HER2-overexpressing Advanced Breast Cancer Research Articles

Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy

Purpose: The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy.Methods: The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) ± trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment.Results: Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification.Conclusions: Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.

Incorporating Trastuzumab into the Neoadjuvant Treatment of HER2-Overexpressing Breast Cancer

We sought to provide a brief overview of the available results of trastuzumab in the neoadjuvant treatment of women with locally advanced, HER2-overexpressing breast cancer. A review of published reports was conducted by the use of Medline computer searching and manual searching of abstracts presented at the Annual Meeting of the American Society of Clinical Oncology and the San Antonio Breast Cancer Symposium between 2002 and 2004. Several phase II trials and one phase III trial show that trastuzumab-containing regimens are feasible and yield high rates of clinical and pathologic complete response in women with locally advanced HER2-overexpressing breast cancer. Moreover, the neoadjuvant approach allows serial monitoring of biologic phenomena that occur during the administration of therapy, which acquires particular importance in the case of targeted therapies like trastuzumab. The incorporation of trastuzumab into neoadjuvant therapy for breast cancer appears promising. However, no data on long-term survival and safety are available at present. Welldesigned clinical trials are needed to establish the optimal trastuzumab-based neoadjuvant strategy.

A multicenter phase II study of docetaxel, gemcitabine and trastuzumab administration as first-line treatment in patients with advanced breast cancer (ABC) overexpressing HER-

728 Background: To evaluate the activity and toxicity of the docetaxel-gemcitabine-trastuzumab combination in the first-line treatment of ABC overexpressing HER-2. Methods: Previously untreated patients with 2+ or 3+ HER-2 overexpressing ABC who had measurable disease received trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly thereafter followed by docetaxel 65 mg/m2 and gemcitabine 1500 mg/m2 every two weeks without prophylactic growth factor support. One cycle equals one biweekly administration. Results: Thirty-four patients have been entered in this study and all were evaluable for toxicity and 30 for response. Median age was 56 years (range 33–75), 25(73%) patients were post-menopausal, 32(94%) had performance status of 0–1 and 20(59%) had previously received adjuvant and/or neoadjuvant chemotherapy. Complete response was observed in 1(3%) and partial response in 18(53%) patients for an overall response rate of 56% (95% C.I. 39.1–72.5). The median duration of response was 12 months (range 1.5–26.5) ...

A multicenter phase II study of docetaxel, gemcitabine and trastuzumab administration as first-line treatment in patients with advanced breast cancer (ABC) overexpressing HER-

728 Background: To evaluate the activity and toxicity of the docetaxel-gemcitabine-trastuzumab combination in the first-line treatment of ABC overexpressing HER-2. Methods: Previously untreated patients with 2+ or 3+ HER-2 overexpressing ABC who had measurable disease received trastuzumab 4 mg/kg loading dose and 2 mg/kg weekly thereafter followed by docetaxel 65 mg/m2 and gemcitabine 1500 mg/m2 every two weeks without prophylactic growth factor support. One cycle equals one biweekly administration. Results: Thirty-four patients have been entered in this study and all were evaluable for toxicity and 30 for response. Median age was 56 years (range 33–75), 25(73%) patients were post-menopausal, 32(94%) had performance status of 0–1 and 20(59%) had previously received adjuvant and/or neoadjuvant chemotherapy. Complete response was observed in 1(3%) and partial response in 18(53%) patients for an overall response rate of 56% (95% C.I. 39.1–72.5). The median duration of response was 12 months (range 1.5–26.5) ...

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/m² 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/m²/week (range 16–25 mg/m²/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.

HER2-Positive Breast Cancer: Update on Breast Cancer International Research Group Trials

HER2 gene amplification occurs in approximately 20% of primary breast cancers and is associated with a poor prognosis. Recently, trastuzumab, a humanized murine monoclonal antibody directed against the extracellular domain of HER2, was introduced for the treatment of patients with HER2-overexpressing advanced breast cancer. Trastuzumab has activity as both a single agent and in combination with chemotherapy. However, trastuzumab in conjunction with anthracyclines produces an unacceptably high rate of cardiac toxicity, which has prompted the search for alternative regimens. Docetaxel and the platinum salts are logical candidates to be combined with trastuzumab since these agents exhibit potent synergy with the antibody in preclinical experiments. Furthermore, the available phase II clinical data using the TCH (docetaxel/platinum/trastuzumab) regimen suggest this combination has significant activity. The Breast Cancer International Research Group (BCIRG) 006 trial is a 3-arm adjuvant study comparing doxorubicin/cyclophosphamide followed by docetaxel, the same regimen with trastuzumab administered with docetaxel (TH), and TCH in 3150 women with nodepositive or high-risk node-negative, HER2-positive breast cancer. BCIRG 007 compares TH and TCH as firstline therapy in patients with HER2-positive metastatic breast cancer. In both trials, entry is restricted to patients whose tumors are positive for HER2 gene amplification as determined by fluorescence in situ hybridization. The data from these trials, in addition to the results from other ongoing randomized studies, will help define the optimal way to utilize trastuzumab in the management of patients with HER2-positive breast cancer.

Emerging Antibody-Based HER2 (ErbB-2/neu) Therapeutics

Targeting HER2(ErbB-2/neu) overexpressing tumor cells to selectively deliver anticancer agents and thereby reduce host toxicity represents a rational and emerging strategy for the treatment of breast and other epithelial cancers. The extracellular domain of the HER2 receptor tyrosine kinase is readily accessible to systemically administered antibody-based therapeutics, including growth-inhibiting monclonals such as rhuMAbHER2 (trastuzmab/Herceptin) as well as anti-HER2 immunotoxins, antibody-dependent enzyme prodrug therapy (ADEPT), and immune cell recruiting bispecific antibodies. In addition to summarizing recent advances in these antibody-based strategies, this review focuses on preclinical advances in the development of anti-HER2 immunoliposomes (ILs) as a platform technology for targeted drug delivery. Extensive in vitro and in vivo testing including efficacy and tumor uptake studies in multiple human tumor xenograft models now provide conclusive evidence for the superior therapeutic efficacy of anti-HER2 ILs-doxorubicin (dox) over free dox or liposomal (Ls)-dox, and even over combinations of dox and Ls-dox with rhuMAbHER2. As anti-HER2 ILs-dox approaches clinical testing in patients with advanced HER2 overexpressing breast cancer, future applications of this novel targeting strategy will also broaden to include intracellular delivery of other anticancer agents as well as therapeutic nucleic acids (oligonucleotides, genes).