Purpose We investigated the clinical impact of genomic and pathway alterations in stage I epidermal growth factor receptor (EGFR)–mutant lung adenocarcinomas, which have a high recurrence rate despite complete surgical resection.
Materials and Methods Out of the initial cohort of 257 patients with completely resected stage I EGFR-mutant lung adenocarcinoma, tumor samples from 105 patients were subjected to analysis using large-panel next-generation sequencing. We analyzed 11 canonical oncogenic pathways and determined the number of pathway alterations (NPA). Survival analyses were performed based on co-occurring alterations and NPA in three patient groups: all patients, patients with International Association for the Study of Lung Cancer (IASLC) pathology grade 2, and patients with recurrent tumors treated with EGFR–tyrosine kinase inhibitor (TKI).
Results In the univariate analysis, pathological stage, IASLC grade, TP53 mutation, NPA, phosphoinositide 3-kinase pathway, p53 pathway, and cell cycle pathway exhibited significant associations with worse recurrence-free survival (RFS). Moreover, RPS6KB1 or EGFR amplifications were linked to a poorer RFS. Multivariate analysis revealed that pathologic stage, IASLC grade, and cell cycle pathway alteration were independent poor prognostic factors for RFS (p=0.002, p < 0.001, and p=0.006, respectively). In the grade 2 subgroup, higher NPA was independently associated with worse RFS (p=0.003). Additionally, in patients with recurrence treated with EGFR-TKIs, co-occurring TP53 mutations were linked to shorter progression-free survival (p=0.025).
Conclusion Genomic and pathway alterations, particularly cell cycle alterations, high NPA, and TP53 mutations, were associated with worse clinical outcomes in stage I EGFR-mutant lung adenocarcinoma. These findings may have implications for risk stratification and the development of new therapeutic strategies in early-stage EGFR-mutant lung cancer patients.
Citations
Citations to this article as recorded by
Stage-specific efficacy of osimertinib in treatment-naïve EGFR-mutant non-small cell lung cancer according to baseline genetic alterations in circulating tumor DNA Yoshihiko Taniguchi, Akihiro Tamiya, Mitsuo Osuga, Shun-ichi Isa, Keiichi Nakamura, Yasuyuki Mizumori, Tsutomu Shinohara, Hidetoshi Yanai, Katsumi Nakatomi, Masahide Oki, Masahide Mori, Tomohito Kuwako, Koji Yamazaki, Masahiro Shimada, Masahiko Ando, Yasu Investigational New Drugs.2025;[Epub] CrossRef
Purpose
The incidence of BRAF V600E mutation in non-small cell lung carcinoma (NSCLC) is lower than 2%, which poses difficulties in finding legitimate patients for targeted therapy. We investigated the predictive factors pertaining to BRAF V600E and the effectiveness of the VE1 antibody as a screening method for patient selection.
Materials and Methods
The study was designed into two steps. In a first group, BRAF-mutated NSCLCs were identified from sequencing data to determine the features of BRAF V600E mutation. The results of the first group helped the collection of adenocarcinomas with a papillary or micropapillary pattern but without EGFR or ALK alterations as a second group so that the frequency of BRAF V600E mutation could be calculated. The sensitivity and specificity of the VE1 were compared with BRAF V600E status.
Results
Among 39 BRAF-mutated NSCLCs in the first group, 20 (51%) were V600E. BRAF V600E mutation was more common in female patients and showed no significant correlation with smoking status. Nineteen cases were adenocarcinomas without EGFR and ALK alterations. The most common patterns of invasion were papillary and micropapillary along with central fibrosis. The sensitivity and specificity of the VE1 were 90.0% and 92.3%, respectively. In the second group, 6.7% of cases were VE1-positive, indicating that the prevalence was significantly higher than that reported in previous studies (0.3-1.8%).
Conclusion BRAF V600E-mutated NSCLCs could be enriched with the application of clinicopathologic parameters, which are not perfect. Therefore, additional VE1 immunohistochemistry may be useful as a screening method.
