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S. Burgers



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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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      P1.06-021 - Validation of DNA Hypermethylation Analysis in Sputum for the Diagnosis of Lung Cancer (ID 1774)

      09:30 - 16:30  |  Author(s): S. Burgers

      • Abstract

      Background
      Lung cancer has the highest mortality of all cancers worldwide with a 5 year survival rate of <15%. The prognosis improves dramatically when the disease is detected at an early stage, and when curative treatment is possible. Current (low dose CT) screening and diagnostic procedures are suboptimal with low specificity. Thus, novel detection methods for lung cancer as stand alone or in combination with other methods are needed. DNA hypermethylation of biomarkers in sputum have shown to distinguish lung cancer cases from cancer-free controls. The aim of the present study was to validate the usage of DNA hypermethylation of biomarkers in sputum samples of lung cancer patients and controls for lung cancer diagnosis, in comparison with sputum cytology.

      Methods
      We prospectively collected sputum of lung cancer patients and controls during 3-9 days in the Amsterdam and Nieuwegein area, The Netherlands. From this sputum bank, a learning set (n=80 lung cancer patients, n=91 controls) and validation set (n=173 lung cancer patients, n=164 controls) were randomly composed. DNA promoter hypermethylation of the following biomarkers was assessed by means of quantitative methylation specific PCR: RASSF1A, APC, cytoglobin, 3OST2, PRDM14, FAM19A4 and PHACTR3. Cut-off values for positive hypermethylation were calculated using Youden’s index. Sputum cytology analysis was performed for all sputum samples. McNemar’s test was used to compare the difference between sensitivity of hypermethylation and sputum cytology for lung cancer diagnosis. A two-sided p-value <0.05 was considered significant.

      Results
      RASSF1A was best able to distinguish cases from controls, with sensitivity of 37-41% and specificity of 91-97% in both learning and validation sets. In multivariate analysis, a panel of RASSF1A, 3OST2 and PRDM14 showed highest sensitivity of 82% [95% confidence interval (CI): 76 – 88%] with a specificity of 68% [95% CI: 61 – 74%] in the learning set, with consistent results in the validation set. Molecular analysis was superior (P<0.001) over sputum cytology (sensitivity of 15%). The sensitivity of the biomarker panel did not improve when it was combined with sputum cytology. There was no association observed between DNA hypermethylation and clinical parameters such as age, smoking status, tumor stage, and histology.

      Conclusion
      This study validates hypermethylation analysis in sputum for the diagnosis of lung cancer. RASSF1A hypermethylation showed high specificity and thereby can have an important role in lung cancer diagnosis in symptomatic patients. A panel of biomarkers RASSF1A, 3OST2 and PRDM14 showed high sensitivity, but relatively low specificity.

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    P2.05 - Poster Session 2 - Preclinical Models of Therapeutics/Imaging (ID 158)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.05-024 - Prediction of drug sensitivity in second line treatment of patients with malignant pleural mesothelioma (ID 3397)

      09:30 - 16:30  |  Author(s): S. Burgers

      • Abstract

      Background
      In second line setting there is no standard treatment for patients with mesothelioma, since all agents tested in clinical trials failed to improve survival. An individual patient however, may actually benefit from second line treatment, considering the patient population is heterogeneous. Yet, there are no predictive markers to identify those patients likely to respond to a certain drug. We developed protocols for in vitro drug sensitivity testing with several cytotoxic agents using primary tumor cells derived from pleural fluid of our patients. Recently, we implemented a personalized second line treatment protocol. Here we will report the outcome of the pilot study.

      Methods
      Cells were isolated from pleural fluid, drawn from patients with mesothelioma for symptom relief. Diagnosis of each mesothelioma patient was confirmed by regular pathological staining. Cells were plated and incubated with a five point concentration range of 5 single drugs and 2 two-drug combinations for 72 hours. Cell viability was determined by a metabolic assay. Each concentration point was measured in triplo and a biological duplo experiment was performed to check reproducibility. The drugs used in this screen were all previously tested in clinical mesothelioma trials. Patients with pleural fluid that were fit and progressed after standard first line treatment were considered for second line chemotherapy. Choice of second line treatment was based on screening results.

