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M. Alloisio



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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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      MO10.10 - Detection of RET fusions by FISH in unselected NSCLC (ID 2434)

      16:15 - 17:45  |  Author(s): M. Alloisio

      • Abstract
      • Presentation
      • Slides

      Background
      Activation of the RET gene by fusion has been described in 1-2% of unselected population of non-small-cell lung cancer (NSCLC) and there is early evidence suggesting that patients with RET activated tumors obtain clinical benefit from RET inhibitors. The major fusion partner is KIF5B, but CCDC6, NCOA4 and TRIM33 have also been reported. The prevalence of RET fusions in different lung cancer subtypes and clinicopathologic characteristics of remain unclear. In this study, we sought to identify RET rearrangements in NSCLC using FISH and to investigate the association with histology and clinical features.

      Methods
      A 3-target, 3-color FISH probe set [3’RET in red, 5’RET in green, 5’KIF5B in yellow] was developed to simultaneously detect (a) disruption between 3’ and 5’ RET and (b) specific fusion between 5’KIF5B-3’RET. This probe set was used to interrogate a cohort of Caucasian NSCLC patients using tumor microarray. Inclusion of specimens on the tissue microarray was independent of gender, age, smoking history, histology and any known molecular profile and was only based on patient informed consent and tissue availability.

      Results
      Among 348 evaluable NSCLC patients, 6 (1.7%) were found to be positive for RET rearrangement (RET+): 2 showed typical KIF5B:RET pattern, 2 showed patterns consistent with CCDC6: RET fusion; and 2 had split 3’-5’ without suggestion of the fusion partner identity. The histology was adenocarcinoma in 4, large cell carcinoma in 1 and squamous cell carcinoma in 1. All RET+ tumors were wild type for EGFR and negative for ALK and ROS1 rearrangements. The mean age of RET+ patients at the time of diagnosis was 62 years (49-74) and they were predominantly male (5) and former (4) or current smokers (1). The 10p11-q11 region displayed high level of genomic instability, with RET doublets, KIF5B and RET doublets, unbalanced KIF5B copy number gain, fusion KIF5B with 5’ and 3’RET, and abnormal separation between KIF5B and RET in 8.5%, 5.1%, 9.6%, 2.3%, and 2% of specimens, respectively. These atypical patterns will be further investigated by RT-PCR.

      Conclusion
      The customized 3-target, 3-color probe set successfully detected KIF5B:RET rearrangements and identified patterns suggestive of RET rearrangements with non-KIF5B partners in small subset of unselected NSCLC. Interestingly, only a minority of RET + patients were never smokers and 1/3 of them had non-adenocarcinoma histology. Despite the benefits of using enrichment strategies based on clinicopathologic variables for molecular testing of NSCLC in search for personalized therapy, these findings argue against using variables such as smoking status and histology for screening selection when the aim is to detect all potential RET+ patients.

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    O05 - Cancer Control (ID 130)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      O05.01 - The DANTE trial, a randomized study of lung cancer screening with spiral CT: 7-year results (ID 1428)

      10:30 - 12:00  |  Author(s): M. Alloisio

      • Abstract
      • Presentation
      • Slides

      Background
      The purpose of this study was to explore the effect of screening with spiral CT on lung cancer mortality in comparison with no screening in a high-risk population. Secondary endpoints were incidence, stage and resectability.

      Methods
      Male subjects, aged 60-75, smokers of 20+ pack-years were randomized to screening with low-dose spiral CT or control. Prospective participants were pre-assessed for eligibility and randomized during a telephone interview, while formal enrolment took place at a later date. All enrolled participants underwent a structured medical interview and physical examination, a baseline, once-only chest X-ray (CXR) and sputum cytology examination. Screening-arm subjects had a LDCT upon accrual, which was repeated every year for four additional years (5 rounds), while controls had a yearly clinical review only, with further testing only if needed.

