Growth Factor Receptor-mutant Lung Cancer Research Articles

Adjuvant therapies in stages I-III epidermal growth factor receptor-mutated lung cancer: current and future perspectives.

Surgical resection followed by adjuvant cisplatin-based chemotherapy is the recommended treatment for patients with completely resected stage IB-IIIA non-small cell lung cancer (NSCLC). Even with the best management, recurrence is common and increases with disease stage (stage I: 26-45%; stage II: 42-62%; stage III: 70-77%). For patients with metastatic lung cancer and tumours that harbour epidermal growth factor receptor (EGFR) mutations, EGFR-tyrosine kinase inhibitors (TKIs) have improved survival. Their effectiveness in advanced stages of NSCLC raises the possibility that these agents may improve outcomes for patients with resectable EGFR-mutated lung cancer. In the ADAURA study, adjuvant osimertinib provided a significant improvement in disease-free survival (DFS) and reduced central nervous system (CNS) disease recurrence in patients with resected stage IB-IIIA EGFR-mutated NSCLC, with or without prior adjuvant chemotherapy. To reap the maximum benefits of EGFR-TKIs for patients with lung cancer, the early and rapid identification of EGFR mutations [and other oncogenic drivers, such as programmed cell death-ligand 1 (PD-L1), with matched targeted therapies] in diagnostic pathologic specimens has become essential. To ensure patients receive the most appropriate treatment, routine, comprehensive histological, immunohistochemical, and molecular analyses (with multiplex next generation sequencing) should be undertaken at the time of diagnosis. The potential for personalised treatments to cure more patients with early-stage lung cancer can only be realised if all therapies are considered when the care plan is formulated, by the multi-specialty experts managing patients. In this review, we discuss the progress and prospects for adjuvant treatments as part of a comprehensive plan of care for patients with resected stages I-III EGFR-mutated lung cancer, and explore how the field could go beyond DFS and overall survival to make cure a more frequent outcome of treatment in patients with resected EGFR-mutated lung cancer.

New prognostic system specific for epidermal growth factor receptor-mutated lung cancer brain metastasis.

Brain metastases (BM) from lung cancer are heterogeneous, and accurate prognosis is required for effective treatment strategies. This study aimed to identify prognostic factors and develop a prognostic system exclusively for epidermal growth factor receptor (EGFR)-mutated lung cancer BM. In total, 173 patients with EGFR-mutated lung cancer from two hospitals who developed BM and received tyrosine kinase inhibitor (TKI) and brain radiation therapy (RT) were included. Univariate and multivariate analyses were performed to identify significant EGFR-mutated BM prognostic factors to construct a new EGFR recursive partitioning analysis (RPA) prognostic index. The predictive discrimination of five prognostic scoring systems including RPA, diagnosis-specific prognostic factors indexes (DS-GPA), basic score for brain metastases (BS-BM), lung cancer using molecular markers (lung-mol GPA) and EGFR-RPA were analyzed using log-rank test, concordance index (C-index), and receiver operating characteristic curve (ROC). The potential predictive factors in the multivariable analysis to construct a prognostic index included Karnofsky performance status, BM at initial lung cancer diagnosis, BM progression after TKI, EGFR mutation type, uncontrolled primary tumors, and number of BM. In the log-rank test, indices of RPA, DS-GPA, lung-mol GPA, BS-BM, and EGFR-RPA were all significant predictors of overall survival (OS) (p ≤ 0.05). The C-indices of each prognostic score were 0.603, 0.569, 0.613, 0.595, and 0.671, respectively; The area under the curve (AUC) values predicting 1-year OS were 0.565 (p=0.215), 0.572 (p=0.174), 0.641 (p=0.007), 0.585 (p=0.106), and 0.781 (p=0.000), respectively. Furthermore, EGFR-RPA performed better in terms of calibration than other prognostic indices.BM progression after TKI and EGFR mutation type were specific prognostic factors for EGFR-mutated lung cancer BM. EGFR-RPA was more precise than other models, and useful for personal treatment.

PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer

AimTo determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC. MethodsConsecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010–31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan–Meier method. Results455 patients were included (267 EGFR-mutated, EGFR-M+; 188 EGFR-wildtype, wt). Median age at diagnosis was 65 years, 52.3% (238/455) of patients were males, 62.9% (286/455) of patients were never-smokers and 92.5% (421/455) of patients had R0 resection. Stage IA comprised 42.4% (193/455) of patients, Stage IB comprised 23.1% (105/455) of patients, Stage IIA comprised 10.8% of patients (49/455), Stage IIB comprised 5.1% of patients (23/455) and Stage IIIA comprised 18.7% (85/455) of patients. Among EGFR-M+, 45.3% (121/267) were Ex19del and 41.9% (112/267) were L858R. PD-L1 ≥1% among EGFR-M+ and EGFR-wt was 45.3% (121/267) and 54.8% (103/188) respectively (p = 0.047).At median follow-up of 47 months, 178 patients had relapsed. Among EGFR-M+, 2-year DFS comparing PD-L1 <1% and PD-L1 ≥1% was 78.1% and 67.6% (p = 0.007) while 5-year OS was 59.5% and 42.8% (p = 0.001), respectively. Controlling for age, gender, lymphovascular invasion, adjuvant therapy and resection margin status, PD-L1 ≥1% (hazard ratio, HR 2.18, 95% CI 1.04–4.54, p = 0.038), stage IIB (HR 7.78, 95% CI 1.72–35.27, p = 0.008) and stage IIIA (HR 4.45, 95% CI 1.44–13.80, p = 0.01) emerged as independent predictors of inferior OS on multivariable analysis.In exploratory analysis, genomic analysis of 81 EGFR-M+ tumours was performed. PD-L1 ≥1% tumours had significantly higher rates of TP53 mutations (36.1% versus 15.6%, p = 0.04), with predominantly missense mutations. ConclusionPD-L1 ≥1% is an independent predictor of worse OS among early-stage EGFR-mutated NSCLC and is associated with inferior DFS regardless of EGFR status. PD-L1 score as a risk stratification factor should be evaluated in prospective adjuvant studies among EGFR-mutated NSCLC.

Overall survival benefits of first-line treatments for Asian patients with advanced epidermal growth factor receptor-mutated non-small cell lung cancer harboring L858R mutation: A systematic review and network meta-analysis.

e21064 Background: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and their biologically synergistic combinations with other treatments for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) as first-line treatment for EGFR-mutant NSCLC have recently gained considerable attention, in particular for those with L858R mutation, a known worse subgroup compared to exon 19 deletions. However, their efficacy, in particular, the long-term overall survival (OS) benefit in Asian patients with the L858R mutation remains unclear. Methods: We performed a systematic review and fixed-effects frequentist network meta-analysis by retrieving relevant literature from PubMed/MEDLINE Ovid, Embase, Cochrane Library, CINAHL Databases, trial registries and other sources. P-score was used to rank the treatments. We included published and gray sources of randomized clinical trials comparing two or more treatments in the first line setting for Asian patients with advanced EGFR mutated NSCLC harboring L858R mutation. This study was registered in the Prospective Register of Systematic Reviews (CRD42022295897). Results: Eighteen trials involved 1852 Asian patients and 12 treatments: including EGFR tyrosine kinase inhibitors (TKIs; osimertinib, dacomitinib, afatinib, erlotinib, gefitinib, and icotinib), pemetrexed-based chemotherapy, pemetrexed-free chemotherapy, and combination treatments (gefitinib plus apatinib, erlotinib plus ramucizumab, erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy). Asian patients with the L858R mutation had no significant OS benefits from all EGFR TKIs or combination treatments over chemotherapies. Gefitinib plus pemetrexed-based chemotherapy, dacomitinib, osimertinib and erlotinib plus bevacizumab were shown to be consistent in yielding the best progression-free survival benefit, with their corresponding P-scores of 93%, 79%, 77% and 70%. Combination treatments caused more toxicity in general, especially erlotinib plus bevacizumab and gefitinib plus pemetrexed-based chemotherapy, which caused the most adverse events of grade 3 or higher. Conclusions: In Asian patients with advanced NSCLC harboring L858R mutation, EGFR TKIs and combination treatments demonstrated no OS benefit when compared with conventional chemotherapies. Further studies are warranted to investigate the resistance mechanism with TKIs and potential combination strategies in patients with the L858R mutation.

