Purpose: Multiple BRAF inhibitor resistance mechanisms have been described, however, their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma.Experimental Design: Fifty-nine BRAF V600 -mutant melanoma metastases from patients treated with dabrafenib or vemurafenib were analyzed. The genetic profile of resistance mechanisms and tumor signaling pathway activity was correlated with clinicopathologic features and therapeutic outcomes.Results: Resistance mechanisms were identified in 58% progressing tumors and BRAF alterations were common. Gene expression analysis revealed that mitogen-activated protein kinase (MAPK) activity remained inhibited in 21% of resistant tumors, and the outcomes of patients with these tumors were poor. Resistance mechanisms also occurred in pretreatment biopsies and heterogeneity of resistance mechanisms occurred within patients and within tumors. There were no responses to subsequent targeted therapy, even when a progressing tumor had a resistance mechanism predicted to be responsive.Conclusions: Selecting sequential drugs based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved responses, and first-line therapies targeting multiple pathways will be required.

Repeat tumor biopsies to study genomic changes during therapy are difficult, invasive and data are confounded by tumoral heterogeneity. The analysis of circulating tumor DNA (ctDNA) can provide a non-invasive approach to assess prognosis and the genetic evolution of tumors in response to therapy. Mutation-specific droplet digital PCR was used to measure plasma concentrations of oncogenic BRAF and NRAS variants in 48 patients with advanced metastatic melanoma prior to treatment with targeted therapies (vemurafenib, dabrafenib or dabrafenib/trametinib combination) or immunotherapies (ipilimumab, nivolumab or pembrolizumab). Baseline ctDNA levels were evaluated relative to treatment response and progression-free survival (PFS). Tumor-associated ctDNA was detected in the plasma of 35/48 (73%) patients prior to treatment and lower ctDNA levels at this time point were significantly associated with response to treatment and prolonged PFS, irrespective of therapy type. Levels of ctDNA decreased significantly in patients treated with MAPK inhibitors (p < 0.001) in accordance with response to therapy, but this was not apparent in patients receiving immunotherapies. We show that circulating NRAS mutations, known to confer resistance to BRAF inhibitors, were detected in 3 of 7 (43%) patients progressing on kinase inhibitor therapy. Significantly, ctDNA rebound and circulating mutant NRAS preceded radiological detection of progressive disease. Our data demonstrate that ctDNA is a useful biomarker of response to kinase inhibitor therapy and can be used to monitor tumor evolution and detect the early appearance of resistance effectors.

Longitudinal assessment of ctDNA in metastatic melanoma patients receiving treatment with PD1 inhibitors is an accurate predictor of tumour response, PFS and OS. Patients who had a persistently elevated ctDNA on therapy had a poor prognosis, and this may guide combination and sequencing of subsequent therapies.

Background Despite being essential to patient care, current clinical handover practices are inconsistent and error prone. Efforts to improve handover have attracted attention recently, with the ISBAR tool increasingly utilised as a format for structured handover communication. However, ISBAR has not been validated in a junior medical officer setting. Objective To assess the effect of the ISBAR handover tool on junior medical officer (JMO) handover communication in an Australian hospital. Methods JMOs who participated in after-hours handover during an 11 week clinical term from June to August 2009 were recruited. After-hours handover was audiotaped, and JMOs completed a survey to assess current handover perception and practice. JMOs then participated in a 1 h education session on handover and use of the ISBAR handover tool, and were encouraged to handover using this method. Following the education session, participants were surveyed to measure perceived changes in handover with use of ISBAR, and handover was again audiotaped to assess differences in information transfer and duration. Results Following the introduction of ISBAR, 25/36 (71%) of JMOs felt there was an overall improvement in handover communication. Specifically, they perceived improvement in the structure and consistency of handover, they felt more confident receiving handover, and they believed patient care and safety were improved. Audio-tape data demonstrated increased transfer of key clinical information during handover with no significant effect on handover duration. Conclusions Use of the ISBAR tool improves JMO perception of handover communication in a time neutral fashion. Consideration should be given to the introduction of ISBAR in all JMO handover settings.