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E.F. Smit



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    P1.06 - Poster Session 1 - Prognostic and Predictive Biomarkers (ID 161)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 2
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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): E.F. Smit

      • 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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      P1.06-054 - Targeting MCL1 amplification in NSCLC through anthracycline-mediated transcriptional suppression (ID 3213)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      Targeting oncogene dependency for effective therapy has been one of the most successful strategies for managing metastatic non-small cell lung cancer (NSCLC). Although validating therapeutically tractable oncogenic driver mutations are a major focus, non-driver mutations may also confer dependencies that may also be exploitable. The prosurvival BCL2 protein, MCL1 prevents mitochondrial apoptosis by blocking interaction of proapoptotic BH3 only proteins with their multidomain proapototic counterparts, BAX and BAK. MCL1 is often mutated in cancers, and ranks as one of the most frequently amplified loci at 1q21.2. MCL1 amplified tumours exhibit addiction to this oncogene. Anthracyclines have been shown to transcriptionally suppress MCL1. Phase IIA studies in NSCLC have shown that epirubicin has useful single agent activity in unselected patients, with a significantly greater response rate than that achieved with standard chemotherapy. We therefore set out to evaluate MCL1 addiction in NSCLC, its correlation with anthracyline induced apoptosis and the prevalence of 1q21.2amplification to support a planned 1q21.2 stratified phase II trial in NSCLC, (EORTC-1303-LCG).

      Methods
      RNAi targeting MCL1was conducted in NCI-H460, NCI-H1299, NCI-H28 and NCI-H23 cell lines. Doxorubicin activity was measured by viability assay and apoptosis was assessed by western blot. gDNA from cell lines was obtained by Phenol-Chloroform extraction. The QIAamp DNA FFPE Tissue Kit was used to extract gDNA from FFPE tissues. MCL1 amplification was quantified by real-time PCR with a set of two primers and one probe (minor groove-binding (MGB) hydrolysis probe assay) for the gene of interest MCL1 and the two reference genes CCT3 and H6PD. Tonsil samples were used as a control diploid population.

      Results
      MCL1 silencing efficiently induced apoptosis in a subset of NSCLC cells, however we identified two cell lines that were resistant to MCL1 knockdown (NCI-H1299 and NCI-H28). Doxorubicin efficiently induced apoptosis in MCL1 addicted cells but exhibited significantly less activity in cells that were not addicted. We developed a genomic DNA based quantitative real time PCR assay to evaluate copy number variation (CNV) at the 1q21.2 locus. A clear correlation r[2] >0.91 was observed for 1q21.2 CNV compared with reference Conan Copy Number Analysis Tool (Cancer genome project, Sanger). Increased 1q21.2 copy number was consistently associated with MCL1addiction; however addiction also occurred in cells lacking 1q21.2 CNV, suggesting that MCL1 amplification represents a subset of MCL1 dependence. The concentration of doxorubicin was titrated against MCL1 protein downregulation into therapeutically sub-micromolar concentration range and we observed that MCL1 downregulation occurred coincidently with cleavage of poly-ADP ribose polymerase. We then screened DNA isolated from 19 adenocarcinomas, and identified 1q21.2 CNVs in 36.8%, with high level amplification (CNV >5) in 1q21.2 in 10.5%.

      Conclusion
      Targeting MCL1 addiction in 1q21.2 amplified NSCLC induces apoptosis and this dependence can be exploited by anthracyclines at therapeutically relevant concentrations. Given its significant prevalence in NSCLC, our data suggests that 1q21.2 amplification could be a novel non-driver mutation predictive for anthracycline response.

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    P1.17 - Poster Session 1 - Bronchoscopy, Endoscopy (ID 182)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pulmonology + Endoscopy/Pulmonary
    • Presentations: 1
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      P1.17-008 - Results of a close surveillance strategy for subjects with pre-invasive endobronchial squamous lesions (ID 2678)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      The dismal overall 5-year survival of non-small cell lung cancer (NSCLC) patients is mainly due to advanced stage of disease at time of initial diagnosis in most and the inability to cure metastatic disease in all patients. In contrast, the prognoses of in situ mucosal and small parenchymal lesions are excellent. Early detection strategies might result in the identification of early-stage, (pre-)invasive lesions that are still eligible for curative treatment. The present study was set out to characterize the risk of lung cancer development in a cohort of high-risk subjects harboring pre-invasive endobronchial lesions and to assess the results of surveillance using autofluorescence bronchoscopy (AFB) and computed tomography (CT) scan.

