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T.Y. Takagaki



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    P2.06 - Poster Session 2 - Prognostic and Predictive Biomarkers (ID 165)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P2.06-008 - Polymorphisms in the exon 20 of EGFR gene in metastatic lung adenocarcinoma: prognostic relevance and sensitivity to erlotinib. (ID 1027)

      09:30 - 09:30  |  Author(s): T.Y. Takagaki

      • Abstract

      Background
      EGFR-activating mutations are predictive of high response rates and overall survival gains in patients (pts) with pulmonary adenocarcinoma, treated with EGFR- tyrosine-kinase inhibitors (EGFR-TKIs), as erlotinib. Mutations in the EGFR gene, especially in the exon 20 (T790M), are related to resistance to EGFR-TKIs. We investigated if a polymorphic DNA sequence in exon 20 (Q787Q, NCBI database 162093G>A, SNP ID: rs1050171) was associated with clinical outcomes in pulmonary adenocarcinomas, treated with erlotinib.

      Methods
      It is a prospective, observational study on all consecutively pts whose tumors were genotyped for EGFR-activating mutations. Tumor samples were formalin-fixed and paraffin-embedded. Tumor areas were selected and macrodissected, followed by whole DNA extraction and amplification by PCR. EGFR genotyping was performed through DNA sequencing (exons 18, 19, 20 and 21) by Sanger´s methodology. Pts with adenocarcinomas harbouring EGFR-activating mutations were treated with erlotinib.

      Results
      191 pts had tumor samples genotyped between Aug/2011 and Apr/2013. Median age was 64 y (17-90), 106 (56%) female. According to ethnicity, 154 pts were Caucasian (81%), 26 African-American (14%) and 11 Asian (6%). Seventy pts were classified as never-smokers (37%), 23 (12%) as light-smokers (≤ 10 p.y.) and 95 as current smokers (51%). EGFR activating mutations could be identified in 54 out of 191 samples (28%): 35 were exon 19 deletions (65%), 15 were L858R mutation in exon 21 (30%), and three were rare mutations (G719S and G719A in exon 18, and V774M in exon 20). Polymorphism Q787Q in EGFR gene (exon 20) was detected in 108 samples (56.5%). The polymorphic status did not correlate with gender (p=0.324), smoking status (p=0.810) or EGFR mutational status (p=0.238), but it was more frequently detected in Caucasian pts (p=0.0002). Considering all 191 studied pts, no difference in median overall survival was detected according to polymorphic status (19.6 mo. vs. 24.3 mo., HR 0.86; 95% CI 0.54-1.38, p=0.541). There was no difference in response rate to erlotinib according to the polymorphic status (p=0.248). In addition, no difference in median overall survival was detected according to polymorphic status among the 38 pts treated with erlotinib and presenting EGFR-activating mutations (not reached in both groups, HR 2.44; 95% CI 0.31-16.01, p=0.425).

      Conclusion
      Polymorphism Q787Q in EGFR gene (exon 20) was commonly detected in pulmonary adenocarcinomas (56.5%), being more frequent in Caucasian pts. The presence of polymorphic status was neither related to sensitivity to erlotinib, nor to survival outcomes in our pts.

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    P2.11 - Poster Session 2 - NSCLC Novel Therapies (ID 209)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 1
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      P2.11-009 - Erlotinib in metastatic pulmonary adenocarcinomas harbouring EGFR activating mutations, in Sao Paulo - Brazil. (ID 1025)

      09:30 - 09:30  |  Author(s): T.Y. Takagaki

      • Abstract

      Background
      Background: EGFR-activating mutations are predictive of high response rates and overall survival gains in patients (pts) with pulmonary adenocarcinomas, treated with EGFR- tyrosine-kinase inhibitors (EGFR-TKIs), as erlotinib. Our objectives in this study were to analyze the efficacy and safety of erlotinib as first-line therapy or later in pts with adenocarcinomas harbouring EGFR-activating mutations.

      Methods
      Methods: It is a prospective, observational study on all consecutively pts whose tumors were genotyped for EGFR-activating mutations. All studied pts were treated in a single institution (ICESP) with erlotinib 150 mg PO daily. Tumor samples were formalin-fixed and paraffin-embedded. Tumor areas were selected and macrodissected, followed by whole DNA extraction and amplification by PCR. EGFR genotyping was performed through DNA sequencing (exons 18, 19, 20 and 21) by Sanger´s methodology.

