Advanced Lung Adenocarcinoma Patients Research Articles

Molecular Subtyping to Predict Risk of Venous Thromboembolism in Patients with Advanced Lung Adenocarcinoma: A Cohort Study

Background Venous thromboembolism (VTE) is a common complication in cancer care and can be predicted based on validated risk assessment tools. Innovative new therapeutics in non-small cell lung cancer (NSCLC) have changed practice patterns and mortality, and new predictors of VTE are therefore needed to better identify high risk patients in this setting. The incidence of VTE according to specific molecular subtypes of NSCLC has not been fully evaluated. The aim of this study was to evaluate rates of VTE in lung adenocarcinoma in relation to their molecular subtype and the association of VTE with survival. Methods We conducted a retrospective cohort study at Cleveland Clinic Taussig Cancer Institute, approved by the institutional review board. We identified advanced lung adenocarcinoma patients from 7/2002 through 07/2017 for whom molecular classification was available and treatment/follow-up was at the Cleveland Clinic. VTE diagnoses including deep-vein thrombosis (DVT) and pulmonary embolism (PE) were identified by electronic medical record review. Patients were classified according to their molecular subtype: wild-type, ALK-mutant or EFGR-mutant. VTE-free survival and overall survival (OS) rates for these categories were estimated by the Kaplan-Meier method and evaluated for association with VTE using Cox proportional hazard regression in each cohort. VTE was analyzed as a conditional, time-dependent covariate with respect to OS. Results The study population included 461 patients, 43.0% male, with a median age at diagnosis of 67 (range, 27-90) years. Of these, 157 (34.1%) were never-smokers. According to molecular subtypes, 165 patients were EGFR-mutant (35.8%), 46 (10.0%) ALK-mutant and 250 (54.2%) were wild-type. All patients had adenocarcinoma and 158 of 211 (74.9%) received a specific tyrosine kinase inhibitor according to their driver mutation. VTE occurred in 98/461 (21.3%) during a follow up of 33.1 months. Highest rates of VTE were observed in patients with ALK-mutant cancers (43.5%, N=20/46) followed by patients with EGFR-mutant cancers (21.2% N=35/165) and wild-type cancers (17.2%, N=43/250) (P < 0.05) (Figure 1). Cumulative rates of VTE at one year of follow-up were 20.7 % for ALK-mutant cancers, 11.1% for EGFR-mutant cancers, and 10.7% for wild-type cancers. The most common VTE event was DVT (49.0%, N=48/98) followed by PE (45.9%, N=45)). Overall survival was significantly worse in patients who experienced VTE in each molecular subgroup: ALK-mutant [HR 2.44 95% CI 1.03 - 5.79, p = 0.043], EGFR-mutant [HR 2.27 95% CI 1.43 - 3.59 p = 0.0005] and wild-type [HR 3.84 95% CI 2.67 - 5.52 p < 0.0001]) Conclusions VTE complicates more than one fifth of advanced lung adenocarcinoma patients. Nearly half of VTE events are PE. VTE is associated with worse survival across molecular subtypes. Patients with ALK-mutant advanced lung adenocarcinomas have the highest rates of VTE, exceeding those observed in patients with pancreas cancers and myeloma. These findings should be taken into consideration in decision-making regarding thromboprophylaxis. Figure 1 Disclosures Velcheti: Foundation Medicine: Consultancy; AstraZeneca: Consultancy; Novartis: Consultancy; Genentech: Consultancy; BMS: Consultancy; Reddy Labs: Consultancy; Alkermes: Consultancy; Boston Scientific: Consultancy; Merck: Consultancy. McCrae:Dova Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pfizer Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Rigel Pharmaceutical: Membership on an entity's Board of Directors or advisory committees; Sanofi Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Khorana:Janssen: Consultancy; Bayer: Consultancy; Pfizer: Consultancy; Sanofi: Consultancy.

The prognostic value of tumor mutation burden in EGFR-mutant advanced lung adenocarcinoma, an analysis based on cBioPortal data base.

