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R. Chiari



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    MO24 - NSCLC - Chemotherapy III (ID 110)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO24.02 - Treatment decisions for elderly patients with advanced non-small cell lung cancer (NSCLC) in Italian clinical practice: results from the RIGHT-3 project by Italian Association of Medical Oncology (ID 3115)

      10:35 - 10:40  |  Author(s): R. Chiari

      • Abstract
      • Presentation
      • Slides

      Background
      In 2004, the Italian Association of Medical Oncology (AIOM) created the RIGHT (Research for the identification of the most effective and highly accepted clinical guidelines for cancer treatment) program. The third step of the program, RIGHT3, aimed to evaluate the concordance between AIOM lung cancer guidelines and clinical practice in Italy. Description of treatment decisions for elderly patients with advanced non-small-cell lung cancer (NSCLC) was among the indicators. According to 2009 AIOM guidelines, single-agent chemotherapy with a third-generation agent was a reasonable choice for elderly patients with advanced NSCLC, whilst evidence about use of platinum-based treatment in the elderly population was judged potentially affected by selection bias and not conclusive.

      Methods
      RIGHT3 was a retrospective observational study conducted in a sample of 53 Italian lung cancer centers, representative of 230 AIOM centers. Patients with NSCLC diagnosis who had their first visit at the oncology center during 2010 and followed-up for at least 6 months were included. Proportion of elderly patients with stage IV disease receiving chemotherapy was among the 14 indicators evaluated.

      Results
      Overall, 306 pts with stage IV NSLSC were enrolled, and 299 were evaluable. Of these, 91 (30.4%) were older than 70. In the elderly subgroup, 81 pts (89%) were treated with first-line chemotherapy. In detail, a single-agent treatment was administered in 28 (34.6%) of cases, and a combination chemotherapy in the other 53 cases (65.4%). Among pts receiving platinum-containing doublets, carboplatin was more frequently used than cisplatin: carbo-gemcitabine (16 pts), carbo-pemetrexed (12 pts), cisplatin-pemetrexed (8 pts), cisplatin-gemcitabine (7 pts), carbo-vinorelbine (4 pts) were the 5 most frequently used regimens.Thirty pts (33%) received a second-line chemotherapy: single-agent in 23 cases, combination chemotherapy in 7 cases.

      Conclusion
      First-line platinum-based combination chemotherapy was commonly used in elderly patients with advanced NSCLC in 2010 by the Italian Lung cancer centers involved. First-line single-agent treatment, recommended by AIOM 2009 guidelines as the treatment choice with highest level of evidence, was used only in a minority of patients.

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    P1.02 - Poster Session 1 - Novel Cancer Genes and Pathways (ID 144)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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      P1.02-005 - Prognostic role of expression levels of FABP3, H19, TFPI2, AKR1B10 CYP3A5, SCGB3A2 genes in adenocarcinoma stage I patients (ID 3208)

      09:30 - 09:30  |  Author(s): R. Chiari

      • Abstract

      Background
      In resected lung cancer, no reliable clinical or molecular predictors are currently available for identifying patients with high risk for developing recurrent disease. In a previous study, we compared gene expression profiling from adenocarcinoma specimens and normal lung tissue with non relapse (NR) and early relapse (ER), using Affimetrix human microarray HG-U133Plus 2.0. We selected 5 genes up-regulated and 4 genes down-regulated were predictive for clustering patients in ER and NR (Siggillino et al. ECCO 2011). Here, we validate our results using an independent cohort of patients with lung adenocarcinoma stage I to identify novel genes involved in the risk of ER compared to NR disease.

