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G. Zalcman



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    MO08 - NSCLC - Early Stage (ID 117)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO08.02 - Adjuvant pazopanib or placebo in resected stage I NSCLC patients: results of the NSCLC adjuvant randomized phase II trial (IFCT-0703) from the French collaborative Intergroup (ID 2274)

      16:20 - 16:25  |  Author(s): G. Zalcman

      • Abstract
      • Presentation
      • Slides

      Background
      Although UFT is approved in eastern countries, most guidelines do not recommend any adjuvant treatment in resected Stage I NSCLC. Pazopanib (P) is a potent, orally active multi-target receptor tyrosine kinase inhibitor of VEGFR-1, -2, -3, platelet derived growth factor (PDGFR) type-α and –β, approved in metastatic renal cell carcinoma and sarcoma. Neoadjuvant P demonstrated single-agent activity in patients with early stage NSCLC. We report the feasibility and tolerance of adjuvant P in stage I NSCLC.

      Methods
      In this double-blind randomized multicenter phase II/III trial, completely resected patients (pts) with stage I NSCLC (7[th] TNM edition) were randomized to receive either placebo or P 800 mg/d during 6 months. The Fleming’s two stage phase II primary endpoint was compliance (i.e. % of pts able to receive at least 3 months of P, whatever the dose). After 64 pts included (interim analysis), IDMC recommended to start with P 400 mg/d because of initial insufficient compliance. A one-step Fleming design was used with the new dose. Phase II design was not comparative.

      Results
      143 pts were randomized in 29 centers between March 2009 and August 2012, 71 and 72 in the placebo and P arms respectively. Most pts were male (61%) and smokers (91%), median age was 60. Pathological stage was IA in 111 pts (78%) and 16% were squamous cell carcinomas. Compliance for P800 was adequate in 38% (95% confidence interval [21-56]) vs. 87% [71-96] in placebo; for P400 in 69% [50-84] (p=0.01, compared to P800) vs. 93% [77-99] in placebo. Dose modifications were seen in 44% and 34% of P800 and P400 groups. The proportion of patient with at least one grade 3/4 toxicity was 53% [35-71] in P800 (13% [4-29] for placebo) and 38% [21-56] in P400 (27% [12-46] for placebo). No toxic deaths were observed. Only 2 pts has grade 4 toxicities in P800 (fatigue in P arm, GGT in the placebo arm). Most common toxicities G3 in P800 were diarrhea (9%), hypertension (9%), and increased transaminases (16% vs. 0% in P400); in P400 gastro-intestinal disorders (16%, 6% diarrhea) and hypertension (6%).

      Conclusion
      IFCT-0703 is the first feasibility study demonstrating that full dose of P is safe but not feasible in the adjuvant setting in NSCLC. Compliance and tolerance with reduced dose appeared acceptable for adjuvant settings.

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    MO15 - Novel Genes and Pathways (ID 89)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
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      MO15.03 - Deciphering the RASSF1A signaling pathway in lung cancer cells reveals a metastasis-suppressor role through YAP-dependent epithelial-mesenchymal transition (EMT) (ID 3189)

      16:25 - 16:30  |  Author(s): G. Zalcman

      • Abstract
      • Presentation
      • Slides

      Background
      RASSF1A gene promoter hypermethylation was previously shown to predict poor overall survival in the IFCT-0002 randomized phase 3 trial of neo-adjuvant platinum-based chemotherapy, in early stage (I & II) NSCLC. We investigated the molecular and cellular basis for such a dramatic influence.

      Methods
      We studied isogenic immortalized bronchial, non-tumorogenic, HBEC3 cell lines only differing by their K-Ras status (wild-type or mutant K-Ras Val12 allele), and a panel of lung cancer cell lines recapitulating the main molecular alterations encountered in lung cancer. RASSF1A protein was depleted by 80% using 2 specific siRNAs, followed by the evaluation of EMT markers and cell motility regualors using qRT-PCR, Western blot or Immunofluorescence. Migration of transfected cells was assayed by 2D wound-healing migration assays or 3D migration assays using transwell devices with or without a matrigel coating mimicking basement membrane (invasion assay), or an endothelial cell monolayer (trans-endothelial cell invasion). Phenotypic rescue was studied by using plasmids encoding full-length RASSF1A or RASSF1C isoform, and a construct encoding a SARAH-deleted RASSF1A protein, unable to interact with the Hippo/MST kinase. We also tested co-transfection of RASSF1A siRNAs together with siRNAs directed against Hippo pathway members LATS1/2, WW45, YAP. Depletion of RASSF1A was finally combined with expression of wild-type, activated or dominant negative RhoA, RhoB, Rac1 or CDC42 constructs.

