Value of radiomics model based on multi-parametric magnetic resonance imaging in predicting epidermal growth factor receptor mutation status in patients with lung adenocarcinoma

BackgroundThe epidermal growth factor receptor (EGFR) is an important therapeutic target for patients with non-small-cell lung cancer (NSCLC). Radiomics and radiogenomics have emerged as attractive research topics aiming to extract mineable high-dimensional features from medical images and show potential to correlate with the gene mutation. Herein, we aim to develop a magnetic resonance imaging (MRI)-based radiomics model for pretreatment prediction of the EGFR status in patients with lung adenocarcinoma.MethodsA total of 92 patients with pathologically confirmed lung adenocarcinoma were retrospectively enrolled in this study. EGFR genotype was analyzed by sequence testing. All patients were randomized into training and test group in a 7:3 ratio using the R software. Radiomics features were extracted from T2 weighted imaging (T2WI), diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC); radiomics signatures were built using the least absolute shrinkage and selection operator (LASSO) and logistic regression. Preoperative clinical factors and image features associated with EGFR were also evaluated. A nomogram including sex, smoking status, and radiomics signatures was constructed. A total of five radiomics models were built, and the area under the curve (AUC) was used to evaluate their performance of EGFR mutation prediction.ResultsAmong the three single-sequence models, the ADC model showed the best prediction performance. The AUCs of the ADC, DWI, T2WI prediction model in the test cohort were 0.805 (95% CI: 0.610 to 1.000), 0.722 (95% CI: 0.519 to 0.924), and 0.655 (95% CI: 0.438 to 0.872), respectively. Compared with the single-sequence model, the multi-sequence prediction model showed better performed [AUC_test =0.838 (95% CI: 0.685 to 0.992)]. The AUC of the nomogram in the training group was 0.925 (95% CI: 0.855 to 0.994) and 0.727 (95% CI: 0.531 to 0.924) in the test group, respectively.ConclusionsThe radiomics model based on MRI might have the potential to predict EGFR mutation in patients with lung adenocarcinoma. The multi-sequence model had better performance than other models.     

Factors that predict progression-free survival in Chinese lung adenocarcinoma patients treated with epidermal growth factor receptor tyrosine kinase inhibitors

Background

Although first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown efficacy in patients with advanced lung cancers, survival predictors with these drugs have not been extensively investigated. This study was performed to explore factors that may predict progression-free survival (PFS) in Chinese lung adenocarcinoma patients treated with EGFR-TKIs.

Methods

We retrospectively collected clinicopathologic data on 208 patients who received either gefitinib, erlotinib or icotinib, including the patients’ EGFR mutation status and levels of six serum tumor markers [carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cancer antigen 125 (CA125), squamous cell carcinoma antigen (SCC), cytokeratin-19 fragments (CYFRA21-1) and lactate dehydrogenase (LDH)]. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with PFS.

Results

At the study cutoff date, 189 (90.9%) of the patients met the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria for progressive disease (PD), while 19 (9.1%) had stable disease (SD). The median PFS of the 208 patients was 12.4 months (95% CI, 11.0–13.8 months). In the multivariate analysis using a Cox proportional hazard model, a non-smoking history [hazard ratio (HR) =2.460; 95% CI, 1.484–4.079; P<0.001], first-line treatment (HR =1.500; 95% CI, 1.062–2.119; P=0.021), and a high pretreatment serum level of CEA (HR =1.424; 95% CI 1.026–1.977; P=0.035) were found to be significant predictors of a longer PFS.

Conclusions

In Chinese lung adenocarcinoma patients treated with EGFR-TKIs, a non-smoking history, first-line EGFR-TKIs treatment and a high serum level of CEA were independent predictors of a longer PFS along with an EGFR-activating mutation.     

