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Y. Yatabe



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    MS21 - Practical Problems in Lung Cancer Diagnosis - Application of the 2011 Adenocarcinoma Classification (ID 38)

    • Event: WCLC 2013
    • Type: Mini Symposia
    • Track: Pathology
    • Presentations: 1
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      MS21.4 - AIS and the Well Differentiated Spectrum (ID 559)

      14:00 - 15:30  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Abstract
      According to the recent trend of increased frequency of CT screening for lung cancer, earlier stage of lung cancer is being detected and removed surgically. In applying the new classification to such lesions, it always becomes problematic to make a differential diagnosis among the three categories: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) and lepidic predominant adenocarcinoma. AIS is defined by a pure lepidic growth pattern with a continuous growth of neoplastic cells along the alveolar septa without disruption of the alveolar structures. MIA is defined as an adenocarcinoma with predominant lepidic growth with less than or equal to 0.5 cm area of sromal invasion. The definitions are summarized in Table. When the invasive area is more than 0.5 cm and lepidic growth is predominant, the tumor is diagnosed as lepidic predominant adenocarcinoma. The distinction is clinically important because AIS and MIA have been shown to have 100%5 year recurrence free-survival, whereas lepidic predominant adenocarcinoma can recur. However, the major difficulty for the differential diagnosis has in roots in the identification of stromal invasion and measurement of the invasive area. Histological stromal invasion is determined by tumor cell and stromal factors. Because the area where the tumor cells show invasive structure is regarded as an invasive area, it is important to recognize the differentiation of lepidic pattern from papillary or acinic pattern. However, the distinction is often difficult in practice. In terms of the stromal factor, it is also difficult to differentiate an invasive scar (myofibroblastic stroma) from a scar due to collapse. Physicians should know this room for discussion, and practical solutions should be shared with pathologists. Figure 1

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    O04 - Molecular Pathology I (ID 126)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Pathology
    • Presentations: 2
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      O04.01 - Identification of CD74-NRG1, a new recurrent fusion gene in invasive mucinous lung adenocarcinomas of never smokers (ID 4022)

      10:30 - 12:00  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Background
      Lung adenocarcinoma (AD) of patients who have never smoked frequently bear targetable genome kinase alterations, such as EGFR mutations and translocations affecting ALK, ROS1, and RET genes. These mutations correlate with kinase inhibitor sensitivity in mouse models or in patients. Unfortunately, therapeutically relevant kinase alterations are not present in all lung cancer specimens. Thus, additional genome alterations need to be discovered in order to provide a therapeutic opportunity for the remaining patients.

      Methods
      We collected a cohort of 25 AD specimens of never smokers lacking mutations in KRAS or EGFR, in which we performed transcriptome sequencing with the aim of identifying new oncogenic driver genes.

      Results
      We were able to identify known kinase fusions affecting ALK, ROS1 and RET genes in 3 cases each. Moreover, we detected one sample carrying a novel chimeric transcript fusing the first six exons of CD74 to the EGF-like domain of the NRG1 III-β3 isoform, leading to the expression of its EGF-like domain in an otherwise NRG1-negative tumor tissue. The fusion gene was further detected in four additional cases out of 94 pan-negative* ADs of never smokers. In total, all 5 cases were identified in stage I invasive mucinous lung adenocarcinomas (IMA) of never smoker females. This tumor type frequently presents with multifocal unresectable disease, for which no effective treatment has been yet established. IMA is highly associated with KRAS mutations; indeed, out of 15 IMA analysed, 6 carried a KRAS mutation (40%), and 4 the CD74-NRG1 fusion (27%). Given the fact that NRG1 signals through ERBB3 and ERBB4 receptors, we aimed to determine which receptor CD74-NRG1 provides the ligand for. We observed that ERBB4 was not expressed in the index case, while ERBB3 was relatively highly expressed and this expression also correlated with a positive phospho-ERBB3 (p-ERBB3) signal in the tumoral tissue of all 5 CD74-NRG1 positive cases. In order to test if this phosphorylation of ERBB3 was statistically significant, we stained a cohort of 241 ADs and found that p-ERBB3 was only positive in 6 of them (p-value<0.0001). Additionally, although both EGFR and ERBB2 were expressed in the index case, only ERBB2 expression correlated with a p-ERBB2 positive signal. These data suggest that CD74-NRG1 might provide the ligand for ERBB3, which may form heterodimers with ERBB2, since ERBB3 is devoid of intrinsic kinase activity and cannot support linear signaling in isolation. This is in line with previous studies showing that NRG1 induces an oncogenic signal through ERBB2-ERBB3 heterodimers engaging the PI3K-AKT pathway. This was further supported by the activation of the PI3K-AKT, but not the MAPK pathway, in CD74-NRG1 transduced H2052 lung cells, after 24h starvation. *pan-negative: EGFR, KRAS, ALK, HER2, BRAF, ROS1 and RET wild-type

