Journal of Pathology and Translational Medicine

Original Articles

Molecular Screening of Small Biopsy Samples Using Next-Generation Sequencing in Korean Patients with Advanced Non-small Cell Lung Cancer: Korean Lung Cancer Consortium (KLCC-13-01): Bo Mi Ku, Mi Hwa Heo, Joo-Hang Kim, Byoung Chul Cho, Eun Kyung Cho, Young Joo Min, Ki Hyeong Lee, Jong-Mu Sun, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Tae Jung Kim, Ho Yun Lee, Hojoong Kim, Kyung-Jong Lee, Myung-Ju Ahn; J Pathol Transl Med. 2018;52(3):148-156. Published online March 26, 2018; DOI: https://doi.org/10.4132/jptm.2018.03.12

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Background
Non-small cell lung cancer (NSCLC) is a common type of cancer with poor prognosis. As individual cancers exhibit unique mutation patterns, identifying and characterizing gene mutations in NSCLC might help predict patient outcomes and guide treatment. The aim of this study was to evaluate the clinical adequacy of molecular testing using next-generation sequencing (NGS) for small biopsy samples and characterize the mutational landscape of Korean patients with advanced NSCLC.
Methods
DNA was extracted from small biopsy samples of 162 patients with advanced NSCLC. Targeted NGS of genomic alterations was conducted using Ion AmpliSeq Cancer Hotspot Panel v2.
Results
The median age of patients was 64 years (range, 32 to 83 years) and the majority had stage IV NSCLC at the time of cancer diagnosis (90%). Among the 162 patients, 161 patients (99.4%) had novel or hotspot mutations (range, 1 to 21 mutated genes). Mutations were found in 41 genes. Three of the most frequently mutated genes were TP53 (151, 93.2%), KDR (104, 64.2%), and epidermal growth factor receptor (EGFR; 69, 42.6%). We also observed coexistence of EGFR and other oncogene (such as KRAS, PIC3CA, PTEN, and STK11) mutations. Given that 69.6% (48/69) of EGFR mutant patients were treated with EGFR tyrosine kinase inhibitors, EGFR mutant status had higher prognostic ability in this study.
Conclusions
These results suggest that targeted NGS using small biopsy samples is feasible and allows for the detection of both common and rare mutations in NSCLC.

Citations

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Hengrui Liang, Caichen Li, Yi Zhao, Shen Zhao, Jun Huang, Xiuyu Cai, Bo Cheng, Shan Xiong, Jianfu Li, Wei Wang, Changbin Zhu, Weiwei Li, Jianxing He, Wenhua Liang
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Transformation to Small Cell Lung Cancer of Pulmonary Adenocarcinoma: Clinicopathologic Analysis of Six Cases: Soomin Ahn, Soo Hyun Hwang, Joungho Han, Yoon-La Choi, Se-Hoon Lee, Jin Seok Ahn, Keunchil Park, Myung-Ju Ahn, Woong-Yang Park; J Pathol Transl Med. 2016;50(4):258-263. Published online May 10, 2016; DOI: https://doi.org/10.4132/jptm.2016.04.19

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242 Download
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Abstract PDF

Background
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first line treatment for a subset of EGFR-mutated non-small cell lung cancer (NSCLC) patients. Although transformation to small cell lung cancer (SCLC) is one of the known mechanisms of resistance to EGFR TKIs, it is not certain whether transformation to SCLC is exclusively found as a mechanism of TKI resistance in EGFR-mutant tumors.
Methods
We identified six patients with primary lung adenocarcinoma that showed transformation to SCLC on second biopsy (n = 401) during a 6-year period. Clinicopathologic information was analyzed and EGFR mutation results were compared between initial and second biopsy samples.
Results
Six patients showed transformation from adenocarcinoma to SCLC, of which four were pure SCLCs and two were combined adenocarcinoma and SCLCs. Clinically, four cases were EGFR-mutant tumors from non-smoking females who underwent TKI treatment, and the EGFR mutation was retained in the transformed SCLC tumors. The remaining two adenocarcinomas were EGFR wild-type, and one of these patients received EGFR TKI treatment.
Conclusions
NSCLC can acquire a neuroendocrine phenotype with or without EGFR TKI treatment.