      Methods
      From tissue banking of 180 consecutive resected NSCLC stage I patients at two Italian institutions, we selected 58 frozen specimens of lung adenocarcinoma tissue with corresponding normal lung. Total RNA was isolated from tumor and normal lung specimens using RNA Universal Tissue Kit and automatically purified by Biorobot-EZ1 instrument (Qiagen). Quantification of mRNA expression levels of 9 genes (5 up-regulated: CLCA2, FABP3, H19, TFPI2, AKR1B10 and 4 down-regulated: CYP3A5, ALDH3A1, SCGB3A2, SCGB1A1, were analyzed by real-time one-step RT-PCR using QuantiFast technology by RotorGeneQ instrument (Qiagen), and the results were compared considering β-actin as the internal reference gene and as calibrator the pool of normal tissues of analyzed patients. The gene expression of all evaluated genes and their association with relapse disease measures were assessed by t-test and logistic regression model was used for multivariate analysis.

      Results
      Fifteen-eight adenocarcinoma stage I patients were evaluable, 17% of which had an ER. Patients characteristics were as follows: median age was 65.8 years (38.7-81.5), 67.2% were male, 91.3% were PS 0, 70.7% were ever-smokers. The expression median values of 9 genes: CLCA2, FABP3, H19, TFPI2, AKR1B10, CYP3A5, ALDH3A1, SCGB3A2, SCGB1A1 were 0.30, 0.71, 0.34, 1.10, 0.26, 0.24, 0.42, 0.53, 0.09, respectively. Among all genes evaluated, the NR vs ER mean expression levels of two genes down-regulated (CYP3A5, 1.09 vs 0.30; SCGB3A2, 2.28 vs 0.98) and two genes up-regulated (AKR1B10, 4.53 vs 34.20; FABP3 1.25 vs 1.55) were superimposable respect to the results of previous microarray analysis. The median disease free survival (DFS) and overall survival (OS) were 21 and 23 months, respectively. In the logistic multivariate analysis the mean expression levels of all genes showed a tendency to predict the ER in the overall population (p=0.07). Nevertheless considering only the expression levels of genes (FABP3, H19, TFPI2, AKR1B10, CYP3A5, SCGB3A2) identified as significant with t-test, the covariates in multivariate analysis increased their capacity of ER prediction (p= 0.028).

      Conclusion
      Our results indicate that it is possible to define, through gene expression, a characteristic gene profiling of early relapse tumor patients with an increased risk of relapse disease. The contemporary expression levels of 6 genes (FABP3, H19, TFPI2, AKR1B10, CYP3A5, SCGB3A2) predicted a worse DFS. Such features may have important implications for future targeted therapies. We thank Italian Association for Cancer Research (AIRC) for supporting the study.

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      P1.02-006 - Identification of targetable driver mutations in molecularly selected never smoker lung adenocarcinomas (ID 2970)

      09:30 - 09:30  |  Author(s): R. Chiari

      • Abstract

      Background
      Approximately 25% of lung cancers occur in lifelong never smokers. Although no dominant risk factor has been identified yet, the discover of molecular drivers potentially targetable with biological agents, makes lung cancer in never smokers a unique disease, candidate for a personalized therapy. Through the FISH test, we performed a screening for ALK, ROS1, and RET rearrangements, in a highly selected population of lung adenocarcinoma never smoker patients, previously demonstrated to be wild-type for EGFR and K-RAS mutations.

      Methods
      We collected archived histological material of 28 EGFR and K-RAS wild-type patients (pts), from a 200 never-smoker advanced lung adenocarcinomas database, to be analyzed for the presence of rearrangements in ALK, ROS1 and RET genes. All pts were treated at the Division of Medical Oncology of the S Maria della Misericordia Hospital in Perugia from October 2003 to February 2013. 20 specimens were included in a tissue microarray (TMA) analysis, whereas 8 were screened in separate subset, due to the scarce samples. FISH test was performed using a combination of commercial reagents and custom designed probes. Median overall survival (OS) of mutated pts compared to the pan-negative ones, was evaluated by Cox multivariate analysis.

