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H.J. Lee



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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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      MO10.11 - Genetic polymorphisms of TERT and TP63 genes are associated with exon 18 and exon 21 mutations of EGFR in adenocarcinoma of the lung. (ID 3046)

      17:15 - 17:20  |  Author(s): H.J. Lee

      • Abstract
      • Presentation
      • Slides

      Background
      The presence of mutations of epidermal growth factor receptor (EGFR) is related to phenotypical characteristics such as ethnicity, gender and smoking status. Such observations led us to explore associations between genetic polymorphisms and EGFR mutational status.

      Methods
      We set up a set of samples from 677 primary pulmonary adenocarcinoma. We tested two genetic polymorphisms (rs2736100 and rs10937405), which were discovered previously as to be associated with the risk of lung adenocarcinoma. The association between EGFR mutational status and genetic polymorphisms were evaluated using logistic regression analysis.

      Results
      In 673 patients, four exons (18, 19, 20, 21) of EGFR were completely evaluated. Presence of EGFR mutations were found in 382 (56.8%) patients. In logistic regression analysis, female gender (aOR, 1.7 with 95% CI, 1.0-2.9) and smoking status (ex-smoker, aOR, 0.6 with 95% CI, 0.4-1.1; current smoker aOR, 0.4 with 95% CI, 0.2-0.8) were associated with presence of EGFR mutations. None of two single nucleotide polymorphism (SNP) sites showed significant association. In the analysis of individual type of EGFR mutations, however, we found a significant association between EGFR exon 18 mutations and a SNP rs27366100T/G located in TERT. The G/G genotype showed a 2.8-fold increase in the occurrence of the EGFR exon 18 mutations compared to T/T+G/T genotypes (aOR, 2.8 with 95% CI, 1.2-8.7). Additionally, C/T+T/T genotypes of rs10937405C/T SNP in TP63 showed frequnt occurrences of EGFR exon 21 mutations compared to CC genotype (aOR, 1.5 with 95% CI, 1.0-2.3).

      Conclusion
      Our findings suggest that the somatic mutations of EGFR may be closely associated with genetic polymorphisms. Further investigation of this field may enable us to identify patients who may get a benefit from EGFR inhibitors.

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    P3.18 - Poster Session 3 - Pathology (ID 177)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Pathology
    • Presentations: 2
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      P3.18-016 - The usefulness of frozen section diagnosis as for the decision making milestone during the surgery for pulmonary ground glass nodules: embedding medium inflation technique (ID 2946)

      09:30 - 09:30  |  Author(s): H.J. Lee

      • Abstract

      Background
      The appropriate intraoperative decision making of surgical resection for the pulmonary ground glass nodules (GGN) is often difficult. We aimed to evaluate the role of frozen section diagnosis (FSD) as for the intraoperative decision making milestone and compared its accuracy to that of preoperative CT based practice as an interim result.

      Methods
      We retrospectively reviewed FSD of 171 consecutive pulmonary GGN from February 2005 to June 2013 and compared the diagnostic accuracy. Initially, we used only conventional method (Group A) but recently, we adapted a embedding medium inflation method (Group B) for FSD. The qualities of FSD were compared with the final pathologic diagnoses of corresponding permanent paraffin sections. Also, we calculated the sensitivity, specificity, and predictive values of assessing the size of invasive portion in GGN between FSD using the inflation method and preoperative CT based practice.

      Results
      There were no differences in nodule sizes between two groups (1.45±0.6 versus 1.51±0.5, p=0.63). In group A, a correct differential diagnosis between malignancies and benign lesions were made in 138 nodules. Thirteen nodules were erroneously classified and reported as false-positive or false-negative frozen section diagnoses (Sensitivity 95.6%, Specificity 53.8%). Three nodules were under-diagnosed in FSD. One patient required a secondary operation because of false-negative frozen diagnosis at the time of initial surgery. In group B, all of 17 nodules were correctly classified by frozen section. There were no false-positive or false-negative diagnoses in terms of making a diagnosis of malignancy, resulting in 100%-sensitivity and -specificity. (Figure 1) Thirteen nodules were correctly classified as being either minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma. Three nodules were diagnosed as MIA by frozen section through measuring invasive tumor size (<5mm) concomitantly. With regards to the estimating the size of invasive components of GGN, FSD in group B was superior to measurement of solid component in GGO nodules on HRCT. (Table 1)Figure 1

      Conclusion
      The accuracy of FSD using the embedding medium inflation method in GGO nodules was outstanding compared to the conventional frozen method. Furthermore, this method can help surgeons plan the appropriate surgical treatment after wedge resection of a GGO nodule by providing accurate size estimation of the invasive components of the GGN.

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      P3.18-020 - The mutational profile of lung adenocarcinoma in Korean population (ID 3097)

      09:30 - 09:30  |  Author(s): H.J. Lee

      • Abstract

      Background
      Recent development of molecular target agents encouraged us to investigate the presence of driver mutations in patients with non-small cell lung cancer. As the prevalence of individual driver mutation is different in each ethnic group, understanding of mutational profiles of a specific country is important for clinical practice as well as for decision-making process of health care. Hence, we investigated the genetic profile of lung adenocarcinoma in Korean population.

