A phase II study of the halichondrin B analog eribulin mesylate in gemcitabine refractory advanced pancreatic cancer.

BACKGROUND: Eribulin mesylate is a halichondrin B analog that inhibits microtubule dynamics. Pre-clinical studies have suggested anti-tumor activity in pancreatic cancer. This phase II study of eribulin in patients with advanced pancreatic cancer previously treated with gemcitabine was conducted by the Princess Margaret Hospital Phase II consortium. PATIENTS AND METHODS: Eligibility criteria included locally advanced or metastatic pancreatic adenocarcinoma and previous treatment with gemcitabine. The study was a single arm phase II trial using a Simon 2-stage design. The primary endpoint was response rate, secondary endpoints included time to progression and overall survival. RESULTS: Fifteen patients were enrolled, 14 received treatment, and 12 were evaluable for response. The median age was 61, and the majority of patients were ECOG performance status 1. Grade 3 or greater adverse events included neutropenia (29%), fatigue (14%), peripheral neuropathy (7%) and thrombosis (7%). There were no complete or partial responses and therefore the study was closed after the first stage. The best response was stable disease in 5/12 (42%) of patients. Of these five patients, three had stable disease for 9 months or greater. Median time to progression was 1.4 months, and median overall survival was 6.1 months. CONCLUSION: Eribulin was well tolerated but did not result in any objective responses in gemcitabine refractory pancreatic cancer. However, several patients had prolonged stable disease, suggesting that further studies of eribulin in pancreatic cancer may be warranted.

HER-2 and topoisomerase II as predictors of response to chemotherapy.

HER2 overexpression or amplification has been shown to be associated with a poor prognostic effect in women with breast cancer. At least eight analyses based on randomized trials have examined the relationship between HER2 and the differential effect of anthracycline compared with non-anthracycline-containing regimens. Only three of these studies were sufficiently powered to show a significant interaction between HER2 and anthracycline- versus non-anthracycline-containing treatments, but because all of the study results tended to be in the same direction, it is not surprising that three recent meta-analyses of published data have suggested that anthracycline-containing regimens provide more benefit than non-anthracycline-containing regimens in women whose tumors are overexpressed or amplified (positive) for HER2. Since topoisomerase II is a known target of the anthracyclines, it has been postulated that this relationship is actually based on the proximity of HER2 to the topoisomerase II alpha gene (TOP2A) in the 17q chromosome. At least four recent studies have suggested that deletion and amplification of the TOP2A gene are associated with poor prognosis and are predictive of greater response to anthracycline-containing than to non-anthracycline-containing regimens. However, in at least one of those studies, HER2 positivity was as or more predictive. Although it has been suggested that HER2 positivity is predictive of better response to higher-dose anthracycline-containing regimens compared with standard anthracycline-containing regimens and to taxane- compared with non-taxane-containing regimens, these relationships have not been robust or consistent. Additional studies will be required to clarify these relationships.

HER2/neu in systemic therapy for women with breast cancer: a systematic review.

BACKGROUND: Amplification and/or overexpression of the HER2/neu gene is associated with a poor prognosis in breast cancer. Many studies have suggested that this gene may be associated with the relative efficacy of chemotherapy and endocrine therapy options. METHODS: A systematic review of the evidence was conducted. MEDLINE, EMBASE, the Cochrane Library, the American Society of Clinical Oncology annual meeting proceedings, and the San Antonio Breast Cancer Symposia proceedings were all searched to November 2006 for reports of analysis by HER2/neu status of the relative efficacy of the treatment arms in randomized controlled trials. RESULTS: Thirty-five trials were identified. A meta-analysis of trials of tamoxifen versus observation found no significant interaction between treatment and HER2/neu status, although one trial not included in the meta-analysis did find interaction. A meta-analysis of adjuvant anthracycline-based chemotherapy trials found a significant interaction (difference in disease-free survival log-hazard ratios -0.31, 95% confidence interval -0.50 to -0.13; difference in overall survival log-hazard ratios -0.34, 95% confidence interval -0.53 to -0.14). Significant interaction was also found in a meta-analysis of disease-free survival in trials of adjuvant taxane therapy versus non-taxane therapy (difference in disease-free survival log-hazard ratios -0.36, 95% confidence interval -0.68 to -0.04). HER2/neu overexpression and/or amplification was associated with greater efficacy of the anthracycline or taxane regimen. CONCLUSIONS: Current evidence supports the conclusion that the benefit of both anthracycline-based and taxane-based adjuvant chemotherapy is associated on HER2/neu status, with patients with HER2/neu-positive cancers benefiting more from these therapies than those with HER2/neu-negative cancers.