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Non-small Cell Lung Cancer with Concomitant EGFR, KRAS, and ALK Mutation: Clinicopathologic Features of 12 Cases: Taebum Lee, Boram Lee, Yoon-La Choi, Joungho Han, Myung-Ju Ahn, Sang-Won Um; J Pathol Transl Med. 2016;50(3):197-203. Published online April 18, 2016; DOI: https://doi.org/10.4132/jptm.2016.03.09

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305 Download
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Abstract PDF

Background
Although epidermal growth factor receptor (EGFR), v-Ki-ras2 Kirsten rat sarcoma viral oncogene (KRAS), and anaplastic lymphoma kinase (ALK) mutations in non-small cell lung cancer (NSCLC) were thought to be mutually exclusive, some tumors harbor concomitant mutations. Discovering a driver mutation on the basis of morphologic features and therapeutic responses with mutation analysis can be used to understand pathogenesis and predict resistance in targeted therapy.
Methods
In 6,637 patients with NSCLC, 12 patients who had concomitant mutations were selected and clinicopathologic features were reviewed. Clinical characteristics included sex, age, smoking history, previous treatment, and targeted therapy with response and disease-free survival. Histologic features included dominant patterns, nuclear and cytoplasmic features.
Results
All patients were diagnosed with adenocarcinoma and had an EGFR mutation. Six patients had concomitant KRAS mutations and the other six had ALK mutations. Five of six EGFR-KRAS mutation patients showed papillary and acinar histologic patterns with hobnail cells. Three of six received EGFR tyrosine kinase inhibitor (TKI) and showed partial response for 7–29 months. All six EGFR-ALK mutation patients showed solid or cribriform patterns and three had signet ring cells. Five of six EGFR-ALK mutation patients received EGFR TKI and/or ALK inhibitor and four showed partial response or stable disease, except for one patient who had acquired an EGFR mutation.
Conclusions
EGFR and ALK mutations play an important role as driver mutations in double mutated NSCLC, and morphologic analysis can be used to predict treatment response.

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Analysis of Mutations in Epidermal Growth Factor Receptor Gene in Korean Patients with Non-small Cell Lung Cancer: Summary of a Nationwide Survey: Sang Hwa Lee, Wan Seop Kim, Yoo Duk Choi, Jeong Wook Seo, Joung Ho Han, Mi Jin Kim, Lucia Kim, Geon Kook Lee, Chang Hun Lee, Mee Hye Oh, Gou Young Kim, Sun Hee Sung, Kyo Young Lee, Sun Hee Chang, Mee Sook Rho, Han Kyeom Kim, Soon Hee Jung, Se Jin Jang, The Cardiopulmonary Pathology Study Group of Korean Society of Pathologists; J Pathol Transl Med. 2015;49(6):481-488. Published online October 13, 2015; DOI: https://doi.org/10.4132/jptm.2015.09.14

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Abstract PDF

Background
Analysis of mutations in the epidermal growth factor receptor gene (EGFR) is important for predicting response to EGFR tyrosine kinase inhibitors. The overall rate of EGFR mutations in Korean patients is variable. To obtain comprehensive data on the status of EGFR mutations in Korean patients with lung cancer, the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists initiated a nationwide survey. Methods: We obtained 1,753 reports on EGFR mutations in patients with lung cancer from 15 hospitals between January and December 2009. We compared EGFR mutations with patient age, sex, history of smoking, histologic diagnosis, specimen type, procurement site, tumor cell dissection, and laboratory status. Results: The overall EGFR mutation rate was 34.3% in patients with non-small cell lung cancer (NSCLC) and 43.3% in patients with adenocarcinoma. EGFR mutation rate was significantly higher in women, never smokers, patients with adenocarcinoma, and patients who had undergone excisional biopsy. EGFR mutation rates did not differ with respect to patient age or procurement site among patients with NSCLC. Conclusions: EGFR mutation rates and statuses were similar to those in published data from other East Asian countries.