      Results
      Clinicopathological characteristics: among the 28 patients, 27 were never smokers and 1 former light smoker, with a good performance status; 20 (72%) presented with a metastatic disease at diagnosis, 8 (28%) were locally advanced; median age was 56 years-old, with a predominance of female sex (18/28, 64%). All cases were invasive adenocarcinomas and classified into 18 (64%) solid predominant type, 1 (3.5%) mixed acinar/lepidic pattern, 1 (3.5%) papillary, no predominant subtype for 8 (28%) patients, because of unsufficient histological material available. Of the 28 never smoker cases, we identified 7 gene fusions (25%), including 2 pts ALK+ (7.1%), 3 pts ROS1+ (10.7%) and 2 RET+ cases (7.1%), one compatible with KIF5B:RET and other with CCDC6:RET fusion. Median OS for the entire cohort was 24.5 months (mo), 61.2 mo for mutated pts (any rearrangement) vs 24.1 mo for not-mutated, respectively (P = .292).

      Conclusion
      Molecularly selected never smoker lung adenorcinomas associates with a high incidence of driver genes mutations and further investigations to confirm our frequencies in larger cohorts are needed. In line with literature data, our findings suggest a different survival outcome among genotypes, and identification of specific subsets in this special population can lead to successful treatment with target therapies.

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    P1.11 - Poster Session 1 - NSCLC Novel Therapies (ID 208)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P1.11-033 - Afatinib in EGFR mutant non-small-cell lung cancer patients with acquired resistance to reversible EGFR-TKIs (ID 2285)

      09:30 - 09:30  |  Author(s): R. Chiari

      • Abstract

      Background
      Afatinib, an irreversible EGFR-HER2 dual inhibitor, demonstrated superiority versus standard platinum-based chemotherapy as front-line therapy in non-small-cell lung cancer patients (NSCLC) with activating Epidermal Growth Factor Receptor (EGFR) mutations. In pretreated NSCLC afatinib failed to improve survival when compared to placebo in patients refractory to gefitinib or erlotinib and not selected for EGFR status. Aim of the present study was to evaluate clinical efficacy of afatinib in EGFR mutant NSCLC patients (pts) with secondary resistance to reversible EGFR-TKIs.

      Methods
      We retrospectively analyzed a cohort of 97 EGFR mutant lung cancer pts resistant to EGFR-TKI according to criteria used in the LUX-Lung 1 trial (Miller VA, Lancet Oncol 2012) and treated with Afatinib at the daily dose of 40-50 mg. The drug was given as compassionate use.

      Results
      The study included individuals with a median age of 62,5 year. The majority were females (N=63/64.9%), never/former smokers (N=94/96,9%), with good performance status (ECOG PS 0-1; N=90/90.2%) and pretreated with > 3 therapy lines (N=68/70.0%). EGFR status was assessed in tumor tissue obtained at the time of original diagnosis. The majority of pts (N=64, 66%) harbored a deletion in exon 19, while T790M mutation was detected in two cases including one case with double exon 19 and T790M mutation. Among the 95 pts evaluable for toxicity, 54.7% had any grade skin rash, including 11.6% with grade 3, and 50,5% had any grade of diarrhea, with grade 3 recorded in 10,5%. Among the 87 pts evaluable for efficacy, response rate (RR) was 11.5%, with a median progression free-survival and overall survival of 3.9 months and 7.3 months respectively. In 25 pts a tumor biopsy was repeated immediately before starting Afatinib therapy and 1 patient out of 5 individuals harboring T790M mutation showed a short extracerebral partial response, with following brain progression.

      Conclusion
      Our findings suggest that afatinib is modestly effective in EGFR mutant NSCLC with acquired resistance to reversible EGFR-TKIs.

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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-028 - ERCC1 mRNA expression and KRAS mutation status in EGFR wild type (WT) advanced non-small cell lung cancer (NSCLC) patients (ID 2405)

      09:30 - 09:30  |  Author(s): R. Chiari

      • Abstract

      Background
      In a previous report of EGFR WT advanced NSCLC patients treated with first-line platinum-based chemotherapy we observed a worse clinical outcome for KRAS-mutants compared with KRAS WT patients (Metro et al. ESMO 2012). Here, we assessed whether this phenomenon could be due to different levels of ERCC1 expression.

