EGFR Wild-type Lung Adenocarcinoma Research Articles

Ferroptosis-related gene signature for predicting prognosis and identifying potential therapeutic drug in EGFR wild-type lung adenocarcinoma

Epidermal growth factor receptor wild type lung adenocarcinoma (EGFRWT LUAD) still has limited treatment options and unsatisfactory clinical outcomes. Ferroptosis, as a form of cell death, has been reported to play a dual role in regulating tumor cell survival. In this study, we constructed a 3-ferroptosis-gene signature, FeSig, and verified its accuracy and efficacy in predicting EGFRWT LUAD prognosis at both the RNA and protein levels. Patients with higher FeSig scores were found to have worse clinical outcomes. Additionally, we explored the relationship between FeSig and tumor microenvironment, revealing that enhanced interactions between fibroblasts and tumor cells in FeSighigh patients causing tumor resistance to ferroptosis. To address this challenge, we screened potential drugs from NCI-60 (The US National Cancer Institute 60 human tumour cell line anticancer drug screen) and Connectivity map database, ultimately identifying 6-mercatopurine (6-MP) as a promising candidate. Both in vitro and in vivo experiments demonstrated its efficacy in treating FeSighigh EGFRWT LUAD tumor models. In summary, we develop a novel FeSig for predicting prognosis and guiding drug application.

EP.06G.04 Clinicopathological Differences between EGFR Mutated and EGFR Wild-Type Lung Adenocarcinoma with Papillary Predominant Pattern

EP.06G.04 Clinicopathological Differences between EGFR Mutated and EGFR Wild-Type Lung Adenocarcinoma with Papillary Predominant Pattern

321 (PB309): Proteogenomic Characterization Identifies Clinical Subgroups in EGFR and ALK Wild-type Never-smoker Lung Adenocarcinoma

321 (PB309): Proteogenomic Characterization Identifies Clinical Subgroups in EGFR and ALK Wild-type Never-smoker Lung Adenocarcinoma

The efficacy of postoperative radiotherapy in resected pⅢA-N2 EGFR mutant and wild-type lung adenocarcinoma

The resected pⅢA-N2 non-small-cell lung cancer (NSCLC) patients who could benefit from postoperative radiotherapy (PORT) are not well-defined. The study explored the role of PORT on EGFR mutant and wild-type NSCLC patients. We retrospectively searched for resected pIIIA-N2 lung adenocarcinoma patients who underwent EGFR mutation testing. 80 patients with EGFR wild-type and 85 patients with EGFR mutation were included. 62 patients received PORT. In overall population, the median disease-free survival (DFS) was improved in PORT arm compared to non-PORT arm (22.9 vs. 16.1months; p= 0.036), along with higher 2-year locoregional recurrence-free survival (LRFS) rate (88.3% vs. 69.3%; p= 0.004). In EGFR wild-type patients, PORT was associated with a longer median DFS (23.3 vs. 17.2months; p= 0.044), and a higher 2-year LRFS rate (86.8% vs. 61.9%; p= 0.012). In EGFR mutant patients, PORT was not significantly correlated with improved survival outcomes. EGFR wild-type may a biomarker to identify the cohort that benefits from PORT.

Investigation of RBM10 mutation and its associations with clinical and molecular characteristics in EGFR-mutant and EGFR-wildtype lung adenocarcinoma