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Noni Novisari Soeroso, Fannie Rizki Ananda, Johan Samuel Sitanggang, Noverita Sprinse Vinolina
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Comprehensive analysis of NGS and ARMS-PCR for detecting EGFR mutations based on 4467 cases of NSCLC patients
Changlong He, Chengcheng Wei, Jun Wen, Shi Chen, Ling Chen, Yue Wu, Yifan Shen, Huili Bai, Yangli Zhang, Xueping Chen, Xiaosong Li
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Unique characteristics of G719X and S768I compound double mutations of epidermal growth factor receptor (EGFR) gene in lung cancer of coal-producing areas of East Yunnan in Southwestern China
Jun-Ling Wang, Yu-Dong Fu, Yan-Hong Gao, Xiu-Ping Li, Qian Xiong, Rui Li, Bo Hou, Ruo-Shan Huang, Jun-Feng Wang, Jian-Kun Zhang, Jia-Ling Lv, Chao Zhang, Hong-Wei Li
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The role of oncogenes and tumor suppressor genes in determining survival rates of lung cancer patients in the population of North Sumatra, Indonesia
Noni Novisari Soeroso, Fannie Rizki Ananda, Johan Samuel Sitanggang, Noverita Sprinse Vinolina
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Adverse Event Profiles of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Adenocarcinoma Lung Patients in North Sumatera Population
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Open Access Macedonian Journal of Medical Sciences.2022; 10(T7): 134. CrossRef
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Traditional Chinese Medicine Syndromes are Associated with Driver Gene Mutations and Clinical Characteristics in Patients with Lung Adenocarcinoma
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Exosome-based detection of EGFR T790M in plasma and pleural fluid of prospectively enrolled non-small cell lung cancer patients after first-line tyrosine kinase inhibitor therapy
Yoonjung Kim, Saeam Shin, Kyung-A Lee
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Molecular biomarker testing for non–small cell lung cancer: consensus statement of the Korean Cardiopulmonary Pathology Study Group
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Journal of Pathology and Translational Medicine.2021; 55(3): 181. CrossRef
Osimertinib in Patients with T790M-Positive Advanced Non-small Cell Lung Cancer: Korean Subgroup Analysis from Phase II Studies
Myung-Ju Ahn, Ji-Youn Han, Dong-Wan Kim, Byoung Chul Cho, Jin-Hyoung Kang, Sang-We Kim, James Chih-Hsin Yang, Tetsuya Mitsudomi, Jong Seok Lee
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Long non-coding RNA ATB promotes human non-small cell lung cancer proliferation and metastasis by suppressing miR-141-3p
Guojie Lu, Yaosen Zhang, Klaus Roemer
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Prognostic Role of S100A8 and S100A9 Protein Expressions in Non-small Cell Carcinoma of the Lung
Hyun Min Koh, Hyo Jung An, Gyung Hyuck Ko, Jeong Hee Lee, Jong Sil Lee, Dong Chul Kim, Jung Wook Yang, Min Hye Kim, Sung Hwan Kim, Kyung Nyeo Jeon, Gyeong-Won Lee, Se Min Jang, Dae Hyun Song
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Epidermal growth factor receptor T790M mutations in non-small cell lung cancer (NSCLC) of Yunnan in southwestern China
Yongchun Zhou, Yuhui Ma, Hutao Shi, Yaxi Du, Yunchao Huang
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Does the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor differ according to the type of EGFR mutation in non-small cell lung cancer?
Yong Won Choi, Jin-Hyuk Choi
The Korean Journal of Internal Medicine.2017; 32(3): 422. CrossRef
Molecular Testing of Lung Cancers
Hyo Sup Shim, Yoon-La Choi, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Mee Sook Roh, Tae-Jung Kim, Seung Yeon Ha, Jin-Haeng Chung, Se Jin Jang, Geon Kook Lee
Journal of Pathology and Translational Medicine.2017; 51(3): 242. CrossRef
MET Exon 14 Skipping Mutations in Lung Adenocarcinoma: Clinicopathologic Implications and Prognostic Values
Geun Dong Lee, Seung Eun Lee, Doo-Yi Oh, Dan-bi Yu, Hae Min Jeong, Jooseok Kim, Sungyoul Hong, Hun Soon Jung, Ensel Oh, Ji-Young Song, Mi-Sook Lee, Mingi Kim, Kyungsoo Jung, Jhingook Kim, Young Kee Shin, Yoon-La Choi, Hyeong Ryul Kim
Journal of Thoracic Oncology.2017; 12(8): 1233. CrossRef
Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) of Yunnan in southwestern China
Yongchun Zhou, Yanlong Yang, Chenggang Yang, Yunlan Chen, Changshao Yang, Yaxi Du, Guangqiang Zhao, Yinjin Guo, Lianhua Ye, Yunchao Huang
Oncotarget.2017; 8(9): 15023. CrossRef
Detection of EGFR and KRAS Mutation by Pyrosequencing Analysis in Cytologic Samples of Non-Small Cell Lung Cancer
Seung Eun Lee, So-Young Lee, Hyung-Kyu Park, Seo-Young Oh, Hee-Joung Kim, Kye-Young Lee, Wan-Seop Kim
Journal of Korean Medical Science.2016; 31(8): 1224. CrossRef
MassARRAY, pyrosequencing, and PNA clamping for EGFR mutation detection in lung cancer tissue and cytological samples: a multicenter study
Kyueng-Whan Min, Wan-Seop Kim, Se Jin Jang, Yoo Duk Choi, Sunhee Chang, Soon Hee Jung, Lucia Kim, Mee-Sook Roh, Choong Sik Lee, Jung Weon Shim, Mi Jin Kim, Geon Kook Lee
Journal of Cancer Research and Clinical Oncology.2016; 142(10): 2209. CrossRef
Clinicopathologic characteristics of EGFR, KRAS, and ALK alterations in 6,595 lung cancers
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Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma: Eunhyang Park, Soo Young Park, Hyojin Kim, Ping-Li Sun, Yan Jin, Suk Ki Cho, Kwhanmien Kim, Choon-Taek Lee, Jin-Haeng Chung; J Pathol Transl Med. 2015;49(5):382-388. Published online August 4, 2015; DOI: https://doi.org/10.4132/jptm.2015.07.10

