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A gene expression signature of microvascular invasion in hepatocellular carcinoma in formalin fixed-paraffin embedded biopsies. Aurélie Beaufrère 1,2 , Stefano Caruso 3 , Gabrielle Couchy 3 , Jessica Zucman-Rossi 3 , Nicolas Poté 1,2 , Valérie Paradis 1,2

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  1. A gene expression signature of microvascular invasion in hepatocellular carcinoma in formalin fixed-paraffin embedded biopsies Aurélie Beaufrère1,2, Stefano Caruso3, Gabrielle Couchy3, Jessica Zucman-Rossi3, Nicolas Poté1,2, Valérie Paradis1,2 1Pathology Department., Beaujon Hospital, Clichy, France. 2INSERM UMR 1149, Centre de Recherche sur l'Inflammation, Paris, France. 3INSERM, UMR 1162, Génomique Fonctionnelle des Tumeurs Solides, Institut Universitaire d'Hématologie, Paris, 75010, France.

  2. Disclosure • No conflict of interest

  3. Vascular invasion in HCC • Vascular invasion : • Major prognostic factor associatedwithmortality and tumorrecurrence • Macroscopic or microscopic (mVI) • Definition of mVI: presence of clusters of tumor cells in vessels located within the tumor capsule and/or in the surrounding liver parenchyma • Presence (or absence) of mVi = not assessable on biopsy Onlydetectable by microscopicexamination of the surgicalspecimen Main limit for optimal management of patients NTL HCC HCC: hepatocellularcarcinoma, NTL: non tumoral liver Sumie S et al. Ann Surg Oncol. 2008;15(5):1375‑82. Imamura H et al. J Hepatol. 2003;38(2):200‑7. Lim K-C et al. Ann Surg. 2011;254(1):108‑13. Rodríguez-Perálvarez M et al. Ann SurgOncol. 2013;20(1):325‑39.

  4. Biomarkersof mVI Mínguez et al, J Hepatol 2011 • Several gene expression signatures of mVI, obtained from surgical samples of HCC described in the literature none of these signatures have been validated so far in formalin-fixed and paraffin-embedded (FFPE) HCC biopsies • Several proteins biomarkers of mVI also published Ex: PIVKA-II, H4K20, H4K16 Limited performance (Identification of 40% of HCC with mVI in FFPE biopsies (Se: 43%, Sp:95%) Ho et al. Ann SurgOncol. 2006;13(11):1474‑84. Tanaka et al. Surgery. 2010;147(3):405‑14. Minguez et al. J Hepatol. 2011; 55(6):1325-31. Poté N et al. Hepatology. 2013;58(3):983‑94. Poté N et al. J Hepatol. 2015;62(4):848‑54. 35-gene signature, AUC: 0.60 (Se=0,70, Sp=0.51)

  5. NanostringTechnology • Transcriptomic technology based on direct measurement of transcript abundance (maximum 800 different transcripts), by using multiplexed, color-coded probe pairs No step of reverse transcription of mRNA or cDNA amplification • More sensitive than microArray analysis • Requirement of a small amount of RNA good relevance in FFPE biopsy • Validated in breast cancer and in mantle cell lymphoma in FFPE biopsies Geiss GK et al. Nat Biotechnol. 2008;26(3):317‑25. Reis PP et al. BMC Biotechnol. 2011;11:46. Prat A, et al. Clin Cancer Res. 2016;22(3):560‑6. Scott DW et al. J Clin Oncol 2017;35(15):1668‑77.

  6. Aim of the study Define a gene expression signature associated with mVI in HCC, applicable on FFPE biopsies using a Nanostring approach

  7. Study design Test set (N=69) HCC Biopsies (N=30) HCC Surgicalspecimens (N=39) Definition of the mVI signature NANOSTRING VALIDATION set HCC Biopsies (N=39) Validation of the mVI signature

  8. Methods • Constitution of two sets from archived FFPE tissue samples of HCC (Department of Pathology, Beaujon Hospital, 1994-2017): For all FFPE biopsies of HCC included, the corresponding surgical specimen is available • Clinicopathological data were collected for each cases • Pathological review: Definition of two groups of tumors according to the presence (mVI+) or the absence (mVI-) of mVI on the surgical specimen • Nanostring technology: use of a signature of 200 genes established according to literature and RNA sequencing data

  9. Results

  10. Similarclinico-pathological data betweenbothcohorts

  11. Excellent correlationbetween HCC biopsies and correspondingsurgicalsamples Meancorrelation index : 0.97 [0.87-0.95]

  12. Definition of a mVItranscriptomic signature (test set) Unsupervisedanalysis (200 gene signature) Differential gene expression analysis 39 differentially expressed genes (logFC ≥ |0.5| & Adj Pvalue < 0.1) mVI No mVI Up-regulated Down-regulated IVm

  13. Definition of a mVItranscriptomic signature Predictionalgorithm : k Nearest Neighbor analysis Molecularfunctions

  14. Performance of 10-gene mVI signature : validation set Sensitivity: 0.92 Specificity: 0.62 Accuracy: 0.82 AUC: 0.77

  15. Discussion • Excellent transcriptomiccorrelationbetween HCC biopsies and correspondingsurgicalspecimens • Sucessfultranscriptomicanalysis on FFPE samples, and particularly on biopsies Transcriptomicanalysisisachievable on HCC routine biopsies • Good performance of the mVI signature obtainedcompared to the literature Se: 92%, Sp: 62 % vs Se: 70%, Sp: 51% (Mínguez et al, J Hepatol. 2011;55(6):1325‑31) • Signature limited to 10 genes best relevance for a routine use

  16. Conclusion Surgicalresection HCC withoutmVI Adaptation of therapeuticstrategy TranscriptomicmVI signature Resectable HCC Biopsy HCC withmVI TACE beforesurgery

  17. Thankyou

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