BackgroundRBM10 is commonly mutated in lung adenocarcinoma (LUAD). However, its role in the pathogenesis of LUAD remains undefined. EGFR-mutant LUAD represents a distinct subset of non-small cell lung cancer (NSCLC). The function of RBM10 in tumor pathogenesis is supposed to differ between EGFR-mutant and EGFR-wt LUAD. This study aimed to interrogate the prevalence of RBM10 mutation in a large cohort of Chinese patients with LUAD and investigate the association of RBM10 mutation with clinical and molecular characteristics of EGFR-mutant and EGFR-wt LUAD. MethodsTumor sequencing data from 2848 Chinese patients with LUAD were retrospectively reviewed and analyzed. The prevalence of RBM10 was also compared with other three cohorts: OrigMed (n = 1222), MSKCC (n = 1267), and TCGA (n = 566). The associations of RBM10 mutation with clinical and molecular characteristics were assessed. An external cohort of 182 patients with LUAD who received PD-1 inhibitor were used to investigate the association of RBM10 mutation with clinical outcomes upon immunotherapy. ResultsOur cohort showed a higher prevalence of RBM10 in EGFR-mutant LUAD than in EGFR-wt LUAD (14.8 % vs. 6.5 %, p < 0.001). The enrichment of RBM10 mutations in EGFR-mutant LUAD was also seen in another Chinese cohort (OrigMed: 14.9 % vs. 7.8 %, p < 0.001), but not in the two western cohorts (MSKCC: 7.4 % vs. 9.5 %, p = 0.272; TCGA: 8.1 % vs. 6.7 %, p = 0.624). RBM10 mutations co-occurred more frequently with EGFR L858R mutations (23.7 %) than with other types of EGFR mutations (19 del: 7.7 %; other: 7.1 % in others, p < 0.001). In EGFR-mutant LUAD, RBM10 mutations were more commonly found in stage I (18.2 %) and II (21.8 %) vs. stage III (9.4 %) and IV (11.3 %) tumors (p < 0.001). The proportion of PD-L1 positive expression in EGFR-mutant LUAD with concomitant RBM10 mutation was not different from that those without RBM10 mutations (41.8 % vs. 47.9 %, p = 0.566). In contrast, RBM10 mutation occurred more frequently in EGFR-wt LUAD at stage II-IV (stage II: 12.0 %, stage III: 8.7 %, stage IV: 6.6 %) than at stage I (2.8 %). EGFR-wt LUAD with concomitant RBM10 mutations had higher proportions of PD-L1 expression positivity (78.9 % vs. 61.9 %, p = 0.014) and higher tumor mutational load (8.97 vs. 2.99 muts/Mb, p < 0.001) than those without. Patients with EGFR-wt LUAD who also harbored RBM10 loss of function (LOF) mutations had a longer median PFS upon immunotherapy than those with RBM10 non-LOF mutations (7.15 m vs. 2.60 m, HR = 4.83 [1.30–17.94], p = 0.010). ConclusionWe comprehensively investigated RBM10 mutations in a Chinese cohort with LUAD. Compared to western cohorts, a significant enrichment of RBM10 mutations in EGFR-mutant LUAD compared to EGFR-wildtype LUAD in the Chinese population. RBM10 mutation shows different associations with clinical and molecular characteristics between EGFR-mutant and EGFR-wt LUAD, suggesting a divergent mechanism between these two subsets via which RBM10 deficiency contribute to tumor pathogenesis. The findings contribute to our understanding of the molecular landscape of LUAD and highlight the importance of considering population-specific factors in cancer genomics research.

Discovery of gefitinib-1,2,3-triazole derivatives against lung cancer via inducing apoptosis and inhibiting the colony formation

A series of 20 novel gefitinib derivatives incorporating the 1,2,3-triazole moiety were designed and synthesized. The synthesized compounds were evaluated for their potential anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H1299, A549) and human lung adenocarcinoma cells (NCI-H1437) as non-small cell lung cancer. In comparison to gefitinib, Initial biological assessments revealed that several compounds exhibited potent anti-proliferative activity against these cancer cell lines. Notably, compounds 7a and 7j demonstrated the most pronounced effects, with an IC50 value of 3.94 ± 0.17 µmol L−1 (NCI-H1299), 3.16 ± 0.11 µmol L−1 (A549), and 1.83 ± 0.13 µmol L−1 (NCI-H1437) for 7a, and an IC50 value of 3.84 ± 0.22 µmol L−1 (NCI-H1299), 3.86 ± 0.38 µmol L−1 (A549), and 1.69 ± 0.25 µmol L−1 (NCI-H1437) for 7j. These two compounds could inhibit the colony formation and migration ability of H1299 cells, and induce apoptosis in H1299 cells. Acute toxicity experiments on mice demonstrated that compound 7a exhibited low toxicity in mice. Based on these results, it is proposed that 7a and 7j could potentially be developed as novel drugs for the treatment of lung cancer.