Cytoplasmic expression of G protein-coupled estrogen receptor 1 correlates with poor postoperative prognosis in non-small cell lung cancer

BackgroundA hormonal role in the development of non-small cell lung cancer (NSCLC) has been well documented, and the classic estrogen receptors (ERs)—ERα and ERβ have been extensively investigated over the past decade. The expression of ERβ was found to be high and display biological activity in NSCLC, but anti-estrogen therapy targeting this receptor has shown limited efficacy for the disease. The third estrogen receptor, G protein-coupled estrogen receptor 1 (GPER1/GPR30), was recently found to be highly expressed in NSCLC. Herein, we aimed to investigate the expression profile of GPER1 and correlate it with clinicopathological factors as well as postoperative prognosis in NSCLC.MethodsWe examined GPER1 and ERβ expression using immunohistochemistry among 183 NSCLC cases, including 132 lung adenocarcinoma (LUAD) with identified epidermal growth factor receptor (EGFR) mutation status and 51 squamous cell carcinoma (SCC) patients. We then conducted correlation analysis between the expression of GPER1 and clinicopathological factors and patients’ postoperative prognosis.ResultsPositive expression of GPER1 was categorized into 2 main classes: nuclei-GPER1 (nGPER1) and concurrent nuclei-and cytoplasm-GPER1 (n/cGPER1), according to its subcellular localization. The LUAD with wild-type EGFR (wt-EGFR) had a higher frequency of n/cGPER1 (50%) but a lower frequency of nGPER1 (31%) when compared with those with mutated EGFR (n/cGPER1: 31%, nGPER1: 41%, respectively). The expression of GPER1, regardless of subcellular localization, was positively correlated with tumor stage and lymph node metastasis. The median recurrence-free survival (mRFS) and overall survival (OS) were significantly worse in participants with n/cGPER1 expression than in those with nGPER1 or without GPER1 expression.ConclusionsThis study revealed that GPER1 is aberrantly highly expressed and presents a unique GPER1 expression profile in NSCLC. The n/cGPER1 expression was significantly associated with EGFR mutation status, tumor stage, lymph node metastasis, and poor postoperative prognosis in NSCLC.     

The role of ramucirumab with docetaxel in epidermal growth factor receptor mutant and wild-type non-small cell lung cancer

BackgroundRamucirumab paired with docetaxel extends progression free survival and overall survival in non-small cell lung cancer (NSCLC) following progression on platinum therapy. There is some data that epidermal growth factor receptor (EGFR) mutant disease would respond better to vascular endothelial growth factor receptor (VEGFR) therapy than EGFR wild type disease.MethodsThis retrospective, single-institution cohort study reports outcomes of patients who received docetaxel with or without ramucirumab according to EGFR status. Clinical data including age, performance status, metastatic burden and prior treatment history was obtained and reported with time on treatment and overall survival as primary endpoints. Data analysis was performed for three cohorts: EGFR mutant disease receiving docetaxel and ramucirumab (EGFR-doce/ram), EGFR mutant disease receiving docetaxel alone (EGFR-doce) and EGFR wild type disease receiving docetaxel and ramucirumab (WT-doce/ram).ResultsPatients in the EGFR-doce/ram cohort had a median time on docetaxel of 1.4 months (95% CI: 0.72–5.2 months) and of 0.8 months (95% CI: 0.2–6.5 months) on ramucirumab. Patients in the EGFR-doce cohort were on docetaxel for a median 1.4 months (95% CI: 0.9–2.4 months). Patients in the WT-doce/ram cohort had a median time on docetaxel of 2.3 months (95% CI: 1.6–4.1 months) and on ramucirumab of 1.4 months (95% CI: 0.8–3.2 months). There was no significant difference between time on ramucirumab or docetaxel between the cohorts. Overall survival for the three cohorts was noted to be 6.7 months (95% CI: 2.5–16.2 months) for the EGFR-doce/ram cohort, 4.9 months (95% CI: 4.2–12.5 months) for the EGFR-doce cohort and 6.6 months (95% CI: 4.3–12.8 months) for the WT-doce/ram cohort. There was no significant difference in overall survival between the cohorts.ConclusionsOur data did not support the initial hypothesis that patients with EGFR mutant disease would do better with the addition of ramucirumab. Our study was limited by small sample size, retrospective nature and inability to control for confounders including prior bevacizumab or immune checkpoint inhibitor (ICI) exposure. This study offers real-world estimates to clinicians and patients about the length of time they can expect to derive benefit from the combination of ramucirumab and docetaxel.     

