Abstract Introduction The identification of pathways involved in carcinogenesis, the emergence of high-throughput technologies enabling tumor molecular analysis and the development of targeted therapies have led to the concept of precision medicine. Higher response rates and longer survivals have been achieved in recent genomic-driven clinical trials. However, genomic-driven cancer medicine is hindered by multiple obstacles. Our aim was to assess the feasibility of incorporating real-time targeted gene sequencing (TGS) of DNA derived from metastatic biopsies into daily clinical practice. Experimental procedures Precision-f (NCT01932489) is a pilot trial conducted at the Jules Bordet Institute. Patients with metastatic colorectal cancer (CRC), melanoma or non-small cell lung (NSCLC) cancer were enrolled. Two FFPE blocks and one fresh frozen sample embedded in OCT were collected from newly performed metastatic biopsies as well as one whole blood sample. The FFPE samples were checked for tumor cellularity and 5×5 μm sections were cut and sent to 2 laboratories. Targeted gene sequencing was performed on DNA extracted for the same sample using the Illumina TruSeq Amplicon Cancer Panel performed on a MiSeq Desktop Sequencer, and the Life Technologies Ion AmpliSeq Cancer Hotspot Panel performed on an Ion Personal Genome Machine. Results were reported to the institutional sequencing tumor board for discussion, annotation and treatment assignment. The main objectives were the evaluation of biopsy quality, turnaround time, the presence of “actionable” alterations, technology cross-validity and treatment assignments. Results Thirty-four patients were enrolled between December 2013 and August 2014: 13 NSCLC patients, 11 CRC patients, 10 melanoma patients. Successful molecular results were achieved from 32/34 biopsies (94%). The most frequent site of biopsy was the liver (10) followed by the lung (7), the skin (5) and lymph nodes (5). 27/34 (79%) samples had ≥ 20% tumor cells. 31/34 (91%) of samples had > 10 ng of DNA for TGS. The median turnaround time for results reporting was 15 calendar days [8-22]. “Actionable” mutations were found for 66% (21/32) of patients, 76% (16/21) of which were treated with therapy according to the identified molecular alteration. Reasons for non-targeted therapy were: non-eligibility (2), unavailable drugs (2) and patient refusal (1). The results of the comparison of TGS data across the 2 platforms is ongoing and will be presented at the meeting. Conclusion The precision-f pilot trial has demonstrated the feasibility and clinical relevance of a molecular screening program in a clinical pharmacology unit. A Belgian national initiative will follow in order to enhance patient participation in genomic-driven clinical trials. Citation Format: Philippe G. Aftimos, Marion Maetens, Catherine Sibille, Jean-François Laes, Sylvain Brohée, Thierry Berghmans, Joseph Kerger, Alain Hendlisz, Alexandre Irrthum, Olivier De Henau, Amélie Deleporte, Stylianos Drisis, Denis Larsimont, Jalal Vakili, Christos Sotiriou, Martine Piccart, Ahmad Awada. Tackling the obstacles facing the implementation of a molecular screening program in an early drug development unit: The Jules Bordet Institute Program for Molecular Profiling of Metastatic Lesions - feasibility (Precision-f). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3891. doi:10.1158/1538-7445.AM2015-3891