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44th ASCO Annual Meeting May 30-June 3, 2008 McCormick Place, Chicago, Illinois

44th ASCO Annual Meeting May 30-June 3, 2008 McCormick Place, Chicago, Illinois. Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment.

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44th ASCO Annual Meeting May 30-June 3, 2008 McCormick Place, Chicago, Illinois

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  1. 44th ASCO Annual Meeting May 30-June 3, 2008 McCormick Place, Chicago, Illinois Evaluation of PTEN expression in colorectal cancer (CRC) metastases (mets) and in primary tumors as predictors of activity of cetuximab plus irinotecan treatment F. Loupakis1,6, L. Pollina2, I. Stasi1, G. Masi1, N. Funel2, M. Scartozzi3, I. Petrini4, D. Santini5, S. Cascinu3, A. Falcone1,6. 1Department of Oncology, Azienda USL 6 - Istituto Toscano Tumori Livorno, Italy, 2Division of Pathology, AOUP, Pisa, Italy, 3Division of Medical Oncology, Azienda Ospedaliera Ospedali Riuniti, Università Politecnica delle Marche, Ancona, Italy, 4Division of Medical Oncology, AOUP, Pisa, Italy, 5Division of Medical Oncology, Campus Biomedico University, Rome, Italy, 6Department of Oncology, Transplants and New Technologies in Medicine, University of Pisa, Italy

  2. Main EGFR signalling pathways ASCO General COI Fotios Loupakis, MD I have no relevant relationships to disclose

  3. Main EGFR signalling pathways Ligands Anti-EGFR MoABs EGF receptor RAS PIP2 RAF PI3K PTEN PIP3 MEK ERK AKT mTOR Nucleus

  4. PTEN Ligands • PTEN (phoshatase and tensin homologue deleted on chromosome 10) geneencodes a phosphatase, whose major substrate is PIP-3 • Loss of PTEN (mono or bi-allelic inactivation, but also epigenetic silencing) results in increased PIP-3 concentration • Increase of PIP-3 leads to AKT hyperactivation • PROTECTION FROM APOPTOSIS EGF receptor PIP2 PI3K PTEN PIP3 AKT Nucleus mTOR

  5. KRAS • KRAS (human homolog of the Kirsten rat sarcoma-2 virus oncogene) encodes a small self-inactivating signal-transducing GTP-binding protein • KRAS can harbor oncogenic mutations that yield a constitutively active protein • Activated Ras stimulates Raf-1, which leads to MAPK phosphorylation • CELL PROLIFERATION Ligands EGF receptor RAS RAF MEK ERK Nucleus

  6. BACKGROUND • Recent data suggest a possible predictive role for PTEN loss of expression, evaluated on primary tumors, in metastatic CRC patients treated with cetuximab-containing therapies (Frattini M. et al. BJC 2007) • Several retrospective studies have underlined the role of KRAS mutations as predictors of resistance to EGFR MoAbs in CRC (from Lievre A. et al. Can Res 2006 to Amado RG. et al. JCO 2008 and over…) • Recent data suggest a lack of correlation for EGFR, pAKT, MAPK tested with IHC on primary tumors and related metastases from CRC (Scartozzi M. et al. JCO 2004 and Scartozzi M. et al. BJC 2007)

  7. OBJECTIVES • To evaluate the correlation between primaries and related CRC mets in terms of PTEN immunoreactivity and KRAS mutational status • To investigate the role of PTEN loss and KRAS status in predicting the activity of cetuximab plus irinotecan, in terms of RR and PFS, for pre-treated metastatic CRC patients both on primary tumors and related mets

  8. STUDY DESIGN and TREATMENT DESIGN Retrospective evaluation of 102 EGFR-positive metastatic CRC patients treated with Cetuximab plus Irinotecan and progressed after previous Irinotecan-containing therapies Centers: 4 Medical Oncology Divisions from Central Italy TREATMENT • Cetuximabinitial dose of 400 mg/sqm i.v. d1 followed by 250 mg/sqm i.v. weekly or 500 mg/sqm i.v. d1 every 2 weeks. • Irinotecan130-180 mg/sqm i.v. d1 every 2 weeks.

  9. METHODS: PTEN • IHC performed on 3 µm tissue section obtained from paraffin-embedded specimens • anti-PTEN antibody clone 17.A, Neomarkers • Scoring: A B A: PTEN positive B: PTEN negative Score ≥4 PTEN positive

  10. MATERIALS 102 patients 3 mm tissue sections from FFPE blocks of primaries and/or mets 96 Primary tumours 59 Metastatic Sites 53 Paired samples

  11. PATIENTS’ CHARACTERISTICS

  12. DEFINITION of RESPONDERS Responders: CR+ PR (RECIST CRITERIA) + SD6 SD6 patients clearly progressed on previous irinotecan-based regimen with a Time To Progression <3 months that obtained a SD (RECIST) lasting >6 months

  13. ACTIVITY

  14. PTEN (on primaries): ACTIVITY Responders vs NOT Responders Fisher’s Exact Test: p=0.25

  15. Concordance between primaries and mets: PTEN 45 primaries and related mets evaluable Concordance: 27/45 = 60% (95% CI: 46-74%) Among a total of 155 IHC performed (96 primaries + 59 mets), the analysis has been repeated twice in 78 cases (50%), always confirming previous findings.

  16. PTEN (on mets): ACTIVITY Responders vs NOT Responders Fisher’s Exact Test: p=0.008

  17. Concordance between primaries and mets: KRAS 43 primaries and related mets evaluable Concordance: 41/43 = 95% (95% CI: 84-99%)

  18. KRAS (on primaries): ACTIVITY Responders vs NOT Responders Fisher’s Exact Test: p=0.023

  19. PTEN + (on mets) and KRAS wt vs All Others: ACTIVITY Responders vs NOT Responders Fisher’s Exact Test: p=0.0008

  20. PTEN (on mets) and PFS PTEN + Median PFS : 4.7 mos PTEN - Median PFS : 3.3 mos Logrank Test: p=0.005 HR=0.49 95% CI: 0.20-0.75

  21. PTEN (on mets) and OS • PTEN + Median OS : 11.2 mos • PTEN - Median OS : 10.6 mos • Logrank Test: p=0.37 • HR=0.76 95% CI 0.38-1.43

  22. PTEN + (on mets) and KRAS wt vs All Others, PFS • PTEN+ and KRAS wt Median PFS : 5.5 mos • All Others Median PFS : 3.8 mos • Logrank Test: p=0.001 • HR = 0.42 95% CI: 0.17-0.65

  23. PTEN + (on mets) and KRAS wt vs All Others, OS • PTEN+ and KRAS wt Median OS : 15.1 mos • All Others Median OS : 10.6 mos • Logrank Test: p=0.006 • HR = 0.39 95% CI: 0.18-0.75

  24. CONCLUSIONS • Primaries and related mets from CRC differed in terms of PTEN immunoreactivity in 40% of cases. • KRAS mutations found on primaries are almost always (95% of cases) confirmed on mets. Such analysis may be ruled out on any available tumor sample. • Loss of PTEN tested on mets predicted lack of activity of cetuximab plus irinotecan combination treatment in metastatic CRC pts. • KRAS is confirmed to be a predictor of resistance to cetuximab plus irinotecan combination treatment in metastatic CRC pts. • The combination of PTEN IHC performed on mets and KRAS mutational analysis identified a subgroup of patients with higher chances of benefiting from cetuximab plus irinotecan treatment.

  25. Thanks to all investigators and patients!

  26. fotiosloupakis@gmail.com

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