Dimitrios Tryfonopoulos

Membrane transport proteins in human melanoma: associations with tumour aggressiveness and metastasis.

Background:Malignant melanoma, generally described as incurable, is notoriously refractory to chemotherapy. The mechanisms contributing to this have not yet been defined and the contributions of drug efflux pumps, implicated in chemo-resistance of many other cancer types, have not been extensively investigated in melanoma.Methods:In this study, expression of multi-drug resistant (MDR1/P-gp and MRP-1) proteins was examined, by immunohistochemistry, in archival specimens from 134 melanoma patients. This included 92 primary tumours and 42 metastases.Results:On assessing all specimens, MRP-1 and MDR1/P-gp expression was found to be common, with the majority (81%) of melanomas expressing at least one of these efflux pumps. Although there is significant association between expression of these pumps (P=0.007), MRP-1 was found to be the predominant (67% of cases) form detected. χ2 analysis showed significant associations between expression of MRP-1 and/or MDR1/P-gp and the aggressive nature of this disease specifically increased Breslows depth, Clarks level and spread to lymph nodes. This association with aggressiveness and spread is further supported by the observation that a significantly higher percentage of metastases, than primary tumours, express MRP-1 (91% vs 57%; P<0.0001) and MDR1/P-gp (74% vs 50%; P=0.010).Conclusion:The predominant expression of these pumps and, in particular, MRP-1 suggests that they may be important contributors to the inherent aggressive and resistant nature of malignant melanoma.

Impact of timing of trastuzumab initiation on long-term outcome of patients with early-stage HER2-positive breast cancer: the “one thousand HER2 patients” project

BackgroundThe optimal timing of (neo)adjuvant trastuzumab initiation with respect to chemotherapy and surgery remains undefined.MethodsRetrospective analysis of a large institutional database of HER2-positive patients who received anti-HER2 therapy. We included all Stage I to III patients treated with trastuzumab with a minimum follow up of 3 years. The date of first breast biopsy was recorded as initial diagnosis.ResultsA total of 506 patients [adjuvant: 386 (76%)-neo-adjuvant: 120 (24%)] were included. The median time-to-first-trastuzumab (TFT) from diagnosis was 12 weeks (range 1.9–122.3). Median follow-up is 73.3 months (range 1.4–176.3). TFT was significantly shorter in the neo-adjuvant than in the adjuvant cohort (median: 4.4 vs. 14 weeks, p < 0.00001). Despite the neo-adjuvant cohort having significantly more node-positive patients (75 vs. 53%, p < 0.0001), DFS rate (neo-adjuvant: 12.5 vs. adjuvant: 18%, p = 0.094) was numerically superior in neo-adjuvant patients. A TFT ≤ 12 weeks was associated with significantly superior DFS and OS over TFT > 12 weeks. Early concomitant regimens were associated with superior DFS over delayed-concomitant and sequential regimens.ConclusionsInitiating trastuzumab more than 12 weeks from diagnosis has a negative impact on clinical outcome. Neo-adjuvant anti-HER2 therapy could be the optimal strategy to treat early stage HER2-positive breast cancer.