Dynamic Plasma EGFR Mutation Status as a Predictor of EGFR-TKI Efficacy in Patients with EGFR-Mutant Lung Adenocarcinoma

AbstractBackground. The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice.Patients and methods. We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival.Results. Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later.Conclusions. Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.

Download Full-text

Impacts of EGFR-mutation status and EGFR-TKI on the efficacy of stereotactic radiosurgery for brain metastases from non-small cell lung adenocarcinoma: A retrospective analysis of 133 consecutive patients

Lung Cancer ◽

10.1016/j.lungcan.2018.03.013 ◽

2018 ◽

Vol 119 ◽

pp. 120-126 ◽

Cited By ~ 4

Author(s):

Shoji Yomo ◽

Kyota Oda

Keyword(s):

Brain Metastases ◽

Lung Adenocarcinoma ◽

Stereotactic Radiosurgery ◽

Retrospective Analysis ◽

Egfr Mutation ◽

Small Cell ◽

Small Cell Lung ◽

Mutation Status ◽

Egfr Tki

Download Full-text

Deep CNN Model Using CT Radiomics Feature Mapping Recognizes EGFR Gene Mutation Status of Lung Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.598721 ◽

2021 ◽

Vol 10 ◽

Author(s):

Baihua Zhang ◽

Shouliang Qi ◽

Xiaohuan Pan ◽

Chen Li ◽

Yudong Yao ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

Ct Images ◽

Feature Mapping ◽

Mutation Status ◽

Egfr Gene ◽

Non Invasive ◽

External Test ◽

Egfr Tki ◽

Egfr Gene Mutation

To recognize the epidermal growth factor receptor (EGFR) gene mutation status in lung adenocarcinoma (LADC) has become a prerequisite of deciding whether EGFR-tyrosine kinase inhibitor (EGFR-TKI) medicine can be used. Polymerase chain reaction assay or gene sequencing is for measuring EGFR status, however, the tissue samples by surgery or biopsy are required. We propose to develop deep learning models to recognize EGFR status by using radiomics features extracted from non-invasive CT images. Preoperative CT images, EGFR mutation status and clinical data have been collected in a cohort of 709 patients (the primary cohort) and an independent cohort of 205 patients. After 1,037 CT-based radiomics features are extracted from each lesion region, 784 discriminative features are selected for analysis and construct a feature mapping. One Squeeze-and-Excitation (SE) Convolutional Neural Network (SE-CNN) has been designed and trained to recognize EGFR status from the radiomics feature mapping. SE-CNN model is trained and validated by using 638 patients from the primary cohort, tested by using the rest 71 patients (the internal test cohort), and further tested by using the independent 205 patients (the external test cohort). Furthermore, SE-CNN model is compared with machine learning (ML) models using radiomics features, clinical features, and both features. EGFR(-) patients show the smaller age, higher odds of female, larger lesion volumes, and lower odds of subtype of acinar predominant adenocarcinoma (APA), compared with EGFR(+). The most discriminative features are for texture (614, 78.3%) and the features of first order of intensity (158, 20.1%) and the shape features (12, 1.5%) follow. SE-CNN model can recognize EGFR mutation status with an AUC of 0.910 and 0.841 for the internal and external test cohorts, respectively. It outperforms the CNN model without SE, the fine-tuned VGG16 and VGG19, three ML models, and the state-of-art models. Utilizing radiomics feature mapping extracted from non-invasive CT images, SE-CNN can precisely recognize EGFR mutation status of LADC patients. The proposed method combining radiomics features and deep leaning is superior to ML methods and can be expanded to other medical applications. The proposed SE-CNN model may help make decision on usage of EGFR-TKI medicine.

Download Full-text

Clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20588 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20588-e20588

Author(s):