      Results
      Results: 49 pts were treated with erlotinib from Nov/2010 to May/2013, as first-line (11 pts, 22%), second-line (31 pts, 63%) or third-line therapy (7 pts, 14%). Erlotinib was administered during a median time of 4 mo. (0.2-23.6 mo.). Among these 49 pts, 38 (78%) were diagnosed with adenocarcinomas harbouring EGFR-activating mutations: 26 with exon 19 deletions, 10 with L858R mutation in exon 21 and one presented a rare mutation in exon 18 (G719S). As expected, erlotinib was well tolerated, and acneiform rash and diarrhea were the most commonly observed toxicities. No treatment-related deaths were seen. Tumor response assessment was done in 42 pts: progressive disease was observed in 15 pts (36%) and 27 pts (64%) presented either partial response or disease stabilization. In a mean follow-up of 14 mo., 13 pts were dead. Median overall survival was not reached for the 38 pts with EGFR-mutated adenocarcinomas, and 1-year overall survival rate was 94% in these pts. In those pts with wild-type EGFR tumors, median overall survival was 15.6 mo (HR 0.17; 95% CI 0.02-0.33, p=0.0004). No difference in overall survival was observed between pts with EGFR-mutated adenocarcinomas if treated with erlotinib either as first-line therapy or later (HR 1.11; 95% CI 0.20-6.15, p=0.895). No difference in overall survival was observed between pts with EGFR-mutated adenocarcinomas according to the type of mutations (exon 19 deletions or others, p=0.147).

      Conclusion
      Conclusions: High rate of disease control (64%) and an impressive 1-year overall survival rate (94%) were observed among pts with metastatic pulmonary adenocarcinomas harbouring EGFR-activating mutations, as expected, with a favorable toxicity profile. These results do reinforce the importance of the correct identification of this subgroup of pts with EGFR-activating mutations and their treatment with an EGFR-TKI as a targeted therapy.

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    P3.22 - Poster Session 3 - Epidemiology, Etiology (ID 168)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Prevention & Epidemiology
    • Presentations: 1
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      P3.22-003 - EGFR genotyping and epidemiology, clinical and pathological features in 191 patients with metastatic pulmonary adenocarcinoma in Sao Paulo - Brazil. (ID 1026)

      09:30 - 09:30  |  Author(s): T.Y. Takagaki

      • Abstract

      Background
      EGFR activating mutations in pulmonary adenocarcinoma does confer better prognosis and are also predictive of higher response rates to both chemotherapy and EGFR-tyrosine kinase inhibitors. Therefore, EGFR genotyping in these patients (pts) is a very helpful biomarker for treatment selection. Here we aimed to report the results of consecutive EGFR genotyping in our Institution in Sao Paulo - Brazil.

      Methods
      It is a prospective, observational study on all consecutively tested samples from pts diagnosed with pulmonary adenocarcinoma and treated at ICESP. All samples were formalin-fixed and paraffin-embedded. Tumor areas were selected and macrodissected, followed by whole DNA extraction and amplification by PCR. EGFR genotyping was performed through DNA sequencing (exons 18, 19, 20 and 21) by Sanger´s methodology.

      Results
      191 pts had tumor samples genotyped between Aug/2011 and Apr/2013. Median age was 64 y (17-90), 106 (56%) female. According to ethnicity, 154 pts were Caucasian (81%), 26 African-American (14%) and 11 Asian (6%). Seventy pts were classified as never-smokers (37%), 23 (12%) as light-smokers (≤ 10 p.y.) and 95 as current smokers (51%). EGFR activating mutations could be identified in 54 out of 191 samples (28%): 35 were exon 19 deletions (65%), 15 were L858R mutation in exon 21 (30%), and three were rare mutations (G719S and G719A in exon 18, and V774M in exon 20). These mutations were found to be more frequent in females than in males (56% vs. 45%, p=0.035), and in never-smokers and light-smokers than in current smokers (77% vs. 20%, p<0.0001). It is noteworthy to mention that 11 mutations were detected in current smokers. All tumors harboring EGFR activating mutations presented TTF-1 expression by immunohistochemistry, and among those seven TTF-1-negative adenocarcinomas, no mutation was detected (p=0.0969). In a mean follow-up of 12 months, 77 pts were dead. Median overall survival was not reached in those pts whose tumors harboring EGFR-activating mutations, versus 19 months in pts with wild-type EGFR tumors (HR 0.40; 95%CI 0.29-0.78, p=0.003).

      Conclusion
      In this group of pts, the frequency of EGFR activating mutations was 28%, being more frequent in females, and never-smokers or light smokers, as previously described. Indeed, the presence of EGFR activating mutations was a favorable prognostic factor. The data here presented does reinforce the importance of testing EGFR activating mutations in all pts with TTF-1-positive, pulmonary adenocarcinoma.