Prognostic significance associated with the number of compound mutations in epidermal growth factor receptor-mutated non-small cell lung cancer.

Prognostic significance associated with the number of compound mutations in epidermal growth factor receptor-mutated non-small cell lung cancer.

Histologic transformation of epidermal growth factor receptor–mutated lung cancer

PurposeThis study aimed to determine the incidence and clinical course of epidermal growth factor receptor (EGFR)-mutated lung cancer with histologic transformation (HT). Patients and methodsWe conducted a multicentre, retrospective, cohort study of patients with advanced EGFR-mutated lung cancer who received EGFR-tyrosine kinase inhibitors (TKIs) between 2012 and 2019. The primary outcome was the incidence of HT. The secondary outcome was treatment efficacy in patients with HT. ResultsIn total, 6356 patients were enrolled. In 2624 patients, the histological type was proven by rebiopsy after acquiring resistance to EGFR-TKIs. Among them, 74 patients had HT (incidence rate: 2.8% [95% confidence interval: 2.3%–3.5%]). The median progression-free survival after EGFR-TKIs and first-line therapy after confirming HT was 10.4 and 4.4 months, respectively, which was not significantly different between patients with transformation to high-grade neuroendocrine carcinoma and those with transformation to another subtype of non–small cell lung cancer. Overall survival after confirming HT was 12.2 months. Twenty-seven patients received immune checkpoint inhibitors: 6 and 21 received immune checkpoint inhibitors before and after confirming HT, respectively. No patients achieved 1-year progression-free survival. The median progression-free survival after immune checkpoint inhibitor therapy after confirming HT was 1.6 months. ConclusionHT occurred in approximately 3% of EGFR-mutated patients who developed resistance to EGFR-TKIs. Cytotoxic agents are likely to be effective in patients with HT. However, the therapeutic effectiveness of immune checkpoint inhibitors was limited in these patients. Given the rarity of HT and absence of prospective trials, our findings are important to inform the treatment of these patients.

Targeted therapy for drug-tolerant persister cells after imatinib treatment for gastrointestinal stromal tumours.

Despite the effectiveness of tyrosine kinase inhibitors (TKI), gastrointestinal stromal tumours (GIST) develop after the withdrawal of TKI. Based on previous studies, a subpopulation of drug-tolerant cells called "persister cells" may be responsible for the recurrence and have thus, gained attention as a novel target in cancer therapy. The metabolic changes were investigated in imatinib-derived persister GIST cells. We investigated the efficacy and the mechanism of GPX4 inhibitor, which is known as a major inducer of "ferroptosis". We also evaluated the effects of RSL3 to the gefitinib-derived persister lung cancer cells. We demonstrated a downregulation of glucose metabolism, subsequent decrease in the glutathione level and sensitivity to glutathione peroxidase 4 (GPX4) inhibitor, RSL3 in persister cells. As the cell death induced by RSL3 was found to be "iron-dependent" and "caspase-independent", loss of GPX4 function could have possibly induced selective persister cell ferroptotic death. In the xenograft model, we confirmed the inhibition of tumour regrowth after discontinuation of imatinib treatment. Moreover, RSL3 prevented the growth of gefitinib-derived persister lung cancer cells. RSL3 combined with TKI may be a promising therapy for both GIST and epidermal growth factor receptor-mutated lung cancer.

Cost-effectiveness analysis of tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib and osimertinib) as first-line therapy for epidermal growth factor receptor-mutated advanced non-small cell lung cancer

Cost-effectiveness analysis of tyrosine kinase inhibitors (erlotinib, gefitinib, afatinib and osimertinib) as first-line therapy for epidermal growth factor receptor-mutated advanced non-small cell lung cancer

Adjuvant Targeted Therapy for Patients With Epidermal Growth Factor Receptor–Mutant Lung Cancer

Adjuvant Targeted Therapy for Patients With Epidermal Growth Factor Receptor–Mutant Lung Cancer

Anaplastic Lymphoma Kinase Fusion: A Review of Therapeutic Drugs and Treatment Strategies.