      Results
      In each bronchial/lung cancer cell line tested, RASSF1A silencing led to EMT resulting in E-cadherin, Syndecan1, Zo-1, miR200 decrease and concurrent N-cadherin, vimentin, Twist1, miR-21 increase. RASSF1A silencing-induced EMT was associated with cytoplasmic to nucleus translocation of YAP transcription factor, the terminal effector of the Hippo signaling pathway. RASSF1A silencing reduced cell adhesion and increased 2D cell motility with collective migration features. RASSF1A knock-down increased 3D migration, invasion as trans-endothelial migration. These effects correlated with the up-regulation of RhoA, RhoC, CDC42, MMP2/14 mRNAs and down-regulation of RhoB, DIA1 and MMP9 mRNAs. We also observed an increase of adhesion/invasion signaling proteins, i.e. CD44v6, cofilin, ERM and NF2, cofilin being activated by inhibition of LIMK-induced phosphorylation. Finally we report that immortalized non-tumorogenic cell lines, unable to grow without adhesion, acquired the capacity to grow in soft agar when RASSFIA was knocked-down. Those effects were rescued by co-transfection of RASSF1A siRNAs with full-length RASSF1A cDNA, showing the specificity of the motile phenotype induced by RASSF1A silencing, but not by RASSF1C nor SARAH-deficient RASSF1A plasmids. SiRASSF1A-induced cell migration was inhibited by LATS1/LATS2/WW45 or YAP siRNAs, showing the involvement of the Lats/YAP signaling cascade. We finally show that RASSF1A knockdown-promoted migration was inhibited by using RhoB-Val14 constitutively active cDNA but not RhoBN19 dominant negative construct, and by specific RhoB GEFs or RhoB effectors (DIA1) constructs.

      Conclusion
      In lung cells, the RASSF1A protein acts as a migration-suppressor protein by regulating the LIMK/cofilin pathway through RhoB signaling. RASSF1A prevents YAP induced EMT by inhibiting its nuclear accumulation through LATS1/2 signaling, whereas Hippo/MST kinase seemed dispensable. We thus provide evidence, for the first time in human lung cancer cells, for a direct connection between RASSF1A signaling and the LATS/YAP pathway.

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    O18 - Cancer Control and Epidemiology II (ID 133)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Prevention & Epidemiology
    • Presentations: 2
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      O18.03 - The BioCAST / IFCT-1002 study: a comprehensive overview of demographic, risk exposure and somatic mutations of non-small cell lung cancer occurring among French never smokers (ID 3293)

      10:50 - 11:00  |  Author(s): G. Zalcman

      • Abstract
      • Presentation
      • Slides

      Background
      Lung cancer occurring in never-smoker (LCINS) is a particular entity. Although the definition is strict (less than 100 cigarette in lifetime) never-smokers are frequently misclassified and no study gives a comprehensive analysis of this group, particularly in a European setting.

      Methods
      All consecutive never-smoker patients diagnosed with a non-small cell lung cancer in one of the 75 participating centers throughout France, between November 2011 and January 2013, were included in this prospective survey. All patients underwent a detailed questionnaire supported by a trained staff during a phone interview. Somatic mutations and cancer clinical and histological data were also recorded from medical charts.

