Biomarker Analysis in a Phase II Study of Sunitinib in Patients with Advanced Melanoma.

AIM: To investigate the efficacy of sunitinib in patients with advanced melanoma and to correlate angiogenic biomarkers with response and survival. PATIENTS AND METHODS: We performed a phase II study in patients with advanced pre-treated melanoma. The primary endpoint was tumor response. Blood samples for biomarker analysis including vascular endothelial growth factor (VEGF), and its receptors VEGFR1 and -2, placental growth factor (PlGF) and circulating endothelial cells (CEC) were collected at baseline and during the first cycle. RESULTS: Four out of 39 patients (13%) achieved a partial response and eight (26%) stable disease. Time to progression was at least six months in seven patients. High baseline VEGFR1 levels and high baseline PlGF levels were both associated with a non-significant worse survival (p=0.08 for both). CONCLUSION: Sunitinib demonstrates limited activity in unselected patients with refractory advanced melanoma, but a minority of patients experienced long-term disease control. Identification of these patients remains a challenge.

Phase II study of a triple combination of oral vinorelbine, capecitabine and trastuzumab as first-line treatment in HER2-positive metastatic breast cancer.

UNLABELLED: Chemotherapy plus trastuzumab is the standard first-line treatment for Human Epidermal Receptor 2-positive (HER2-positive) metastatic breast cancer. The aim of this international phase II trial was to determine the efficacy and safety profile of an oral chemotherapy doublet, oral vinorelbine plus capecitabine, and trastuzumab in this setting. PATIENTS AND METHODS: In this single-arm, multicenter, open-label phase II study, in the first-line metastatic setting, patients received 3-weekly cycles of oral vinorelbine at 80 mg/m(2) (first cycle dose 60 mg/m(2)) day 1 and day 8, plus capecitabine at 1000 (750 if ≥ 65 years) mg/m(2) twice daily on days 1-14, plus trastuzumab at 4 mg/kg intravenously (i.v.) on day 1 (loading dose) then 2 mg/kg i.v. weekly thereafter. Treatment was continued until progression or unacceptable toxicity. RESULTS: Fifty patients with a median age of 53.5 years were enrolled. Most (82%) had visceral involvement and 34% had more than two metastatic sites. The objective response rate (RECIST 1.0) in 44 evaluable patients was 77% [95% Confidence Interval (CI)=62-89%], including complete response in 21%. The clinical benefit rate (response or stable disease for ≥ 6 months) was 93% [95% CI=81-99%]. Median duration of response was 13.3 [95% CI=9.8-15.7] months, median progression-free survival was 12.8 [95% CI=10.8-16.9] months and median overall survival was 47.0 [95% CI=30.5-64.3] months. Median number of cycles was 10 (range 1-81). The majority of patients (72%) received more than 18 weeks and 32% more than 48 weeks of treatment. The most frequent treatment-related grade 3/4 adverse events were neutropenia (71%), hand-foot syndrome (20%) and diarrhea (16%). A low-rate of grade 2 alopecia was observed (14%). CONCLUSION: The triple combination of oral vinorelbine, capecitabine and trastuzumab is highly active in terms of response rate, progression-free survival and overall survival, with a manageable toxicity profile.

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.

High-dose oral medroxyprogesterone acetate or tamoxifen as adjuvant hormone therapy for node-negative early-stage breast cancer: randomized trial with 7-year update.

A randomized adjuvant trial compared tamoxifen 20 mg daily for 5 years with high-dose oral medroxyprogesterone acetate (MPA) 1 g orally for 9 months. One hundred ninety-four patients with histologically proven primary node-negative breast carcinoma were enrolled between December 1990 and October 1996, with 98 patients randomized into the tamoxifen arm and 96 into the MPA arm. At a median follow-up of 86 months, 25 relapses and 13 deaths were recorded. The relapse-free survival rate at 7 years in the tamoxifen arm was 93%, versus 81% in the MPA arm (P = 0.02). The difference was observed in patients with stage T2 disease (100% in the tamoxifen group vs. 64% in the MPA group; P = 0.01), in younger and/or premenopausal patients (in patients < 50 years of age, 100% in the tamoxifen arm vs. 81% in the MPA arm [P = 0.02], and in patients > or = 50 years of age, 90% in the tamoxifen arm vs. 82% in the MPA arm [P = 0.16]). Also, the overall survival rate at 7 years was lower in women < 50 years of age (P = 0.04).