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E.M. Speel



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    MO03 - Thymic Malignancies (ID 123)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO03.09 - Detection of Human Polyomavirus 7 in thymomas (ID 1829)

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

      • Abstract
      • Presentation
      • Slides

      Background
      Thymomic pathologies are associated with the autoimmune disease myasthenia gravis (MG). The thymomagenesis have been studied extensively but the etiology of human thymoma remains poorly understood. Based on the consistent finding that murine polyomavirus induces thymomas in mice we tested the presence of Human Polyomavirus 7 (HPyV7) in human thymic epithelial tumors.

      Methods
      We applied HPyV7 DNA Fluorescence in situ hybridization (FISH), DNA PCR and immunohistochemistry (IHC) in 37 thymomas (19 female, 18 male; mean age 58.3 years; range 34 – 82 years). Of these, 26 were previously diagnosed with MG. In addition, 2 thymic carcinomas, 20 follicular hyperplasia and 20 fetal thymus tissues were tested for HPyV7.

      Results
      HPyV7 FISH revealed specific nuclear hybridization signals within the thymoma cells of 23 thymomas (62.2%). Fifteen thymomas revealed strong to very strong hybridization signals, whereas 8 revealed only weak positivity. With one exception the HPyV7 FISH data highly correlated with the HPyV7 DNA-PCR data. IHC showed the presence of HPyV7 on the translational level and immunohistochemical double stainings confirmed the presence of HPyV7 in the epithelial thymoma cellular compartment. One thymus carcinoma was HPyV7 positive the other negative. All fetal thymus tissues were tested HPyV7 negative. The follicular hyperplasia results are pending.

      Conclusion
      We conclude that HPyV7 is frequently present in human thymic epithelial tumors and absent in fetal thymic tissues. No convincing association on HPyV7 and MG could be found. In as much HPyV7 is of relevance to human thymomagenesis remains to be established.

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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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      MO10.07 - ALK immunohistochemistry and fluorescence in-situ hybridization in Lung adenocarcinomas from the ETOP Lungscape tumour cohort (ID 2267)

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

      • Abstract
      • Presentation
      • Slides

      Background
      The European Thoracic Oncology Platform LungScape database contains 2614 cases of primary resected lung carcinoma from 16 centres with patient demographics, pathological tumour data and detailed clinical follow-up. A total of 1281 cases of adenocarcinoma with >2 years clinical follow-up were selected for analysis of ALK status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Test positive cases were matched, in order of importance at ratio 1:2, by stage, gender, smoking status, study centre, year of surgery and age with test negative cases -both for IHC and for FISH testing.

      Methods
      Testing was performed in all centres using the same protocol (IHC: Novocastra 5A4 clone antibody at 1:10 dilution, Novolink detection system. FISH: Abbott Vysis ALK break-apart probe). Each centre passed an external QA test using unknown cases in a tissue microarray before conducting the LungScape tumour testing. IHC was scored according to three intensity scores (1+, 2+, 3+) using ‘objective’ methodology previously described [1]. Maximum staining intensity was recorded. Any IHC staining was defined as IHC positive result. FISH preparations were assessed according to the Vysis protocol on all 82 IHCpositive cases plus their 164 IHCnegative matches.

      Results

      IHC cases, n=1281 FISH positive(264 tested)
      IHC negative 1199 (93.6%) 0 (0.0% of 164 controls) FISH specificity: 100%
      IHC 1+ 43 (3.35%) 2 (4.6% of IHC 1+)
      IHC 2+ 16 (1.25%) 6 (37.5% of IHC 2+)
      IHC 3+ 23 (1.8%) 20 (87% of IHC 3+)
      IHC any positive 82 (6.4%) 28 (34.1% of IHC+) FISH sensitivity: 34.1%
      FISH sensitivity was 87% for IHC 3+. IHCpositive/FISHnegative cases (n=54) were mostly IHC 1+ (75.9%), sometimes IHC 2+ (18.5%) and rarely IHC 3+ (5.5%). The frequency of never smokers was higher in the ALK IHCpositive group (29.3%) versus IHCnegative group (18.3%) {p=0.011}. Age, gender and tumour stage did not differ between IHC groups. The hazard of an event for IHCpositive cases decreases by 32% in relapse-free survival {RFS; p=0.03} and by 38% in either time-to-relapse {TTR; p=0.02} or overall survival {OS; p=0.016}. Multivariate models -adjusted for patient and tumour characteristics- indicated that IHC-ALK was a significant predictor for all three time-to-event outcomes (RFS, TTR, OS). In stratified Cox analysis, significantly higher OS was retained in the IHCpositive (HR=0.59, p=0.04) and FISHpositive (HR=0.34, p=0.03) cases in the matched cohorts, while conditional logistic regression yielded non-significant associations with 3-year survival status.