      Conclusion
      Altogether, these data shows that CD74-NRG1 is a new recurrent oncogenic fusion gene, highly associated with IMA of never smokers. It also suggests that CD74-NRG1 fusion protein signals through the ERBB2-ERBB3 receptors complex leading to the activation of the PI3K-AKT pathway, providing a therapeutic opportunity for a tumor type with, so far, no effective treatment.

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      O04.06 - An international standardization study using the ALK IHC antibody D5F3 and a sensitive detection kit demonstrates high concordance between ALK IHC and ALK FISH and between evaluators (ID 2875)

      10:30 - 12:00  |  Author(s): Y. Yatabe

      • Abstract
      • Presentation
      • Slides

      Background
      The goal of personalized medicine is treating patients with a therapy predicted to be efficacious based on the molecular characteristics of the tumor, thereby sparing the patient futile or detrimental therapy. Anaplastic lymphoma kinase (ALK) inhibitors are effective against ALK positive non-small cell lung cancer (NSCLC) tumors, but to date the only US Food and Drug Administration approved companion diagnostic is a break-apart fluorescence in situ hybridization (FISH) assay. Immunohistochemistry (IHC) is a clinically applicable cost-effective test that is sensitive and specific for ALK protein expression. The purpose of this study was to assemble an international team of expert pathologists to evaluate and standardize the interpretation of a new automated standardized ALK IHC assay.

      Methods
      Archival NSCLC tumor specimens (n=103) previously tested for ALK rearrangement by FISH were provided by the international collaborators. These specimens were stained by IHC with the anti-ALK (D5F3) primary antibody (Ventana Medical Systems, Inc) combined with OptiView DAB IHC detection and OptiView amplification (Ventana Medical Systems, Inc). The evaluators went through an interpretation training session and scored the specimens as positive, if strong granular cytoplasmic brown staining was present in tumor cells, or negative. IHC results were compared to the FISH results and inter-evaluator agreement comparisons made.

      Results
      Overall for the 100 evaluable cases the ALK IHC assay was highly sensitive (90%), specific (95%) and accurate (93%) relative to the ALK FISH results. Similar results were observed using a majority score. For the discrepant cases IHC negativity was scored by 7/7 on 3 FISH positive cases and 6/7 evaluators on 2 additional FISH positive cases. IHC positivity was scored on 2 FISH negative cases by 7/7 readers. There was agreement among 7/7 and 6/7 readers on 88% and 96%% of the cases before a consensus review, respectively, and following a review there was agreement among 7/7 and 6/7 on 95% and 97% of the cases, respectively.

      Conclusion
      Based on expert evaluation the ALK IHC assay using the D5F3 antibody combined with Optiview Detction and Optiview amplification is sensitive, specific and accurate, relative to FISH, and a majority score of multiple readers does not improve these results over an individual reader’s score. Excellent inter-reader agreement was observed for the IHC assay. These data support the algorithmic use of ALK IHC as a screening procedure for ALK protein expression in NSCLC.

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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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      P1.06-004 - ROS1 Immunohistochemistry Among Major Genotypes of Non-Small Cell Lung Carcinoma (ID 739)

      09:30 - 16:30  |  Author(s): Y. Yatabe

      • Abstract

      Background
      ROS1 (c-ros oncogene 1) is a receptor tyrosine kinase that can become constitutively active and drive cellular proliferation in a variety of cancers. Approximately 1-2% of patients with non-small cell lung cancer (NSCLC) harbor activating ROS1 gene fusions and these patients may benefit from ROS1-targeted inhibitor therapy.