Linping Gu ◽

Bei Zhang ◽

Ding Zhang ◽

Hong Jian

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

De Novo ◽

Egfr Mutations ◽

Genomic Profiling ◽

Small Cell Lung ◽

Genetic Characteristics ◽

Egfr Mutant ◽

Lung Adenocarcinomas ◽

Egfr T790m

e20588 Background: Transformation from non-small cell lung cancer (NSCLC) to small cell lung cancer (SCLC) is one of the resistance mechanism of EGFR tyrosine kinase inhibitors. However, the clinical course of transformed SCLC and the difference of genomic profiling between de novo SCLC patients and transformed SCLC patients are still poorly characterized. Methods: Patients from our hospital diagnosed with SCLC were enrolled retrospectively in this study, including de novo SCLC patients and SCLC patients transformed from EGFR-mutant lung adenocarcinomas. Genomic profiling was performed on formalin-fixed paraffin-embedded tumor samples by next generation sequencing (NGS). In statistical analysis, fisher ‘exact test was used. All tests were bilateral, with P<0.05 indicating significant statistical difference. Results: In total, 16 patients with SCLC transformed from EGFR-mutant lung adenocarcinomas and 230 de novo SCLC patients were included in our study. Transformed SCLC patients were more in younger (p=0.007), female (p<0.001) and non-smokers (p<0.001) than de novo SCLC patients. In transformed SCLC patients, 12 patients (75%) occurred SCLC transformation within 2 years after the lung adenocarcinomas diagnosis. Median transformation time was 20 months. During the treatment of adenocarcinomas, the overall response rate (ORR) was 75% and the median progression-free survival was 12 months. After the initiation of SCLC therapy, the ORR of 1st line chemotherapy was 40%. For the genomic profiling, EGFR mutations, including exon 19 deletion (56%), L858R (38%), and others (6%), were detected. 11 patients with acquired resistance were received EGFR T790M test, 82% of patients had acquired EGFR T790M mutation. 11 patients after transformation to SCLC had NGS test, 100% maintained their founder EGFR mutation, and other recurrent mutations included TP53, RB1 and EGFR amplification. Compared with the genetic alterations in de novo SCLC patients, TP53 mutations were significantly decreased (p=0.006) while EGFR mutations were significantly elevated (p<0.001) in transformed SCLC patients. However, no significant difference on RB1, ALK and ROS1 mutations were observed. Interestingly, a 60-year-old woman in our transformed SCLC cohort harbored EGFR 19 del mutant at allele frequency of 50.39%，she received osimertinib plus epirubicin/cyclophosphamide as 1st line treatment and reached partial response, with survival of 4 years to date. Conclusions: We demonstrated the clinical and genetic characteristics of EGFR-mutant lung adenocarcinoma transformed SCLC and found one patient still benefited from EGFR-TKI. Our study suggested that SCLC patients with EGFR mutation who transformed from lung adenocarcinoma may be potential benefit population using EGFR inhibitors.

Download Full-text

CT imaging-based histogram features for prediction of EGFR mutation status of bone metastases in patients with primary lung adenocarcinoma

Cancer Imaging ◽

10.1186/s40644-019-0221-9 ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 4

Author(s):

Tong-xu Shen ◽

Lin Liu ◽

Wen-hui Li ◽

Ping Fu ◽

Kai Xu ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Bone Metastases ◽

Egfr Mutation ◽

Ct Imaging ◽

Mutation Status ◽

Primary Lung Adenocarcinoma

Download Full-text

Immunohistochemistry Profile Predicts EGFR Mutation Status in Lung Adenocarcinoma

International Journal of Surgical Pathology ◽

10.1177/1066896920909427 ◽

2020 ◽

Vol 28 (5) ◽

pp. 502-506

Author(s):

Wencheng Li ◽

Angela G. Niehaus ◽

Stacey S. O’Neill

Keyword(s):

Lung Adenocarcinoma ◽

Egfr Mutation ◽

Growth Factor Receptor ◽

Egfr Mutations ◽

Molecular Testing ◽

Mutation Status ◽

Thyroid Transcription Factor 1 ◽

Thyroid Transcription Factor ◽

Napsin A ◽

Therapeutic Decisions

Significant advances in targeted therapy have been made in recent years for patients with lung adenocarcinoma. These targeted therapies have made molecular testing of paramount importance to drive therapeutic decisions. Material for testing is often limited, particularly in cytology specimens and small core biopsies. A reliable screening tool is invaluable in triaging limited tissue and selection for epidermal growth factor receptor ( EGFR) mutation testing. We hypothesized that the immunohistochemistry (IHC) profile of lung adenocarcinoma predicts EGFR mutation status. In this retrospective study, we evaluated the thyroid transcription factor-1 (TTF-1)/napsin A IHC profile and EGFR mutation status in 339 lung adenocarcinomas at our academic institution. In our cohort, we found that 92.3% of cases were positive for TTF-1 and/or napsin A by IHC with an EGFR positivity rate of 17.3%. Importantly, 7.7% of the cases were dual TTF-1/napsin A negative, and none of these cases contained EGFR mutations. This finding supports the use of TTF-1 and napsin A IHC to identify cases where EGFR mutation status will be negative, thus preserving limited tissue for other ancillary testing.

Download Full-text

Unique MicroRNA and mRNA Interactions in EGFR-Mutated Lung Adenocarcinoma

Journal of Clinical Medicine ◽

10.3390/jcm7110419 ◽

2018 ◽

Vol 7 (11) ◽

pp. 419 ◽

Cited By ~ 3

Author(s):

Sophia Subat ◽

Kentaro Inamura ◽

Hironori Ninomiya ◽

Hiroko Nagano ◽

Sakae Okumura ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Mrna Expression ◽