      Results
      Overall, 384 never-smokers were included and 336 interviews were completed. Most of them were women (n=319, 83.1%). The mean age at diagnosis was 69.8 ± 12.02 and 10.9% were under 55 years-old. None reported alternative smoking (pipe, cigar, water-pipe, gum, or cannabis). Most of them originated from Western and Southern Europe (90.5%). Overall, 219 (65.6%) reported a passive smoking exposure in a domestic setting (n=198; 59.3%), and/or at workplace (n=60; 18.0%). Patients had a personal history of pneumonia in 6.2%, tuberculosis in 8.3%, COPD in 13.0%, and a cancer at another site in 16.6%. Eighty patients reported at least two relatives with lung cancer (24.0%). Definite occupational exposure was observed in 12.0% (n=44) for diesel, 7,1% (n=26) for asbestos, 3.3% (n=12) for poly-aromatic hydrocarbons, 2.4% (n=9) for silica, 0.8% (n=3) for chrome, and 0.5% (n=2) for painting. Exposure to cooking oil was noted in 123 patients (36.8%) with a mean of 49.4 ± 356.7 cooking-dish year. Moreover, 79.7% (n=259) patients were ever exposed to solid fuel fumes for cooking or heating (21.2% during more than 50% of their lifetime). Among women, 91.7% already reached menopause (mean age 49.3 ± 5.6 years-old), 115 (41.7%) were ever-exposed to oral contraceptive (mostly oestrogen-containing drugs), and 25.5% to post-menopause hormone replacement therapy (oral or transdermal). Most of lung cancers were adenocarcinoma (n=327, 85.2%) followed by squamous cell carcinoma (n=29, 7.6%) and large cell carcinoma (n=17; 4.4%). Among adenocarcinoma, 71% were invasive, 4% in-situ, 2% minimally-invasive, 2% variant of invasive, and 20.0% were NOS. Cancer stage was I in 9.2%, II in 5.8%, III in 11.8% and IV in 73.2%. At least one biomarker was tested in 359 patients (93.5%). We found 148 patients with EGFR mutations (43.5% out of the EGFR-tested patients), 20 with KRAS mutations (6.8%), 24 with ALK translocation (12.5%), 10 with BRAF mutation (4.5%), 8 with HER2 mutation (4.0%) and 4 with PIK3CA (2.1%). Overall, 27.0% samples remain wild type, 2.1% with multiple mutations, 71.0% with a single mutation, and 20.6% with missing data.

      Conclusion
      We provide here the largest cohort of LCINS in a European setting with reliable data on tobacco intoxication, occupational exposure, and hormonal treatments, since collected by a trained staff through phone interview. In this perfectly clinically characterized cohort, molecular analyses showed that 72% of tumors exhibited oncogenic targetable mutations.

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      O18.04 - Impact of Passive Smoking on molecular pattern in Never Smokers with Non-Small Cell Lung Cancer: Findings from the BioCAST / IFCT-1002 Study (ID 3305)

      11:00 - 11:10  |  Author(s): G. Zalcman

      • Abstract
      • Presentation
      • Slides

      Background
      EGFR and HER2 mutations are usually associated with never-smokers while KRAS and BRAF mutations are thought to be link with smoking behavior in Non-Small Cell Lung Cancer (NSCLC). Passive smoking exposure is a well-known risk factor for lung cancer. Only EGFR and KRAS mutations were investigated in association with passive smoking and showed conflicting results. We aimed to investigate mutation rate of EGFR, HER2, KRAS, BRAF and ALK in a cohort of never smokers regarding their passive smoke exposure.

      Methods
      The BioCAST / IFCT-1002 study is a prospective cohort of NSCLC patients diagnosed in French never-smokers patients (less than 100 cigarettes in lifetime) between November 2011 and January 2013, Passive smoking exposure was evaluated through standardized questionnaire. We obtained biomarkers mutation results through routine testing. We used Fisher, Chi-square, median test and Mann-Whitney U test for comparisons as appropriate. We used logistic regression to calculate adjusted odds ratio for risk of each mutations.

      Results
      Out of the 384 patients included in the BioCAST database, 334 (87.0%) had available data on passive smoking exposure. Among them, 219 patients (65.6%) were ever exposed to passive smoking in their lifetime. 198 (59.3%) reported a domestic exposure (122 during childhood at least) and 60 (18.0%) a workplace exposure. Result of at least one biomarker mutation was available in 313 patients (93.7%). including 128 EGFR mutations in 297 patients, 8/174 HER2 mutations, 18/256 KRAS mutations, 10/196 BRAF mutations, and 20/171 ALK gene rearrangements. We found no difference in mutation rate according to passive smoke exposure (cf. Table 1). There was no difference when comparing cumulative year of exposure, smoker-year or passive-pack year (as continuous variable) to the mutation rate, for any biomarker. When considered as categorical variable – after division in quartiles – we found also no difference. Results were similar when focusing on domestic (childhood versus adulthood included) and workplace exposure only. Finally, we found no significant increased risk for mutation for any biomarker in logistic regression adjusted for most of other lung cancer risk factors.