      Methods
      From a prospectively maintained database of EGFR WT advanced NSCLC patients diagnosed at a single Institution between January 2006 and November 2012, we identified the individuals who had a known KRAS mutation status and tissue available for assessment of ERCC1 mRNA expression. Total RNA was isolated from paraffin-embedded tumor specimens using RNeasy Mini kit and automatically purified by QiaCube instrument (Qiagen). Quantification of mRNA expression levels of ERCC1 was analyzed by real-time one-step RT-PCR using QuantiFast technology by RotorGeneQ instrument (Qiagen), and the results were compared considering β-actin as the internal reference gene.

      Results
      One hundred and eleven patients were evaluable, 60 of which were KRAS-mutants. Among KRAS-mutants, the rate of codon 12/13/61 mutations were 80%/13.3%/6.7% respectively. Baseline patients characteristics were as follows: median age was 62 years (35-84), 36.9% were male, 63.9% were stage IV, 78.3% were PS 0 or 1, 87.3% were ever-smokers, and 71.1% had received a first-line platinum-based chemotherapy. More ever-smokers were present in the KRAS-mutant subgroup compared with WTs (90% versus 76.5%, respectively, P = 0.08). ERCC1 average scores ranged from 0.1 to 26.7, the values being not normally distributed (Kolmogorov-Smirnov test, P<0.0001). Median and mean overall ERCC1 values for all patients were 1.3 and 2.2 [standard deviation (SD) 3.4], respectively. There was no statistically significant difference in terms of ERCC1 median values betwen KRAS-mutants and KRAS WTs (1.4 vs. 1.3, respectively, P = 0.27). Nevertheless, mean ERCC1 expression levels were found to be significantly higher in KRAS-mutants compared with KRAS WTs [2.9 (SD 4.5) vs. 1.4 (SD 0.8), respectively, P = 0.02]. This finding was due to 7 KRAS-mutant patients (ERCC1 high) coming out with ERCC1 levels higher than 5.0, thus notably incresing mean ERCC1 values. In the group of patients treated with first-line platinum-based chemotherapy (n = 79), median progression-free survival was 1.9 months for KRAS-mutant, ERCC1 high patients (n = 6), 5.1 months for KRAS-mutant, ERCC1 low patients (n = 38), and 7.1 months for KRAS WT patients (n = 35) (P = 0.003).

      Conclusion
      KRAS-mutant NSCLCs may express higher levels of ERCC1 compared with KRAS WTs, which could translate into poor sensitivity to first-line platinum-based chemotherapy. Combination strategies of platinum-based chemotherapy plus KRAS-targeting agents may represent an appealing upfront strategy for KRAS-mutants advanced NSCLCs, particularly in presence of concomitant expression of high ERCC1 levels.

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    P2.24 - Poster Session 2 - Supportive Care (ID 157)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P2.24-048 - Prevalence of pulmonary embolism in patients with oncogene addicted advanced lung adenocarcinoma (ID 2967)

      09:30 - 09:30  |  Author(s): R. Chiari

      • Abstract

      Background
      Non-small cell lung cancer is associated with a higher risk of thromboembolic events in comparison with SCLC. Adenocarcinoma represent roughly 75% of NSCLC patients. Lung adenocarcinomas harboring EGFR and KRAS mutations as well as EML4/ALK rearrangements represent distinct subsets of this disease. No data are available concerning the prevalence of pulmonary embolism in lung adenocarcinoma patients with these mutations. The aim of the study was to evaluate the prevalence of pulmonary embolism in patients with stage IIIB and IV lung adenocarcinomas harboring EGFR and KRAS mutations as well as EML4/ALK traslocations.

      Methods
      Patients with stage IIIB or IV NSCLC referred to Division of Medical Oncology at the Hospital of Perugia between 2008 and 2012 were included in the study. In these patients, contrast-enhanced CT scans of the chest were reviewed for the presence of pulmonary embolism by a panel composed by three radiologists. In the same patients, data regarding the molecular characteristics (EGFR exons 18-21 and KRAS exon 2 mutations as well as EML4/ALK traslocations) were collected.

