapy. Treatment was well-tolerated with grade 4 neutropenia in 6 patients, grade 3 thrombocytopenia and grade 3 anemia in 1 patient, and grade 3 asthenia in 4 patients. Fifteen patients obtained an objective response (response rate, 50%; C.I. 95%, range, 31.3-68.7%). Among the patients with HER-2/neu 3+, the response rate was 73.3%. Noteworthy were 4 objective responses observed in patients with brain metastasis. Also, 7 patients had stable disease (23.3%). Median progression-free survival was 7 months (range 5-10), and median overall survival was 15 months (range 5-33). T-gem-vin is a safe and active regimen in this subgroup of patients with poor prognosis, and the efficacy of such a schedule was particularly satisfactory in patients with HercepTest 3+.