      Methods
      Immunohistochemistry for ROS1 expression was performed on 33 NSCLC specimens previously characterized for the presence of genetic abnormalities. These specimens were selected for ROS1 gene rearrangements (6 specimens) detected by RT-PCR and FISH, ALK gene rearrangements (5 specimens), EGFR mutations (5 specimens), KRAS mutations (5 specimens), HER2 mutations (3 specimens), RET gene rearrangements (3 specimens), and pan-negative (6 specimens). Immunohistochemistry was performed in a CLIA-certified laboratory with manual application of the ROS1 DFD6 antibody (Cell Signaling Technology, Inc) for 1 hour. ROS1 protein expression was evaluated by a pathologist with a hybrid (H)-score scale of 0 (no expression in any tumor cells) to 300 (intense expression in all tumor cells). ROS1 over-expression was defined as an H-score greater than 100.

      Results
      ROS1 protein over-expression was detected by immunohistochemistry in all 6 of the NSCLC specimens with ROS1 gene fusions detected by RT-PCR (example in figure below). None of the remaining 27 lung cancer specimens with ALK gene rearrangements, EGFR mutations, KRAS mutations, HER2 mutations, RET gene rearrangements, or pan-negative exhibited ROS1 protein over-expression. Figure 1

      Conclusion
      Detection of ROS1 over-expression by immunohistochemistry exhibited 100% concordance with results of ROS1 gene rearrangement for 33 NSCLC specimens and did not overlap with any of the other genetic alterations. Six specimens were positive for ROS1 gene rearrangement by both RT-PCR and immunohistochemistry. Tumors positive for genetic alterations associated with the ALK, EGFR, KRAS, HER2, and RET genes were all negative for ROS1 gene rearrangement and ROS1 immunohistochemistry. ROS1 immunohistochemistry is a sensitive, specific and cost-effective method for identification of a subset of patients with lung cancer that may benefit from ROS-1 targeted-therapy.

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    P1.07 - Poster Session 1 - Surgery (ID 184)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Surgery
    • Presentations: 1
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      P1.07-021 - The risk factor of late recurrence in patients with completely resected non-small cell lung cancer (ID 1542)

      09:30 - 16:30  |  Author(s): Y. Yatabe

      • Abstract

      Background
      Recurrences in patients with completely resected non-small cell lung cancer (NSCLC) rarely occur more than 5 years after operation. Various follow-up programs for postoperative patients are recommended in each guideline. The purpose of this study is to clarify the risk factor of late recurrence and to determine which patients might benefit from routine computed tomography (CT) follow-up more than 5 years after operation.

      Methods
      Between January 1995 and December 2006, 1,437 consecutive patients with NSCLC underwent pulmonary resections at our institution. Of these, 617 patients remained recurrence-free for 5 years after resection. We retrospectively analyzed the clinicopathological features of these patients. Disease free survival (DFS) was defined as endpoint and was analyzed using Cox proportional hazards model. Variables for univariate analysis were as follows: age, gender, smoking history, carcinoembryonic antigen, operative procedure, pathological type, pathological stage, and pleural lavage cytology (PLC).

      Results
      At the median follow-up time of 7.5 years, 20 patients (3.2%) developed late recurrence more than 5 years after resection. Distant metastasis occurred in 15 patients and locoregional recurrence occurred in 5 patients (Table 1). There were 3 patients (15%) with positive PLC in late recurrence group and 7 patients (1.2%) in recurrence free group. In univariate analysis, only PLC was significant. In a multivariate analysis, PLC was a significant predictor of late recurrence. The Hazard ratio (HR) for positive PLC in comparison to negative PLC was 5.75 (95% CI 1.16–19.26; p=0.04)Figure 1.

      Conclusion
      PLC is a strong independent factor for late recurrence. Patients with positive PLC might be good candidates for routine chest CT more than 5 years after resection.

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    P1.21 - Poster Session 1 - Diagnosis and Staging (ID 169)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P1.21-002 - A survey of EGFR mutation frequency and testing practices in Asia Pacific (ID 1213)

      09:30 - 16:30  |  Author(s): Y. Yatabe

      • Abstract

      Background
      The efficacy of EGFR TKIs in EGFR mutation-positive NSCLC patients has led to a need for accurate, timely EGFR mutation testing worldwide. Although EGFR mutation testing has been adopted by many laboratories in Asia, accurate data are lacking on the proportion of NSCLC patients tested in each country, and the most commonly used testing methods. The objectives are to investigate the practice of EGFR mutation analysis in Asian Pacific countries and document the prevalence of routine testing in this population.