      Methods
      Between November 1995 and December 2012, one hundred and sixty-four at risk individuals with pre-invasive endobronchial lesions were monitored by repeated AFB and CT. During the course of surveillance, progression of lesions to cancer (in situ), recurrences and second primary cancers were treated with different modalities (e.g. endobronchial techniques, surgery, radiotherapy), depending on tumor stage and location. Log-rank tests were performed to examine the relation between baseline characteristics and progression-free and overall survival (PFS and OS, respectively). Cox regression was used for multivariate survival analysis.

      Results
      Demographical and clinical variables of the cohort are shown (Table). At inclusion, 80 individuals were identified with one or more high-grade pre-invasive lesions (severe dysplasia or CIS; HGD), whereas 84 subjects were identified solely with lower grade pre-invasive lesions (LGD). During close surveillance (median follow-up (FU) of 30 months, range 4-152), sixty-one lung cancers were detected (26 CT-detected, 35 AFB-detected cancers) in 55 individuals within a median time to event of 16.5 months. Mean PFS was similar between individuals with radiographically occult lesions vs. FU after surgery for early-stage NSCLC/ENT ca (122.3 vs. 126.9 months, p=0.237) and COPD vs. non-COPD (118.8 vs. 136.8 months, p=0.162). There was a relatively large difference in PFS between LGD and HGD groups (142.6 vs. 93.7 months, p=0.057). Independent risk determinants for OS were indication for surveillance (FU after surgery for early-stage NSCLC/ENT ca vs. radiographically occult lesions, p=0.008) and COPD-status (COPD vs. non-COPD, p<0.001).

      Referral for radiographically occult lesion Follow-up after surgery for early-stage NSCLC / ENT ca
      total
      individuals, n 164 92 72
      Gender
      male 134 72 62
      female 30 20 10
      Age at baseline
      years, mean (range) 64.2 (42-83) 64.8 (42-81) 64.0 (43-82)
      Smoking status
      current smoker 75 44 31
      former smoker 74 36 38
      unknown 15 12 3
      Smoking history
      Pack-years, mean (range) 45 (4-137) 45 (4-120) 40 (15-137)
      COPD-status
      COPD 100 56 44
      non-COPD 45 22 23
      unknown 19 14 5
      AF Bronchoscopies
      Number, mean (range) 7 (1-27) 5 (2-27) 6 (1-18)
      CT-scans
      Number, mean (range) 3 (0-20) 2 (0-20) 3 (0-18)
      No. of detected lung cancers
      During surveillance period 61 29 32
      Parenchymal cancer 21 12 9
      Site-specific lesion progression 24 13 11
      Interval cancer 10 4 6
      Recurrences previous primaries 6 0 6
      Patient outcome
      alive 80 56 24
      died of lung cancer 33 13 20
      died of other/unknown cause 51 23 28

      Conclusion
      Our findings demonstrate that individuals with pre-invasive endobronchial lesions are at high risk of developing (second primary) lung cancers. Combined surveillance using AFB in addition to CT screening facilitated early detection and early (endobronchial) intervention in most patients. Future clinical trials are warranted to determine whether the current approach improves patient outcome.

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    P2.04 - Poster Session 2 - Tumor Immunology (ID 154)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.04-001 - Myeloid derived suppressor cells (MDSC) are increased in patients with advanced non-squamous lung cancer (aNSQ) compared to healthy controls and early stage non-squamous lung cancer (eNSQ) and are related to the WHO performance status. Subanalysis of the NVALT12 study (ID 1802)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      Background: recent evidence shows a role for immunotherapy via checkpoint antibodies in a subgroup of patients with non-small cell lung cancer (NSCLC). We have recently published the complex interplay between tumors and the immune system[1]. The modulating effect of the tumor on the immune system, mainly immunosuppressive, is challenging. MDSC are described to play a major role in this tumor associated immune suppression by inhibiting cytotoxic Tcell function. The aim of the present study is to relate the number of MDSC to two well-known prognostic factors in NSCLC: stage of the disease and WHO performance status.

      Methods
      Methods: MDSC were determined in peripheral blood mononucleair cell fractions of 195 treatment-naive NSCLC patients (185 stage IV (aNSQ), 10 stage I-III(eNSQ), and 20 healthy controls (HC)). WHO performance status was determined by experienced investigators prior to the start of treatment. In this abstract the relation between clinical data and polynucleair MDSC are presented. Flowcytometric analysis was performed within 5 hours after the blood was drawn. MDSC were characterized as CD16low,CD11b+,CD14-,HLA-DR-,CD15+, and CD33+.

