PO-513 Using MAPK and PI3K signalling to predict patient outcome in resectable stage IIIB/C melanoma patients neoadjuvantly treated with dafrafenib and trameitinib

Abstract

IntroductionIn the recent decade, significant progress has occurred in the treatment of stage IV metastatic melanoma, which is now being applied to patients with earlier stages of disease. Targeted therapies that combine Dabrafenib (BRAF inhibitor) and Trametinib (MEK inhibitor) have achieved a median progression-free-survival of 9.4 months in stage IV patients. However 50% of the patients on the combination therapy progress at 9–10 months. This can occur through MAPK reactivation of MAPK/ERK signalling and the PI3K/AKT/mTOR pathway.Material and methodsIn our study, we performed multispectral immunofluorescent staining on 26 Stage III metastatic melanoma patients who received neoadjuvant treatment with combination Dabrafenib and Trametinib. Patients were categorised into complete responder (CR) or non-complete responder (non-CR) based on their pathological response. Longitudinal biopsies were taken before therapy (PRE) and early during treatment (EDT) (day 4–7), with a full lymph node dissection at 12 weeks. PRE, EDT and 12 week (non-CR only) were assessed using quantitative pathology for phosphorylated-ERK (p-ERK), p-AKT and Ki-67 positivity in melanoma cells.Results and discussionsIn CRs, pERK decreased by 97% from PRE to EDT, whilst non-CRs decreased by 89%. Expression of pERK increased by 61% from EDT to the 12 week dissection in non-CR patients. There was no change between PRE and EDT in pAKT expression in either CR and non-CR patients; however in non-CRs, pAKT expression increased by 37% from EDT to 12 weeks. In CRs, Ki67 expression decreased by 85% from PRE to EDT (p=0.019), with higher ki-67 expression in non-CR than CR patients at baseline (23% and 11% respectively, p=0.069).ConclusionThis study highlights that patients who achieve a CR on Dabrafenib+Tremetinib therapies have a significant decrease in their Ki67 expression from their PRE to EDT biopsies.