Revealing distinct immune landscape in EGFR mutant and EGFR wild type lung adenocarcinoma by using single-cell RNA sequencing.

e21008 Background: Non-small cell lung cancer (NSCLC) with EGFR mutations displays heterogeneity in the extent of intratumoral immunocytes infiltration compared to those with EGFR wild types, which may explain their variable responsiveness to PD-1 blockade. Here, we performed single-cell RNA sequencing (scRNA-seq) to unveil the immunescape and heterogeneity of lung adenocarcinoma (LUAD) between EGFR mutant (EGFR-mut) patients and wild type (EGFR-wt) patients. Methods: Eleven EGFR-mut and 7 EGFR-wt NSCLC tumor samples were analyzed. Immune cells (CD45+) were enriched through fluorescence-activated cell sorting (FACS) and subjected to single-cell RNA sequencing (scRNA-seq) using the 10X Genomics platform. Sequencing reads were normalized and analyzed using the R/Seurat package. Cellular components of each sample were determined based on known marker genes. Wilcox test was used to compare promotion by subtype composition and immune cell infiltrates. Results: Different immune cell compositions were observed between EGFR-mut and EGFR-wt LUAD tumor samples. We found EGFR-wt tumors are marked by an enrichment of CCL15+ tumor-associated macrophages(TAMs), which display pro-inflammatory properties and high expressions of TNF-a-signaling genes. In contrast, EGFR-mut tumors exhibit enrichment of SPARCL1+TAMs, which are involved in epithelial-mesenchymal transition (EMT) and angiogenesis. EGFR-wt tumors exhibited enrichment of CD8-Teff-MX1 and Gamma delta T cells, both of which displayed higher cytotoxic and naive features. Moreover, the high expression of Gamma delta T corresponds with a better clinical prognosis. In contrast, CD8-Teff-XCL1 and NKT-FGFBP2 were found enriched in EGFR-mut tumors, both of which contributed to higher exhaustion and decreased cytotoxic function. Additionally, NK-IL32 was found enriched in EGFR-mut tumors, showing a downregulated T cell receptor signaling and stronger exhausted features. The high expression of this subcluster correlated with poor outcomes in LUAD patients harboring EGFR mutation. Conclusions: Our study provided a deeper understanding of the immune landscape of EGFR-mut and EGFR-wt LUAD and gained better insights into the immunological mechanisms involved in the response to ICIs. The results of our study could be instructive for the development of future immunotherapy strategies for NSCLC patients harboring EGFR mutations.

Salvage anlotinib showed sustained efficacy in heavily pretreated EGFR wild-type lung adenocarcinoma

Rationale:Anlotinib has been proved to be effective in advanced refractory non-small cell lung cancer.Patient concerns:A 47-year-old female non-smoker was admitted due to persistent chest tightness for a month.Diagnoses:Epidermal growth factor receptor (EGFR) wild-type advanced primary lung adenocarcinoma without brain or bone metastasis.Interventions:The patient failed 2 lines of pemetrexed/docetaxel plus carboplatin and third-line erlotinib. Fourth-line anlotinib was administered thereafter.Outcomes:The pulmonary lesions showed partial remission 5 months after anlotinib monotherapy. The patient demonstrated a progression-free survival of more than 7 months and an overall survival of >12 months. The adverse events including hypertension and fatigue were well-tolerated.Lessons:Salvage anlotinib might be a reasonable choice in EGFR wild-type lung adenocarcinoma after failure of chemotherapy. Further well-designed trials are warranted to verify this occasional finding.

Src-Homology 2 Domain-Containing Phosphatase 2 in Resected EGFR Mutation-Positive Lung Adenocarcinoma