      Results
      Results: A large variation in the number of MDSC was observed in patients with NSCLC, also in the same stage of the disease and WHO performance status. In a subgroup of patients with eNSQ high MDSC levels were found, but also in patients with aNSQ low levels of MDSC were found. For the group as a whole, however, an increased number of MDSC was found in patients with aNSQ compared to HC and eNSQ (p<.001, in both comparisons). Comparison of the limited number of patients with of eNSQ and HC no statistical difference was found but there is a tendency for an increase in the number of MDSC per stage of NSCLC. The number of MDSC increased with worse WHO performance status ( p=0.05 between 0 and 2). Whether the number of MDSC has prognostic or predictive value to response to chemotherapy in all patients is subject of current research. Follow up data in all patients with response to chemotherapy, progression free survival and overall survival are at present collected.

      Conclusion
      Conclusion: Peripheral blood MDSC levels are increased in patients with aNSQ compared to eNSQ and HC. MDSC are increased in patients with worse WHO performance status. The number of MDSC shows large variation between patients with similar stage of the disease, showing the complex interplay between tumor and immune system. 1 Aerts JG, Hegmans JP, Cancer Research 2013

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    P2.18 - Poster Session 2 - Pathology (ID 176)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 1
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      P2.18-022 - <strong>Do <i>EGFR</i>- and <i>KRAS</i>-mutations occur in squamous cell lung carcinomas?</strong> (ID 3398)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      Adenocarcinoma (ADC) of the lungs may harbor EGFR- and KRAS-mutations, which are relevant for treatment decisions. Approximately 35% of non-small cell lung cancer (NSCLC) biopsies are diagnosed as not-otherwise-specified (NOS).To improve segregation between ADC and squamous cell carcinoma (SqCC), the classification of lung cancer was updated in 2011, adding immunohistochemistry (IHC) for p63 and TTF-1 to the diagnostic algorithm. The aim of our study was to investigate the hypothesis, that additional IHC reliably delineates lung cancer harboring EGFR- and KRAS-mutations.

      Methods
      From an institutional lung cancer database of specimens routinely analyzed for the presence of EGFR- or KRAS-mutations (n=816), cases harboring a mutation were selected (n=343) and corresponding original histological diagnoses and IHC for TTF-1, p63 and PAS-D were collected. Cases with a pattern compatible with SqCC were histologically reassessed.

      Results
      From the 343 cases 25% were resection specimen, 70% biopsy and 5% cytology specimens. 69% of cases had a KRAS-mutation and 31% an EGFR-mutation. IHC-data were conclusive in 89%. The combination of positive TTF-1 and/or mucin stain and a negative p63 stain, favoring ADC, was found in 264 cases (77%). Six (1.7%) specimens were positive for p63 only, favoring SqCC.

      Conclusion
      The current 2011 classification of lung tumors, based on histology and immunohistochemistry for TTF-1, p63 and mucin, segregates specimens of ADC and SqCC sufficiently well. Our study results support the use of IHC in the diagnosis of lung cancer.

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    P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.20-004 - DNA copy number aberrations in endobronchial lesions: a validated predictor for cancer (ID 1166)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      Individuals who present with squamous metaplastic and dysplastic lesions are considered at high risk of lung cancer. However, these lesions behave erratically and only a minority progresses towards lung cancer. Therefore, biomarkers need to be discovered that can aid in assessing an individual’s risk for subsequent cancer. We recently identified a DNA copy number aberration (CNA)-classifier, including changes at 3p26.3-p11.1, 3q26.2-29, and 6p25.3-24.3, as a risk predictor for cancer in individuals presenting with endobronchial squamous metaplasia (van Boerdonk et al, AJRCCM, 2011). The current study was set out to validate this classifier in an independent series of endobronchial squamous metaplastic and dysplastic lesions.

      Methods
      DNA copy number profiles (i.e., chromosomal gains and losses) were determined in a set of endobronchial lesions (8 squamous metaplasia (SqM), and 28 dysplasias (Dys) of various grades), identified and biopsied during autofluorescence bronchoscopy, of 36 high-risk subjects using a nested case-control design. Of the 36 patients, 12 cases had a carcinoma in situ or invasive carcinoma at the same site at follow-up (median 11 months, range 4-24), while 24 controls remained cancer-free (median 78 months, range 21-142). DNA copy number profiles were related to lesion outcome. The prediction accuracy of the predefined CNA-based classifier to predict endobronchial carcinoma (in situ) in this series was determined.