Citations
Citations to this article as recorded by
The rapidly changing field of predictive biomarkers of non-small cell lung cancer László József Tóth, Attila Mokánszki, Gábor Méhes Pathology and Oncology Research.2024;[Epub] CrossRef
BRAF V600E Mutation of Non-Small Cell Lung Cancer in Korean Patients Hyo Yeong Ahn, Chang Hun Lee, Min Ki Lee, Jung Seop Eom, Yeon Joo Jeong, Yeong Dae Kim, Jeong Su Cho, Jonggeun Lee, So Jeong Lee, Dong Hoon Shin, Ahrong Kim Medicina.2023; 59(6): 1085. CrossRef
The Impact of Liquid Biopsies Positive for EGFR Mutations on Overall Survival in Non-Small Cell Lung Cancer Patients Jonnathan Roldan Ruiz, Marta Fuentes Gago, Luis Chinchilla Tabora, Idalia Gonzalez Morais, José Sayagués, Mar Abad Hernández, Maria Cordovilla Pérez, Maria Ludeña de la Cruz, Edel del Barco Morillo, Marta Rodriguez Gonzalez Diagnostics.2023; 13(14): 2347. CrossRef
Usefulness of BRAF VE1 immunohistochemistry in non–small cell lung cancers: a multi-institutional study by 15 pathologists in Korea Sunhee Chang, Yoon-La Choi, Hyo Sup Shim, Geon Kook Lee, Seung Yeon Ha Journal of Pathology and Translational Medicine.2022; 56(6): 334. CrossRef
A 61-year-old male patient was simultaneously diagnosed with lung adenocarcinoma and inflammatory myofibroblastic tumor (IMT). The lung adenocarcinoma and IMT harbored two distinct types of ALK translocation, LOC101927285-ALK, and TPM3-ALK, respectively. The ALK Ventana showed strong positivity on both lesions. The patient was therefore given an endobronchial cryotherapy and ALK inhibitor crizotinib. The tumors showed durable response however the left lung adenocarcinoma relapsed at 17th month post-crizotinib treatment. Tissue re-biopsy on the resistant tumor revealed an ALK exon 23 C1156Y missense mutation in addition to LOC101927285-ALK mutation. Further RNA-based sequence uncovered that the noncoding region rearrangement is the fusion mutation of EML4-ALK. The patient was therefore received alectinib, and the tumor exhibited partly response. Overall, it is very rare that two types of pulmonary tumors exist in one patient driven by two distinct ALK fusions, which emphasizes the necessity of gene sequencing in clinical decision-making and individualized therapy.
Citations
Citations to this article as recorded by
Successful treatment of a non‐small‐cell lung cancer patient harboring HIP1‐ALK (H28:A20) and CTNNB1 p.S45del with alectinib Vito Longo, Francesco Pesola, Rosanna Lacalamita, Annamaria Catino, Michele Montrone, Ilaria Marech, Pamela Pizzutilo, Elisabetta Sara Montagna, Stefania Tommasi, Domenico Galetta Thoracic Cancer.2024; 15(31): 2283. CrossRef
Coexistence of a novel SV2B-ALK, EML4-ALK double-fusion in a lung poorly differentiated adenocarcinoma patient and response to alectinib: a case report and literature review Huang Chen, Menglan Zhang, Liyan Bai, Yun Niu, Xiaowei Wang, Ruiying Jiang, Ye Wang, Qianqian Feng, Bei Wang, Tingli Dai, Mingming Yuan, Rongrong Chen, Yujuan Qi, Dingrong Zhong Frontiers in Oncology.2024;[Epub] CrossRef
Novel treatment of endobronchial inflammatory myofibroblastic tumor in a child Jessica Reyes‐Angel, Louis B. Rapkin, Jeffrey P. Simons, Hiren Muzumdar Pediatric Pulmonology.2022; 57(1): 330. CrossRef
Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer Yan Xiang, Shiyu Zhang, Xiaoxu Fang, Yingying Jiang, Tingwen Fang, Jinwen Liu, Kaihua Lu Current Oncology.2022; 29(10): 7816. CrossRef
Crizotinib in Sarcomatous Malignancies Harboring ALK Fusion With a Definitive Partner(s): Response and Efficacy Jinchun Wu, Yongbin Hu, Omar Abdihamid, Gengwen Huang, Sheng Xiao, Bin Li Frontiers in Oncology.2021;[Epub] CrossRef
Purpose
Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD)
Materials and Methods
We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing.
Results
Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions.
Conclusion
Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.