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100 Download
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Abstract PDF

Background
Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that has attracted considerable attention as a potential therapeutic target, although its clinical significance in non-small cell lung cancer (NSCLC) is controversial. This study aimed to clarify the clinical significance of IGF1R expression in human NSCLC. Methods: IGF1R protein expression was evaluated using immunohistochemistry in 372 patients with NSCLC who underwent curative surgical resection (146 squamous cell carcinomas [SqCCs] and 226 adenocarcinomas [ADCs]). We then analyzed correlations between expression of IGF1R and clinicopathological and molecular features and prognostic significance. Results: Membranous and cytoplasmic IGF1R expression were significantly higher in SqCCs than in ADCs. In patients with SqCC, membranous IGF1R expression was associated with absence of vascular, lymphatic, and perineural invasion; lower stage; and better progression-free survival (PFS) (hazard ratio [HR], 0.586; p = .040). In patients with ADC, IGF1R expression did not have a significant prognostic value; however, in the subgroup of epidermal growth factor receptor (EGFR)-mutant ADC, membranous IGF1R expression was associated with lymphatic and perineural invasion, solid predominant histology, and higher cancer stage and was significantly associated with worse PFS (HR, 2.582; p = .009). Conclusions: Lung ADC and SqCC showed distinct IGF1R expression profiles that demonstrated prognostic significance. High membranous IGF1R expression was predictive of poor PFS in EGFR-mutant lung ADC, while it was predictive of better PFS in SqCC. These findings will help improve study design for subsequent investigations and select patients for future anti-IGF1R therapy.