      Results
      All SqM and Dys lesions of controls showed no or a relatively low number of CNAs (i.e., quiescent profile with on average 0.2% altered probe features, range 0.0 – 2.4%), while the majority of lesions of cases showed multiple CNAs (i.e. highly aberrant profile with on average 38.8% altered probe features, range 0.0 – 76.7%). The previously defined CNA-classifier demonstrated 92% accuracy for cancer (in situ) prediction in the current series. All nine subjects with CNA-classifier-positive endobronchial lesions at baseline had cancer as final outcome (i.e., a positive predictive value of 100%). The negative predictive value of the classifier was 89%, i.e., all 24 controls and 3 cases were classified as being low-risk.

      Conclusion
      CNAs are a highly accurate biomarker for assessing the progression risk of endobronchial squamous metaplastic and dysplastic lesions. This classifier could assist in selecting subjects with endobronchial lesions who might benefit from more aggressive therapeutic interventions.

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    P3.06 - Poster Session 3 - Prognostic and Predictive Biomarkers (ID 178)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.06-024 - Retrospective analysis of rebiopsies in a cohort of EGFR-mutated NSCLC-patients with TKI-resistance; incidence of the T790M mutation. (ID 2162)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      Epidermal Growth Factor Receptor mutated (EGFR+) NSCLC patients have a median progression free survival (PFS) of approximately 12 months when treated with EGFR-tyrosine kinase inhibitors (TKI). One of the resistance mechanisms described is the T790M mutation. This mutation is reported in 49-65% of patients who are rebiopsied at disease progression. Here, we report on the incidence of T790M mutation in a cohort of patients who were sequentially rebiopsied.

      Methods
      EGFR+ patients or with TKI-response>24weeks and progressive disease on TKI’s were retrospectively analysed. Patients should have had at least 2 separate biopsies. All biopsies and treatments were collected from the medical record and pathological reports. Survival was calculated according to Kaplan-Meier. Overall survival (OS) was calculated from date of 1[st] diagnosis until death or June 2013, which ever was first

      Results
      68 patients with 2 biopsies or more were available for analysis. In the first biopsy at TKI-resistance; T790M mutation was detected in 34 patients (50,0%). 26/68 patients had later biopsies available; showing gain and loss of T790M in later biopsies (figure 1). Overall development of T790M was 57.4% (39/68). 7 patients had >3 biopsies available (figure 2). Patients developing T790M had numerically longer median OS of 3.8 years (range 2.8 – 4.9) as compared to median OS in T790M-patients (2.5 years, range 1.0 – 3.9) (P = 0.204).Figure 1Figure 2

      Conclusion
      57.4% of patients developed T790M. OS in patients developing T790M was longer than in patients not developing T790M, however the difference was not significant. Sequential data show that some patients ‘loose’ the T790M later on in the course of the disease. Data from this cohort suggests that T790M development is a dynamic process.

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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.F. Smit

      • 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

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    P3.21 - Poster Session 3 - Diagnosis and Staging (ID 171)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.21-007 - <em>EGFR</em> mutation analysis in sputum of lung cancer patients: a multicenter multitechnique study (ID 1782)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      Mutations in the epidermal growth factor receptor (EGFR) gene have been identified in lung adenocarcinomas and are associated with a high response to EGFR tyrosine kinase inhibitors. EGFR mutations can be detected in tumour tissue, cytology specimens and blood from lung cancer patients. Thus far, EGFR mutation analysis has not been systematically demonstrated for sputum samples. The aim of the present study was to determine whether EGFR mutation analysis is feasible on sputum samples, employing different assays in a multicenter study.

      Methods
      Sputum samples were collected from 10 lung cancer patients with confirmed EGFR mutation in their tumour tissue, 10 lung cancer patients without evidence of an EGFR mutation, and 10 patients with chronic obstructive pulmonary disease (COPD). DNA was isolated from the sputum and used for mutation analysis by Cycleave PCR, COLD-PCR, PangaeaBiotech SL technology (PST), and High Resolution Melting, respectively. Targeted resequencing (TruSeq Amplicon Cancer Panel) and droplet digital PCR were additionally performed on the 10 samples with EGFR mutation.

      Results
      Dependent on the assay, EGFR mutations could be detected in 30-50% of the sputum samples of patients with EGFR mutations (Table). The different techniques revealed consistent results, with slightly higher sensitivity for PST. Neither the lung cancer patients without EGFR mutation nor the COPD controls tested positive for EGFR mutations in their sputum samples, indicating high clinical specificity of all assays.