Tumor mutation burden (TMB) is novel biomarker of promising predict value in prediction of immune checkpoint inhibitors (ICPis) in non-small cell lung cancer (NSCLC). However, the distribution of TMB in epidermal growth factor receptor (EGFR)-mutant advanced lung adenocarcinoma (LUAD) patients and the impact on overall survival (OS) time are not well demonstrated. Information regarding gene mutations and patients' survival time in advanced LUAD was downloaded from The Cancer Genome Atlas (TCGA) database. The diversity of TMB in different EGFR-mutant types was observed and the predicted value of TMB for OS as well as other co-mutations were analyzed. The diversity of TMB was also observed in another Chinese cohort of advanced LUAD patients. The median TMB values of EGFR wild-type, other types of EGFR mutations, exon 19 deletions and L858R were 6.12, 5.66, 3.77 and 4.72, differences between wild-type and EGFR sensitive mutations (exon 19 deletion or L858R) were significant (P<0.001 and P<0.01). OS time of high TMB group was inferior to that of the low TMB group (24.03 months vs. not reached, P=0.0020). TMB and TP53 together will make more accurate prediction of OS in EGFR-mutant advanced LUAD patients. Distribution of TMB in another Chinese cohort had the same trend. In advanced LUAD patients, TMB was lower in patients with EGFR-mutant group than EGFR wild group. TMB was a negative prognostic biomarker of OS in EGFR-mutant LUAD patients, especially when TP53 was mutated together.

Glycodelin As A Biomarker Of Advanced Lung Adenocarcinoma Brain Metastases In Patients Treated With EGFR Tyrosine Kinase Inhibitors.

ObjectiveBrain metastasis (BM) is a serious complication of advanced lung adenocarcinoma and is a prominent factor leading to lung cancer mortality. In this study, the expression of the glycodelin protein was analyzed in EGFR-mutant tyrosine kinase inhibitor-sensitive advanced lung adenocarcinoma.MethodsThis study features a retrospective analysis of 74 advanced lung adenocarcinoma patients treated at our hospital from January 2010 to December 2017. The expressions of glycodelin were assessed by standard immunohistochemistry and correlated with clinicopathological factors and overall survival (OS) outcomes.ResultsPatients with advanced lung adenocarcinoma with glycodelin overexpression were prone to BM (P < 0.05), and exhibited significantly shortened OS (11.8 months vs 20.4 months, P < 0.05). Multivariate regression analysis showed that overexpression of glycodelin and brain metastases were independent factors affecting the prognosis of advanced lung adenocarcinoma (P < 0.05).ConclusionThe overexpression of glycodelin is closely related to the presence of brain metastasis in lung adenocarcinoma, and can be used as an auxiliary diagnostic index for prognosis of advanced lung adenocarcinoma.

Efficacy of first generation EGFR-TKIs and chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations

Objective: To investigate the clinical effects of first generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) compared with platinum-based chemotherapy as first-line therapy in advanced lung adenocarcinoma patients with uncommon EGFR mutations. Methods: Clinical data of 4 276 patients diagnosed as advanced lung adenocarcinoma (ⅢB/Ⅳ) underwent EGFR gene detection at the Affiliated Cancer Hospital of Zhengzhou University from January 2012 to February 2018 were collected and 99 cases with uncommon EGFR mutations were selected. The clinical pathological features, treatment outcomes, treatment options and prognosis after first-line treatment of the 99 cases were analysed and compared with other patients with common EGFR mutations. Results: The objective response rates of patients with uncommon EGFR mutations receiving EGFR-TKIs or platinum-based chemotherapy were 33.0% and 27.1%, respectively. The disease control rates were 76.5% and 87.5%, respectively. The progression-free survival (PFS) of patients treated with EGFR-TKIs was 7.2 months, significantly superior than 4.9 months of patients receiving chemotherapy (P=0.009). The overall survival of patients treated with EGFR-TKIs was 14.3 months, significantly worse than 20.7 months of patients receiving chemotherapy (P=0.034). Multivariate analysis showed that distant metastases (P=0.001) and smoking history (P=0.013) were independent prognostic factors for OS of lung adenocarcinoma patients with EGFR uncommon mutations. Conclusions: Compared with chemotherapy, the usage of first generation of EGFR-TKIs as first-line therapy can improve the short-term efficacy of advanced lung adenocarcinoma patients with EGFR uncommon mutations. However, platinum-based chemotherapy shows a longer overall survival.