      Methods
      This is a retrospective database survey of records from NSCLC patients tested for EGFR mutations from 1 January 2011 to 1 January 2012 at participating sites across the Asia Pacific region. The majority of eligible hospitals/laboratories that participated had performed ≥ 100 EGFR mutation tests during that period. Accessible patient records were used to complete an online questionnaire, with data being stored in a central database. Primary objectives were to determine the number of NSCLC patients tested for EGFR mutations and the rate of EGFR mutation positivity: overall, by histological subtype, and by demography. Other variables included the number of NSCLC cases diagnosed, EGFR mutation testing methods used, and tumour sample characteristics and processing. The proportion of EGFR mutation-positive patients and 95% CI were calculated; other variables will be summarized descriptively. An interim analysis has been conducted using data collected from more than 18,000 newly diagnosed NSCLC patients at 29 sites.

      Results
      The data from surveyed sites indicates that the overall proportion of NSCLC patients tested for EGFR mutations was 31.9% (95% CI 31.2-32.6%), with an EGFR mutation positivity rate of 40.2% (95% CI 39.1-41.4%) overall, ranging from 28.7% to 53.4% (Table). Additional data on demographic and histological subgroups and current testing practices (methods, sample types, sample preparation) will be presented. [*: Wilson score confidence interval. **: Note that the sites from Vietnam (one site) and Philippines (one site) did not test ≥ 100 patients. N.D.: No data.]

      Table: Proportion of Patients Tested and EGFR Mutation Rates at Participating Sites
      Country Total number of newly diagnosed NSCLC patients Proportion of patients tested, % (95% CI*) EGFR mutation positivity, % (95% CI*)
      Total 18,050 31.9 (31.2-32.6) 40.2 (39.1-41.4)
      Japan 2,379 64.8 (62.9-66.7) 30.2 (28.0-32.6)
      China 12,086 18.3 (17.6-19.0) 38.1 (36.3-39.9)
      Taiwan 2,530 52.9 (50.9-54.8) 53.4 (50.7-56.0)
      Hong Kong 399 31.1 (26.7-35.8) 49.2 (40.6-57.9)
      Malaysia 357 98.6 (96.8-99.4) 45.7 (40.6-51.0)
      Thailand 249 57.8 (51.6-63.8) 45.1 (40.6-49.8)
      Vietnam** 50 100.0 (92.9-100.0) 36.0 (24.1-49.9)
      Philippines** N.D. Not Known 38.9 (29.5-49.2)
      Indonesia N.D. Not Known 28.7 (20.8-38.2)

      Conclusion
      The data collected in this survey indicate that, in 2011, testing practices varied widely across the region, despite the well-known high incidence of the mutation. The data provide an insight into these practices and provide a reference platform on which to compare and build on for the future of EGFR mutation testing and molecular diagnosis of NSCLC in Asia Pacific.

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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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      P2.05-010 - Several receptor tyrosine kinase is activated but orchestrated by EGFR in EGFR-TKI acquired resistant lung adenocarcinoma cells with EGFR mutation (ID 1387)

      09:30 - 16:30  |  Author(s): Y. Yatabe

      • Abstract

      Background
      Lung adenocarcinomas with EGFR mutation initially show good responses to EGFR- tyrosine kinase inhibitors (TKIs). However, emergence of acquired resistance is almost inevitable. To analyze molecular mechanisms underlying acquired resistance, we established a cell line from a patient who acquired resistance to gefitinib/erlotinib.