      Methods
      Among the patients who underwent surgical resection for lung adenocarcinoma between 2001 and 2011, we set up a total of 477 patients whose fresh frozen lung cancer tissues and paraffin blocks were available. We retrospectively searched medical records of the EGFR exons 18-21 mutation tests results. Then, we selected patients who did not harbor EGFR mutations or who had not tested for EGFR mutations. DNA was extracted from those patients’ samples, and EGFR exons 18-21 and KRAS mutation test were performed by Sanger sequencing method. Tissue microarray was made for all 477 patients, and the EML4-Alk fusion was tested by a break-apart FISH method. We also tested KIF5B-RET fusion by using a break-apart FISH method and also by inversion specific long-range PCR. We investigated any correlation between mutational status and clinical variables, such as age, gender, smoking status, stage, and long term survivals.

      Results
      Among 477 patients, 321 patients (67.3%) were harboring at least one of four driver mutations. The EGFR mutations were the most frequently detected (270, 56.6%), followed by KRAS mutations (37, 7.8%), and EML4-Alk fusion (19, 4.0%). We also found five patients who had KIF5B-RET fusion mutations (1.0%). There were 10 patients who had more than two driver mutations; EGFR and KRAS mutations in 4, EGFR and EML4-Alk fusion in 4, KRAS and EML4-Alk fusion in one, and EGFR and KIF5B-RET fusion in one patient. The presences of EGFR mutations were frequently observed in patients with female gender (p=0.000). Although the EGFR mutations were associated with longer overall survival in univariate analysis (log-rank test rank test p=0.007), the presence of EGFR mutation was not a prognostic factor in multivariate analysis (Cox’s regression test p=0.469). The mutational statuses were associated with neither the disease-free survival nor fthe reedom from recurrence.

      Conclusion
      Based on our work, we found as high as 67.3% of lung adenocarcinoma patients in Korean populations were harboring at least one driver mutation, which may get a benefit from target agents. We also found as high as 2% of patients harbored multiple driver mutations. As the target agent will eventually develop resistance, it is recommended to test each driver mutation thoroughly even if one driver mutation was detected. Furthermore, our observation suggests future molecular testing should be based on the next generation sequencing platform.

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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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      P3.21-006 - The N-classification Based on the Number of Metastatic Lymph Node is Superior to Regional N-classification in Predicting Outcomes After Surgical Resection for Non-small Cell Lung Cancer. (ID 1764)

      09:30 - 09:30  |  Author(s): H.J. Lee

      • Abstract

      Background
      In many cancers, the N-classification of current TNM stage is categorized by the number of positive lymph nodes. However, for non-small cell lung cancer (NSCLC), it is classified by the involvement of specific regional node groups. The aim of this study is to make a new N-classification grouping (nN stage) based upon the number of metastatic lymph nodes and to evaluate its prognostic significance in predicting outcome after resection of NSCLC.

      Methods
      Between January 2000 and April 2011, 2319 patients underwent surgery for NSCLC in our hospital. A total of 1982 patients was selected by excluding patients who received preoperative induction therapy or did not get curative resection and those with pN3 metastatic lymph nodes. Prospectively collected clinical information as well as pathologic variables were retrospectively analyzed. The recursive partitioning analysis was applied to define the most significant cut-off number of metastatic lymph nodes. We then analyzed overall and disease-free survival using the new nN stage grouping to test if it can provide more accurate classification compared to the conventional N stage grouping.

      Results
      Recursive partitioning analysis identified patients could be divided into three distinct groups according to the number of metastatic lymph nodes: nN0 (none), nN1 (1-7), nN2 (>7). Among 1982 patients, 1371 patients were nN0, 538 were nN1, and 73 were nN2. The 5-year overall survival rates were 79.8%, 62.1% and 36.1% for nN0, nN1, and nN2, respectively, and they were statistically different (p < 0.001, log-rank test). For conventional N stage, 1371 patients were pN0, 284 were pN1, and 327 were pN2. The 5-year survival rates were 79.8%, 63.8%, and 54.8% for pN0, pN1, and pN2 stages, respectively (p < 0.001, log-rank test). The chi-square value of nN stage was superior to that of pN stage (141.02 vs. 117.16). When we further analyzed those with pN2 patients, the nN1/pN2 group showed a significantly better survival rate than nN2/pN2 group (p < 0.001, log-rank test). Moreover, the overall survival of nN1/pN2 patients was not different from that of nN1/pN1 patients. (p = 0.074, log-rank test) Figure 1

      Conclusion
      The nN-classification seemed to predict long-term survival more accurately compared to conventional N stage grouping. Our result suggested the new N stage grouping based on the number of metastatic lymph node should be considered for the next revision of the TNM classification system for NSCLC.