      Results
      A total of 209 patients with stage IIIB or IV NSCLC were included in the study. A histologic diagnosis of lung adenocarcinoma was done in 173 patients (82.7%). In 127 of these patients sequence analysis for known EGFR (exon 18-21) and KRAS (exon 2) mutations was performed. In this population 31/173 patients were EGFR mutated (17.9%), 27/173 were K-RAS mutated (15.6 %) and 17/173 were EML4/ALK positive (9.8%). 41 patients with lung adenocarcinoma had a diagnosis of pulmonary embolism at CT scan (23.7%). Of these, 34.1% had no oncogene mutations in comparison with 28.8% of the patients without pulmonary embolism. Of the 41 patients with a diagnosis of pulmonary embolism 12.1% had an EGFR mutation and 12.1% a KRAS mutation, in comparison with 19.7% and 16.6% of patient without pulmonary embolism, respectively. In patients with lung adenocarcinoma, EML4/ALK rearrangements was observed in 19.5% among patients with pulmonary embolism and in 6.8% among patients without it. The risk of pulmonary embolism was 3.3-fold higher in presence of EML4/ALK rearrangements in comparison with no EML4/ALK rearrangements [OR: 3.3 (95%CI 1.2-9.2)].

      Conclusion
      In lung adenocarcinoma patients, the presence of EML4/ALK traslocation seems to be associated with a high risk of pulmonary embolism and could help in identifying patients at particular high risk who might benefit from an antithrombotic prophylaxis. These preliminary data need to be confirmed by further studies.

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    P3.24 - Poster Session 3 - Supportive Care (ID 160)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Supportive Care
    • Presentations: 1
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      P3.24-048 - Prevalence of unexpected pulmonary embolism at contrast-enhanced CT scan performed for cancer staging in patients with advanced lung cancer (ID 3111)

      09:30 - 09:30  |  Author(s): R. Chiari

      • Abstract

      Background
      Patients with advanced lung cancer have been reported to be at high risk for venous thromboembolism (VTE). In patients with cancer, a rate of unexpected pulmonary embolism (UPE) of about 1.5% has been reported.The aim of the study was to determine the prevalence of UPE in patients with stage IIIB or IV NSCLC or extensive SCLC who underwent CT scans for cancer staging.

      Methods
      We reviewed the contrast-enhanced CT scans of the chest performed for routine cancer staging in consecutive patients with advanced lung cancer (stage IIIB or IV NSCLC or extensive SCLC) referred to the Division of Medical Oncology at the hospital of Perugia between 2008 and 2012. All CT scans were reviewed by an ad hoc panel composed by 3 radiologists. PE was defined as unexpected when a filling defect in central, lobar, segmental or sub-segmental pulmonary arteries was observed in absence of clinical suspicion of PE.

      Results
      Overall, 223 patients were included in the analysis: 180 patients with stage IV-NSCLC, 24 patients with stage IIIB-NSCLC, and 19 patients with extensive SCLC. A total of 899 CT scans were reviewed. The prevalence of UPE was 19.7% (44/223): 34 (77.3%) in patients with stage IV-NSCLC, 7 (15.9%) in patients with stage IIIB-NSCLC, and 3 (6.8%) in patients with advanced SCLC. Patients with UPE were 26 males and 18 females and had a mean age of 58 years (range 24-78). UPE was monolateral in 30 patients and bilateral in 14 patients. UPE involved central pulmonary arteries in 6 patients, lobar arteries in 16 patients and segmental arteries in 19 patients. 3 patients had an isolated sub-segmental UPE. The mean time between cancer diagnosis and UPE was 11.8 months. 27% of cancer patients with UPE had the positive CT scan at diagnosis and 50% within 3 months. A recurrence of UPE was observed in one patient.

      Conclusion
      Patients with stage IIIB or IV NSCLC or extensive SCLC have a high rate of UPE at CT scan performed for cancer staging. UPE was bilateral in about one third of patients. A minority of UPE involved isolated sub-segmental arteries.