IntroductionEGFR mutation-positive lung adenocarcinoma (LUAD) displays impaired phosphorylation of ERK and Src-homology 2 domain-containing phosphatase 2 (SHP2) in comparison with EGFR wild-type LUADs. We hypothesize that SHP2 expression could be predictive in patients positive with resected EGFR mutation versus patients with EGFR wild-type LUAD. MethodsWe examined resected LUAD cases from Japan and Spain. mRNA expression levels of AXL, MET, CDCP1, STAT3, YAP1, and SHP2 were analyzed by quantitative reverse transcriptase polymerase chain reaction. The activity of SHP2 inhibitors plus erlotinib were tested in EGFR-mutant cell lines and analyzed by cell viability assay, Western blot, and immunofluorescence. ResultsA total of 50 of 100 EGFR mutation-positive LUADs relapsed, among them, patients with higher SHP2 mRNA expression revealed shorter progression-free survival, in comparison with those having low SHP2 mRNA (hazard ratio: 1.83; 95% confidence interval: 1.05–3.23; p = 0.0329). However, SHP2 was not associated with prognosis in the remaining 167 patients with wild-type EGFR. In EGFR-mutant cell lines, the combination of SHP099 or RMC-4550 (SHP2 inhibitors) with erlotinib revealed synergism via abrogation of phosphorylated AKT (S473) and ERK1/2 (T202/Y204). Although erlotinib translocates phosphorylated SHP2 (Y542) into the nucleus, either RMC-4550 alone, or in combination with erlotinib, relocates SHP2 into the cytoplasm membrane, limiting AKT and ERK1/2 activation. ConclusionsElevated SHP2 mRNA levels are associated with recurrence in resected EGFR mutation-positive LUADs, but not in EGFR wild-type. EGFR tyrosine kinase inhibitors can enhance SHP2 activation, hindering adjuvant therapy. SHP2 inhibitors could improve the benefit of adjuvant therapy in EGFR mutation-positive LUADs.

Abstract 6491: Prognostic potential of carcinoembryonic antigen expression patterns in lung adenocarcinoma

Abstract Carcinoembryonic antigen (CEA) is one of the most commonly used tumor markers. Although the suitability of CEA as an effective marker for lung cancer remains debatable, characteristics such as noninvasiveness and lack of other reliable markers make CEA an attractive option in lung cancer. Divergent CEA expression patterns before and after EGFR-tyrosine kinase inhibitor (TKI) treatment have been reported. However, whether these patterns are associated with tumor progression remain elusive. We hypothesized that divergent patterns of serum carcinoembryonic antigen at initial diagnosis (CEAIn) and disease progression (CEAPd) may reflect the diversity of lung cancer cells selected by TKI, conferring distinct progression profiles in patients. Our objective was to verify the prognostic potential of divergent CEA patterns before and after TKI treatment in lung cancer patients with wild-type or mutant EGFR. Of the 1736 lung cancer patients identified from the cancer registry group between 2011 to 2016, we selected 517 patients with advanced stage adenocarcinoma, data on EGFR mutation status and CEAIn, among whom were 288 patients with data on CEAPd, eligible for inclusion in the correlation analysis of clinical characteristics and survival. EGFR wild-type lung adenocarcinoma patients displayed lower CEAIn level than those with EGFR mutations. Multivariable analysis revealed that CEAIn expression was associated with poor progression-free survival in patients harboring mutant EGFR but not in those with wild-type EGFR. Moreover, CEAIn and CEAPd were associated with the good and poor post-progression survival, respectively, only in the EGFR-mutant and not in the wild-type group. In vitro cell line experiments revealed that CEA expression, cancer dissemination, and chemoresistant properties can be affected by EGFR-TKI selection. EGFR-mutant patients, exhibiting high CEAIn (≥ 5 ng/mL) and low CEAPd (&amp;lt; 5 ng/mL), showed a potential toward displaying new metastasis. Our findings support the notion that EGFR mutation status is a critical factor in determining prognostic potential of CEAIn and CEAPd in patients under EGFR-TKI treatment, and divergent CEAIn and CEAPd patterns are associated with distinct cancer progression profiles. Citation Format: Ming-Yi Zheng, Yen-Shou Kuo, Yu-Ting Chou. Prognostic potential of carcinoembryonic antigen expression patterns in lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6491.