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EGFR Gene Amplification and Protein Expression in Invasive Ductal Carcinoma of the Breast: Won Hwangbo, Jeong Hyeon Lee, Sangjeong Ahn, Seojin Kim, Kyong Hwa Park, Chul Hwan Kim, Insun Kim; Korean J Pathol. 2013;47(2):107-115. Published online April 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.2.107

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Abstract PDF

Background

The epidermal growth factor receptor (EGFR) is a surrogate marker for basal-like breast cancer. A recent study suggested that EGFR may be used as a target for breast cancer treatment.

Methods

A total of 706 invasive ductal carcinomas (IDC) of the breast were immunophenotyped, and 82 cases with EGFR protein expression were studied for EGFR gene amplification.

Results

EGFR protein was expressed in 121 of 706 IDCs (17.1%); 5.9% were of luminal type, 25.3% of epidermal growth factor receptor 2 (HER-2) type, and 79.3% of basal-like tumors. EGFR gene amplification and high polysomy (fluorescent in situ hybridization [FISH]-positive) were found in 18 of 82 cases (22.0%); 41.2% of the HER-2⁺, EGFR⁺, cytokeratin 5/6^- (CK5/6^-) group, 11.2% of the HER-2^-, EGFR⁺, CK5/6^- group, and 19.1% of the HER-2^-, EGFR⁺, CK5/6⁺ group. FISH-positive cases were detected in 8.3% of the EGFR protein 1⁺ expression cases, 15.9% of 2⁺ expression cases, and 38.5% of 3⁺ expression cases. In group 2, the tumors had a high Ki-67 labeling (>60%), but the patients showed better disease-free survival than those with tumors that co-expressed HER-2 or CK5/6.

Conclusions

EGFR-directed therapy can be considered in breast cancer patients with EGFR protein overexpression and gene amplification, and its therapeutic implication should be determined in HER-2 type breast cancer patients.

Citations

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Review & Perspective

Guideline Recommendations for EGFR Mutation Testing in Lung Cancer: Proposal of the Korean Cardiopulmonary Pathology Study Group: Hyo Sup Shim, Jin-Haeng Chung, Lucia Kim, Sunhee Chang, Wan-Seop Kim, Geon Kook Lee, Soon-Hee Jung, Se Jin Jang; Korean J Pathol. 2013;47(2):100-106. Published online April 24, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.2.100

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Abstract PDF

Mutations of the epidermal growth factor receptor (EGFR) are the strongest predictive factor for response to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. EGFR TKIs are approved in Korea as a first-line treatment for lung cancer patients with mutated EGFR. Rapid and accurate EGFR mutation testing is essential for patient selection and establishing targeted therapies with EGFR TKIs. Thus, a standard set of guideline recommendations for EGFR mutation testing suitable for the Korean medical community is necessary. In this article, we propose a set of guideline recommendations for EGFR mutation testing that was discussed and approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

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Original Articles

Comparison of Direct Sequencing, PNA Clamping-Real Time Polymerase Chain Reaction, and Pyrosequencing Methods for the Detection of EGFR Mutations in Non-small Cell Lung Carcinoma and the Correlation with Clinical Responses to EGFR Tyrosin: Hyun Ju Lee, Xianhua Xu, Hyojin Kim, Yan Jin, Pingli Sun, Ji Eun Kim, Jin-Haeng Chung; Korean J Pathol. 2013;47(1):52-60. Published online February 25, 2013; DOI: https://doi.org/10.4132/KoreanJPathol.2013.47.1.52

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Abstract PDF

Background

The aims of this study were to evaluate the abilities of direct sequencing (DS), peptide nucleic acid (PNA) clamping, and pyrosequencing methods to detect epidermal growth factor receptor (EGFR) mutations in formalin-fixed paraffin-embedded (FFPE) non-small cell lung carcinoma (NSCLC) samples and to correlate EGFR mutational status as determined by each method with the clinical response to EGFR tyrosine kinase inhibitors (TKIs).