The prognosis of advanced non-small cell lung cancer (NSCLC) patients has improved in recent decades, especially for patients with an oncogenic driver mutation. Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) are effective for patients with the echinoderm microtubule-associated protein-like 4-ALK fusion gene. Several ALK-TKIs have been established: the first-generation ALK-TKI, crizotinib; second-generation ALK-TKIs, alectinib and ceritinib; and third-generation ALK-TKI, lorlatinib. Some ALK-TKIs are effective for tumors that are resistant to other ALK-TKIs; however, as is known in epidermal growth factor receptormutant lung cancer, tumor resistance is inevitable. ALK-positive NSCLCs acquire resistance via various mechanisms, making it a heterogeneous disease. Therefore, it is necessary to develop next-generation treatment strategies, such as the use of next-generation ALK-TKIs for secondary mutations, or combination therapies with ALK-TKIs and other TKIs. In this review, we summarize the development and use of ALK-TKIs, prior pivotal clinical trials, and resistance mechanisms.

Patterns of brain metastasis in anaplastic lymphoma kinase - rearranged and epidermal growth factor receptor-mutated lung cancer patients in magnetic resonance imaging.

Introduction:The optimal management of neuroparenchymal lesions in cases of lung cancer is exigent as this frequent yet notorious complication negatively impacts the morbidity and mortality index.Aims:This study is aimed at recognizing various patterns of neuroparenchymal metastasis in patients of lung cancer with epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-positive mutations.Material and Methods:The radiological findings of the neuroparenchymal lesions were analyzed and the statistical data were charted. We identified two groups of patients with neuroparenchymal lesions among a cohort of 340 patients having EGFR-positive (68) and ALK-positive (24) mutations (total: 24 + 68 = 92).Results:We observed that among the ALK group, leptomeningeal spread was less compared to EGFR group (2/24 as opposed to 18/68). Morphological heterogeneity and central necrosis in the parenchymal lesion which were associated with unfavorable outcomes were predominant in ALK group (8/24) as opposed to EGFR group (2/68). Ancillary findings but pertinent to survival and morbidity such as presence of perilesional edema, hemorrhage, and hydrocephalus on magnetic resonance imaging were also analyzed. The mutation-specific differential imaging spectrum could be attributed to biological differences between these cancers.

The predictive and prognostic significance of liquid biopsy in advanced epidermal growth factor receptor-mutated non-small cell lung cancer: A prospective study

ObjectiveTo determine the predictive and prognostic roles of three blood-based biomarkers: circulating tumour DNA (ctDNA), circulating tumour cells (CTC) and carcinoembryonic antigen (CEA), in patients with advanced epidermal growth factor receptor-mutated (EGFR+) lung cancer. Materials and methodsWe recruited 28 patients with 103 serial blood samples. We performed mutational analyses for EGFR mutations using droplet digital PCR (ddPCR) on ctDNA. We evaluated the accuracy of EGFR mutation detection in ctDNA compared with tissue biopsy. We also quantified CTCs, ctDNA and CEA in serially collected blood samples, and evaluated the baseline and changes in these blood-based biomarkers with clinical outcomes. ResultsEGFR mutation detection in plasma was highly concordant as compared with tissue biopsy. Detectable baseline ctDNA was associated with higher disease burden (p < 0.01). Early disappearance of ctDNA at 4 weeks was associated with radiological response at 12 weeks of treatment (p = 0.01) and improved progression free survival (PFS) (HR 5.47, 95%CI 1.32–22.72, p = 0.02) and overall survival (OS) (HR 5.46, 95%CI 1.28–23.22, p = 0.02). A decrease in CTC count at 4 weeks was associated with improved PFS (HR 3.81, 95%CI 1.13–12.79, p = 0.03) but not OS. 85% of patients with radiological progression had a ctDNA rise compared with 22% of patients with stable disease (p=0.01). ctDNA rise was seen on average 170 days prior to radiological progression. There is a significant association between the rise of CEA level with radiological progression (p=0.001). ConclusionEarly change in ctDNA, CTC and CEA levels may be long-term predictors of treatment benefit and failure prior to availability of radiological response data.