Tracking longitudinal genetic changes of circulating tumor DNA (ctDNA) in advanced Lung adenocarcinoma treated with chemotherapy

IntroductionPemetrexed combined with platinum complexes can be used as first-line treatment for advanced non-squamous non-small cell lung cancer (NSCLC), however, the efficacy and safety is varying from individuals. There is a need to better understand the genetic variations associated with platinum response.Materials and MethodsWe performed next-generation sequencing (NGS) based on BGI Oseq-ctDNA panel to analyze 98 longitudinal plasma samples from 32 lung adenocarcinoma patients during platinum-based chemotherapy, and a bioinformatic pipeline was developed to detect point mutations.ResultsWe found that mutation burden was decreased after chemotherapy, which reflected chemotherapy sensitivity, especially the frequency of C>G and C>A substitutions. Moreover, neoplastic cells carrying a specific set of somatic mutations, such as EGFR(L858R), KRAS (p.G12C) were obviously correlated with platinum treatment. In addition, the MAPK pathway was found to have a pivotal role in NSCLC and platinum based response. Finally, we found that smokers benefit less from platinum-based chemotherapy.ConclusionsCollectively, this work described the dynamic changes of ctDNA mutation status during platinum-based treatment, which may contribute to advanced lung adenocarcinoma patients stratification and precision treatment.

KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy.

Bevacizumab, combined with platinum-based chemotherapy, has been widely used in the treatment of advanced-stage lung adenocarcinoma (LADC). Although KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) mutation is the most common genetic alteration in human LADC and its role in promoting angiogenesis has been well established, its prognostic and predictive role in the above setting remains unclear. The association between KRAS exon 2 mutational status and clinicopathological variables including progression-free survival and overall survival (PFS and OS, respectively) was retrospectively analyzed in 501 Caucasian stage IIIB-IV LADC patients receiving first-line platinum-based chemotherapy (CHT) with or without bevacizumab (BEV). EGFR (epidermal growth factor receptor)-mutant cases were excluded. Of 247 BEV/CHT and 254 CHT patients, 95 (38.5%) and 75 (29.5%) had mutations in KRAS, respectively. KRAS mutation was associated with smoking (p = 0.008) and female gender (p = 0.002) in the BEV/CHT group. We found no difference in OS between patients with KRAS-mutant versus KRAS wild-type tumors in the CHT-alone group (p = 0.6771). Notably, patients with KRAS-mutant tumors demonstrated significantly shorter PFS (p = 0.0255) and OS (p = 0.0186) in response to BEV/CHT compared to KRAS wild-type patients. KRAS mutation was an independent predictor of shorter PFS (hazard ratio, 0.597; p = 0.011) and OS (hazard ratio, 0.645; p = 0.012) in the BEV/CHT group. G12D KRAS-mutant patients receiving BEV/CHT showed significantly shorter PFS (3.7 months versus 8.27 months in the G12/13x group; p = 0.0032) and OS (7.2 months versus 16.1 months in the G12/13x group; p = 0.0144). In this single-center, retrospective study, KRAS-mutant LADC patients receiving BEV/CHT treatment exhibited inferior PFS and OS compared to those with KRAS wild-type advanced LADC. G12D mutations may define a subset of KRAS-mutant LADC patients unsuitable for antiangiogenic therapy with BEV.

P2.03-32 Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC

Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC). We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs). 290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs. Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.

P2.14-40 Tumor-Stromal Microenvironment Interactions in a PDX Model of EGFR TKI Drug Tolerance

Sixty to eighty percent of advanced stage lung adenocarcinoma patients with sensitizing epidermal growth factor receptor (EGFR) mutated tumors respond to EGFR tyrosine kinase inhibitors (TKIs). However, the vast majority of patients eventually progress due to acquired resistance. In vitro evidence suggests that minor populations of drug tolerant cells (DTCs) may be important for tumors surviving TKI. These studies cannot investigate changes in non-cancerous cell populations found within tumors. Yet, stromal cells have been implicated in protecting cancer cells from treatment-induced death and early stage lung adenocarcinomas responding to neoadjuvant EGFR TKI exhibited DTCs within large areas of fibrosis (NCT00188617). We hypothesize that molecularly characterizing DTCs in vivo in comparison to an untreated tumor in a patient-derived xenograft (PDX) model may delineate stromal changes that sustain DTCs, and potentially mimic clinical events. DTCs were harvested after one month of chronic erlotinib exposure in a lung adenocarcinoma PDX model harboring an exon 19 deletion; an untreated baseline (BL) tumor was also harvested. Histological characterization and single-cell RNA-sequencing (scRNA-seq) of DTCs and BL tumors were compared. ScRNAseq cell-types were assigned using reference component analysis. RNA expression levels of receptor/ligands were explored in cell populations. Post-erlotinib treatment, cell-type proportions within the tumor shifted dramatically, with substantially fewer cancer cells and more fibroblasts, mesenchymal stem cells (MSCs), and natural killer cells (NKCs). Two antigen presenting cell transcriptomic states (APC1 and APC2) were identified in both DTC and BL tumors: APC1s exhibited translation-related gene expression profiles while APC2s exhibited immune-response profiles. BL tumors contained mostly APC1s, whereas DTC tumors exhibited more equal proportions of both APC types. Expression profiles for some cell-types also shifted after treatment. Fibroblasts and NKCs exhibited shifts toward more inflammatory and immune-responsive expression profiles post-treatment. Fibroblasts and endothelial cells demonstrated gene expression shifts towards decreased angiogenesis and vasculature development. Paired ligand-receptor interactions between cancer-stromal cells were increased or decreased congruently post-treatment. Specifically, fibroblasts exhibited a shift from alpha-SMA+ myofibroblastic to more IL6+ inflammatory phenotypes, by mRNA and equivalent immunohistochemistry, post-treatment. Cancer cells exhibited a reciprocal increase in IL6R receptor expression post-treatment. Using an EGFR mutant PDX model sensitive to EGFR TKIs, we see substantial post-treatment changes after chronic TKI exposure in non-cancerous (stromal) cell population composition involving their proportions, expression profiles, and their inferred communication with cancer cells. Understanding these potentially protective shifts in non-cancerous cell populations post-TKI-treatment may help identify clinically-relevant mechanisms of drug tolerance.

