A targeted genomic alteration analysis predicts survival of melanoma patients under BRAF inhibitors
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Baptiste Louveau1,2,3, Julie Delyon1,2,4, Coralie Reger De Moura2,3, Maxime Battistella1,5,6, Fanelie Jouenne1,2,3, Lisa Golmard7, Aurelie Sadoux1,2,3, Marie-Pierre Podgorniak1,2,3, Ichrak Chami4, Oren Marco8, Julie Caramel9, Stephane Dalle9,10, Jean-Paul Feugeas11, Nicolas Dumaz1,2, Celeste Lebbe1,2,4,* and Samia Mourah1,2,3,*
1Paris-Diderot University, Sorbonne Paris Cité, Paris, France
2Paris-Diderot University, Inserm, UMR_S976, Paris, France
3Department of Pharmacogenomics, Saint-Louis Hospital, AP-HP, Paris, France
4Department of Dermatology, Saint-Louis Hospital, AP-HP, Paris, France
5Department of Pathology, Saint-Louis Hospital, AP-HP, Paris, France
6Paris Diderot University, Inserm, UMR_S1165, Paris, France
7Department of Genetics, Pôle de Médecine Diagnostique et Théranostique, Institut Curie, Paris, France
8Department of Plastic, Reconstructive and Esthetic Surgery, Saint-Louis Hospital, AP-HP, Paris, France
9Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France
10Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre Bénite, France
11Université de Franche-Comté, Inserm, UMR_1137, Paris, France
Samia Mourah, email: firstname.lastname@example.org
Keywords: melanoma; BRAF inhibitors; targeted genomic alteration; predictive analysis; targeted therapy resistance
Received: March 22, 2018 Accepted: January 31, 2019 Published: March 01, 2019
Several mechanisms have been described to elucidate the emergence of resistance to MAPK inhibitors in melanoma and there is a crucial need for biomarkers to identify patients who are likely to achieve a better and long-lasting response to BRAF inhibitors therapy. In this study, we developed a targeted approach combining both mRNA and DNA alterations analysis focusing on relevant gene alterations involved in acquired BRAF inhibitor resistance. We collected baseline tumor samples from 64 melanoma patients at BRAF inhibitor treatment initiation and showed that the presence, prior to treatment, of mRNA over-expression of genes’ subset was significantly associated with improved progression free survival and overall survival. The presence of DNA alterations was in favor of better overall survival. The genomic analysis of relapsed-matched tumor samples from 20 patients allowed us to uncover the largest landscape of resistance mechanisms reported to date as at least one resistance mechanism was identified for each patient studied. Alterations in RB1 have been most frequent and hence represent an important additional acquired resistance mechanism. Our targeted genomic analysis emerges as a relevant tool in clinical practice to identify those patients who are more likely to achieve durable response to targeted therapies and to exhaustively describe the spectrum of resistance mechanisms. Our approach can be adapted to new targeted therapies by including newly identified genetic alterations.
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