Sporadic synchronous triple primary cancers in elderly female: Microsatellite instability high resectable colon cancer, epidermal growth factor receptor-mutated metastatic lung cancer, and neuroendocrine tumor of appendix

Colorectal cancer and lung cancer are the most common malignancies in the world. However, not all pulmonary nodules in a case of colon cancer are considered as metastasis, especially with features suggestive of limited colon disease without any nodal or liver involvement. The morphology of the pulmonary nodules is also an important consideration before subjecting the patient to another invasive procedure, as solitary pulmonary nodule with irregular margins, suggestive of another primary lesion. We describe a case of a patient with colon cancer, nonsmall cell lung cancer with single bone lesion, and neuroendocrine tumor of appendix. Initially suspected to be a case of metastatic colon cancer, the patient was later diagnosed as epidermal growth factor receptor-mutant metastatic pulmonary adenocarcinoma, with localized microsatellite instability high phenotype colon cancer.

Decreased human antigen�R expression confers resistance to�tyrosine kinase inhibitors in epidermal growth factor receptor-mutant lung cancer by inhibiting Bim expression

Primary resistance to epidermal growth factor receptor‑tyrosine kinase inhibitors (EGFR‑TKIs) is an obstacle for the treatment of non‑small cell lung cancer (NSCLC); however, the associated mechanisms are not well understood. Studies have reported that Bim expression levels may be associated with the efficacy of EGFR‑TKI treatment in NSCLC patients harboring EGFR mutations. Human antigenR (HuR) regulates the mRNA and protein expression of target genes, including certain B‑cell lymphoma2 family members. The present study investigated whether HuR mediates resistance to EGFR‑TKIs via the regulation of Bim. The results demonstrated that decreased levels of HuR and Bim protein expression are associated with primary resistance to EGFR‑TKIs and reduced median progression‑free survival in NSCLC patients. Invitro assays also revealed that knockdown of HuR resulted in primary EGFR‑TKI resistance and reduced gefitinib‑induced apoptosis in HCC827 cells by decreasing Bim expression. Furthermore, elevated HuR expression restored gefitinib sensitivity and enhanced gefitinib‑induced apoptosis in H1650 cells by increasing Bim expression. Invivo, it was further demonstrated that overexpression of HuR was able to restore the gefitinib sensitivity of H1650 cells. Therefore, altered HuR/Bim expression is proposed to be a novel mechanism of EGFR‑TKI resistance in NSCLC.

Abstract 2414: Interrogating cellular metabolism reveals mTORC2 as a new biomarker to stratify epidermal growth factor receptor-mutant non-small cell lung cancer

Abstract Most non-small cell lung cancer (NSCLC) patients with epidermal growth factor (EGFR) mutations initially respond to EGFR tyrosine-kinase inhibitors (TKIs), but these inhibitors are only effective for approximately one year, thus limiting the benefits to patients' survival. Stratification of patients with EGFR-mutant NSCLC would help physicians personalize and optimize patient treatment plans. To this end, we hypothesized that factors residing in the tumor microenvironment play a pivotal role in the evolutionary dynamics of therapeutic response to anti-EGFR therapies. We used the Operetta® High Content Imaging System to track cell dynamics over time under different microenvironmental stresses, and we found that the growth of TKI-resistant cells is more sensitive to glucose starvation than TKI-sensitive cells. To further interrogate cellular metabolism in TKI-sensitive and resistant cells, we utilized both seahorse metabolic assays and fluorescence lifetime imaging microscopy to monitor the changes in glycolysis and oxidative phosphorylation of living cells. We found TKI-resistant cells have higher glycolysis and lower oxidative phosphorylation rates compared to TKI-sensitive cells. Such metabolic reprogramming rendered TKI-resistant cells with lower metabolic plasticity to cope with metabolic stress. Using both genetic and pharmacologic approaches, we then demonstrated that mTORC2 activation contributes to the different metabolic phenotypes between TKI-sensitive and resistant cells. Furthermore, gene set enrichment analysis showed that the oxidative phosphorylation gene set is significantly enriched in patients with low mTORC2 activation, and the glycolysis gene set is upregulated in patients with high mTORC2 activation, which is correlated with shorter progression-free and overall survival time in patients. Overall, these data suggest that TKI-resistant cells use and require distinct metabolic programs that can be employed to stratify EGFR-mutant NSCLC patients for treatment with EGFR-TKIs. Citation Format: Chun-Te Chiang, Nolan Ung, Alexandra N. Demetriou, Chi-Li Chiu, Niha Choudhury, Cosimo Arnesano, Scott E. Fraser, David B. Agus, Naim Matasci, Dan L. Ruderman, Shannon M. Mumenthaler. Interrogating cellular metabolism reveals mTORC2 as a new biomarker to stratify epidermal growth factor receptor-mutant non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2414.