      EGFR Mt (n=297) HER2 Mt (n=171) KRAS Mt (n=256) BRAF Mt (n=196) ALK Fusion (n=171)
      % % % % %
      Overall exposure Never 46.5 3.5 6.7 5.9 13.0
      Ever 41.3 5.1 7.2 4.7 11.1
      Domestic exposure Never 45.8 2.9 7.7 6.4 11.1
      Ever 41.3 5.7 6.6 4.2 12.0
      Exposure at workplace Never 43.3 5.5 7.0 5.4 12.2
      Ever 42.3 0 7.0 3.6 8.3
      Total 43.1 4.6 7.0 5.1 11.7
      Exposure in childhood Ever 40.5 3.0 6.5 2.7 14.7
      Only in adulthood 42.6 10.3 6.8 6.7 7.5

      Conclusion
      Although we report the largest and more comprehensive study focusing on this topic, we found no significant difference in the biomarker mutation profile of NSCLC occurring in French never-smokers regarding their exposure to passive smoking as compared with the pattern of mutations described never-smoker patients with any passive smoking.

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    P3.09 - Poster Session 3 - Combined Modality (ID 214)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Combined Modality
    • Presentations: 1
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      P3.09-018 - IFCT-0803 Trial: a phase II study of cetuximab, pemetrexed, cisplatin and concurrent radiotherapy in patients with locally advanced, unresectable, stage III, non squamous, non-small cell lung cancer (NSCLC): preliminary safety analysis (ID 3281)

      09:30 - 09:30  |  Author(s): G. Zalcman

      • Abstract

      Background
      Cisplatin-based chemotherapy and concurrent radiotherapy are the standard treatments for locally advanced unresectable NSCLC. New therapeutic combinations using molecular targeted drugs are needed. IFCT-0803 Trial is a phase II study evaluating the benefit of adding cetuximab to a combination of concomitant radio-chemotherapy with cisplatin and pemetrexed in patients with stage III, non-squamous NSCLC. Data on safety and tolerance during the first 16 weeks of treatment, available after the inclusion of the first 62 eligible patients, are presented.

      Methods
      Based on a two-stage Simon approach, 106 patients will be included in IFCT-0803 trial. An interim analysis of the first 34 patients authorized the continuation of the study. Eligible patients receive conformal thoracic radiation with no elective nodal irradiation (66 Gy in 33 fractions, ICRU) along with cisplatin (75 mg/m[2]) and pemetrexed (500 mg/m[2]) on day 1 administered intravenously every 21 days for four cycles; weekly cetuximab (400 mg/m[2] for the first week, then 250 mg/m[2]) is added from the first week of therapy for a total of 12 doses. The primary objective is to assess the disease control rate at the 16[th] week, one month after treatment completion

      Results
      62 patients were included (37 male, 56 years mean age), PS 0 = 39 and PS 1 = 23, ever smoker = 57, stage IIIA = 31 and IIIB = 31, adenocarcinoma = 50. Compliance for the first 62 patients included was as follows: Day 1 chemotherapy was administered to 100% of patients on cycles 1 and 2, to 98.4% on cycle 3 and to 96.6% on cycle 4. Radiotherapy protocol was respected: median was 33 for number of fractions, 66 Gy for total dose, 46 days for duration of treatment, 39 patients had a maximal toxicity of grade 3 and 6 of grade 4. Table 1 lists the number of patients for the main categories of toxicity.

      n=62 grade 1/2 grade 3 grade 4
      anemia 32 4 0
      neutropenia 24 20 5
      thrombocytopenia 30 4 2*
      general toxicity 42 13 0
      skin toxicity 51 9 0
      digestive toxicity (nausea and vomiting) 42 6 0
      esophageal toxicity 43 10 0
      febrile neutropenia - 5 0
      renal toxicity 4 3 0
      neurologic toxicity 11 0 0
      * :One patient died consecutively to a subdural hematoma caused by a fall, he had a grade 4 thrombocytopenia

      Conclusion
      IFCT-0803 trial is ongoing, the end of the inclusions is scheduled for October 2013. This combination therapy is feasible without any unexpected side effects.