B7-H4 and HHLA2, members of B7 family, are aberrantly expressed in EGFR mutated lung adenocarcinoma

BackgroundIn order to find new immune targets for lung cancer with different EGFR mutant status, we describe differential expression profiles of checkpoint molecules of the new discovery B7 family member to find new immune targets for lung cancer with different EGFR statuses. MethodsWe performed immunohistochemistry with antibodies of B7-H3, B7-H4, VISTA, B7-H6, HHLA2, IDO-1, PD-L1 and CD8 in lung adenocarcinoma tissues constructed from 372 cases in the discovery cohort and 231 cases in the validation set. The differential expression profiles of these indices in EGFR mutant and wild-type lung adenocarcinoma was described and compared. ResultsIn the discovery cohort, the median IHC scores of B7-H4 and HHLA2 for the EGFR mutant group were significantly higher than those in the wild-type group (median score [interquartile range], mutant vs. wild type: 3.250 [0−7.000] vs. 5.000 [1.000−7.000], P = 0.045 for B7-H4; 8.000 [6.000−10.500] vs. 7.000 [5.000−8.630] P = 0.003 for HHLA2). Meanwhile, the median IHC scores of IDO-1 and PD-L1 in the wild-type group were significantly higher than those in the mutant group (median score [interquartile range], mutant vs. wild type: 1.000 [0−5.000] vs. 3.000 [0−8.500], P = 0.000 for IDO-1; 0 [0−3.500] vs. 3.000 [0−6.000], P = 0.000 for PD-L1). Results above was confirmed in the discovery cohort. The increased CD8 and decreased HHLA2 expression levels were associated with long disease-free survival in lung adenocarcinoma (P = 0.000 for CD8 expression and P = 0.004 for HHLA2 expression). ConclusionsB7-H4 and HHLA2 are promising immune targets for lung adenocarcinoma, especially for patients with EGFR mutation.

The role of EGFR mutations in predicting recurrence in early and locally advanced lung adenocarcinoma following definitive therapy.

Introduction: Roughly one third of new non-small cell lung cancer (NSCLC) is diagnosed at early stages. While lobectomy can improve mortality in this group, about 30–55% of patients will experience disease recurrence. Increased investigation into the factors affecting recurrence, particularly tumor molecular genetics such as EGFR mutations, is needed.Materials and Methods: We conducted a single-center retrospective study of 282 patients with early or locally advanced lung adenocarcinoma, with or without EGFR mutations, who underwent definitive therapy. We then assessed recurrence, stage at recurrence, time to recurrence and progression-free survival (PFS).Results: We identified 142 patients with EGFR-mutated and 140 EGFR-wildtype lung adenocarcinoma. Overall progression between groups was equivalent at ~40% at 5 years; no difference in PFS was observed at any time-point. However, among those who recurred, EGFR-mutated lung cancer had increased rates of metastatic recurrence compared to EGFR-wildtype disease (97% vs 68%, p = 0.007).Conclusions: EGFR-mutated disease may be associated with a higher risk of metastatic recurrence. Molecular testing may be a promising tool for risk stratification and surveillance following definitive management for early stage disease. Future prospective, multi-center cohort studies are needed to confirm these findings and improve our understanding of how EGFR mutation contributes to prognosis and clinical outcomes.

Immune checkpoint inhibitors combined with chemotherapy/radiotherapy, for EGFR wild-type lung cancer: Efficacy in real-world study.

e15117 Background: The role of immune checkpoint inhibitors (anti-PD-1 antibody, ICI) combined with chemotherapy/radiotherapy for EGFR wild-type lung cancer is controversial, especially in 2nd-line or later treatment. The purpose of this study was to investigate the possible beneficial factors for immunotherapy for EGFR wild-type lung cancer. Methods: A total of 279 patients with EGFR wild-type lung cancer who received ICI were retrospectively analyzed, including 138 adenocarcinoma, 76 squamous carcinoma and 31 SCLC patients. Beneficial factors were determined by multivariable Cox proportional hazards model for PFS. PFS and ORR were compared between different therapies. Results: The specific results are shown in table. In multivariable analysis, ICI combined radiotherapy (P = 0.018; HR, 0.152(95% CI: 0.032, 0.727)) was identified as an effective independent factor for EGFR wild-type lung adenocarcinoma. PFS in patients who received ICI combined radiotherapy was significantly longer than that in those who received ICI monotherapy ((p = 0.032; not reached vs. 9.6 m (95% CI: 5.627, 13.640))). Among lung adenocarcinoma patients who received ICI as 2nd-line treatment, patients treated by ICI combined chemotherapy showed more benefit than those treated by ICI monotherapy (P = 0.003; HR, 0.012(95% CI: 0.001, 0.213)).ICI combined chemotherapy can significantly prolong PFS compared with those treated by ICI monotherapy (p = 0.015; 14.3 m [95% CI: 8.711, 19.822] vs. 1.1 m (95% CI: 0.25, 1.883)) in the 2nd-line treatment. However, ORR showed no significant different between ICI monotherapy and ICI combined chemotherapy(P = 0.626). Conclusions: ICI combined with radiotherapy showed better result than those who didn’t receive radiotherapy for EGFR wild-type lung adenocarcinoma. The addition of chemotherapy to ICI for the 2nd-line treatment in EGFR wild-type lung adenocarcinoma patients seems get more clinical benefit than ICI monotherapy. [Table: see text]