Osimertinib a new weapon in epidermal growth factor receptor-mutated non-small cell lung cancer patients

Non-small-cell lung cancer (NSCLC) accounts for about 85% of all new lung cancer diagnoses every year worldwide (1). Unfortunately, in most cases the diagnosis is made when the disease is already in a metastatic stage with the systemic therapy being the standard-of-care. In approximatively 20% of Caucasian NSCLC patients (2), and in about 50% of Eastern Asian ones (3), an oncogene-addicted NSCLC is diagnosed, due to the presence of epidermal growth factor receptor ( EGFR ) activating mutations or anaplastic lymphoma kinase ( ALK ) and proto-oncogene tyrosine-protein kinase ROS ( ROS1 ) rearrangements. These gene alterations identify patients who benefit from the use of correspondent inhibitors (4,5).

Impact of different timing of radiation therapy in patients with brain metastases from epidermal growth factor receptor-mutant non-small cell lung cancer.

e20667 Background: To perform a retrospective analysis of patients with brain metastases (BM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to evaluate the preferred treatment timing of EGFR-tyrosine kinase inhibitors (TKIs) in this population. Methods: Of 94 initial or recurrent patients diagnosed BM from EGFR-mutant NSCLC between Jan 1, 2012, and Jun 31, 2016, 30 received upfront brain RT followed by EGFR-TKI, 39 EGFR-TKI combined with concurrent brain RT, and 25 upfront EGFR-TKI then brain RT. Disease-specific-graded prognostic assessment was similar among all 3 groups. The primary endpoint was overall survival (OS), and the second endpoint was intracranial progression-free survival. Results: Although the median OS was not significantly different among the upfront RT, concurrent treatment, and upfront EGFR-TKI groups (29.0 vs 24.0 vs 17.0 months; P = 0.186), however, it was longer in the upfront RT group compared with the upfront EGFR-TKI group (P = 0.035). On subgroup analysis, the exon 19 deletions patients had longer OS than the exon 21 mutations patients in upfront EGFR-TKI group (23.0 vs 15.0 months; P = 0.048), but the upfront RT (34.0 vs 23.0 months; P = 0.186) and the concurrent treatment groups (24.0 vs 13.0 months; P = 0.827) did not. According to multivariate COX analysis, KPS (≥ 70) and intracranial metastasis alone was associated with a longer OS. The median intracranial progression-free survival was significantly improved in patients receiving upfront RT compared with those receiving concurrent treatment or upfront EGFR-TKI (not reached vs 40.0 vs 9.0 months; P = 0.003). Conclusions: The present study suggests that the use of upfront brain radiotherapy, and the deferral of EGFR-TKI may result in superior OS in patients with brain metastases from EGFR-mutant NSCLC. Also, upfront brain radiotherapy management could significantly reduce the risk of intracranial progression. A prospective, multi-institutional, randomized trial of upfront EGFR-TKI then RT versus upfront RT followed by EGFR-TKI is urgently needed, especially based on different subgroup population.

Epidermal growth factor receptor-mutant lung cancer in Down syndrome: a case presentation and review of the literature.

