Implementing personalised medicine in melanoma patients

MR GIROTTI, D. ROTHWELL, A. VIROS, A. MANDAL, K. H. J. LIM, G. GREMEL, S. FURNEY, M. PEDERSEN, J. ROGAN, J. SWAN, R.LEE, M. SMITH, A. FUSI, D. OUDIT, G. BRADY, P. LORIGAN, C.DIVE, R. MARAIS.

San Francisco

Conferencia; Society of Melanoma Research Annual Conference; 2016

BRAF is mutated in about 50% of human melanomas andtreatment with BRAF or MEK inhibitors have resulted inincreased progression-free and overall survival in melanomapatients. However, the majority of patients relapse after arelatively short period of disease control. Furthermore, aftertreatment with targeted therapy, most patients derive littlebenefit from immune checkpoint inhibitors. Resistance totargeted agents is driven by several mechanisms, so selectingsecond line therapies is challenging. Current advice includes theoption to continue treatment beyond progression, but it isunclear how to select the patients that will benefit from this, sodetecting disease progression early and elucidating themechanisms of resistance to therapy will help optimise theclinical care of these patients. Treatment options are also neededfor the ~50% of melanoma patients who are BRAF wild-type.Weused whole exome sequencing (WES) to provide insight into themechanisms of resistance to BRAF inhibition and identify newtherapeutic strategies for BRAF wild-type melanomas. Wepresent the case of a patient that was wild-type for V600BRAF, but carried HRAS and Rb1 mutations, allowing us topredict that the patient?s tumour would be sensitive to thecombination of a MEK inhibitor plus paclitaxel and we validatedthis therapy in a xenograft derived from the patient (PDX). Thuswe show that genome analysis can be used to develop novelhypothesis-driven therapeutic strategies for patients and weshow that these treatments can be validated in the patients?PDXs. Finally, we describe the use of circulating tumour DNA(ctDNA) as a predictive biomarker of response to therapy and asa powerful approach to reveal and then monitor mechanisms ofresistance. In summary, we are implementing a powerfulcombination of techniques for personalised medicine toimprove clinical management of BRAF wild-type and BRAFmutant melanoma patients.