      Results
      Thirty-nine mesothelioma patients had pleural fluid drawn for culture of primary tumor cells and subsequent drug sensitivity screening. Drug screens were successful in 22 patients (56%). Drug sensitivity profiles were available within two weeks after isolation of tumor cells, which is appropriate for clinical decision making. Agents tested for were cisplatin or carboplatin, pemetrexed, gemcitabine, vinorelbine, oxaliplatin, a combination of cisplatin and pemetrexed and of oxaliplatin and gemcitabine. Individual dose-response curves showed different sensitivity to the various cytotoxic agents. Ten patients were chemo-naive at the time of the drug sensitivity screen. Five of them received first line chemotherapy (cisplatin and pemetrexed). Two of them had progressive disease. Both demonstrated evident resistance to cisplatin and pemetrexed in their drug sensitivity profile. Four patients received second line treatment based on the drug sensitivity profile of their primary tumor cells. To date, treatment response is evaluated for two patients. Both patients received a combination of oxaliplatin and vinorelbine. The first patient had a clinical response. For the second patient, oxaliplatin/vinorelbine was the best option, although her in vitro profile suggested a rather resistant tumor. She was progressive and showed an unusual large amount of necrosis on repeated CT imaging. Patient three and four are currently treated with oxaliplatin and gemcitabine and gemcitabine monotherapy, respectively. Their treatment responses have to be awaited.

      Conclusion
      Personalized drug screening using primary tumor cells is feasible within a clinically relevant time period and may yield new treatment combinations with better responses.

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    P2.12 - Poster Session 2 - NSCLC Early Stage (ID 205)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.12-005 - Results of radical treatment of non-small cell lung cancer patients with a single synchronous metastasis (ID 1103)

      09:30 - 16:30  |  Author(s): S. Burgers

      • Abstract

      Background
      Stage IV non-small cell lung cancer (NSCLC) patients are considered incurable and mainly treated for palliation. The purpose of this study is to investigate the overall survival (OS) and disease free survival (DFS) of NSCLC patients, diagnosed with synchronous oligometastatic disease treated with curative intent of the intrathoracic disease as well as the metastasis.

      Methods
      Patients treated between 2008 and 2013 were included in this retrospective analysis. Main inclusion criteria were: synchronous presentation of NSCLC and oligometastatic disease at diagnosis with only 1 extra-thoracic metastasis, and multidisciplinary consent on a radical treatment of both the intrathoracic disease and the solitary metastasis. Treatment of the intrathoracic disease consisted of radical radiotherapy (> 55 Gy biological effective dose) or surgical resection. Treatment of the metastasis consisted of radical/stereotactic radiotherapy or surgical resection or radiofrequency ablation (RFA).

      Results
      Twenty-two patients, 13 men and 9 women, were included. The mean age was 61 years (range 41-79) and all were in good condition (WHO 0-1). The sites of the solitary metastases were brain (13), bone (6), liver (1), soft tissue (1) and adrenal gland (1). The intrathoracic tumor stage (ignoring M-status) was IA in 2 patients, IB in 1 patient, IIA in 4 patients, IIB in 1 patient, IIIA in 8 patients and IIIB in 6 patients. Nineteen patients were treated with radiotherapy and 3 patients had a surgical intervention for the primary tumor. Eighteen patients (82%) received chemotherapy, 3 concurrently and 15 sequentially. The metastases were treated with ablative/stereotactic radiotherapy (19), surgical intervention (2) and RFA (1). The median follow-up was 47 months (95% CI 24-69). Seventeen patients developed recurrent disease of whom 12 died. Only 2 recurrence occurred within the irradiated area. Both infield recurrences were brain metastasis after a stereotactic irradiation of 15 Gy and 18 Gy. The other recurrences where mostly pulmonary (7) and brain metastases (6). The median DFS was 14 months (range 1-47, 95% CI 9 – 19) and the median OS was 32 months (95% CI 12– 52). The 1- and 2-year OS was 78.7% (95% CI 52.7-91.5) and 59.5% (95% CI 32.8-78.5), respectively. The 1- and 2-year DFS was 54.5% (95% CI 30.5-73.2) and 24.9% (95% CI 8.1-46.3), respectively.

      Conclusion
      Radical treatment of a highly selected group of NSCLC patients in good condition presenting with a single synchronous extra-thoracic metastasis resulted not only in adequate local control, but also in favorable long-term DFS and OS.

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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): S. Burgers

      • 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