JCSE01.16 Metastatic Lymph Nodes as High Immunogenicity Media for Perioperative Immunotherapy in Locally Advanced NSCLC

Perioperative chemotherapy showed limited survival benefit and increased toxicities while neoadjuvant immunotherapy achieved great success in early phase trials. Both inter/intra-tumoral heterogeneity (ITH) between primary lesion and metastatic lymph nodes (mLNs), and rationale of superior efficacy for immunotherapy remained poorly explored in locally advanced non-small cell lung cancer (NSCLC). Methods: We retrospectively collected 6 locally advanced lung adenocarcinoma (LUAD) patients. 15 tissue samples were performed multi-region whole exosome sequencing and TCR repertoire analysis as well as 18 matched metastatic lymph nodes (mLNs). 290 somatic mutations in average were identified in primary LUAD (PL) and 441.6 for mLNs. Tumor mutation burden as well as tumor neoantigen burden was significant higher in mLNs than in primary LUAD (median value, 6.6mut/Mb vs. 3.4mut/Mb, P=0.0376; 229.5 neo counts vs. 165 neo counts, P=0.0287). Increased transversion ratio was found in mLNs compared to primary lesions. The genomic concordance between primary lesions and mLNs was 58.4%±12.5% and 33.3% for EGFR-mutation. 87 copy number variants were detected in 14 samples with 3q, 8q and X chromosome as frequently mutated cytobands. Small cell lung cancer functional pathway was enriched in mLNs exclusively. Both expression of PD-L1 and CD8 revealed high level (median value 20% and 40%) and consistence (5/6, 83.3%) between primary and metastatsis lesions. TCR clonality was 17.2% and 9.1% for primary and metastasis lesions, respectively with higher T cell diversity and intra-tumoral heterogeneity of TCR found in mLNs. Extensive genomic and TCR ITH was found between primary LUAD and mLNs which may lead to mixed response to perioperative treatment. mLNs may serve as a better immunogenicity media for perioperative immunotherapy suggesting a potential adjuvant modality of immunotherapy performing lymph nodes sampling during surgery. Results of an initiated single cell sequencing program including paired samples were pending to further provide insights of diverse immune-microenvironment.

EP1.14-19 Efficacy and Safety of Afatinib for Advanced Lung Adenocarcinoma Patients with Sensitive EGFR Mutations in Chinese Population

EP1.14-19 Efficacy and Safety of Afatinib for Advanced Lung Adenocarcinoma Patients with Sensitive EGFR Mutations in Chinese Population

P1.03-07 Advantages and Setbacks of EGFR Mutation Testing from Liquid Biopsy of Advanced Lung Adenocarcinoma Patients in Serbia

P1.03-07 Advantages and Setbacks of EGFR Mutation Testing from Liquid Biopsy of Advanced Lung Adenocarcinoma Patients in Serbia

BRAF Mutations Classes I, II, and III in NSCLC Patients Included in the SLLIP Trial: The Need for a New Pre-Clinical Treatment Rationale.