Regulatory Network ◽

Egfr Mutation ◽

Expression Profiles ◽

Integrative Analysis ◽

Future Research ◽

Mutation Status ◽

Egfr Mutated ◽

Insight Into

The EGFR gene was one of the first molecules to be selected for targeted gene therapy. EGFR-mutated lung adenocarcinoma, which is responsive to EGFR inhibitors, is characterized by a distinct oncogenic pathway in which unique microRNA (miRNA)–mRNA interactions have been observed. However, little information is available about the miRNA–mRNA regulatory network involved. Both miRNA and mRNA expression profiles were investigated using microarrays in 155 surgically resected specimens of lung adenocarcinoma with a known EGFR mutation status (52 mutated and 103 wild-type cases). An integrative analysis of the data was performed to identify the unique miRNA–mRNA regulatory network in EGFR-mutated lung adenocarcinoma. Expression profiling of miRNAs and mRNAs yielded characteristic miRNA/mRNA signatures (19 miRNAs/431 mRNAs) in EGFR-mutated lung adenocarcinoma. Five of the 19 miRNAs were previously listed as EGFR-mutation-specific miRNAs (i.e., miR-532-3p, miR-500a-3p, miR-224-5p, miR-502-3p, and miR-532-5p). An integrative analysis of miRNA and mRNA expression revealed a refined list of putative miRNA–mRNA interactions, of which 63 were potentially involved in EGFR-mutated tumors. Network structural analysis provided a comprehensive view of the complex miRNA–mRNA interactions in EGFR-mutated lung adenocarcinoma, including DUSP4 and MUC4 axes. Overall, this observational study provides insight into the unique miRNA–mRNA regulatory network present in EGFR-mutated tumors. Our findings, if validated, would inform future research examining the interplay of miRNAs and mRNAs in EGFR-mutated lung adenocarcinoma.

Download Full-text

Squamous cell histological transformation beyond EGFR TKI treatment against EGFR-mutant lung adenocarcinoma

Annals of Oncology ◽

10.1093/annonc/mdv472.147 ◽

2015 ◽

Vol 26 ◽

pp. vii138

Author(s):

Hayato Koba ◽

Shingo Nishikawa ◽

Taro Yoneda ◽

Takashi Sone ◽

Hideharu Kimura ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Squamous Cell ◽

Histological Transformation ◽

Tki Treatment ◽

Egfr Mutant ◽

Egfr Tki

Download Full-text

Comparative Analysis of Two Methods for the Detection of EGFR Mutations in Plasma Circulating Tumor DNA from Lung Adenocarcinoma Patients

Cancers ◽

10.3390/cancers11060803 ◽

2019 ◽

Vol 11 (6) ◽

pp. 803 ◽

Cited By ~ 1

Author(s):

Ming-Szu Hung ◽

Jr-Hau Lung ◽

Yu-Ching Lin ◽

Yu-Hung Fang ◽

Shu-Yi Huang ◽

...

Keyword(s):

Lung Cancer ◽

Egfr Mutation ◽

Circulating Tumor Dna ◽

Egfr Mutations ◽

Cancer Tissue ◽

Lung Cancer Tissue ◽

First Line ◽

Mutation Status ◽

Egfr Tki ◽

Tumor Dna

Mutations in the epidermal growth factor receptor (EGFR) are associated with various solid tumors. This study aimed to compare two methods for the detection of EGFR mutations in circulating tumor DNA (ctDNA) from lung adenocarcinoma (LUAD) patients and to evaluate the clinical significance of EGFR mutations in ctDNA. In this prospective cohort study, the EGFR mutation status of 77 patients with stage IIIB or IV LUAD was first determined using lung cancer tissue. The amplification refractory mutation system (ARMS) and single allele base extension reaction combined with mass spectroscopy (SABER/MassARRAY) methods were also used to detect EGFR mutations in plasma ctDNA from these patients and then compared using the EGFR mutation status in lung cancer tissue as a standard. Furthermore, the relationship between the presence of EGFR mutations in ctDNA after receiving first-line EGFR-tyrosine kinase inhibitor (EGFR-TKI) therapy and survival was evaluated. The overall sensitivity and specificity for the detection of EGFR mutations in plasma ctDNA by ARMS and SABER/MassARRAY were 49.1% vs. 56% and 90% vs. 95%, respectively. The agreement level between these methods was very high, with a kappa-value of 0.88 (95% CI 0.77–0.99). Moreover, 43 of the patients who carried EGFR mutations also received first-line EGFR-TKI therapy. Notably, patients with EGFR mutations in plasma ctDNA had significantly shorter progression-free survival (9.0 months, 95% CI 7.0–11.8, vs. 15.0 months, 95% CI 11.7–28.2; p = 0.02) and overall survival (30.6 months, 95% CI 12.4–37.2, vs. 55.6 months, 95% CI 25.8–61.8; p = 0.03) compared to those without detectable EGFR mutations. The detection of EGFR mutations in plasma ctDNA is a promising, minimally invasive, and reliable alternative to tumor biopsy, and the presence of EGFR mutations in plasma ctDNA after first-line EGFR-TKI therapy is associated with poor prognosis.

Download Full-text