e16018 Background: S-GC neoadjuvant chemotherapy (NACT) was active in a phase 2 trial in MIBC, showing a response rate (downstaging to pT < 2) of 54.3% in 46 pts within a single-arm, phase 2 trial ( Necchi et al, GU ASCO 2017). The addition of S to GC may help investigators unravelling key molecular features underlying response in MIBC. Methods: Analyses were made on pre- and post-treatment TURB and cystectomy (Cy) specimens (10µm sections) and matched germline DNA of 29/46 pts. Analyses included measurements of ERCC1 (by immunohistochemistry, IHC) on TURB specimens, baseline circulating VEGF levels (ELISA), copy number variations (CNV, Affymetrix), and next generation sequencing (NGS, custom gene panels through the Ion AmpliSeq Library Kit2.0™ and the Ion Torrent Personal Genome Machine™ platform). Results: We analyzed TURB samples from 15 responders (R) and 4 non-R (NR). An additional 10 Cy samples were used for NR. Baseline VEGF levels were not associated with PFS or OS on univariable analyses (p = 0.943 and p = 0.669, respectively). Differences in R vs. NR pts were found according to CNVs and NGS. CN gains on regions of chromosome (chr) 18 and 20 and loss in chr 5 were found in 56-60% of R and in none of the NR. Gains on regions of chr 3 and losses in chr 1 and 20 were more frequent in the NR ( > 50%) vs. R ( < 20%). The median number of somatic mutations (mut) per sample was 3 (range, 0-19). Missense mut in DNA-repair genes ( POLK; FANCM; PRKDC; BLM; MSH2; MSH6; RAD50) were found in 63.6% R vs 16.7% NR, in RAS-RAF pathway genes ( CDKN2A; RAC1; KRAS; NF1) in 45.4% vs 7.1%, in chromatin-remodelling genes ( ARID1A; ARID2; KDM5C; SMARCA4; ATRX; KMT2C; DAXX; SETD2) in 54.5% vs 16.7%, and in HER-family genes in R only (36.4%). ERCC1 IHC expression was found in 55.6% R vs 93.3% NR (p = 0.047). Conclusions: We identified distinct molecular features of R vs NR to S-GC in MIBC. These features may be linked to a potentially-additive effect of S and CT. The identification of the targets of CNVs will further elucidate the underlying biology. These results may help developing personalized medicine in MIBC with new more potent targeted agents with CT. Clinical trial information: NCT01222676.