Concurrent somatic alterations of TP53 and RB1 in Chinese lung adenocarcinoma with or without EGFR mutations.

e21526 Background: Endothelial growth factor receptor (EGFR)-mutant lung adenocarcinoma displays diverse responses to tyrosine kinase inhibitor therapy. Concurrent somatic alterations represent different biological substantial proportion of patients with EGFR mutations and impacts their prognosis. Methods: We conducted this retrospective study to clarify the comprehensive concurrent genetic alterations of TP53 and RB1 and tumor mutational burden (TMB) in 712 EGFR-mutant or EGFR-wild type lung adenocarcinoma by next generation sequencing-based gene panel tests. Results: EGFR was the most frequently mutated gene altered in 58.0% (413/712) of lung adenocarcinoma, followed by TP53 altered in 56.7%, KRAS altered in 13.3%, and RBM10 altered in 11.2% of all patients. Concurrent genetic alteration of TP53 and RB1 is more likely to be found in EGFR-mutant patients than in EGFR-wild type patients, with a frequency of 11.4% (45/413) and 4.3% (13/299), respectively (p = 0.003). However, the frequency of TP53 and RB1 concurrent alteration was similar in lung cancer with sensitive EGFR mutation compared to those with non-sensitive mutation (10.5% versus 11.6%). TP53 mutation was most frequently found in patients with RB1 mutation (58/61), irrespective of EGFR mutational status. Furthermore, significant difference was found regarding median TMB in patients with mutant EGFR compared to those with non-mutant EGFR (3.8 versus 4.3; p &lt; 0.001). Median TMB was higher for patients with TP53 and RB1 concurrent alteration than those without concurrent alteration in all patients (5.4 versus 4.3, p = 0.018). Conclusions: Our data showed that high prevalence of concurrent somatic alterations of TP53 and RB1 genes among lung adenocarcinoma patients with EGFR mutations, which might help understand several key biological processes and develop potential therapeutic strategies.

Prognosis of EGFR-mutant Lung Adenocarcinoma Patients With Malignant Pleural Effusion Receiving First-line EGFR-TKI Therapy Without Pleurodesis: A Single-institute Retrospective Study.

The survival benefit of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy without pleurodesis in EGFR-mutant lung adenocarcinoma patients with malignant pleural effusions (MPE) remains unclear. We retrospectively evaluated overall survival (OS) among EGFR wild-type lung adenocarcinoma patients with MPE who received chemotherapy with pleurodesis (CT+PLD) and without pleurodesis (CT-PLD), and EGFR-mutant lung adenocarcinoma patients with MPE who received EGFR-TKI therapy with pleurodesis (TKI+PLD) and without pleurodesis (TKI-PLD). There was no difference in OS between the CT+PLD and the CT-PLD groups (10.8 months vs. 7.4 months). As compared to the TKI+PLD group, OS tended to be longer in the TKI-PLD group (21.8 months vs. 31.1 months). Patients in the TKI-PLD group had no hypoalbuminemia or deterioration of performance status during management of MPE and could receive second- and further-line therapy. EGFR-mutant patients with MPE who received first-line EGFR-TKI therapy without pleurodesis may show a better prognosis than those with pleurodesis.

Tumor Mutation Burden and Efficacy of EGFR-Tyrosine Kinase Inhibitors in Patients with EGFR-Mutant Lung Cancers

Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wild-type (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82-17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.See related commentary by Cheng and Oxnard, p. 899.

FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy

IntroductionThere is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. MethodsWe performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line– and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti–EGFR therapy–treated adenocarcinoma. ResultsWe have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor–treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line– and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. ConclusionThese results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.

Abstract 2642: CBLC is a potential biomarker for the susceptibility to paclitaxel in lung adenocarcinoma

Abstract CBL family proteins have been reported as E3 ubiquitin ligases of receptor tyrosine kinases. CBLC is the most divergent member of CBL family in human due to lack of the distal part of C terminus found in other two proteins, CBL and CBLB. By data mining from TCGA database, CBLC expression was frequently upregulated in lung adenocarcinoma. However, very little is known about the tumorigenic functions of CBLC compared to other CBL family proteins. Although patients with lung adenocarcinoma harboring EGFR mutations can be treated with tyrosine kinase inhibitors (TKIs), there is no good target therapy for treating lung adenocarcinoma patients with EGFR wild-type or TKIs resistance. Here, this study is to investigate if CBLC can be a good target for treatment to benefit these patients. In lung adenocarcinoma cells, CBLC knockdown significantly decreased cell viability, while CBLC overexpression increased the ability to form colonies in soft agar. Flow cytometry analyses revealed that CBLC depletion decreased the cell population of G2/M phase and increased cell apoptosis. Our study also showed that CBLC knockdown in EGFR wild-type cells increased the drug resistance to paclitaxel, which is widely used as a first-line chemotherapy drug in lung adenocarcinoma patients with EGFR wild-type or TKI resistance. Taken together, these findings indicate that CBLC might play a role in promoting cell mitosis and could be a potential biomarker of paclitaxel susceptibility for patients with EGFR wild-type lung adenocarcinoma. Citation Format: Yi-Ping Lin, Shiao-Ya Hong, Yu-Rung Kao, Cheng-Wen Wu. CBLC is a potential biomarker for the susceptibility to paclitaxel in lung adenocarcinoma [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 2642.

An EGFR ligand promotes EGFR-mutant but not KRAS-mutant lung cancer in vivo.

EGFR ligands (e.g., EGF and TGFA) have been shown to be clinically associated with poor survival in lung cancer. Since TGFA itself initiates autochthonous tumors in liver, breast, and pancreas but not in the lung in transgenic mice in vivo, it would appear that an EGFR ligand may not initiate but rather promote lung cancer. However, it has not been proven in vivo whether lung cancer is promoted by an EGFR ligand. Using transgenic mouse models conditionally expressing EGFRL858R or KrasG12D with TGFA (an EGFR ligand) in lung epithelium, we determined that TGFA promoted the growth of EGFRL858R-lung tumors in airway regions but not that of KrasG12D-lung tumors. Analysis of TCGA datasets identified ΔNp63 and AGR2 as potential key tumor-promoting regulators, which were highly induced in the TGFA-induced EGFRL858R-lung tumors. The expression of AGR2 was positively correlated with the expression of TGFA in human EGFR-mutant lung adenocarcinomas. The expression of TGFA in human EGFR-mutant lung adenocarcinomas but not in the EGFR wild-type lung adenocarcinoma was associated with poor survival. These results suggest that targeting EGFR ligands may benefit patients who carry EGFR-mutant lung tumors but will not benefit patients with KRAS-mutant lung tumors.

Survival Benefit from RectroNectin-Activated Cytokine-Induced Killer Cells Combined with Chemotherapy in Advanced EGFR Wild-Type Lung Adenocarcinoma

To investigate the efficacy of chemotherapy and RectroNectin-activated cytokine-induced killer (R-CIK) cell immunotherapy in patients with advanced EGFR wild-type lung adenocarcinoma. Using data gathered from a single institution, 125 patients with stage IIIB or IV EGFR wild-type lung adenocarcinoma between January 2009 and June 2015 were identified and enrolled in this retrospective study. The disease control rates and median overall survival was better in R-CIK group compared with control group. Multivariate survival analysis showed that R-CIK cell treatment was an independent prognostic factor for overall survival. R-CIK cell immunotherapy may prolong survival of patients with advanced EGFR wild-type lung adenocarcinoma.