Clinicopathological and prognostic significance of epidermal growth factor receptor overexpression in patients with esophageal adenocarcinoma: a meta‐analysis

The prognostic significance of epidermal growth factor receptor (EGFR) overexpression in patients with esophageal adenocarcinoma (EAC) remains controversial. Eligible studies that investigated the association between survival in EAC and the expression status of EGFR were identified by an electronic search of PubMed, EMBASE, and ISI Web of Science. A meta‐analysis was performed to clarify the impact of EGFR overexpression on clinicopathological parameters or overall survival (OS) in EAC. A total of seven studies including 1028 patients were subjected to the final analysis. The overall results suggested that overexpression of EGFR was significantly correlated with not only the depth of invasion, lymph node status, and tumors stage of EAC, with a pooled odds ratio of 2.99 (95% confidence interval [CI]: 1.07–8.35; Z = 2.09; P = 0.037), 3.05 (95% CI: 1.77–5.27; Z = 4.00; P < 0.001), and 5.37 (95% CI: 2.49–11.57; Z = 4.29; P < 0.001), respectively, but also the poorer OS with a pooled hazard ratio of 2.20 (95% CI: 1.47–3.31; Z = 3.79; P < 0.001). Overexpression of EGFR correlates with not only the clinicopathological features, but also the worse OS, and it might be useful as a predictive biomarker in clinical practice, yet the clinicopathological and prognostic role of EGFR in EAC still needs further confirmation by well‐designed prospective studies.     

Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma

Abstract: Transforming growth factor alpha (TGF-alpha) is thought to be involved in liver regeneration, cellular proliferation, and hepatocarcinog-enesis. We have looked at the relationship between TGF-alpha and it's receptor, and have attempted to relate the expression of TGF-alpha and it's receptor to the differentiation of hepatocellular carcinoma (HCC) on serial sections of HCC. We examined immunohistochemically the expression of the TGF-alpha and of epidermal growth factor receptor (EGFR) proteins in the same area of 53 nodules (<5 cm in diameter) of HCC obtained from patients. Immnnoreactive proteins were visualized by using a biotin-streptoavidin system (LSAB Kit, Dako). TGF-alpha was strongly expressed in 29 of 53 (54.7%) nodules. Specimens strongly positive for TGF-alpha were found mainly in well-differentiated HCC, while specimens positive for EGFR were found mainly in poorly differentiated HCC (p<0.05). In the tissues that stained weakly positive for TGF-alpha, the expression of EGFR differed significantly, according to the degree of HCC histologic differentiation (p<0.05). These results led us to speculate that the expression of TGF-alpha and EGFR might be related to the pattern of histologic differentiation of HCC.     

促愈颗粒对胃溃疡实验大鼠胃黏膜表皮生长因子及其受体表达的影响

[目的]研究促愈颗粒对乙酸烧灼型胃溃疡(GU)大鼠胃黏膜表皮生长因子(EGF)及其受体(EGFR)表达的影响。[方法]将大鼠随机分为4组:正常对照组,模型组,促愈颗粒组和雷尼替丁组。乙酸制备慢性GU大鼠模型后,于给药14 d和28 d后分2次处死大鼠,观察胃黏膜组织形态,免疫组织化学技术检测大鼠胃黏膜EGF及EGFR水平。[结果]与模型组比较,促愈颗粒组和雷尼替丁组囊状扩张腺体数量均显著减少(P<0.01,<0.05),EGF及EGFR水平均显著增高(P<0.01,<0.05),且促愈颗粒组作用均优于雷尼替丁组(均P<0.05)。[结论]促愈颗粒可能通过增加胃黏膜EGF和EGFR的水平,进而提高GU再生黏膜结构和功能成熟度,从而促进溃疡愈合,提高溃疡愈合质量,并防止溃疡复发。     