Citations
Citations to this article as recorded by
Gene Expression Profiles of Multiple Synchronous Lesions in Lung Adenocarcinoma Jisun Lim, Yeon Bi Han, Soo Young Park, Soyeon Ahn, Hyojin Kim, Hyun Jung Kwon, Choon-Taek Lee, Sukki Cho, Jin-Haeng Chung Cells.2021; 10(12): 3484. CrossRef
PURPOSE A number of factors related to overall survival (OS) have been addressed in advanced non-small cell lung cancer (NSCLC). This study was conducted to determine the impact of whole-body metastatic regions on survival outcome in advanced non-squamous NSCLC. MATERIALS AND METHODS Between March 2005 and February 2011, 112 eligible patients with newly confirmed stage IV non-squamous NSCLC, available for epidermal growth factor receptor (EGFR) mutation status 18-21 analysis, and accessible for the determination of pretreatment whole-body metastatic regions were enrolled in this retrospective study. The total number of synchronous metastatic regions was scored according to the following disease sites: abdomen/pelvis, lung to lung/pulmonary lymphangitic spread, bone, pleura/pleural effusion/pericardial effusion, neck/axillary lymph nodes, other soft tissue, brain. RESULTS The median age of the cohort was 65 years (range, 31 to 88 years). The median whole-body metastatic score was 2 (range, 1 to 6), and bone and lung to lung were the most common metastatic sites. EGFR mutations were observed in 40 (35.7%) patients with a deletion in exon 19 and Leu858Arg mutation in exon 21 being detected in 16 (40.0%) and 19 (47.5%) patients, respectively. Multivariate analysis for OS revealed that treatment factors (p=0.005), performance status (p=0.006), whole-body metastatic score (p<0.001), and EGFR mutation status (p=0.095) were significantly or marginally associated with OS. CONCLUSION The results of the present study demonstrated that whole-body metastatic extent strongly affects survival outcome, even after adjustment for other significant variables in advanced non-squamous NSCLC. The clinical validity of more curative multimodal approaches in cohorts with limited metastases remains to be explored.
Citations
Citations to this article as recorded by
Clathrin‐mediated EGFR endocytosis as a potential therapeutic strategy for overcoming primary resistance of EGFR TKI in wild‐type EGFR non‐small cell lung cancer Boyeon Kim, Young Soo Park, Jae Sook Sung, Jong Won Lee, Saet Byeol Lee, Yeul Hong Kim Cancer Medicine.2021; 10(1): 372. CrossRef
O impacto da histologia do carcinoma pulmonar na frequência das metástases ósseas Marcelo Bragança dos Reis Oliveira, Larissa Costa Souza, Ermides Javier Garcia Sampayo, Gustavo Sobral de Carvalho, Fernanda Carvalho de Queiroz Mello, Marcos Eduardo Machado Paschoal Revista Brasileira de Ortopedia.2019; 54(05): 524. CrossRef
Brain Metastases at Presentation in Patients With Non–Small Cell Lung Cancer Saiama N. Waqar, Sadaf H. Waqar, Kathryn Trinkaus, Carlos A. Gadea, Cliff G. Robinson, Jeffrey Bradley, Mark A. Watson, Varun Puri, Ramaswamy Govindan, Daniel Morgensztern American Journal of Clinical Oncology.2018; 41(1): 36. CrossRef
Differential effects of two therapeutic cancer vaccines on short- and long-term survival populations among patients with advanced lung cancer Lizet Sanchez, Leacky Muchene, Patricia Lorenzo-Luaces, Carmen Viada, Pedro C. Rodriguez, Sailyn Alfonso, Tania Crombet, Elia Neninger, Ziv Shkedy, Agustin Lage Seminars in Oncology.2018; 45(1-2): 52. CrossRef
Impact of number versus location of metastases on survival in stage IV M1b non-small cell lung cancer Amanda Jane Williams Gibson, Haocheng Li, Adrijana D’Silva, Roxana A. Tudor, Anifat A. Elegbede, Shannon Mary Otsuka, D. Gwyn Bebb, Winson Y. Cheung Medical Oncology.2018;[Epub] CrossRef
PATHOLOGICAL FRACTURES DUE TO BONE METASTASES FROM LUNG CANCER: RISK FACTORS AND SURVIVAL Marcelo Bragança dos Reis Oliveira, Bruno de Carvalho Marques, Rosa Aurílio Matos, César Rubens da Costa Fontenelle, Fernanda Carvalho de Queiroz Mello, Marcos Eduardo Machado Paschoal Acta Ortopédica Brasileira.2018; 26(6): 388. CrossRef
Serum lactate dehydrogenase levels at presentation in stage IV non-small cell lung cancer: predictive value of metastases and relation to survival outcomes Dong Soo Lee, Kyung Ran Park, Seung Joon Kim, Mi Joo Chung, Yun Hee Lee, Ji Hyun Chang, Jin Hyoung Kang, Sook Hee Hong, Myung Sin Kim, Yeon Sil Kim Tumor Biology.2016; 37(1): 619. CrossRef
Distinctive Patterns of Initially Presenting Metastases and Clinical Outcomes According to the Histological Subtypes in Stage IV Non-Small Cell Lung Cancer Dong Soo Lee, Yeon S. Kim, Chul S. Kay, Sung H. Kim, Chang D. Yeo, Jin W. Kim, Seung Joon Kim, Young K. Kim, Yoon H. Ko, Jin H. Kang, Kyo Y. Lee Medicine.2016; 95(6): e2795. CrossRef