      Methods
      A 64-year-old woman underwent a pulmonary resection for lung adenocarcinoma in February 2009 (pT2aN0M0, EGFR L858R mutation). In April 2010, pulmonary metastases, mediastinal lymph node metastases, and right pleural effusion were identified. Gefitinib was started and this led to a complete response. However, despite continuous treatment with gefitinib, pleural effusion and serum carcinoembryonic antigen (CEA) levels gradually increased. In December 2010, gefitinib was switched to erlotinib but the serum CEA level continued to increase, and erlotinib was stopped on March, 2011. Even though she received no treatment after erlotinib withdrawal, interestingly, the serum CEA level was decreased significantly (from 89.5ng/ml on March 2011 to 19.2ng/ml on April 2011), and erlotinib was re-started on April 2011. The serum CEA level increased after re-administration of erlotinib (55.7ng/ml on May 2011). Therefore the regimen was switched to cisplatin/pemetrexed and she responded to this combination chemotherapy (CEA 9.1ng/ml on July 2011). This clinical experience may be an actual case of “drug addiction phenomenon” that we and others have observed in preclinical acquired resistance models (Suda K, et al. Lung Cancer 2012; Das Thakur M, et al. Nature 2013). We established a cell line from her pleural effusion obtained on March 2011 in drug-free condition (designated as ACC-GR1 cells). We analyzed this cell line to evaluate the efficacy of erlotinib and dacomitinib, an irreversible EGFR-TKI. In addition, we examined phosphorylation status of 42 receptor tyrosine kinase (RTK) of ACC-GR1 cells using Human Phospho-RTK Array Kit (R&D Systems) with/without erlotinib or dacomitinib. We also examined PC9 lung adenocarcinoma cell line for phosphorylation status of RTKs with/without erlotinib.

      Results
      ACC-GR1 cells harbored the T790M mutation, in addition to the original L858R mutation in the EGFR gene. ACC-GR1 cells do not have amplification of MET proto-oncogene. IC~50~ values for erlotinib and dacomitinib were 2.9 uM and 0.05 uM, respectively. Phospho-RTK array analysis revealed marked activation of EGFR and MET, in addition, activation of ERBB2, ERBB3, RET, and AXL in a culture condition without EGFR-TKI. Treatment with 1 uM of erlotinib led to mild inhibition of EGFR and MET phosphorylation (71% and 58%, respectively, compared with control), and phosphorylation of other RTKs fell below detectable limits. Treatment with 1 uM of dacomitinib led to further inhibition of EGFR phosphorylation (35% compared with control). In PC9 cells, phosphorylation of EGFR and MET were also observed in drug-free condition, and remarkably inhibited by 1 uM erlotinib treatment (10% and 64%, respectively, compared with control).

      Conclusion
      A cell line model established from pleural effusion of a patient who acquired resistance to gefitinib/erlotinib harbored T790M mutation and responded to dacomitinib in vitro. The acquired resistant cells showed activation of several RTKs in drug free condition, and these are remarkably inhibited by EGFR-TKI treatment.

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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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      P2.18-008 - Transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib and received subsequent chemotherapies (ID 1723)

      09:30 - 16:30  |  Author(s): Y. Yatabe

      • Abstract

      Background
      Non-small-cell lung cancers (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangement are highly sensitive to the ALK kinase inhibitor crizotinib, but drug resistance invariably emerges. Morphological transformation from adenocarcinoma to SCLC represents one acquired resistance mechanism to epidermal growth factor receptor tyrosine kinase inhibitors. We present the case of transformation to sarcomatoid carcinoma in ALK-rearranged adenocarcinoma which developed acquired resistance to crizotinib.

      Methods
      not applicable

      Results
      A 32-year-old man presented with cough and bloody sputum. Computed tomography (CT) showed a mass in the S6 segment and diffuse consolidation throughout the lower lobe of the left lung. Transbronchial lung biopsy revealed adenocarcinoma with lymphangiosis. Immunohistochemistry (IHC) showed ALK protein expression and break-apart fluorescent in-situ hybridization (FISH) showed ALK gene rearrangement. First-line chemotherapy with cisplatin and docetaxel was started. After tumor progression, the patient was enrolled in the clinical trial and was allocated to the pemetrexed arm. Subsequently, he was enrolled in other trial to receive crizotinib in July 2011. After partial response was observed, a nodule in the S9 segment developed to 2cm in February 2012, and crizotinib was discontinued. CT scans performed after 4 cycles of carboplatin and gemcitabine showed a mixed response, with improvements in lymphadenopathy and lymphangiosis but progression of the mass in S9. CT-guided core-needle biopsy revealed ALK-positive atypical cells but it was impossible to distinguish histological types because of degeneration and necrosis. Thereafter, carboplatin, paclitaxel, and bevacizumab were administered, but the same mixed response was observed. The mass in S9 increased rapidly and reached 7 cm. 　Left lower lobectomy was performed. The primary tumor in S6 was diagnosed as adenocarcinoma positive for thyroid transcription factor (TTF)-1 immunostaining, whereas the tumor in S9 was TTF-1-negative sarcomatoid carcinoma. ALK was positive with IHC in both tumors, and FISH revealed high-level gene amplification of the ALK fusion gene only in the sarcomatoid carcinoma. Reverse transcriptase polymerase chain reaction revealed the same variant of echinoderm microtubule-associated protein like 4-ALK (E13; A20) and it indicated that these tumors have the same origin. Moreover, in the sarcomatoid carcinoma, DNA sequencing revealed no additional resistance point mutations from ALK exon 20 to exon 23. Brain metastases occurred 2 months after pulmonary resection and he underwent brain surgery. The tumor was diagnosed as sarcomatoid carcinoma. Ten days later, he died due to exacerbation of lymphangiosis To discuss potential epithelial-to-mesenchymal transition (EMT), we performed E-cadherin and keratin staining as epithelial markers, and vimentin staining as a mesenchymal marker in 4 specimens. The specimens were pre-crizotinib specimen in S6, surgical specimen in S6, rebiopsied specimen in S9 after carboplatin and gemcitabine, and surgical specimen in S9. Rebiopsied specimen in S9 was unevaluable for IHC staining because of degeneration and necrosis. All of the 3 evaluable specimens showed positive expression of vimentin and only surgical specimen in S9 showed negative of epithelial markers.