EGFR mutation types and abundance were associated with the overall survival of advanced lung adenocarcinoma patients receiving first-line tyrosine kinase inhibitors

BackgroundEpidermal growth factor receptor tyrosine kinases inhibitors (EGFR-TKIs) are currently recognized as the standard treatment for advanced non-small cell lung cancer (NSCLC) patients with EGFR mutations. Clinically found patients with different EGFR mutational status have different prognosis.MethodsA retrospective cohort study was performed to explore the relationship between EGFR mutations and abundance with patient survival by using patient data from the Affiliated Cancer Hospital of Zhengzhou University between January 2013 and November 2016. All patients involved in the present study had sensitive EGFR mutations [either exon 19 deletion (DEL) or exon 21 L858R] and treated by EGFR-TKIs. They were followed up every three months until lost or dead. Mutation abundance was calculated as the copies of EGFR mutation divided by copies of EGFR locus, and the cut-off values for 19DEL and L858R were 4.9% and 9.5%, respectively.ResultsTotal of 236 patients were included, comprising 116 (49.2%) patients with 19DEL mutation and 120 (50.8%) patients with L858R mutation. The median follow-up duration was 23.2 months (95% CI: 14.9–26.7 months). Overall survival (OS) was significantly longer in patients with 19DEL mutation (20.9 months, 95% CI: 17.7–24.1 months versus 17.0 months, 95% CI: 14.4–19.6 months in patients with L858R; P=0.008) and in patients with high mutation abundance (20.9 months, 95% CI: 18.3–23.5 months versus 13.0 months, 95% CI: 10.3–15.7 months in patients with low mutation abundance; P<0.001). Multivariate Cox regression including age, performance status and tumor stage revealed that longer OS was independently associated with 19DEL mutation (HR: 0.48, 95% CI: 0.39–0.67, P=0.033) and high mutation abundance (HR: 0.62, 95% CI: 0.50–0.79, P=0.027).ConclusionsEGFR mutation types and abundance was associated with the patients’ survival which might be used to predict the efficacy of targeted therapy by EGFR-TKIs.     

Correlation between epidermal growth factor receptor mutations and nuclear expression of female hormone receptors in non-small cell lung cancer: a meta-analysis

Background

Compared with male, female non-small cell lung cancer (NSCLC) patients have better response when treated with epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), suggesting a potential association between female hormones and EGFR mutation. However, the results provided by previous studies were inconclusive and controversial. We sought to examine the link between the expression of nuclear female hormone receptors and EGFR mutations in NSCLC.

Methods

Electronic databases were used to search the relevant articles. The involved hormone receptors included estrogen receptor (ER) and progesterone receptor (PR). The primary endpoint was the occurrence of ER/PR expression and EGFR mutation in NSCLC patients.

Results

Five studies fulfilled the criteria and were included in our analysis. Patients with high ER-β expression had higher positive EGFR mutation than low ER-β patients (44.2% vs. 23.7%), and there was a significant difference between the two groups [odds radio (OR) 3.44, 95% confidence interval (CI): 2.40-4.93, Z=6.72, P<0.001]. However, there is no significant correlation between EGFR mutations and ER-α (when included ER-α3, OR 1.20, 95% CI: 0.62-2.33, Z=0.55, P=0.58; and when included ER-α4, OR 1.18, 95% CI: 0.62-2.25, Z=0.51, P=0.61) or PR (OR 1.29, 95% CI: 0.40-4.10, Z=0.43, P=0.67). No significant publication bias was observed.

Conclusions

High nuclear expression of ER-β, but not ER-α or PR is correlated with EGFR mutations in NSCLC. The underlying mechanism and potential translational relevance warrant further investigation.     

EGFR immunoexpression,RAS immunoexpression and their effects on survival in lung adenocarcinoma cases

Background

The impacts of epidermal growth factor receptor (EGFR) immunoexpression and RAS immunoexpression on the survival and prognosis of lung adenocarcinoma patients are debated in the literature.

