Click
here to close Hello! We notice that
you are using Internet Explorer, which is not supported by Echinobase
and may cause the site to display incorrectly. We suggest using a
current version of Chrome,
FireFox,
or Safari.
Transl Cancer Res
2020 Dec 01;912:7562-7571. doi: 10.21037/tcr-20-1675.
Show Gene links
Show Anatomy links
Druggable driver gene alterations in redefined large cell carcinoma in Chinese patients: an observational study.
Yang J
,
Li Y
,
Ma B
,
Xie H
,
Chen L
,
Gao X
,
He W
.
???displayArticle.abstract???
BACKGROUND: Few reports have investigated the genetic status of large cell carcinoma (LCC) in Chinese patients under the 2015 World Health Organization (WHO) classification. We aimed to analyze the distribution of druggable driver gene alterations, including mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma 2 viral oncogene homolog (KRAS), proto-oncogene B-Raf (BRAF), and phosphatidylinositol-4,5 biphosphate 3-kinase catalytic subunit alpha (PIK3CA) and translocations in echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) and ROS proto-oncogene 1 (ROS1), in a large population of patients with LCC under the 2015 WHO classification, and to assess the clinical outcomes of patients with LCC harboring these genetic alterations.
METHODS: A cohort of 322 patients with LCC resected between June 2015 and December 2018 was included in this study. The clinical characteristics of the patients and data on the distribution of EGFR, KRAS, BRAF, PIK3CA, EML4-ALK, and ROS1 alterations were retrospectively collected. The disease-free survival (DFS) of patients with LCC was analyzed using the log-rank test.
RESULTS: Among the patients with redefined LCC, the proportion of males was much higher than that of females. Detection of LCC was more frequent in patients >60 years of age (71.4%). Mutations of EGFR were found in 3.6% of the LCC participants, predominantly in non-smokers. Mutations in KRAS were observed in 7.8% of the LCC patients, mainly in males and smokers. Mutations in PIK3CA and EML4-ALK translocations comprised 2.1% and 0.52% of the identified alterations, respectively. No alterations were identified in ROS1 and BRAF. After molecular stratification, no significant difference in DFS was identified between wild-type (WT) and mutation groups (29.91±3.83 vs. 25.33±6.04 months, P=0.48).
CONCLUSIONS: Under the 2015 WHO criteria, LCC was more frequently detected in elderly male patients with inferior prognoses. The frequency of EGFR and KRAS mutations was found to be the highest. Mutations in EGFR occurred more frequently in non-smokers, whereas KRAS mutations occurred predominantly in males and smokers. The PIK3CA mutations and EML4-ALK translocations were rare in patients with LCC. Our data revealed that the identification of clinically actionable molecular alterations in LCC may help guide personalized cancer treatment decisions in the future.
Figure 1. Histological features of large cell carcinoma (LCC). (A,B,C) hematoxylin and eosin (HE) staining and immunohistochemical (IHC) staining features of lung adenocarcinoma (LUAD); (D,E,F) HE and IHC staining features of lung squamous cell carcinoma (LUSC); (G) morphological features of LCC in HE-stained tissue sections; (H,I,J,K,L,M,N) IHC staining for TTF-1, napsin A, chromogranin A (Chr A), synaptophysin (Syn), p40, p63, and CK5/6 (magnification 100×). Under the 2015 WHO criteria, IHC staining-negative phenotypes are classified as LCC.
Figure 2. Flowchart illustrating the inclusion of redefined LCC patients and study design. LCC, large cell carcinoma.
Figure 3. Kaplan-Meier curves of disease-free survival (DFS) according to mutation status in patients with LCC. The P value for the difference between the two curves was determined by log-rank test. LCC, large cell carcinoma.
Castellanos,
Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer.
2017, Pubmed
Castellanos,
Driven by Mutations: The Predictive Value of Mutation Subtype in EGFR-Mutated Non-Small Cell Lung Cancer.
2017,
Pubmed
Chaft,
Coexistence of PIK3CA and other oncogene mutations in lung adenocarcinoma-rationale for comprehensive mutation profiling.
2012,
Pubmed
Cox,
Drugging the undruggable RAS: Mission possible?
2014,
Pubmed
Dearden,
Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap).
2013,
Pubmed
Gao,
Clinical And Imageological Features Of Lung Squamous Cell Carcinoma With EGFR Mutations.
2019,
Pubmed
Gkolfinopoulos,
Beyond EGFR and ALK: targeting rare mutations in advanced non-small cell lung cancer.
2018,
Pubmed
Janes,
Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.
2018,
Pubmed
Liu,
Clinicopathological and genetic characteristics of pulmonary large cell carcinoma under 2015 WHO classification: a pilot study.
2017,
Pubmed
Lynch,
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.
2004,
Pubmed
Maemondo,
Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR.
2010,
Pubmed
Micke,
The Impact of the Fourth Edition of the WHO Classification of Lung Tumours on Histological Classification of Resected Pulmonary NSCCs.
2016,
Pubmed
Misale,
KRAS G12C NSCLC Models Are Sensitive to Direct Targeting of KRAS in Combination with PI3K Inhibition.
2019,
Pubmed
Molina-Arcas,
Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer.
2019,
Pubmed
Pelosi,
Dissecting Pulmonary Large-Cell Carcinoma by Targeted Next Generation Sequencing of Several Cancer Genes Pushes Genotypic-Phenotypic Correlations to Emerge.
2015,
Pubmed
Ramalingam,
Overall Survival with Osimertinib in Untreated, EGFR-Mutated Advanced NSCLC.
2020,
Pubmed
Romero,
Two new agents target KRAS G12C.
2020,
Pubmed
Rosell,
Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.
2012,
Pubmed
Sandler,
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer.
2006,
Pubmed
Scagliotti,
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer.
2008,
Pubmed
Sequist,
Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors.
2011,
Pubmed
Shaw,
Crizotinib versus chemotherapy in advanced ALK-positive lung cancer.
2013,
Pubmed
Spoerke,
Phosphoinositide 3-kinase (PI3K) pathway alterations are associated with histologic subtypes and are predictive of sensitivity to PI3K inhibitors in lung cancer preclinical models.
2012,
Pubmed
Travis,
The 2015 World Health Organization Classification of Lung Tumors: Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification.
2015,
Pubmed
Tu,
A comprehensive review of uncommon EGFR mutations in patients with non-small cell lung cancer.
2017,
Pubmed
Wang,
Analytic and Clinical Validation of an Ultrasensitive, Quantitative Polymerase Chain Reaction Assay for EGFR Mutation Analysis With Circulating Tumor DNA.
2017,
Pubmed
Wang,
An integrative pharmacogenomics analysis identifies therapeutic targets in KRAS-mutant lung cancer.
2019,
Pubmed
Wen,
Concurrent oncogene mutation profile in Chinese patients with stage Ib lung adenocarcinoma.
2014,
Pubmed
Wu,
New data on clinical decisions in NSCLC patients with uncommon EGFR mutations.
2017,
Pubmed
Yamamoto,
PIK3CA mutations and copy number gains in human lung cancers.
2008,
Pubmed