      Conclusion
      The transformation from adenocarcinoma to sarcomatoid carcinoma could be interpreted as kind of EMT. This transformation might represent a novel acquired resistance mechanism to crizotinib, although there is another possibility that subsequent chemotherapies induced this transformation.

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    P2.19 - Poster Session 2 - Imaging (ID 180)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P2.19-010 - The association between baseline clinical-radiological characteristics and growth of pulmonary nodules with ground-glass opacity (ID 1729)

      09:30 - 16:30  |  Author(s): Y. Yatabe

      • Abstract

      Background
      Pulmonary nodules with ground-glass opacity (GGO) are frequently encountered. We previously reported that, based on natural history of 108 pulmonary nodules that were 3 cm or less and had 50 % or more GGO component, these nodules should be followed for at least 3 years to accurately evaluate lesion growth. However, it remains unclear whether all GGOs should be followed for as long as 3 years. To establish reasonable follow-up plan, it would be useful to if we could predict which of GGO lesions tend to grow by any of clinical-radiographic characteristics. The purpose of this study was to clarify which baseline clinical and radiological characteristics were associated with growth of these nodules.

      Methods
      We retrospectively studied patients between 1999 and 2013 with pulmonary nodules that met the following criteria: (1) lesion diameter of ≤ 3 cm, (2) GGO proportion of ≥ 50%, and (3) observation without treatment in the prior 6 months. We evaluated the changes in lesion size on serial computed tomography. Two endpoints, “Time to 2-mm growth” and “2-mm growth incidence”, were analyzed using Cox proportional hazards and logistic regression models, respectively.Variables for univariate analysis were as follows: age; gender; smoking history; past history of lung cancer; lesion multiplicity; lesion diameter; and solid proportion. Factors for which p-value was < 0.05 in univariate analysis, as well as past history of lung cancer which was reported as a predictor in previous reports, were included in multivariate analysis. To strictly define “no growth”, we excluded lesions which had been observed for less than 3 years in logistic regression analyses.

      Results
      120 pulmonary lesions in 67 patients fulfilled inclusion criteria. At the median observation period of 4.2 years, 34 lesions had become larger by 2mm or more, whereas the remaining 86 had persisted without changing in size. Smoking history and initial lesion diameter were statistically significant in both regression and time-to-event analyses. In terms of time to 2mm growth, hazard ratio (HR) for smoking history was 3.67 (P < 0.01). Compared to those ≤ 1 cm, HRs for 1.1–2 cm and 21-3 cm lesions were 2.23 (P = 0.08) and 5.08 (P = 0.04), respectively. In contrast, odds ratio (OR) for the likelihood of 2mm growth for smoking history was 6.51 (P < 0.01), and OR for lesion diameter of 1.1–3 cm in comparison to ≤ 1 cm was 4.06 (P = 0.02).

      Conclusion
      Smoking history and initial lesion diameter are significantly associated with the growth of these nodules. These results suggested that closer follow up of larger size GGO in smoking patients be recommended.

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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): Y. Yatabe

      • 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.