Methods

Twenty-six patients, who underwent pulmonary resections between 2002 and 2007 in our clinic, and whose pathologic examinations yielded adenocarcinoma, were included in the study. EGFR and RAS expression levels were examined by immunohistochemical methods. The results were compared with the survival, stage of the disease, nodal involvement, lymphovascular invasion, and pleural invasion. Nonparametric bivariate analyses were used for statistical analyses.

Results

A significant link between EGFR immunoexpression and survival has been identified while RAS immunoexpression and survival have been proven to be irrelevant. Neither EGFR, nor RAS has displayed a significant link with the stage of the disease, nodal involvement, lymphovascular invasion, or pleural invasion.

Conclusions

Positive EGFR immunoexpression affects survival negatively, while RAS immunoexpression has no effect on survival in lung adenocarcinoma patients.     

Clinicopathological features and epidermal growth factor receptor mutations associated with epithelial–mesenchymal transition in non-small cell lung cancer

Background and objective:   Small molecular inhibitors of the epidermal growth factor receptor (EGFR) have been extensively studied in non-small cell lung cancer (NSCLC) patients. The discovery of molecular biomarkers that identify the subgroups of NSCLC patients benefiting from EGFR tyrosine kinase inhibitor (TKI) has become an important area of investigation. Recent studies have suggested that epithelial–mesenchymal transition (EMT) in tumours decreases the cellular requirements for EGFR signalling pathway, and this may provide a molecular signature to define those NSCLC patients most likely to respond to treatment with targeted EGFR TKI. This research explored the clinicopathological features and EGFR mutations associated with EMT in NSCLC.
Methods:   The EMT status in surgically resected specimens from 62 patients with NSCLC was tested by immunohistochemical staining. The frequency of tumour epithelial phenotype was calculated and the strength of the association with clinicopathological features and EGFR genotype was determined by logistic regression.
Results:   The overall frequency of the epithelial phenotype was 35.48% (22 of 62). Based on univariate analyses, the frequency of the epithelial phenotype (E-cadherin-positive) was greater for EGFR mutants versus wild types (77.78% vs 18.18%; P  < 0.0001) and women versus men (54.55% vs 25%; P  = 0.02). Multivariate logistic analysis showed that only the EGFR genotype (odds ratio, 0.063; 95% CI: 0.013–0.3; P  = 0.0005) was significantly associated with the epithelial phenotype.
Conclusion:   In patients with NSCLC, there is a higher frequency of epithelial markers in patients with EGFR mutation.     

非小细胞肺癌患者EGFR、ALK基因突变及临床病理特征与预后的相关性研究

目的探讨非小细胞肺癌(NSCLC)患者EGFR、ALK基因突变状态及病理特征,分析二者与患者预后情况相关性。方法收集2015年1月至2018年1月苏州大学附属第一医院病理确诊的NSCLC病例262例,记录患者临床病理特征及转归,采用突变增阻滞系统(ARMS)-Taqman探针法及RT-PCR检测患者肿瘤样本的EGFR和ALK基因外显子突变情况,采用Kaplan-Meier法和Cox风险回归考察不同基因突变情况的预后、临床病理特征与临床结局的相关性。结果262例NSCLC患者中,168例为野生型,ALK突变12例,突变率4.6%;EGFR突变82例,突变率31.30%,其中18号外显子突变2例,19号外显子突变37例,20号外显子突变9例,21号外显子突变31例;各组间年龄、病理类型比较差异有统计学意义,P<0.05;Wild type组中位OS时间11.6月,ALK组中位OS时间15.0月,EGFR组中位OS时间36.8月,EGFR组OS明显优于ALK组OS时间及Wild type组OS时间,P<0.05;EGFR19号外显子突变组、21号外显子突变组OS生存时间显著高于18号外显子突变组和20号外显子突变组,P<0.05;EGFR阴性(RR=15.751,95%CI:9.252~26.816)、鳞癌(RR=18.344,95%CI:6.187~54.388)为OS的危险因素。结论EGFR突变状态、病理类型对非小细胞肺癌预后具有良好的预测价值,鳞癌和EGFR阴性患者生存期短。EGFR基因少见突变(18号外显子、20号外显子)患者的中位OS时间更短。     