      Subject Gender Age (years) Tumour stage EGFR mutation status of tumour tissue[1] EGFR mutation analysis on sputum specimens[2]
      Cycleave PCR COLD-PCR PST[3] HRM-sequencing Cytology[4]
      A F 72 IV Del E746-A750 0 0 0 0 0
      B M 66 I Del E746-A750 0 2 0 0 0
      C[6] F 78 IV Del E746-A750 1 1 1 1 2
      D F 46 III Del E746-A750 0 0 1 0 0
      E[6] M 54 IV Del E746-A750 1 1 1 1 0
      F F 49 III Del E746-A750 & c.2369C>T [p.T790M] 0 0 0 0 0
      G F 54 IV Del E746-A750 & c.2369C>T [p.T790M] 0 0 1[5] 0 1
      H F 73 IV c.2753T>G [p.L858R] 0 0 0 0 0
      I F 61 IV c.2753T>G [p.L858R] 0 0 0 0 0
      J[6] M 60 IV Del E746-A750 1 1 1 1 2
      [1 ]del E746-A750= deletion exon 19 [2] mutation identified: 0=no, 1=yes, 2=dubious [3] exclusively del19 and L858R were assessed [4] tumour cells: 0=no, 1=yes, 2=in related sample of same patient [5 ]only del19 detected [6 ]TSACP and ddPCR both tested EGFR mutation (del19) positive.

      Conclusion
      EGFR mutations can be detected in sputum samples from patients with EGFR-mutated non-small cell lung cancer, which may replace biopsy procedure for some patients.

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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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      P3.24-029 - Progression of radiation induced esophageal stenosis in a non-small cell lung cancer (NSCLC) patient treated with sorafenib (ID 1882)

      09:30 - 16:30  |  Author(s): E.F. Smit

      • Abstract

      Background
      Sorafenib is an orally available multikinase inhibitor with antiproliferative and anti-angiogenic activity. Reported oral adverse events of any grade are stomatitis/mucositis (11-38%, mostly ≤ CTC-AE grade 2), oral mucosal pain and dysphagia in the absence of clinical lesions. Sorafenib is under investigation in NSCLC. We report a patient who developed symptomatic progression of an esophageal stenosis during sorafenib treatment.

      Methods
      not appicable

      Results
      Case: A 67-year old male presented at the outpatient clinic with dysphagia CTC-AE grade 3. He was diagnosed with a cT3N3M1a (oligometastatic adenocarcinoma, KRAS mutated) NSCLC in January 2011 for which he was treated with concurrent chemoradiotherapy. Treatment was complicated with grade 3 radiation esophagitis (confirmed with duodenogastroscopy) for which he was treated with a feeding tube and proton pump inhibition. Because of remaining grade 1 dysphagia, duodenogastroscopies were performed in August 2011 and February 2012. A stable relative stenosis of the upper esophagus was found, easy to pass with the duodenogastroscope. Because of progressive disease he was subsequently treated with erlotinib/ pemetrexed (September 2011, study) and docetaxel monotherapy (August 2012). February 2013 he progressed again with subsequent participation in a phase II study with sorafenib 400 mg BID and metformin 1000 mg BID. Within three weeks he developed dysphagia for solid foods. A chest computed tomography showed no external compression of the esophagus and no tumor progression. Duodenogastroscopy revealed a stenosis with ulceration in the upper part of the esophagus, passing the stenosis was only possible with a baby-duodenogastroscope. Because of swallowing problems, sorafenib was temporarily stopped and placement of a percutaneous feeding tube was planned. However, two days after stopping sorafenib, his dysphagia completely resolved and food passage was normal. So, ten days later sorafenib was restarted with dose reduction (200 mg BID). After restarting sorafenib his dysphagia returned with grade 3 within six weeks. Again, sorafenib was temporarily stopped and in a couple of days his dysphagia resolved. After another restart of sorafenib at the latter dose he again developed dysphagia, but this time manageable.

      Conclusion
      We present a patient who developed a grade 3 stenosis of the esophagus during treatment with sorafenib which clinically resolved shortly after stopping sorafenib but reoccurred after rechallenge with sorafenib at a lower dose. Dysphagia resolved again after stopping the sorafenib with again complaints after restarting. No other explanation was found (e.g. progression of malignancy, external compression). 1.5 year before, after concurrent chemoradiotherapy, he was diagnosed with a relative stenosis of the upper esophagus, but this remained stable until sorafenib treatment was started. He scored 8/13 points on the Naranjo score, making sorafenib a probable cause of the stenosis. The underlying mechanism is unknown. A possible explanation is sorafenib inhibition of the VEGF and MAP-kinase pathway. These pathways are both involved in the process of mucosal defense and repair, and it could be that blocking this pathway combined with sensitization by previous irradiation caused progression of the stenosis. This case stresses the importance of being aware of unusual side effects of medication and taking into account possible interactions with previous treatments.