The Korean Journal of Medicine

The Korean Association of Internal Medicine (대한내과학회)
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Predicting the Treatment Response Using a Direct Sequencing Method for EGFR in Non-Squamous, Non-Small Cell Lung Cancer

비편평, 비소세포폐암에서 EGFR 염기서열 분석법의 치료 반응 예측

  • Park, Ji-Young (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Jang, Seung-Hun (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Kim, Hyo-Jung (Division of Hematology and Oncology, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Park, Yong-Bum (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Kangdong Sacred Heart Hospital) ;
  • Kwon, Jung-Hye (Division of Hematology and Oncology, Department of Internal Medicine, Kangdong Sacred Heart Hospital) ;
  • Song, Hun-Ho (Division of Hematology and Oncology, Department of Internal Medicine, Kangdong Sacred Heart Hospital) ;
  • Lee, Kyung-Wha (Hallym Institute for Genome Application) ;
  • Kim, Jin-Hee (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Kim, Joo-Hee (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Park, Sung-Hoon (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Hwang, Yong-Il (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Kim, Dong-Gyu (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital) ;
  • Jung, Ki-Suck (Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal Medicine, Hallym University Sacred Heart Hospital)
  • 박지영 (한림대학교 성심병원 호흡기-알레르기내과) ;
  • 장승훈 (한림대학교 성심병원 호흡기-알레르기내과) ;
  • 김효정 (한림대학교 성심병원 혈액종양내과) ;
  • 박용범 (강동성심병원 호흡기-알레르기내과) ;
  • 권정혜 (강동성심병원 혈액종양내과) ;
  • 송헌호 (강동성심병원 혈액종양내과) ;
  • 이경화 (한림유전체응용연구소) ;
  • 김진희 (한림대학교 성심병원 호흡기-알레르기내과) ;
  • 김주희 (한림대학교 성심병원 호흡기-알레르기내과) ;
  • 박성훈 (한림대학교 성심병원 호흡기-알레르기내과) ;
  • 황용일 (한림대학교 성심병원 호흡기-알레르기내과) ;
  • 김동규 (한림대학교 성심병원 호흡기-알레르기내과) ;
  • 정기석 (한림대학교 성심병원 호흡기-알레르기내과)
  • Published : 2011.11.01
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Abstract

Background/Aims: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers (NSCLCs) have emerged as a key predictive biomarker for EGFR tyrosine kinase inhibitor (EGFR-TKI) treatment and should be the primary standard for selecting patients for first-line treatment with EGFR-TKIs. This retrospective study evaluated the ability of direct DNA sequencing to predict the EGFR-TKI response. Methods: We sequenced exons 18-21 of the EGFR tyrosine kinase domain from genomic DNA isolated from 122 NSCLCs, using paraffin-embedded tissues or cytological specimens. Mutation status was compared with clinicopathological features. Clinical outcomes were assessed based on EGFR genotypes. Results: EGFR gene mutations were identified in 36 patients. EGFR mutations were significantly more frequent in non-smokers or light smokers than in heavy smokers (44.8% vs. 10.9%, p < 0.001) and in females than in males (41.8% vs. 19.4%, p = 0.007). The response rate to EGFR-TKIs in patients with an EGFR mutation was 42.1% (8/19), in contrast to 18.9% (7/37) in patients without a mutation (p = 0.064). Patients with an EGFR mutation had significantly prolonged progression-free survival (8.5 vs. 1.5 months; p = 0.003) and overall survival (40.0 vs. 13.3 months; p = 0.006) with EGFR-TKI treatment, compared with patients without a mutation. Among the 15 patients who responded to EGFR-TKIs, 46.7% (7/15) had wild-type EGFR by the direct sequencing method. Conclusions: EGFR-TKIs conferred substantial clinical benefit in patients with NSCLCs and EGFR mutations. Detection of an EGFR mutation currently relies on direct sequencing, which cannot be performed on small diagnostic specimens, and the method lacks sensitivity. Sensitive assays are needed to detect EGFR mutations in routine clinical samples.

목적: 비편평, 비소세포폐암에서 EGFR 돌연변이는 EGFR-TKI의 효과를 결정하는 가장 중요한 인자로서 EGFR-TKI를 1차 항암 치료제로 사용할 수 있는 환자를 선별하는 기준으로 사용된다. 표준 방법으로 사용되고 있는 EGFR 직접 염기서열 분석법의 EGFR-TKI 치료 효과에 대한 예측력을 평가하였다. 방법: 편평세포암을 제외한 비소세포폐암 환자 122명의 임상정보와 EGFR 돌연변이 검사 결과를 의무기록 중심으로 후향적으로 분석하였다. 돌연변이 검사는 EGFR gene의 kinase domain (exons 18-21)에 대한 직접 염기서열 분석을 실시하였다. 임상 요소에 따른 돌연변이 발견율과 검사 결과에 따른 EGFR-TKI 치료 효과를 평가하였다. 결과: 총 36명에서 EGFR 돌연변이를 발견하였다. 여성에서(44.8% vs. 10.9%; p < 0.001), 비흡연 또는 10갑년 이하의 경도 흡연자에서(41.8% vs. 19.4%; p = 0.007) 유의하게 높은 빈도로 돌연변이가 발견되었다. EGFR-TKI 치료 반응률은 돌연변이형에서 42.1% (8/19), 야생형에서 18.9% (7/37)였다(p = 0.064). EGFR-TKI 사용의 무진행 생존기간은 돌연변이형에서 8.5개월, 야생형에서 1.5개월로 차이를 보였다(p = 0.003). EGFR-TKI 투여받은 환자의 중앙 생존기간은 돌연변이형에서 40.0개월, 야생형에서는 13.3개월로 차이를 보였다(p = 0.006). EGFR-TKI 치료로 부분관해 이상의 반응을 보인 환자들 중 직접 염기서열 분석법에서 야생형이었던 환자가 46.7% (7/15)로 다수 있었으며 야생형 환자 중에서 EGFR-TKI에 부분 관해 이상의 반응을 보인 환자는 18.9% (7/37)이었다. 결론: 비편평, 비소세포폐암 환자에서 직접 염기서열 분석법을 통한 EGFR 돌연변이 환자군이 야생형 환자군과 비교하여 EGFR-TKI 치료에 반응률 높고 무진행 생존기간과 중앙 생존기간이 연장됨을 확인할 수 있었다. 반면 직접 염기서열 분석법으로 EGFR 야생형으로 분류된 환자 중 적지않은 수에서 EGFR-TKI에 부분 관해 이상의 반응을 보였기 때문에 작은 검체에서도 민감하게 EGFR 돌연변이를 찾을 수 있는 검사 방법 개발과 표준화가 필요하다.

Keywords

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