      Results
      Between March 2001 and February 2006, 2811 subjects were pre-assessed and randomized (CT arm: 1403, control arm:1408). 20 cases of double registration and two test records have been identified in the database, and 2540 subjects actually appeared for assessment (1229 CTR arm, 1299 CT arm), of whom 2450 (1264 CT arm and 1186 Controls) were eligible and enrolled. The two study groups are comparable for age, smoking exposure, and comorbid conditions. As per inclusion criteria, all subjects are males and 99.8 % are 60 or older. As of December 2012, median follow-up was 73.1 months in the control arm and 75.5 months in the screening arm. Altogether, 152 patients were detected during active follow-up with 161 lung cancers: 92 CT-arm subjects (7.27%) versus 60 controls (5.05%), p< 0,0237. 82% of CT-arm lung cancers were detected at scheduled CT examinations, and 55% were stage I disease at the time of diagnosis compared with 27% in the Control arm. The absolute number of lung cancer cases with stage II-IV disease was virtually the same as in the control arm. Resectability rate was similar in the two groups. After linkage with population registries, vital status information is now available for 2528 subjects (99.5%). Overall, 370 subjects have died, for 104 of whom we are currently investigating mortality causes.

      Conclusion
      While the number of participants is relatively small, smoking exposure and average age of participants are higher than in similar trials. A comparatively high number of events has been observed. To date, 28% of such events cannot yet be attributed to a specific cause. Health registry data necessary to complete mortality comparisons is expected to become available in the next few weeks. Merging of all European trials may yield robust data about this strategy in the future.

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    P3.12 - Poster Session 3 - NSCLC Early Stage (ID 206)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.12-021 - The role of pentraxin 3, an acute phase protein, and of smoldering inflammation at the tumor site in lung cancer progression and prognosis. A clinicopathologic study (ID 3290)

      09:30 - 16:30  |  Author(s): M. Alloisio

      • Abstract

      Background
      The prognosis remains dismal for most lung cancer patients, even for early cases, suggesting the existence of sophisticated pathogenetic mechanisms that are not reflected by pathological stage. Although a number of studies have been carried out in relatively recent times [], our understanding of the role and clinical significance of inflammation and immunity in human lung cancer is still limited. We investigated in detail the diagnostic and prognostic role of two acute phase proteins, Pentraxin 3 (PTX3) and C-reactive protein (CRP), in high-risk subjects and lung cancer patients.

      Methods
      A cohort of high-risk, cancer-free subjects enrolled in a lung cancer early-detection trial with spiral CT, a group of screening-detected lung cancer patients, and two groups of consecutive non-small cell lung cancer patients admitted to our Thoracic Surgery Department between January 2009 to June 2010 were included. Serum CRP and PTX3 levels were determined in the high-risk, healthy cohort (N=1434) and in patients with non-small cell lung cancer. Pre-treatment blood samples were prospectively collected prior to surgical resection in lung cancer patients. PTX3 expression was determined by immunohistochemistry and scored using semiquantitatively. Survival curves were calculated by the method of Kaplan and Meyer. Prognostic factors were analyzed by multivariate Cox regression.

      Results
      No significant association was found between PTX3 or CRP serum levels and the risk of subsequently developing lung cancer or any malignancy in the high-risk-cohort. 119 patients harbouring 124 primary lung cancers were evaluable. Screening and clinically detected lung cancer patients were comparable as to age and comorbidity. There was a significantly higher rate of stage I disease among screening patients (p=0.01). Preoperative serum CRP and PTX3 levels in lung cancer patients were significantly higher than in the tumour-free, high-risk population, p<0.001). In the tumour stroma, PTX3 expression was low or moderate in 55% and intense in 10%. Tumour cells stained weakly positive in 24%. Staining for PTX3 was virtually absent in the normal lung interstice. Median follow-up was 27 months (0-140), Median 2-year disease-free survival was 71 % and median overall 2-year survival was 75% Preoperative serum levels of CRP and PTX3 did not correlate with survival. Instead, age (p=0.029), stage (p=0.001) and interstitial PTX3 expression (p<0.001) were independent prognostic factors

      Conclusion
      PTX3 and CRP levels are not linked to a higher risk of developing lung cancer or any cancer in a healthy high-risk population. Nonetheless, mean CRP and PTX3 concentrations in patients with lung cancer are significantly higher than in the blood of healthy high risk subjects, and a significant and independent correlation was found for interstitial PTX3 expression with lung cancer prognosis after surgery. Altogether this data suggests a connection between smoldering inflammation in the tumor bed and lung cancer progression that warrants further investigation.