Chromosomal imbalances in lung adenocarcinomas with or without mutations in the epidermal growth factor receptor gene

Background and objective: Epidermal growth factor receptor (EGFR) mutations are common in lung adenocarcinomas of Asian patients, implying a good response to treatment with the EGFR tyrosine kinase inhibitors, gefitinib and erlotinib. However, the distinct chromosomal imbalances between lung adenocarcinomas with and those without EGFR mutations have not been fully elucidated. Methods: Seventy‐seven patients of surgically resected lung adenocarcinoma were analysed for the EGFR exon 19 deletion and the L858R mutation, using mutant‐enriched PCR, and for chromosomal imbalance alterations using comparative genomic hybridization. Results: EGFR mutations were detected in 42 (54.5%) patients, including 22 with the exon 19 deletion and 20 with the L858R mutation. The mean number of chromosomal arms with imbalance alterations was significantly higher in tumours with EGFR mutations than in those lacking these two mutations. The minimal regions with gain on 1q23–q31, 6p12–p21.1 and 7q11.2, and loss on 3p21, 8p22–p23, 9q33, 10q25 and 13q13, differed significantly between lung adenocarcinomas with or without EGFR mutations. However, neither EGFR mutations, nor any of the common chromosomal imbalance alterations alone, exhibited significant associations with tumour stage or disease‐specific survival of the patients. Conclusions: These results indicate that imbalance alterations at several chromosomal regions occur significantly more frequently in lung adenocarcinomas with EGFR mutations than in those without such mutations. Tumour growth‐related genes in these chromosomal regions should be further investigated to improve our understanding of the common genetic alterations in lung adenocarcinomas with EGFR mutations.     

Impact of EGFR mutation status on tumor response and progression free survival after first-line chemotherapy in patients with advanced non-small-cell lung cancer: a meta-analysis

Objectives

Non-small-cell lung cancer (NSCLC) patients harboring sensitive epidermal growth factor receptor (EGFR) mutations derive greater benefits from EGFR-tyrosine kinase inhibitors (EGFR-TKIs) than those with wild type tumors. However, whether EGFR mutation status is associated with the efficacy of cytotoxic chemotherapy or prognosis in advanced NSCLC patients remained controversial. Thus, we sought to conduct a meta-analysis to answer this question.

Methods

Electronic databases were searched for eligible literatures. The primary outcomes were objective response rate (ORR) and 6-month progression-free survival (PFS) rate. The pooled odds ratio (OR) was calculated using random-effects model. Subgroup analyses stratified by study types, EGFR mutation detection methods, chemotherapy regimens, and patient origins were proposed.

Results

A total of 14 studies involving 1,772 advanced NSCLC patients with known EGFR mutation status who had received first-line chemotherapy were included. Patients with positive EGFR mutation had numerically higher ORR than wild type patients (36.2% vs. 30.1%) without significant differences (OR 1.24, 95% CI, 0.90 to 1.70; P=0.19). However, patients with EGFR mutants had significantly superior 6-month PFS rate than wild-type patients (58.6% vs. 47.2%; OR 1.88, 95% CI, 1.33 to 2.65; P=0.0003). Results of the subgroup analyses were concordant with the overall ones.

Conclusions

This comprehensive analysis revealed that advanced NSCLC patients with sensitivity EGFR mutation had higher 6-month PFS rate and potentially greater ORR compared with wild-type patients after first-line chemotherapy. It suggested that EGFR mutation status should be considered a significant factor for patient stratification in evaluating the efficacy of antitumor agents in addition to EGFR-TKIs.     

