Precision medicine is a promising approach to select effective treatments for cancer pts. Here we report the use of WES and RNA-seq analysis in routine clinical practice, to select targeted therapies (TT) for pretreated metastatic cancer pts.
CRC and NSCLC pts without druggable genetic alterations were selected during a multidisciplinary medical board. Fresh frozen (FF) and/or formalin-fixed paraffin embedded (FFPE) tissue of the primary and/or metastasis tumors were collected. Re-biopsy was performed when possible. Blood was drawn for comparative germline analysis. WES was performed on tumor/germline DNA, and RNA-seq on FF tumor RNA. Pts were systematically referred for genetic counseling and written informed consent was recorded. Results were reviewed during a second medical board, to identify molecular alterations and propose a relevant TT.
Between 09/2014 and 4/2016, 35 pts were selected; 1 pt refused WES analysis. 34 pts (13 CRC, 21 NSCLC) had WES and/or RNA-seq of their tumor; 1 pt refused to be informed of incidental germline mutations. The median age was 49 years (27-74). 8 pts had undergone a tumor re-biopsy. 45 tumor tissues (17 primary/28 metastatic) and 30 germline samples were tested. Germline mutations (BRCA2, STK11, MEN1, COL3A1, MYBPC3) were found in 5 pts. An average of 1.3 tumors (1-3) by pt was tested. WES was done on 37 FF and 4 FFPE tissues; 1 analysis failed because of low tumor cellularity. RNA-seq was done on 34 FF tissues. The median analysis turnaround was 21.5 days (8-92). Potential driver alterations were found in 27 pts, most frequently in HER/RAS/MAPK (n = 14), PTEN/PI3K/AKT (n = 6), STK11 (n = 4) pathways. Gene alterations were identified in chromatin organization (ARID1A/ARID2/EZH2, n = 8), cell cycle checkpoint signaling (ATR/ATRX/ATM, n = 4), and DNA repair (BRCA1/BRCA2, n = 4) pathways. Therapy could be personalized in 13 pts, of whom 7 were included in a clinical trial.
These results are encouraging on the feasibility of WES and RNA-seq analysis in routine clinical basis, in order to select dedicated TT in pretreated pts.
Clinical trial identification
Legal entity responsible for the study
Canceropole Ile de France
All authors have declared no conflicts of interest.