      Conclusion
      In this large cohort of surgically resected primary lung adenocarcinoma: ALK IHC positivity was 6.4%. IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity ALK IHC positivity was higher in never smokers and related to better clinical outcome ALK testing can be reliably implemented across multiple laboratories {1} Ruschoff et al. Virchows Arch. 2010;457(299-307).

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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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      P1.06-015 - EGFR mutated patients: different pattern and outcome of metastatic bone disease and brain metastases? (ID 1596)

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

      • Abstract

      Background
      Bone and brain are frequent and problematic sites of metastasis in metastatic non-small cell lung cancer (mNSCLC). Conflicting studies exist whether patients with EGFR mutations develop brain metastases (BM) more often or have a longer survival after diagnosis of mNSCLC than EGFR/KRAS wild type (WT) or KRAS+ patients. For metastatic bone disease (MBD) this is not known. In this retrospective matched control study we compared in EGFR+, KRAS+ and WT patients time from mNSCLC to development of MBD/BM, skeletal related events (SREs) and subsequent survival.

      Methods
      In this retrospective case-control study all EGFR+ patients diagnosed at two molecular pathology departments were selected (VUMC 01-11-2004 to 01-01-2012, MUMC 01-10-2008 to 01-08-2012). For every EGFR+ patient a consecutive KRAS+ and WT mNSCLC patient was selected. Patients with another malignancy within 2 years of mNSCLC diagnosis or no follow up were excluded. Data regarding age, gender, histology, performance score, treatment, MBD and BM diagnosis, SRE and subsequent survival were collected.

      Results
      222 patients were included: 73 EGFR+, 76 KRAS+ and 73 WT (table 1). Respectively 56.2%, 51.3% and 50.7% had MBD (p=0.768) of which respectively 41.5%, 25.6% and 40.5% were diagnosed during follow up (p=0.262). Time to MBD was (mean, [SD]) respectively 13.4 [±10.6], 20.7 [±17.8], 16.8 [±9.6] months (p=0.360). Post MBD survival was (median, [95% confidence interval (CI)]) 15.0 [11.0-19.0], 7.1 [1.3-12.8], 3.2 [0.0-8.3] months respectively (p=0.008). Time to 1[st] SRE was not significantly different (p=0.164). Respectively 28.8%, 39.5% and 34.2% had BM (p=0.444) of which 76.2%, 60.0% and 48.0% were diagnosed during follow up (p=0.148). Mean time to BM was 20.3 [±11.7], 10.8 [±9.3], 14.3 [±10.8] months respectively (EGFR+-KRAS+ p=0.013, EGFR+-WT p=0.176). Post BM survival was 11.0 [2.2-19.8], 6.9 [0-14.1], 12.5 [5.6-19.5] months respectively (p=0.969). Results did not change significantly when patients with only best supportive care were excluded nor when in the EGFR+ group only exon 19/21 patients were included.