BRAF V600 mutations have been found in 1–2% of non-small-cell lung cancer (NSCLC) patients, with Food and Drug Administration (FDA) approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50–80% of BRAF mutations in lung cancer are non-V600, and can be class II, with intermediate to high kinase activity and RAS independence, or class III, with impaired kinase activity, upstream signaling dependence, and consequently, sensitivity to receptor tyrosine kinase (RTK) inhibitors. Plasma cell-free DNA (cfDNA) of 185 newly diagnosed advanced lung adenocarcinoma patients (Spanish Lung Liquid versus Invasive Biopsy Program, SLLIP, NCT03248089) was examined for BRAF and other alterations with a targeted cfDNA next-generation sequencing (NGS) assay (Guardant360®, Guardant Health Inc., CA, USA), and results were correlated with patient outcome. Cell viability with single or combined RAF, MEK, and SHP2 inhibitors was assessed in cell lines with BRAF class I, II, and III mutations. Out of 185 patients, 22 had BRAF alterations (12%) of which seven patients harbored amplifications (32%) and 17 had BRAF mutations (77%). Of the BRAF mutations, four out of 22 (18%) were V600E and 18/22 (82%) were non-V600. In vitro results confirmed sensitivity of class III and resistance of class I and II BRAF mutations, and BRAF wild type cells to SHP2 inhibition. Concomitant MEK or RAF and SHP2 inhibition showed synergistic effects, especially in the class III BRAF-mutant cell line. Our study indicates that the class of the BRAF mutation may have clinical implications and therefore should be defined in the clinical practice and used to guide therapeutic decisions.

Parallel Serial Assessment of Somatic Mutation and Methylation Profile from Circulating Tumor DNA Predicts Treatment Response and Impending Disease Progression in Osimertinib-Treated Lung Adenocarcinoma Patients

Background: Circulating tumor DNA (ctDNA) harboring tumor-specific genetic and epigenetic aberrations allows for early detection and real-time monitoring of tumor dynamics. In this study, we aimed to evaluate the potential of parallel serial assessment of somatic mutation and methylation profile in monitoring the response to osimertinib of EGFR T790M-positive advanced lung adenocarcinoma patients. Methods: Parallel somatic mutation and DNA methylation profiling was performed on a total of 85 longitudinal plasma samples obtained from eight stage IV osimertinib-treated EGFR T790M-positive lung adenocarcinoma patients. Findings: Our results revealed significant correlation between the by-patient methylation level with the maximum allele fraction (maxAF, P=0.0002). The methylation levels were significantly higher in the plasma samples of patients with detectable somatic mutations than patients without somatic mutations (P=0.0003) and healthy controls (P=0.0018). Moreover, analysis of both DNA methylation level and maxAF revealed four trends of treatment response. Collectively, the decrease in methylation level and maxAF reflected treatment efficacy, while the gradual increase reflected impending disease progression. Elevated methylation levels and maxAF were observed in six and five patients in an average lead-time of 3.0 and 1.9 months, respectively, prior to evaluation of disease progression using radiological imaging. Interpretation: DNA methylation profiling has the potential to predict disease relapse prior to being evaluated thru radiological modalities, suggesting that serial assessment of methylation level in combination with somatic mutation profiling are reliable methods for treatment monitoring and should be incorporated with imaging modalities for a more comprehensive work-up of treatment response, particularly for patients treated with targeted therapies. Funding Statement: This work was supported by grants from the National Natural Science Foundation of China (grant number 81772471 to S.Xia), Double First-Class University Plan funding of 2016 from Tongji Medical College, Huazhong University of Science and Technology (grant number 5001540022 to S.Xia) and Qinghai Science and Technology Department Funding (grant number 2017-ZJ-709 to S. Xia). Declaration of Interests: J.Ye, A.Lizaso, J.Su, H.Han-Zhang and S. Chuai are employees of Burning Rock Biotech. The other authors declare no potential conflicts of interest. Ethics Approval Statement: This study was performed according to the Helsinki Declaration of 1964 and its current amendments. The study protocol has been approved by the Ethics Committee of Huazhong University of Science and Technology (approval number: 2015L01374/2015L01373). Written informed consent was provided by all the patients included in the study.

Cytological-negative pleural effusion can be an alternative liquid biopsy media for detection of EGFR mutation in NSCLC patients