Rare occurrence of cavitation of lung metastases following effective targeted therapy: A case report JIACHENG SONG, JING YU, ZHANLONG MA, SHANSHAN LU Oncology Letters.2016; 11(2): 1589. CrossRef
Is second-line systemic chemotherapy beneficial in patients with non-small cell lung cancer (NSCLC)? A multicenter data evaluation by the Anatolian Society of Medical Oncology Hatice Odabas, Arife Ulas, Kubra Aydin, Mevlude Inanc, Asude Aksoy, Dogan Yazilitas, Mehmet Turkeli, Sinemis Yuksel, Ali Inal, Ahmet S. Ekinci, Alper Sevinc, Nebi S. Demirci, Mukremin Uysal, Necati Alkis, Faysal Dane, Mehmet Aliustaoglu, Mahmut Gumus Tumor Biology.2015; 36(12): 9641. CrossRef
Clinical Correlation Between Tumor Maximal Standardized Uptake Value in Metabolic Imaging and Metastatic Tumor Characteristics in Advanced Non-small Cell Lung Cancer Dong Soo Lee, Seung Joon Kim, Hong Seok Jang, Ie Ryung Yoo, Kyung Ran Park, Sae Jung Na, Kyo Young Lee, Sook Hee Hong, Jin Hyoung Kang, Young Kyoon Kim, Yeon Sil Kim Medicine.2015; 94(32): e1304. CrossRef
A case of lung cancer complicated by axillary Castleman's disease Manabu Kakizoe, Kousuke Suzuki, Noriyuki Saeki The Journal of the Japanese Association for Chest Surgery.2015; 29(6): 722. CrossRef
Non-small cell lung cancer metastasis to the oral cavity: a case report JB Olsen, F Sim, A Chandu Australian Dental Journal.2014; 59(4): 520. CrossRef
Lung Cancer Coexisting With Ipsilateral Pleural Effusion Francisco Rodriguez-Panadero, Beatriz Romero-Romero Lung Cancer Management.2014; 3(4): 335. CrossRef
EGFR endocytosis is a novel therapeutic target in lung cancer with wild-type EGFR Ukhyun Jo, Kyong Hwa Park, Young Mi Whang, Jae Sook Sung, Nam Hee Won, Jong Kuk Park, Yeul Hong Kim Oncotarget.2014; 5(5): 1265. CrossRef
In Korea chronic lymphocytic leukemia(CLL) is a rare diesase with evidence immunologic incompetence. The immunodeficiency of patients with CLL could place them at increased risk of new cancers. The incidence of secondary malignancy, including lung cancer has increased in patients with CLL and this should be also considered in the differential diagnosis of a new pulmonary infiltrate appearing in patients with known CLL. A-73-year old male patient with CLL was admitted to our hospital because of dyspnea. Chest X-ray showed multiple scattered small nodules in both lung fields and alveolar consolidation mass at right lower lung.
Histopathological examination of the bronchoscopic biopsy specimen demonstrated that he had a moderatly differentiated adenacarcinoma of lung. Since we experienced a case of metachronous adenocarcinoma of lung in patient with known CLL, we report this with a review of literatures.
The relationships between gross, microscopic and ultrastructural features of pulmonary adenocarcinomas and the morphologic significance of lepidic growth are studied using nine cases of peripheral adenocarcinomas with lepidic growth. They include three bronhioloalveolar carcinomas ( BAC's), two acinar adenocarcinomas, two papillary adenocarcinoms and two metastatic adenocarcinomas. Ill-defined consolidating mass was seen in three cases of BAC's and one acinar adenocarinoma. Other cases of acinar, papillary types and metastatic tumors were classified into secretory type or poorly differentiated type and metastatic adenocarcinomas showed mixture of the types. Mucin secreting cell by light microscopy showed apical clustering of electron-lucent mucin vacuoles by electron microscopy, but non-secretory type showed variable features of electron microscopy, but non-secretory type showed variable features of Clara cell, type II pneumocytes of indeterminate cells. Tumor growing along the alveolar wall was encountered in every type of the cases byt the distribution and microscopic findings were different according to the light microscopic types. The lepidic pattern was seen homogeneously in the whole tumor field in BAC's but was seen only at the peripheral zone of the tumor in the other instances. We could classify the microscopic features of lepidic growth into three patterns based on the findings in BAC's. Regular lepidic growth confined to the alveolar wall was seen only in BAC. One paillary adenocarcinoma and one BAC showed multicentric nodules which was composed of micropapillary projections into the alveolar spaces in addition to the tumor cells covering the preexisting alveolar wall. Other cases showed intraluminal polypoid growth and shedding into the lumina and numerous tumor balls were scattered. The significance of these morphologic patterns of lepidic growth is undetermined, however we could speculate that first and second patterns are well differentiated forms but polypoid shedding pattern is poorly differentiated form with rapid aerogenous spread and has more frequent chance to be detected by sputum cytology.