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    • Five year survival proportions for melanoma are

    2018-11-07

    Five-year survival proportions for melanoma are poor for patients with metastatic disease, however if disease is detected in its early stages, then survival is one of the highest for all cancers. Even for those with metastases, survival differs depending on the extent of disease spread. Patients with metastases confined to regional lymph nodes (stage III disease) have 5-year survival of ~50%, whereas patients with widely disseminated metastases (stage IV disease) have 5-year survival of <15%. Thus better monitoring of a patient\'s tumour burden may improve survival by precipitating earlier therapeutic interventions. In support of this, clinical trials in stage III unresectable and stage IV melanoma patients, treated with ipilimumab (Hodi et al., 2010), vemurafenib (Sosman et al., 2012), combined dabrafenib and trametinib (Flaherty et al., 2014) or anti-PD1 pembrolizumab (Joseph et al., 2014), have observed improved overall survival and response rate in patients with lower disease volume (M1a/M1b) as compared to those with distal disease (M1c). Moreover, it is believed that there is potential for long-term survival if relapses are identified promptly with treatment initiated without delay (Davidson et al., 2014). In clinical practice, there is currently a lack of reliable, sensitive and specific predictive biomarkers for detecting early melanoma progression. This study aimed to identify a more effective biomarker that was sensitive and specific enough to identify early metastatic disease. Since commencement of this study there have been a number of studies investigating the utility of miRNAs to serve as melanoma blood and tissue biomarkers (Fleming et al., 2015; Friedman et al., 2012; Tembe et al., 2015; Leidinger et al., 2010; Greenberg et al., 2013; Margue et al., 2015; Bonazzi et al., 2012). For example, a study by Friedman et al. (2012) screened 355 miRNAs in sera from 80 melanoma patients using a previously characterised panel of serum-expressed miRNAs. The authors found detectable TAPI-1 for 170 miRNAs and a panel of five miRNAs (miR-150, miR-15b, miR-199a-5p, miR-33a, and miR-424) showed a significant association with recurrence-free survival. This five-miRNA signature was able to classify the patients into high and low recurrence risk. Our approach was to identify a panel of melanoma-related miRNAs that involved first screening a panel of melanoma cell lines (n=55) in comparison with a group of other solid malignancies (cell lines were derived from breast, ovarian, colorectal, prostate, etc.) (Stark et al., 2015). Interestingly, the five-miRNA panel indentified by Friedman et al. (2012) was not present in our dataset which may indicate that this panel is not specifically melanoma-related but instead related to the tumourigenic process. We focused on miRNAs that were highly expressed or more predominantly expressed in melanoma with the premise that these may be both ‘diagnostic’ for melanoma and/or more easily detectable in patient serum. Our current approach differed from the aforementioned studies as: 1) this study harnessed the power of our previous comprehensive analysis of known miRNAs (n=1898) in relation to melanoma (Stark et al., 2015); 2) this study validated the cell-line derived miRNA panel (MELmiR-17) in a large of panel of stage III and IV melanoma tissues prior to serum analysis to confirm they were expressed; and 3) this study used an ultra-sensitive method of detection (see Materials and Methods) to ensure that lowly expressed miRNAs could be detected. We have successfully used these approaches in a previous study where a panel of miRNAs were identified that was related to good and poor prognosis in stage III melanoma patients (Tembe et al., 2015). However, our current study was limited by the lack of available serially collected specimens (to detect recurrence as in Friedman et al., 2012) at time of study design. To address this limitation, further studies in larger, independent, prospectively collected melanoma cohorts will be required to strengthen these data.