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S. IACOBELLI , P. Innominato, M. Piantelli,

Tumor clock protein PER2 as a determinant of survival in patients (pts) receiving oxaliplatin-5-FU-leucovorin as 1st line chemotherapy for metastatic colorectal cancer (mCRC). S. IACOBELLI , P. Innominato, M. Piantelli,

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S. IACOBELLI , P. Innominato, M. Piantelli,

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  1. Tumor clock protein PER2 as a determinant of survival in patients (pts) receiving oxaliplatin-5-FU-leucovorin as 1st line chemotherapy for metastatic colorectal cancer (mCRC) S. IACOBELLI, P. Innominato, M. Piantelli, G. Bjarnason, B. Coudert, C. Focan, S. Giacchetti, A. Poncet, C. Garufi, F. Levi, and the ARTBC Chronotherapy Group

  2. Authors’ disclosure • The Authors indicate no potential conflicts of interest

  3. Learning Objectives: • Role of the Circadian Timing System in malignant processes • Evaluate the correlations between the expression of clock proteins in healthy colonic mucosa and primary colon cancer • Assess the prognostic value of the molecular clock in human cancer

  4. The Molecular Clock Levi F, Schibler U. Annu Rev Pharmacol Toxicol 2007;47:593-628 Harmer SL, Panda S, Kay SA. Annu Rev Cell Dev Biol 2001;17:215-53

  5. Role of the molecular clock in malignant processes • Circadian control of drug metabolism; • Tight link between molecular clock components and cell cycle, DNA repair and apoptosis • Mutant clock genes and cancer risk • PER1 & PER2 functioning as oncosuppressors Levi F, Schibler U. Annu Rev Pharmacol Toxicol 2007;47:593-628 Hunt T, Sassone-Corsi P. Cell 2007 May 4;129(3):461-4 Zhu Y, Leaderer D, Guss C, et al. Int J Cancer 2007 Jan 15;120(2):432-5 Zhu Y, Brown HN, Zhang Y, et al. Cancer Epidemiol Biomarkers Prev 2005 Jan;14(1):268-70 Fu L, Pelicano H, Liu J, Huang P, et al. Cell 2002 Oct 4;111(1):41-50. Gery S, Komatsu N, Baldjyan L, et al. Mol Cell 2006 May 5;22(3):375-82

  6. OBJECTIVE • To assess whether the expression patterns of PER1, PER2 and PER3 proteins in primary tumor or healthy mucosa predicts for clinical outcome in chemo-naive patients with mCRC receiving a combination of oxaliplatin, 5-fluorouracil and folinic acid in a randomized phase III trial (EORTC trial 05963) of flat vs. chronomodulated infusion

  7. METHODS • PER1, PER2 and PER3 expression evaluated by immunohistochemistry; • Healthy mucosa samples: categorized according to the % of positive cells • Negative: ≤ 5% • Weakly positive: >5%- ≤ 20% • Strongly positive: > 20% • Primary tumors: % of labelled cells categorized according to terciles.

  8. STATISTICAL ANALYSIS • The correlations between the expression patterns of each PER between healthy mucosa and primary tumor were computed • Univariate and multivariate analyses were performed from time of inclusion in the study till the event using the aforementioned categories.

  9. RESULTS – sample size • Paraffin wax embedded samples of primary tumor were collected for 198 patients. • In 169 of them, healthy mucosa was also present.

  10. RESULTS –patients’ characteristics

  11. RESULTS – PERs expression in mucosa PER1 PER3 PER2 Negative Weak Strong

  12. RESULTS – PER2 in Mucosa Strong Negative Weak

  13. RESULTS – PER2 in Tumor 0% 100%

  14. RESULTS – clinical features • The expression pattern of any PER protein is not influenced by gender, age, site of primary tumor and no. of metastatic sites.

  15. RESULTS – overall survival • The expression pattern of any PER protein in healthy mucosa was not associated with statistically significant differences in OS. • No association was found between the % of labelled tumor cells for PER1 or PER3 and OS.

  16. RESULTS – PER2 & overall survival The greater the % of stained tumor cells for PER2, the longer the survival at univariate analysis (Log-rank, p=0.04; Log-rank for trend, p= 0.013)

  17. RESULTS – PER2 & overall survival Log-rank, p = 0.041 Log-rank for trend p= 0.013 No. At risk 1° tercile 67 45 19 13 10 3 1 1 2° tercile 65 51 21 15 11 7 2 1 3° tercile 66 54 30 19 11 8 3 1

  18. RESULTS – multivariate analysis • A multivariate Cox model was computed using PER2%+Tum terciles, WHO-PS, # of metastatic sites, presence of metastases at diagnosis, age, gender and treatment arm as covariates.

  19. RESULTS – multivariate analysis The independent prognostic value of PER2%+Tum terciles was confirmed, together with PS and # of metastatic sites involved.

  20. Summary • PER3 clock protein expression in healthy mucosa and primary tumor were correlated. • Lower expression of PER2 in tumor cells was associated with a shorter survival.

  21. Conclusions • Down-regulation of core clock gene Per2 in tumors predicted for poor survival in chemo-naive pts with metastatic colorectal cancer. This is the first report of an association between clock gene down regulation and outcome inmetastatic colorectalcancer.

  22. RESULTS – PERs expression in tumor PER1 PER3 PER2 1st tercile 2nd tercile 3rd tercile

  23. RESULTS - correlations A positive correlation between the expression pattern of PER3 in healthy mucosa and primary tumor was found (p=0.002, Pearson’s c2). PER3

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