Methods

Sixty-one NSCLC patients treated with EGFR TKIs were identified to investigate somatic mutations in the EGFR gene (exons 18-21).

Results

Mutations in the EGFR gene were detected in 38 of the 61 patients (62%) by DS, 35 (57%) by PNA clamping and 37 (61%) by pyrosequencing. A total of 44 mutations (72%) were found by at least one of the three methods, and the concordances among the results were relatively high (82-85%; kappa coefficient, 0.713 to 0.736). There were 15 discordant cases (25%) among the three different methods.

Conclusions

All three EGFR mutation tests had good concordance rates (over 82%) for FFPE samples. These results suggest that if the DNA quality and enrichment of tumor cells are assured, then DS, PNA clamping, and pyrosequencing are appropriate methods for the detection of EGFR mutations.

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Intron 1 Polymorphism, Mutation and the Protein Expression of Epidermal Growth Factor Receptor in Relation to the Gefitinib Sensitivity of Korean Lung Cancer Patients.: Mi Jin Kim, Kyeong Cheol Shin, Kwan Ho Lee; Korean J Pathol. 2009;43(6):509-516.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.6.509

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Abstract PDF: BACKGROUND
Epidermal growth factor receptor (EGFR) intron 1 polymorphism in non-small cell lung cancer (NSCLC) has been found to have therapeutic implications for the patients treated with EGFR tyrosine kinase inhibitors. However, its clinical significance as related to gefitinib responsiveness is still controversial. We examined CA repeat polymorphism in intron 1 of the EGFR gene and its relation with the EGFR gene mutation in NSCLC patients who were treated with gefitinib. METHODS: Sixty seven patients who were treated with gefitinib were analyzed for intron 1 polymorphism in the EGFR gene, the EGFR mutations and the EGFR protein expression. Two hundred twenty seven samples of NSCLC were analyzed for EGFR mutations. RESULTS: CA repeat was low in 27 patients (40.3%) and high in 40 (59.7%) patients. The response rate for gefitinib therapy was higher in the patient population with a low number of CA repeats in the EGFR gene (p=0.047) and in the patients with the mutated type of EGFR (p=0.048), though these two factors were not related. Thirty four patients (15.0%) harbored EGFR mutations. CONCLUSIONS: This study suggests that the intron 1 CA repeat polymorphism of the EGFR gene may serve as a predictor of the clinical outcome of NSCLC patients treated with gefitinib, and this without regard for EGFR mutation. Our data further supports the importance of EGFR mutations with regard to a distinct clinical profile and the prognostic implications for NSCLC patients.

Epidermal Growth Factor Receptor Expression of Non-small Cell Carcinoma and Its Relationship with Genomic Mutation.: Sang hee Seok, Mi Jin Kim; Korean J Pathol. 2008;42(2):94-99.

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Abstract PDF: BACKGROUND
It has recently been clarified that epidermal growth factor receptor (EGFR), which is a receptor tyrosine kinase of the erbB family, is abnormally activated in non-small cell lung carcinomas (NSCLC) and this fact is being utilized for creating targeted therapy. In this study, we aimed to identify the frequency of the EGFR expression and gene mutation in NSCLC, and to determine the correlation between them.
METHODS
Immunohistochemical staining for EGFR, C-erbB-2, cytokeratin 7, p53 and thyroid transcription factor-1, and EGFR mutation analysis were performed using paraffin-embedded archival tissue from 228 cases of NSCLC; this included 112 squamous cell carcinomas and 116 adenocarcinomas.
RESULTS
An EGFR expression and gene mutation occurred in 112 casees (53.5%) and 52 cases (22.8%), respectively. EGRF mutation was more frequent in the adenocarcinomas than in the squamous cell carcinomas, in non-smokers than in smokers, and in females than in males. EGFR mutation was significantly associated with an EGFR protein expression, and especially in adenocarcinomas.
CONCLUSION
The EGFR expression in NSCLC was associated with EGFR mutation, and especially in adenocarcinomas. More studies are needed to prove the clinical significance of the EGFR expression for creating targeted therapy to treat NSCLC.

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