ObjectiveThough the possibility of using malignant pleural effusions (MPEs) as alternatives for tumor tissues in epidermal growth factor receptor (EGFR) mutation test has been examined, the diagnosis of MPE is often clinically challenging, especially if the cytology is negative for malignancy. The aim of this study was to examine whether cytological-negative PE (CNPE) is useful in detecting EGFR mutation and evaluated its feasibility for predicting clinical outcomes. MethodIn this study, we performed capture-based targeted sequencing using a panel consisting of 520 lung cancer-related genes to detect EGFR mutation status in 121 MPEs and 40 CNPE samples from 161 advanced lung adenocarcinoma patients. Patients underwent TKI treatment with gefitinib, icotinib or erlotinib if EGFR sensitizing mutations were detected at their tumor biopsies or pleural effusion sediment. ResultsWe revealed a mutation detection rate of 99.2% and 100% for MPE and CNPE, respectively (p = 1). The maximum allelic fraction (maxAF) of MPE and CNPE were 57.4% and 56.8%, respectively (p = 0.77). CNPE supernatant is comparable to MPE in reflecting the mutational profile of lung adenocarcinoma. EGFR activating mutations were detected in 47.5% (19/40) of CNPE supernatant sample and 32.5% (13/40) of matched tumor biopsies. CNPE sample is superior to tumor tissues in identifying EFGR mutation. Among the 72 EGFR-TKI treated patients, 51 were cytology positive and the remaining 21 were cytology negative. Our data showed that MPE patients exhibited comparable PFS (p = 0.41) and OS (p = 0.26) with CNPE patients treated with EGFR-TKI. Among the 21 CNPE patients received TKI treatment, patients harboring either L858R or exon 19 deletion had longer PFS than patients without a detectable mutation (p = 0.036). ConclusionCollectively, we demonstrated that CNPE supernatant provided a comprehensive profile of NSCLC, and can serve as a reliable lipid biopsy media for EGFR mutational detection.

High systemic immune-inflammation index predicts poor prognosis in advanced lung adenocarcinoma patients treated with EGFR-TKIs.

EGFR-TKIs have been widely used in the first-line treatment of NSCLC patients harboring EGFR mutations. However, the prognosis indicators are limited. In the present study, the prognostic value of systemic immune-inflammation index (SII), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) were assessed in EGFR-Mutant lung adenocarcinoma patients treated with first-generation EGFR-TKIs. Two hundred three patients were included in this retrospective analysis. SII was calculated as platelet counts × neutrophil counts / lymphocyte counts. Receiver operating characteristic (ROC) curve was used to evaluate the optimal cut-off value for SII, NLR, and PLR. Univariate and multivariate survival analysis were performed to identify factors correlated with PFS and OS. Applying cut-offs of ≥1066.935 (SII), ≥4.40 (NLR), and ≥182.595 (PLR), higher NLR was associated with worse Eastern Cooperative Oncology Group performance status (ECOG PS) (P = .006), and higher brain metastasis rate (P = .03), higher PLR was associated with smoking history (P = .037), and worse ECOG PS (P = .001), and higher SII groups were associated with worse ECOG PS (P = .002). In univariate analysis, higher NLR (P < .001), higher PLR (P = .002), and higher SII (P < .001) were associated with worse PFS. Higher NLR (P < .001), and higher SII (P < .001) were associated with worse OS. In multivariate analysis, NLR (HR 1.736;95%CI:1.020–2.954; P = .03), PLR (HR 1.823; 95%CI:1.059–3.137; P = .04), and SII (HR2.577; 95%CI:1.677–3.958; P < .001) were independently correlated with PFS. While only SII (HR 2.802; 95%CI:1.659–4.733; P < .001) was independently correlated with OS. The present study demonstrated that SII is an independent prognostic factor for poor survival of advanced EGFR-Mutant lung adenocarcinoma patients treated with first-generation TKIs.

The clinical prognostic factors in advanced lung adenocarcinoma patients with different EGFR mutation subtype.