      table: patient characteristics and results bone and brain metastasis
      Characteristics EGFR+ N = 73 KRAS+ N = 76 Wildtype N = 73 p-value
      Female N (%) 51 (72.6) 44 (57.9) 29 (39.7) 0.001
      Mean age, years (range) 59.6 (29.3-90.7)
      60.6 (35.1-83.3)
      		62.5 (39.6– 81.8) 0.228
      Never smoker N (%) 29 (45.3) 2 (2.7) 10 (15.2) <0.001
      WHO PS 0-2 N (%) 63 (98.4) 72 (97.3) 60 (92.3) 0.270
      Adenoca N (%) 67 (91.8) 63 (84.0) 55 (76.4) 0.209
      1[st] line no treatment 1[st] line chemo 1[st] line EGFR-TKI 3 ( 4.1) 23 (31.5) 47 (64.4) 10 (13.2) 64 (84.2) 2 ( 2.6) 14 (19.2) 54 (74.0) 5 ( 6.8) 0.069 <0.001 <0.001
      MBD N (%) Yes - at diagnosis - during follow up No 41 (56.2) -24 (58.5) -17 (41.5) 32 (43.8) 39 (51.3) -29 (74.4) -10 (25.6) 37 (48.7) 37 (50.7) - 22 (59.5) - 15 (40.5) 36 (49.3) 0.768 0.262
      SRE+ N (%) 22 (53.7) 23 (59.0) 21 (55.3) 0.887
      BM N (%) Yes -at diagnosis -during follow up No 21 (28.8) - 5 (23.8) -16 (76.2) 52 (72.2) 30 (39.5) -12 (40.0) -18 (60.0) 46 (60.5) 25 (34.2) - 13 (52.0) - 12 (48.0) 48 (65.8) 0.444 0.148

      Conclusion
      Incidence of MBD or BM was not different between EGFR+, KRAS+ and WT patients. Time from diagnosis of mNSCLC to MBD, 1[st] SRE or post-BM survival did not differ. However, survival after MBD was significantly longer in EGFR+ patients. This stresses the impact of bone management in these patients and probably warrant more intense screening for MBD. In EGFR+ patients BM remain a serious event with short survival. This should stimulate investigators to search for BM specific treatments in order to prolong survival post BM in EGFR+ patients.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P3.11-037 - A phase II study of sorafenib and metformin in patients with stage IV non-small cell lung cancer (NSCLC) with a KRAS mutation (ID 2701)

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

      • Abstract

      Background
      Previously we reported a phase II study of sorafenib, a multi tyrosine kinase inhibitor, in advanced NSCLC patients with a KRAS mutation [1]. While sorafenib was found active in this group of patients, progression free survival (PFS) and overall survival (OS) were disappointing. Concurrent inhibition of multiple pathways may improve treatment outcome. Metformin is a save and well known antidiabetic drug. It has been described that metformin has inhibitory effects against mTOR, downstream of PI3K. An in vitro study of our group has shown synergistic effects of sorafenib and metformin which provided the rationale for this study [2]. In a post hoc analysis of the previous study, metformin users appeared to be among the longest survivors.

      Methods
      Patients with advanced NSCLC with a KRAS mutation, pretreated with platinum containing chemotherapy were included. Other inclusion criteria were: ECOG performance score (PS) 0-1, adequate organ reserve, creatinine clearance >60 ml/min and provided written informed consent according to local IRB regulations. A tumor biopsy was mandatory to confirm the presence of a KRAS mutation, prior to start of treatment. Treatment consisted of sorafenib 400 mg BID and metformin 1000 mg BID until disease progression or unacceptable toxicity. Dose reductions and discontinuations were specified per protocol in the face of CTC toxicities grade 3 and 4. Primary endpoint: disease control rate (DCR) at 6 weeks according to RECIST version 1.1. Secondary endpoints: duration of response, progression free survival (PFS), overall survival and treatment related toxicities. A 2-stage design was implemented (Simon's optimal design; p0=50%, p1=70%, alpha=0.05, beta=0.20) for a total of 45 evaluable patients.

      Results
      Fifty-five patients were included between 1[st] of July 2012 and 1[st] of June 2013. Median age was 60 (range 34-77) years, 28 female (51 %), ECOG PS 0/1/2 16/32/1, all patients had stage IV disease. Of 47 patients disease evaluation after 6 weeks was available (Fig. 1). Two patients had a partial response, 23 stable disease and 22 patients had progressive disease. DCR was 53%. Results of secondary endpoints will be available at time of the conference.

      Conclusion
      This preliminary analysis suggests that the addition of metformin did not improve DCR, compared to previous reported results of sorafenib monotherapy in pretreated stage IV NSCLC patients with a KRAS mutation. [1] Dingemans AM et al. Clin Cancer Res. 2013 Feb 1;19(3):743-51 [2] Groenendijk FH et al. EJC. 2012 Nov; 48 (suppl. 6): p 48 Figure 1