Faculty Bibliography

PURPOSE/OBJECTIVE:Patients with stage II and resected stage III melanomas have variable clinical outcomes, evidence of underlying biological differences in tumors and/or the patients themselves, beyond stage. The approval of adjuvant immunotherapy for stage IIB/C and resected stage III/IV disease (and adjuvant targeted therapy for resected stage III disease), has created a pressing need to develop biomarkers to accurately distinguish patients at low- versus high-risk for recurrence and death from melanoma. MicroRNAs (miRNAs) are promising biomarkers because of their stability in tissues/fluids and their demonstrated functional and prognostic roles in melanoma. We hypothesized that miRNA expression could be integrated into prognostic models that would more accurately classify 5-year survival outcomes than clinical factors alone. PATIENTS AND METHODS/METHODS:Using a Nanostring miRNA Expression Assay, we analyzed 715 primary melanomas from patients with stage II or stage III disease within the InterMEL consortium, and examined associations between miRNA expression and melanoma-specific death. RESULTS:When integrated into clinical prognostic models for 5-year melanoma-specific survival, miRNA signatures improved the area under the receiver operating characteristic curve (AUC) for stage II patients from 0.71 for a 'clinical factors-only' model to 0.81 for a 'clinical plus miRNA' model in an independent test set, an improvement of 0.10 with 95% CI (0.03, 0.19). The improvement was more modest for stage III patients that were included in the analysis. CONCLUSIONS:Incorporating miRNA expression in primary melanomas may enhance the accuracy of clinical prognostic models, and potentially aid the selection of melanoma patients for adjuvant treatment and clinical trials.

BACKGROUND:Cell-free, circulating tumour DNA (ctDNA) is an established measure of minimal residual disease; however, it is not utilised in melanoma management. We investigated whether ctDNA measurements could predict survival outcomes during adjuvant targeted therapy or placebo treatment in stage III melanoma, thereby identifying patients at high risk and low risk of recurrence. METHODS:-mutant stage III melanoma. Patients were screened for enrolment between Jan 31, 2013, and Dec 11, 2014, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and were randomly assigned (1:1) to the two treatment groups. The primary endpoint was recurrence-free survival, and the results from final analysis have been previously published and will not be described here. Biomarker analysis was a prespecified exploratory endpoint and performed in the intention-to-treat population. We compared associations between survival outcomes and baseline (post-resection) ctDNA copies per mL, tumour mutational burden and interferon gamma (IFNG) gene expression. In a subset of patients, ctDNA quantities during follow-up or at recurrence were measured. The trial is registered with ClinicalTrials.gov, NCT01682083, and has been completed. FINDINGS/RESULTS:Baseline plasma samples were available for 597 of 870 patients (331 male patients and 266 female patients) and samples for assessing the ctDNA positivity rate at landmark follow-up timepoints of 3 months, 6 months, 9 months, and 12 months after treatment initiation were available for 94 of 870 patients. Additionally, samples were available from 118 of 870 patients within a 2-month timeframe before or after clinical or radiographic recurrence. Median follow-up for the biomarker analyses was 60 months (IQR 39-66) in the combination therapy group and 58 months (21-66) for the placebo group. ctDNA was detectable in 79 (13%) of 597 baseline samples. ctDNA positivity rate and mutant copies per mL plasma were significantly higher in patients with higher disease substages. As a binary variable, ctDNA detection was associated with worse recurrence-free survival (placebo group: median 3·71 months [95% CI 2·39-6·89] vs 24·41 months [17·28-43·13]; hazard ratio [HR] 2·91 [95% CI 1·99-4·25], p<0·0001); combination therapy group: median 16·59 months [95% CI 12·02-26·80] vs 68·11 months [50·36-not reached]; HR 2·98 [1·95-4·54], p<0·0001) and overall survival (placebo group: median 33·90 months [13·96-not reached] vs not reached; HR 3·35 [2·01-5·55], p<0·0001); combination therapy group: median 40·31 months [24·90-not reached] vs not reached; HR 4·27 [2·50-7·27], p<0·0001) in the placebo group and combination therapy groups. Baseline ctDNA was more strongly associated with survival outcomes than IFNG gene expression or tumour mutational burden. Patients with adverse longitudinal ctDNA kinetics (molecular relapse or persistently positive) had markedly shorter median recurrence-free survival (8·31 months [95% CI 5·39-12·20] and 5·32 months [2·79-not reached], respectively) compared with patients with favourable kinetics (ie, undetectable after positive baseline result: 19·25 months [16·39-not reached]; and durable undetectable: not reached [38·44-not reached], p<0·0001). INTERPRETATION/CONCLUSIONS:Droplet digital PCR measurements of ctDNA to assess minimal residual disease before adjuvant targeted therapy and during follow-up can identify patients at high risk of early recurrence. Additional studies using ctDNA measurements to guide therapeutic interventions might lead to improvements in the management of resected stage III melanoma. FUNDING/BACKGROUND:Novartis.

Melanoma is an aggressive cancer with rising incidence, particularly among older individuals. Despite advancements in targeted therapies for BRAF and MEK proteins and immunotherapies, many patients either fail to respond or develop resistance. For those progressing on immunotherapy, limited treatment options remain. The Cyclin D-CDK4/6-RB pathway is commonly dysregulated in melanoma, with up to 90% of cases showing alterations that activate it. Although targeting Cyclin-CDK complexes has shown promise in preclinical models, clinical responses have been suboptimal. This review explores the molecular mechanisms behind Cyclin-CDK dysregulation in melanoma and the challenges of targeting this pathway. It also discusses strategies to improve the efficacy of CDK4/6 inhibitors, including combination therapies to overcome resistance and enhance patient outcomes. Understanding these mechanisms can guide the development of more effective treatments for melanoma.