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C. Bennati



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    MO10 - Molecular Pathology II (ID 127)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Pathology
    • Presentations: 1
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      MO10.12 - ROS1 Fusions Diagnosed by Break-Apart FISH in NSCLC (ID 968)

      17:20 - 17:25  |  Author(s): C. Bennati

      • Abstract
      • Presentation
      • Slides

      Background
      Chromosomal rearrangements which generate constitutively activated ROS1 receptor tyrosine kinase (6q22.1) have been found in several tumor types, including non-small cell lung cancers (NSCLC). In clinical trials, the oral kinase inhibitor crizotinib has shown promise in treating tumors with ROS1 rearrangements. Currently, fluorescence in situ hybridization (FISH) using dual-color, break-apart (BA) probes is used to detect ROS1 rearrangements in clinical samples; however, further optimization of this method is necessary to ensure patients are accurately diagnosed. This study explores BA FISH assay characteristics in NSCLC samples.

      Methods
      Tumor sections from 464 NSCLC patients were screened for ROS1 rearrangement using ROS1 BA FISH. Of these samples, 206 were co-screened for ALK rearrangement. The copy number of fused and isolated 3’/5’ signals, as well as the incidence of atypical patterns (doublet and clustered multiple fusions) was investigated. Cells were considered ROS1 positive (ROS1+) when ≥ 15% of nuclei displayed split 5’/3’ signals or single 3’ signals. Specific fusion transcripts in ROS1+ cases were identified by RT-PCR or inverse PCR.

      Results
      ROS1 rearrangements (ROS1+) were found in 21 patients (5%). The copy number of native ROS1 differed significantly between positive and negative tumors (mean of 1.5 versus 2.5, p<0.0001). The percent of cells with FISH patterns compatible with ROS1 rearrangement ranged from 30% to 100%, with a mean of 81%, in ROS1+ patients. The distribution of positive cells between scored regions within ROS1+ tumors was investigated for 13 cases and found to follow a normal distribution, ruling out intra-tumoral heterogeneity. Among ROS1+ specimens, 71% had a split signal pattern, 19% displayed a single 3’ pattern, and 10% had both a split and single 3’ pattern of positivity. For positive tumors, ROS1 fusion partners were identified as SDC4 (S2;R32 and S2;R34), EZR (E10;R34) and CD74 (C6;R32 and C6;R34). Atypical negative patterns such as fused doublets, clusters, 3’ doublets, 5’ doublets, and single 5’ signals were observed in 4%, 1%, 1%, <1%, and <1% of negative patients. ALK and ROS1 were scored simultaneously in the same cells in 206 patients, including 5 ROS1+ and 10 ALK+; no double positive cases were found. In ROS1 negative specimens, mean native ALK copy numbers were significantly higher than native ROS1 in ALK negative samples (3.2 versus 2.3, p<0.0001).

      Conclusion
      ROS1+ tumors were detected in 5% of patients in this large NSCLC cohort. Since these patients were subject to various selection strategies, this frequency cannot be transferred to an unselected NSCLC population. The low native ROS1 copy number in the rearranged cells and lack of evidence of intra-tumoral heterogeneity suggests ROS1 rearrangements occur early in tumorigenesis, consistent with their known oncogenic driver role. Data from this sample also show that, in FISH negative cases, ROS1 copy number was lower than native ALK. This suggests ROS1 may exist in a relatively more stable portion of the genome, potentially explaining why ROS1 rearrangements exist at a lower frequency than ALK rearrangements in NSCLC.

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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): C. Bennati

      • 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: 1
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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): C. Bennati

      • 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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    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): C. Bennati

      • 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): C. Bennati

      • 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): C. Bennati

      • 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.