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S. Pilotto



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P1.06-041 - Prognostic impact of cytoskeleton regulatory protein human Mena (hMena) isoforms in resected, node-negative, non-small-cell lung cancer: validation of a clinic-molecular prognostic model. (ID 2609)

      09:30 - 09:30  |  Author(s): S. Pilotto

      • Abstract

      Background
      Human Mena and the isoform hMena[+11a] are cytoskeleton regulatory proteins involved in adhesion, motility, regulated in the epithelio-mesenchimal transition. Here, we investigated their potential prognostic value in node-negative non-small-cell lung cancer (NSCLC) patients.

      Methods
      Pan-hMena, hMena[+11a], E-cadherin, vimentin, ER-beta, EGFR, HER-2, pAKT, detected immunohystochemically on duplicate TMA and clinical factors (sex, age, histology, grading, T-size, number of resected nodes, RN) were correlated to 3-yr disease-free (DFS), cancer-specific (CSS), and overall survival (OS) using a Cox model. ROC analysis provided optimal cut-off values and model validation. A logistic equation including regression analysis coefficients was constructed to estimate individual patients’ probability (IPP) of relapse. Internal cross-validation (100 simulations with 80% of the dataset) and external validation was accomplished.

      Results
      In a training set of 248 patients (median follow-up: 36 months, range 1-96), Pan-hMmena and hMena+11a were the only biological variables displaying significant correlation with outcome(s), confirmed by the cross-validation (replication rate: 78%, 83%), with a prognostic model accuracy of 61% (standard error 0.04, p=0.0001). Patients with high pan-hMENA expression had a non-significant trend towards a worse outcome, while patients with high hMena+11a expression had a significant and borderline significant advantage in DFS (p=0.03) and OS (p=0.056), respectively, and a non-significant trend towards a better CSS. Univariate and multivariate 3-yr median individual patient probabilities of recurrence were 70.9 (range 40.3-94.4) and 41.2 (range 13.6-86.5), respectively (data not shown). The subgroup of patients with High Pan-hMena/Low hMena11a relative expression fared significantly better than any of the other 3 groups (p≤0.002 for all outcomes). On the basis of the combination between this molecular hybrid variable and T-size and RN, a 3-class risk stratification model was generated; the derived 3-risk class survival model strikingly discriminated between patients at different risk of relapse, cancer-related death, and death for any cause, with a prognostic accuracy of 61% (standard error 0.03, p=0.01), according to ROC analysis. The 3-risk class survival model was externally validated in an independent dataset of 133 patients, and significantly discriminated between patients at Intermediate- and High-Risk of relapse and cancer-related death.

      Conclusion
      The expression of the hMena and its isoform may represent a powerful prognostic factor in early NSCLC and usefully complements clinical parameters to accurately predict individual patient risk..

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    P1.10 - Poster Session 1 - Chemotherapy (ID 204)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.10-032 - Sensitivity and meta-regression analysis exploring potential outcomes predictors in randomized trials (RCTs) evaluating the benefit of 1st-line tyrosine kinase inhibitors (TKIs) for epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma. (ID 1670)

      09:30 - 09:30  |  Author(s): S. Pilotto

      • Abstract

      Background
      Patients affected by lung adenocarcinoma carrying a EGFR sensitizing mutation of significantly benefit from TKIs in terms of progression free survival (PFS), activity and symptoms control. The potential predictive role of clinico-pathological predictors should be investigated in order to optimize the benefit of the currently available drugs.

      Methods
      A literature-based meta-regression and sensitivity analyses to investigate the differential effect of TKIs according to demographic and molecular factors, was accomplished, analyzing all RCTs exploring TKIs versus chemotherapy for 1[st]-line treatment of patients affected by EGFR mutant NSCLC.

      Results
      9 trials (3,741 patients) were identified (EGFR mutant: 1,797). 9 RCTs were evaluable for PFS (1,790 patients) and response (1,733 patients); 7/9 for survival (1,075 patients). With regard to PFS and response, a significant interaction according to ethnicity (Asian versus Caucasian versus mixed, p=0.006 [Cochrane-Q 10.275] and p=0.047 [6.129], respectively), and trial design (retrospective versus prospective EGFR analysis, p=0.024 [5.067] and p<0.0001 [13.633]), was found. No difference was observed in term of survival. A significant interaction for response was found, with an Odds Ratio in favour of afatinib, erlotinib and gefitinib (versus chemotherapy) of 2.70 (95% CI 2.11-3.45), 2.67 (95% CI 1.81-3.93) and 1.81 (95% CI 1.46-4.78).

      Interaction [Cochrane-Q] P value Interaction [Cochrane-Q] P value
      PFS Response
      Overall (ERL vs GEF vs AFA) [4.266] p=0.188 [9.924] p=0.007
      ERL vs AFA [3.321] p=0.068 [0.056] p=0.813
      ERL vs GEF [9.714] p=0.054 [5.169] p=0.023
      AFA vs GEF [0.002] p=0.962 [7.351] p=0.007

      Conclusion
      Although limited by the retrospective nature and the heterogeneity, these data indicate a differential effect of TKIs according to the design and the ethnicity, and in response according to TKIs. These data may constitute the background to develop a clinical predictive model to better estimate the expected benefit when using EGFR TKIs in patients with EGFR mutant NSCLC