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Lorenza Landi Istituto Toscano Tumori, Ospedale Civile, Livorno

Clinical Implications of Micro-RNA in Cancer. Lorenza Landi Istituto Toscano Tumori, Ospedale Civile, Livorno. Background. Anti-EGFR Mabs cetuximab and panitumumab - alone or combination with chemotherapy - demonstrated efficacy in KRAS wild type mCRC patients.

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Lorenza Landi Istituto Toscano Tumori, Ospedale Civile, Livorno

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  1. Clinical Implications of Micro-RNA in Cancer Lorenza Landi Istituto Toscano Tumori, Ospedale Civile, Livorno

  2. Background Anti-EGFR Mabs cetuximab and panitumumab - alone or combination with chemotherapy - demonstrated efficacy in KRAS wild type mCRC patients ..... Unfortunately not all KRAS wt patients gain the same benefit from anti-EGFR MAbs MicroRNAs are a new class of non coding RNAs implicated in cancer biology, with miR128 and Let-7 family implicated respectively, in EGFR and KRAS regulation activity.

  3. Study Design and Main Inclusion Criteria Aim: to define whether miR128 and Let-7 levels affect the outcome of cetuximab or panitumumab in mCRC Molecularly unselected & anti EGFR-MAbs treated mCRC pts with AVAILABILITY of Tumor Tissue and Clinical Data Let-7 and MiR128 levels analysis using Agilent’s miRNA platform Bioinformatic analyses of detected signals and correlation with PFS and OS

  4. miRNA Colon Project (overview) First Cohort April, 2010 PtsScreened N 89 • Ineligible Pts (16%) • Inadequate Tumor Sample • Tumor tissue from mets December, 2010 Preliminary results on MIR 128 and Let 7c ASCO 2011, ECCO 2011 Evaluable for 887 MiRNAs (1° cohort) N 74 Validation Cohort • January, 2011 • Project Extension • Aims: • to validate preliminaryresults • to identify a MicroRNAsignature PtsScreened N 147 Evaluable for 887 MiRNAs (2° cohort) N 114 • Ineligible Pts (22%) • Inadequate Tumor Sample Overallpopulation N 188

  5. Main Patients’ Characteristics *CR: complete response; PR : partial response

  6. First Cohort – MIR 128, Whole population HIGH LEVEL (n= 41) LOWER LEVEL (n= 33) Censored HIGH LEVEL (n= 41) LOWER LEVEL (n= 33) Censored + +

  7. First Cohort – MIR 128, according to KRAS status KRAS wild type HIGH LEVEL (n= 19 ) LOWER LEVEL (n= 19) + Censored HIGH LEVEL (n= 19 ) LOWER LEVEL (n= 19) + Censored p 0 .027 MIR 128 HL 6,2 mos MIR 128 LL 5,6 mos p 0.022 MIR 128 HL NR MIR 128 LL 9,1 mos KRAS mutant HIGH LEVEL (n= 17 ) LOWER LEVEL (n= 15) + Censored HIGH LEVEL (n= 17 ) LOWER LEVEL (n= 15) + Censored p 0 .027 MIR 128 HL 4,4 mos MIR 128 LL 1,8 mos p 0 .046 MIR 128 HL 16,2 mos MIR 128 LL 5,8 mos

  8. First Cohort – LET 7c, Whole population p 0.006, HR = 2.6 [1,25- 5,54] Let7c HL 17 mos Let7c LL 6,8 mos p 0.009, HR = 1,87 [1,1-3,18] Let7c HL 5,8 mos Let7c LL 2,5 mos

  9. First Cohort – Let 7c, according to KRAS status KRAS wild type p 0.16 HR = 1,57 [0,73-3,4] Let7c HL 6.5 mos Let7c LL 4,3 mos p 0 .02, HR = 4,17 [1,1-15,9] Let7c HL 16,7 mos Let7c LL 5,7 mos p 0.15, HR = 1,97 [0,69-5,6] Let7c HL NR Let7c LL 7,7 mos p 0 .08, HR = 1,89 [0,8-4,48] Let7c HL 4,2 mos Let7c LL 2,2 mos KRAS mutant

  10. Validation Cohort – LET 7c, whole population p 0 .007, HR = 1,7 [1,1-2,5] Let7c HL 10,5 mos Let7c LL 7 mos p 0 .003, HR = 1,69 [1,14-2,5] Let7c HL 6,4 mos Let7c LL 3,7 mos

  11. Second Cohort – Let 7c, according to KRAS status KRAS wild type p 0 .004, HR = 1,96 [1,19-3,23] Let7c HL 13,3 mos Let7c LL 7,2 mos p 0 .15, HR = 1,49 [0,75-2,9] Let7c HL 5,5 mos Let7c LL 3,0 mos p 0 .008, HR = 1,79 [1,11-2,9] Let7c HL 6,8 mos Let7c LL 3,8 mos p 0 .33, HR = 1,24 [0,6-2,56] Let7c HL 8,8 mos Let7c LL 6,5 mos KRAS mutant

  12. Conclusions - By regulating EGFR, MiR 128 could be a useful biomarker for selection of patients suitable for anti-EGFR therapy, but a larger sample is needed to confirm its favorable impact - Let 7c could represent an additional biomarker to refine selection of KRAS wtmCRC patients candidate for anti-EGFR therapy, but it must be validated in prospective trials … what about KRAS mutant patients with high LET 7c levels ? Are they a different population or more simply is LET 7c a prognostic factor ?

  13. A peek around the corner Abstract # 3521 MicroRNA signature predicts sensitivity to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC) A. Sacconi, L. Landi, F. Biagioni, V. Ludovini, E. Sensi, C. Lupi, J. Salvini, G. Fontanini, G. Blandino, L. Crinò and F. Cappuzzo Poster Discussion Session , June 1, 2012

  14. Study TEAM Coach Federico Cappuzzo M. Roncalli Pathologist Milano E. Lani Data Manager Livorno A. Sacconi Statistician Roma L. Crinò Physician Perugia G. Blandino Physician Roma L. Landi Physician Livorno A. D’Incecco Physician Livorno G. Fontanini Pathologist Pisa J. Salvini Research Nurse Livorno F. Biagioni Biologist Roma V. Ludovini Biologist Perugia Sponsored by: AIRC - Associazione Italiana Ricerca sul Cancro and AOT - Associazione Oncologica Traslazionale dedicated to AnnaStaccatoLisa

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