FDG‐PET SUV‐max values do not correlate with epidermal growth factor receptor mutation status in lung adenocarcinoma

Previous reports suggest a correlation between positron emission tomography with fluorodeoxyglucose maximum standardized uptake value (SUVmax) and epidermal growth factor receptor (EGFR) mutation status in lung cancer. We analysed positron emission tomography with fluorodeoxyglucose SUVmax in 14 patients with EGFR mutations, and a control group of 14 subjects with wild‐type EGFR adenocarcinomas. The mean SUV value was 10.7 for EGFR‐mutated adenocarcinomas and 9.9 for wild‐type tumours. There was no correlation between SUV values and EGFR mutation status. Omitting EGFR testing in lung cancers with low SUVmax is not appropriate.     

Long-term survival in a patient with advanced non-smoking lung adenocarcinoma and no EGFR mutation after comprehensive therapy with EGFR-TKI-based therapy: A case report

Rationale:This is the first known report to describe a case of advanced non-smoking lung adenocarcinoma with no epidermal growth factor receptor mutation after comprehensive epidermal growth factor receptor-tyrosine kinase inhibitor-based therapy that survived for nearly 12 years.Patient concerns:A 48-year-old Chinese woman that came to our hospital with a left supraclavicular mass.Diagnosis:The final diagnosis was left lung adenocarcinoma with left supraclavicular lymph node metastasis, cT1N3M0 IIIB (International association for the Study of lung cancer 6th version).Interventions:After 4 months of 4 cycles of chemotherapy, gefitinib was administered alone for 5.5 years. Local radiotherapy (40GY/20F) was administered for 1 month, and osimertinib alone was followed for 4.5 years. A combination of pemetrexed with oxaliplatin and hyperthermia at the same time was administered for 4 cycles. Toripalimab and anlotinib were administered for 3 months. Since then, the patient had been taking a double dose of icotinib herself.Outcomes:The patient has survived for nearly 12 years since diagnosis of lung cancer.Lessons:Our case is of significant importance to clinicians involved in the treatment of patients with advanced nonsmoking lung adenocarcinoma and no epidermal growth factor receptor mutations.     

Correlation between familial cancer history and epidermal growth factor receptor mutations in Taiwanese never smokers with non-small cell lung cancer: a case-control study

Background

Lung cancer is a leading cause of cancer deaths in the world. Cigarette smoking remains a prominent risk factor, but lung cancer incidence has been increasing in never smokers. Genetic abnormalities including epidermal growth factor receptor (EGFR) mutations predominate in never smoking lung cancer patients. Furthermore, familial aggregations of patients with these mutations reflect heritable susceptibility to lung cancer. The correlation between familial cancer history and EGFR mutations in never smokers with lung cancer requires investigation.

Methods

This was a retrospective case-control study that evaluated the prevalence of EGFR mutations in lung cancer patients with familial cancer history. Never smokers with lung cancer treated at a hospital in Taiwan between April 2012 and May 2014 were evaluated. Inclusion criteria were never smokers with non-small cell lung cancer (NSCLC). Exclusion criteria involved patients without records of familial cancer history or tumor genotype.

Results

This study included 246 never smokers with lung cancer. The study population mainly involved never smoking women with a mean age of 60 years, and the predominant tumor histology was adenocarcinoma. Lung cancer patients with familial cancer history had an increased prevalence of EGFR mutations compared to patients without family history [odds ratio (OR): 5.9; 95% confidence interval (CI): 3.3-10.6; P<0.001]. Specifically, 57 out of 85 cancer patients (67%) with familial cancer history had these mutations, while 41 out of 161 patients (25%) without family history harbored mutations. Subgroup analysis also revealed that patients with familial lung cancer history had stronger association with EGFR mutations (OR: 7.5; 95% CI: 3.4-16.3; P<0.001) compared to patients with family history of non-pulmonary cancers (OR: 5.0; 95% CI: 2.5-10.0; P<0.001).

Conclusions

The study demonstrated an increased prevalence of EGFR mutations in Taiwanese never smoking lung cancer patients with familial cancer history. Moreover, a sizable proportion of never smoking cancer patients harbored these mutations. These observations have implications for the treatment of lung cancer in never smokers.     

Acquired resistance of non-small cell lung cancer to epidermal growth factor receptor tyrosine kinase inhibitors

Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.