e15576 Background: Molecular diagnostic is now part of routine diagnosis in many solid tumors and multiple technical options are available from extensive sequencing (NGS) to fully-automated targeted PCR (FAPCR). Tumor tissue testing is the gold standard, liquid biopsy is becoming a valuable option. Methods: 417 FFPE tumors, and 28 liquid biopsies were analyzed from 233 non small cell lung cancer (NSCLC), 177 colorectal cancer (CRC), 35 melanoma (MEL) in an ISO 15189 certified, French NCI molecular genetics platform. FAPCR analyses were performed individually, every day, using CE-IVD kits for the exclusive analysis of KRAS, NRAS, BRAF and EGFR mutations in NSCLC, CRC and MEL. NGS analyses were performed weekly as 12 or 24 sample runs using custom multiple gene panel capture sequencing. In all cases, prior to analysis, the specimens were macrodissected to warrant tumor cell content > 10% after examination of hematoxylin eosin stained slide by a pathologist. For liquid biopsy, cfDNA was extracted within 3 days from blood samples collected in cfDNA BCT tubes and analyzed using CE-IVD EGFR mutation kits. Time to results was recorded from registration of the specimen to validation of the results. Results: All FFPE tumors were analyzed using either FAPCR (N = 321) or NGS (N = 110) according to the clinician choice. Less than 2% of samples were not analyzable because of tumor cell content < 10% or degradated DNA. Median time to results was 6 days for FA-PCR (range 1-19) and 18 days for NGS (range 7-28). No significant difference was observed between NSCLC, CRC and MEL. Most cases of delay > median were related to pre-analytical defects and the need for a second specimen. For liquid biopsies, time to result was 6 days (range 1-18). The mutation rates were respectively, 13% for EGFR in NSCLC, 57% for KRAS/NRAS/BRAF in CRC and 69% for BRAF/NRAS in MEL. Using NGS led to the identification of additional molecular targetable alterations that were not analyzed by FAPCR in 44% of NSCLC, 22% of CRC and 14% of MEL. Among the 28 liquid biopsies analyzed mostly at progression under anti-EGFR TKI, EGFR mutations including T790M, were detected in 61% of the cases. Conclusions: Independently of cost-effectiveness, using PCR reduces time to results and can accelerate the initiation of targeted therapy but restricts the range of analysis, while extensive NGS delays time to results but identifies additional biomarkers that could be useful for therapeutic stratification. Using liquid biopsy testing could be an alternative and allow dynamic molecular diagnostic at 1st line and during follow-up.