e20680 Background: The prognostic factors of advanced NSCLC patients with EGFR mutation subtypes remains controversial. This study aimed to investgate the association of clinical prognostic factors with EGFR-TKI efficacy in advanced lung adenocacinoma patients with different EGFR mutation subtypes. Methods: The clinical characteristics, treatment and survival data of advanced lung adenocarcinoma patients with EGFR sensitive mutations who were treated with Icotinib (Betta Pharmaceuticals, China) from January 2011 to December 2017 in our medical center were reviewed. The prognositic factors of patients between with EGFR exon 19 deletion (19-Del) and exon 21 Leu858Arg mutation (L858R) were retrospectively analyzed by using the Kaplan-Meier method, the chi-square test, and multivariate Cox hazards model. Results: A total of 187 patients were enrolled in the study, including 104 patients with EGFR19-Del and 83 patients with EGFR21-L858R. The results showed that no significant difference in mPFS between the two groups (19-Del vs. L858R: 15.0 months, 95% CI 17.2-32.8months vs. 13.0 months 95% CI 11.7-14.3 months, p = 0.347), while the mOS of patients with 19-Del (35months, 95% CI 28.6-41.4 months) was significantly better than that of patients with EGFR21-L858R (25 months, 95%CI 17.2-32.8 months, p = 0.020). For PFS, liver metastasis was an independent prognostic factor in EGFR19-DEL patients (HR 5.009, 95%CI 1.296-19.354, p = 0.019), while gender (HR 5.881, 95%CI 2.105-16.431, p = 0.001), smoking status (HR 6.972, 95%CI 2.851-17.049, p = 0.001), lymph node metastasis (HR 2.676, 95%CI 1.002-7.148, p = 0.050) were independent prognostic factors in patients with L858R. As for OS, age (HR 1.080, 95%CI 1.017-1.147, p = 0.012), brain metastases (HR 23.166, 95%CI 3.946-136.009, p = 0.001), liver metastases (HR 14.088, 95%CI 1.782-111.385, p = 0.012), renal or adrenal metastasis (HR 10.558, 95%CI 1.480-75.326, p = 0.019), TKI initial efficacy (HR 6.638, 95%CI 2.743-16.067, p = 0.001) were independent prognostic factors in patients with 19-del, however, the initial efficacy of TKI (HR 6.089, 95% CI 2.669-13.893, p = 0.001) was an independent prognostic factor in patients with L858R. Conclusions: The mOS of patients with EGFR 19-Del treated with Icotinib was significantly better than that of patients with L858R, while the mPFS of both were similar. Moreover, there are significant differences in prognostic factors of advanced lung adenocarcinoma patients between with 19-Del and L858R subtypes, which may be helpful for the clinical treatment strategy of EGFR-TKI.

Comparative study of EGFR mutations detected in malignant pleural effusion, plasma and tumor tissue in patients with adenocarcinoma of the lung

ObjectivesThe utility of malignant pleural effusion (MPE) as a source for determining EGFR mutations to guide EGFR TKI therapy in advanced adenocarcinoma of the lung remains unclear. This study compared MPE, plasma and tumor tissues as sources of biological samples for EFGR mutational analysis of lung adenocarcinoma patients. Materials and methodsTotal 295 MPE samples were retrospectively collected from lung adenocarcinoma patients. Matched tissue and plasma samples were available for 92 patients, and 248 patients had plasma samples. EGFR exon-19-deletion and exon 21-L858R mutation were detected with Denaturing high performance liquid chromatography (DHPLC). The concordance of EGFR mutation status in MPE, tissue, and plasma were evaluated, and the value of EGFR mutations in MPE with respect to efficacy of EGFR-TKI was investigated. ResultsThe EGFR mutation rate in MPE samples was 39.3% (116/295). The concordance between MPEs and tissues was 87.1% (Kappa = 0.71); the sensitivity and specificity of EGFR mutation in MPEs according to tissues was 71.4% and 96.5%, respectively. And 219 patients received EGFR-TKI, and the objective response rate was similar for patients with EGFR mutation either in MPE, tissues or plasma (57.6% vs 56.0% vs 47.4%, p = 0.51). Similar results were found in progression free survival (8.9 months vs 9.0 months vs 7.7 months, p = 0.077 and overall survival (29.8 months vs 25.9 months vs 25.3 months, p = 0.33). ConclusionMPE is a reliable surrogate for tumor tissue for identifyingEGFR mutations. MPE could offer reference of EGFR mutation to EGFR-TKIs treatment decision for advanced lung adenocarcinoma patients even when tissue and plasma were available.

Efficacy and safety of afatinib in a Chinese population with advanced lung adenocarcinoma with sensitive EGFR mutations.

BackgroundAfatinib is an irreversible ErbB family blocker that improves progression‐free survival (PFS) of advanced EGFR‐mutant lung adenocarcinoma compared to chemotherapy. However, afatinib leads to more adverse events than first‐generation EGFR inhibitors. Hence, exploration of the optimal afatinib initial dose and its efficacy and safety in Asian patients has drawn extensive attention.MethodsWe retrospectively evaluated demographic and clinical information, survival data, and adverse events in advanced non‐small cell lung cancer patients treated with afatinib from 27 February 2017 to 30 October 2018.ResultsA total of 60 patients were included in the study. Thirty‐nine (65%) patients received afatinib as first‐line treatment. The median PFS was 12.3 months (95% confidence internal 7.6–17.0). Multivariate Cox regression analysis revealed that age, gender, smoking history, baseline brain metastasis status, afatinib starting dose, and mutation type did not significantly influence PFS. No significant difference in median PFS between patients treated with an initial dose of afatinib of 40 mg or 30 mg, either in the first‐line (14.5 vs. 5.2 months; P = 0.101) or in a second or later‐line setting (3.0 vs. 5.0 months; P = 0.375) was observed. The incidence of all grades of rash/acne (92.5% vs. 61.1%; P = 0.011) and paronychia (82.5% vs. 50.0%; P = 0.010) in the 40 mg group was significantly higher than in the 30 mg group.ConclusionFirst‐line afatinib treatment is beneficial for advanced lung adenocarcinoma patients with sensitive EGFR mutations. Initial dose and baseline brain metastasis status do not significantly impact PFS.