BackgroundSolid tumors have a markedly decreased incidence in individuals with Down syndrome (DS), including lung cancers.MethodsThe clinical presentation of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) in DS was reported and literature on the subject reviewed.ResultsIn individuals with DS, the risk of lung cancer appears markedly lower. EGFR mutation and EGFR tyrosine kinase inhibitors (EGFR-TKIs) resistance also exist in DS with lung cancer.ConclusionsClinicians should consider EGFR mutation and EGFR-TKIs resistance in lung cancer patients with DS.

Presence of pleural effusion is associated with a poor prognosis in patients with epidermal growth factor receptor-mutated lung cancer receiving tyrosine kinase inhibitors as first-line treatment.

This study was conducted to evaluate the effect of clinical factors on the treatment outcomes of lung cancer patients with active epidermal growth factor receptor (EGFR) mutations treated by first-line tyrosine kinase inhibitors (TKIs). Patients of stage IIIb or IV lung adenocarcinoma harboring mutated EGFR were enrolled between March 2010 and June 2014 and followed up until December 2015. The effects of various clinical features, such as age, sex, smoking history, EGFR mutation types, TKIs used, presence of pleural effusion, metastatic sites on progression-free survival (PFS) and overall survival (OS), were analyzed retrospectively. A total of 104 patients were included in this study. Patients with pleural effusion at initial diagnosis had significantly shorter PFS and OS than those without pleural effusion (median PFS: 8.2 months vs 15.3 months, P = 0.0004; median OS: 16.3 months vs 28.2 months, P = 0.0003). Univariate analysis revealed that being male or a smoker was associated with short PFS, whereas smoking history, bony metastasis and malignant pleural effusion were associated with poor OS. Stepwise multivariate Cox regression analysis showed that the presence of pleural effusion and different TKI use were independent prognostic factors for PFS [hazard ratio [HR] = 2.50 (95% confidence interval [CI], 1.53-4.10), P = 0.0003 and HR = 0.55 (95% CI, 0.31-0.97), P = 0.0396, respectively], whereas the presence of pleural effusion and liver metastasis were associated with poor OS [HR = 2.79 (95% CI: 1.46-5.30), P = 0.0018 and HR = 2.12 (95% CI, 1.02-4.40), P = 0.0440, respectively]. The presence of pleural effusion predicts poor PFS and OS in lung adenocarcinoma patients receiving TKIs as the first-line treatment. Additional studies are warranted to elucidate the underlying mechanisms and determine novel strategies for improving the outcome of these patients.

CUSTOM-SEQ: a prototype for oncology rapid learning in a comprehensive EHR environment.

As targeted cancer therapies and molecular profiling become widespread, the era of "precision oncology" is at hand. However, cancer genomes are complex, making mutation-specific outcomes difficult to track. We created a proof-of-principle, CUSTOM-SEQ: Continuously Updating System for Tracking Outcome by Mutation, to Support Evidence-based Querying, to automatically calculate and display mutation-specific survival statistics from electronic health record data. Patients with cancer genotyping were included, and clinical data was extracted through a variety of algorithms. Results were refreshed regularly and injected into a standard reporting platform. Significant results were highlighted for visual cueing. A subset was additionally stratified by stage, smoking status, and treatment exposure. By August 2015, 4310 patients with a median follow-up of 17 months had sufficient data for survival calculation. As expected, epidermal growth factor receptor (EGFR) mutations in lung cancer were associated with superior overall survival, hazard ratio (HR) = 0.53 (P < .001), validating the approach. Guanine nucleotide binding protein (G protein), q polypeptide (GNAQ) mutations in melanoma were associated with inferior overall survival, a novel finding (HR = 3.42, P < .001). Smoking status was not prognostic for epidermal growth factor receptor-mutated lung cancer patients, who also lived significantly longer than their counterparts, even with advanced disease (HR = 0.54, P = .001). CUSTOM-SEQ represents a novel rapid learning system for a precision oncology environment. Retrospective studies are often limited by study of specific time periods and can lead to incomplete conclusions. Because data is continuously updated in CUSTOM-SEQ, the evidence base is constantly growing. Future work will allow users to interactively explore populations by demographics and treatment exposure, in order to further investigate significant mutation-specific signals.