Combination of icotinib and chemotherapy as first-line treatment for advanced lung adenocarcinoma in patients with sensitive EGFR mutations: A randomized controlled study

ObjectiveTo explore the efficacy and safety of icotinib with chemotherapy as first-line therapy for advanced lung adenocarcinoma in patients with sensitive epidermal growth factor receptor (EGFR) mutations. MethodsThis prospective, randomized, controlled trial was conducted in 10 general hospitals in Shandong Province, China. Previously untreated patients with advanced lung adenocarcinoma and sensitive EGFR mutations were recruited between January 16, 2014 and December 31, 2016 and randomly allocated to the combination group (icotinib plus pemetrexed and carboplatin) or the icotinib only group. The patients were followed up until May 23, 2018. The primary endpoint was progression-free survival (PFS). ResultsThe efficacy analysis (intention-to-treat analysis) include 179 patients (n = 90 in the combination group and n = 89 in the icotinib only group). PFS was significantly longer in the combination group than in the icotinib only group (16.0 months vs. 10.0 months, hazard ratio [HR] = 0.59, 95% confidence interval [CI] 0.42–0.84, P = 0.003). The objective response rate and the disease control rate for the combination group were significantly higher than those for the icotinib only group (77.8% vs. 64.0%, χ2 = 4.094, P = 0.043; 91.1% vs. 79.8%, χ2 = 4.632, P = 0.031). However, overall survival did not differ between the two groups (36.0 months vs. 34.0 months, HR = 0.81, 95%CI 0.54–1.22, P = 0.309). The incidence rates of leukopenia and liver function damage of grades 3–4 were higher in the combination group than in the icotinib only group (12.2% vs. 0%, χ2 = 11.086, P = 0.001; 12.2% vs. 3.5%, χ2 = 4.488, P = 0.034). However, adverse events were resolved in most patients. ConclusionUse of the combination of icotinib and chemotherapy as first-line therapy significantly improved the PFS of advanced lung adenocarcinoma patients with sensitive EGFR mutations. Although the combination therapy increased the incidence of leukopenia and liver function damage, the observed adverse events were tolerable and manageable.

Correlation between pre-treatment serum carcinoembryonic antigen levels and genotypes in a large population of Chinese people with advanced lung adenocarcinoma.

A positive correlation between serum carcinoembryonic antigen (CEA) levels and epidermal growth factor receptor (EGFR) mutations has been reported in lung adenocarcinoma patients. To investigate retrospectively whether serum CEA levels are also associated with genotypes in a large population of advanced lung adenocarcinoma. A large cohort of 701 patients with advanced lung adenocarcinoma was studied retrospectively. EGFR mutations were found in 47.5% (333/701) of advanced lung adenocarcinoma patients, being identified at high frequencies in never-smokers, females, and in patients with abnormal pre-treatment serum CEA levels (53.1% vs 37.5%, P < 0.001). In contrast, anaplastic lymphoma kinase gene rearrangements were found in 7.8% (55/701) of patients, being identified at high frequencies in younger patients, and in patients with normal CEA levels (11.5% vs 5.8%, P = 0.012). Serum CEA levels were divided into four groups: <5, 5-19, 20-99 and ≥100 ng/mL. The rate of EGFR mutations significantly increased as the serum CEA levels increased (37.5%, 49.5%, 53.9% and 57.7%, respectively, P < 0.001). Anaplastic lymphoma kinase gene rearrangements showed the opposite result (11.5%, 7.1%, 5.7% and 4.1%, respectively, P = 0.044). A multivariate analysis revealed that higher pre-treatment serum CEA levels were independently associated with EGFR mutations (95% CI: 1.291-2.487, P < 0.001), but normal serum CEA levels were independently associated with anaplastic lymphoma kinase gene rearrangements (95% CI: 0.275-0.842, P = 0.010). Our study demonstrated that a significant association exists between the serum CEA levels and genotypes in patients with advanced lung adenocarcinoma.