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Backgrounds: Advanced lung adenocarcinoma (LUAD) patient with EGFR mutations often experience resistance to first-line epidermal growth factor tyrosine kinase inhibitors (EGFR-TKIs) therapy. Nonetheless, the mechanism and biomarkers of primary resistance remain unclear. Further exploration of independent prognostic factors will help clinicians identify patients who may not respond to EGFR-TKIs and select appropriate treatment strategies., Methods: A retrospective study involving 124 patients with stage IV LUAD harboring a common sensitizing EGFR mutation (exon 19 deletion or L858R mutation) who received EGFR-TKIs as first-line therapy was performed. All participants were tested by DNA-targeted sequencing in baseline samples, and there were 19 patients with progression-free survival (PFS) ≤ 3 months (cohort 1, C1, primary resistance), 22 patients with 3 < PFS < 8 months (cohort 2, C2, poor response) without known mutations associated with resistance, and 83 patients with PFS ≥ 8 months (cohort 3, C3, normal)., Results: The most commonly mutated genes at baseline in patients prior to treatment within the entire study population. were TP53 (65 %), MYC (19 %), CDKN2A (12 %), MUC16 (12 %) and RBM10 (12 %). The baseline characteristics, except for the proportions of patients with EGFR L858R mutation and exon 19 deletion in C1 plus C2 compared to C3 (p = 0.036), were not significantly different among the cohorts. The frequencies of PIK3C2G, STK11, EPAS1, RARA and BTG2 variation were significantly higher in C1, the primary resistance group. Multivariate Cox analysis revealed that PIK3C2G (HR 15.70 95 % CI 3.24-76.05, p < 0.001), STK11 (HR 17.04, 95 % CI 3.68-78.92, p < 0.001), EPAS1 (HR 11.99, 95 % CI 2.57-56.03, p = 0.002), and BTG2 amplification (HR 9.53, 95 % CI 1.67-54.28, p = 0.011) were significantly associated with shorter PFS., Conclusions: The genomic landscape varies significantly among patients with LUAD, which should be considered when making personalized treatment decisions. This information could provide insights into molecular changes and their effects on clinical treatment in diverse patients with LUAD harboring sensitizing EGFR mutations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is routinely prescribed as first-line therapy for advanced non-small cell lung cancer, regardless of the presence of the T790M resistance mutation. This study reports a rare case of Factor V inhibitor detection during osimertinib therapy in a patient with lung adenocarcinoma. These findings underscore the importance of vigilant monitoring for coagulation abnormalities during EGFR-TKI therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: Advanced non-small cell lung cancer patients harboring EGFR mutation or ALK fusion have achieved significant survival benefit with targeted agents. In contrast, EGFR-wild type and ALK negative lung adenocarcinoma still have poor survival outcome. This study assessed the impact of participating in clinical trials on clinical outcomes in patients with EGFR-wild-type and ALK-negative lung adenocarcinoma., Materials and Methods: This study included patients with advanced EGFR-wild-type and ALK-negative lung adenocarcinoma who received systemic treatment between March 2017 and June 2022. We compared clinical outcomes between patients who participated in clinical trials and those treated with standard-of-care (SOC) using propensity score matching (PSM)., Results: Overall, 1,686 patients with EGFR-wild-type and ALK-negative advanced lung adenocarcinoma were included in the final analysis. Of these, 1,380 (81.9 %) received SOC only and 306 (18.1 %) patients were enrolled in at least one clinical trial during their cancer journey. After PSM (1:1), 612 patients were matched to the SOC (n = 306) and clinical trial (n = 306) groups. Among those who participated in clinical trials, 27.8 % and 72.2 % were included in clinical trials involving targeted therapy and immunotherapy respectively. In the clinical trial group, more patients received targeted therapy (31.7 % vs. 5.5 %, p < 0.001) and immunotherapy (88.6 % vs. 62.8 %, p < 0.001) compared to the SOC group. The median overall survival was 17.1 months (95 % confidence interval [CI], 13.2-21.4) in the SOC group and 27.3 months (95 % CI, 22.1-32.4) in the clinical trial group (hazard ratio = 0.71, [95 % CI, 0.58-0.88, P = 0.002])., Conclusions: This study demonstrated that participating in clinical trials resulted in a survival benefit that reduced the risk of death by 29.6% compared to receiving SOC in EGFR-wild-type and ALK-negative lung adenocarcinoma., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MJ Ahn reports grants and personal fees from MSD, AstraZeneca, BMS, and Roche, outside of the submitted work. JS Ahn reports personal fees from Amgen, Pfizer, AstraZeneca, Menarini, Roche, Eisai, Boehringer Ingelheim, BMS-Ono, MSD, Janssen, and Samsung Bioepis, outside of the submitted work. S-H Lee reports grants and personal fees from MSD, Novartis, AstraZeneca, BMS, and Roche, outside of the submitted work. JM sun reports grants and personal fees from MSD, outside of the submitted work. HA Jung reports grants and personal fees from Yuhan outside of the submitted work., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been approved for EGFR-mutant non-small-cell lung cancer (NSCLC). We aimed to evaluate the efficacy and safety of neoadjuvant osimertinib in patients with EGFR-mutant resectable locally advanced NSCLC., Materials and Methods: This single-arm, phase 2b trial (ChiCTR1800016948) was conducted at six centers in mainland China. Patients with a measurable stage IIA-IIIB (T3-4 N2) lung adenocarcinoma and EGFR exon 19 and/or 21 mutations were enrolled. The patients were treated with osimertinib 80 mg orally once per day for six weeks, followed by surgical resection. The primary endpoint was the objective response rate (ORR) assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1., Results: Between October 17, 2018, and June 08, 2021, 88 patients were screened for eligibility. Forty patients were enrolled and treated with neoadjuvant osimertinib therapy. The ORR was 71.1 % (27/38) (95 % confidence interval: 55.2-83.0) in 38 patients who completed the 6-week osimertinib treatment. Thirty-two patients underwent surgery, and 30 (93.8 %) underwent successful R0 resection. Thirty (75.0 %) of 40 patients had treatment-related adverse events during neoadjuvant treatment, and three (7.5 %) had treatment-related adverse events of grade 3. The most common treatment-related adverse events were rash (n = 20 [50 %]), diarrhea (n = 12 [30 %]), and oral ulceration (n = 12 [30 %])., Conclusions: The third-generation EGFR TKI osimertinib, with satisfying efficacy and acceptable safety profile, could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: Tumor spread through air spaces (STAS) is a unique mechanism of lung cancer metastasis; however, its clinical value for stage I lung adenocarcinoma (ADC) remains unclear at present. We investigated the (1) prognosis of patients after sublobar resection compared with lobectomy for stage I lung adenocarcinoma with STAS; and (2) potential benefits of adjuvant chemotherapy (ACT) for patients with stage I ADC and STAS., Methods: A total of 3328 consecutive patients with stage I ADC were retrospectively identified between 2014 and 2018 at our institution; among them, 600 were diagnosed with STAS. Kaplan-Meier analysis and Cox proportional hazard regression models were used to evaluate the impact of STAS on overall survival (OS) and recurrence-free survival (RFS)., Results: Among stage IA patients with STAS, there was no significant difference between those who underwent sublobar resection and lobectomy in OS (P = 0.919) and RFS (P = 0.066). Multivariate analysis confirmed this result (sublobar resection versus lobectomy, OS: HR = 0.523, 95 % CI, 0.056-18.458, P = 0.714; RFS, HR = 0.360, 95 % CI, 0.115-1.565, P = 0.897). ACT did not improve the prognosis of stage IA patients but did improve the RFS of stage IB patients with high-risk recurrence factors, including poorly differentiated tumors, lymphovascular invasion and visceral pleural invasion (P = 0.046)., Conclusions: Sublobar and lobectomy resection provided a comparable prognosis for stage IA ADC patients with STAS. When STAS was confirmed postoperatively, ACT should be considered for patients with stage IB with high-risk recurrence factors but not for those with stage IA disease., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Co-occurring genomic alterations identified downstream main oncogenic drivers have become more evident since the introduction of next-generation sequencing (NGS) analyses at diagnosis and progression. Emerging evidence has stated that co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC). In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC., Methods: A cohort of 111 patients with advanced NSCLC harboring EGFR-sensitive mutations detected by PCR was analyzed in 5 Latin American oncological centers from January 2019 to December 2020. All eligible patients received upfront therapy with EGFR-TKI. Co-occurring genomic alterations were determined at diagnosis in every patient by the NGS (FoundationOneCDx) comprehensive platform, which evaluates 324 known cancer-related genes., Results: EGFR exon19 deletion was the most frequent oncogenic driver mutation (60.4 %) detected by NGS. According to the NGS assay, 31 % and 68.3 % of patients had 1-2 and ≥ 3 co-occurring genomic alterations, respectively. The most frequent co-occurring genomic alterations were TP53 mutations (64.9 %) followed by CDKN2AB alterations (13.6 %), BRCA2 (13.6 %), and PTEN (12.7 %) mutations. Baseline central nervous system disease was present in 42.7 % of patients. First- or second-generation EGFR TKIs (gefitinib, afatinib, or erlotinib) were the most common treatment in 67.5 % of patients, while osimertinib was administered in 27.9 % of cases. The median PFS in all evaluated patients was 13.63 months (95 %CI: 11.79-15.52). Using ≥ 3 co-occurring alterations as the cut-off point, patients with ≥ 3 co-occurring genomic alterations showed a median PFS, of 12.7 months (95 %CI: 9.92-15.5) vs 21.3 months (95 %CI: 13.93-NR) in patients with 2 or less co-occurring genomic alterations [HR 3.06, (95 %CI: 1.55-5.48) p = 0.0001]. Also, patients with a TP53 mutation had a shorter PFS, 13.6 (95 %CI: 10.7-15.5) vs 19.2 months (95 %CI: 12.8-NR); in wild type TP53 [HR 2.01 (95 %CI: 1.18-3.74) p = 0.12]. In the multivariate analysis, the number (≥3) of concurrent genomic alterations and ECOG PS of 2 or more were related to a significant risk factor for progression [HR 2.79 (95 %CI: 1.49-5.23) p = 0.001 and HR 2.42 (95 %CI: 1.22-4.80) p = 0.011 respectively]., Conclusion: EGFR-mutant NSCLC is not a single oncogene-driven disease in the majority of cases, harboring a higher number of co-occurring genomic alterations. This study finds the number of co-occurring genomic alterations and the presence of TP53 mutations as negative prognostic biomarkers, which confers potentially earlier resistance mechanisms to target therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Asian patients with metastatic non-small cell lung cancer (NSCLC) have a higher prevalence of epidermal growth factor receptor (EGFR) mutations compared to Caucasians, 30-50% and 15%, respectively. Osimertinib is a tyrosine kinase inhibitor approved as first-line therapy in patients with metastatic NSCLC harboring exon 19 or exon 21 EGFR mutations., Case Presentation: We report a 68-year-old treatment-naïve Asian male patient with metastatic NSCLC harboring an exon 19 deletion mutation of EGFR treated with osimertinib. The patient developed an osimertinib-induced syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after approximately two months of therapy. Following fluid restriction and osimertinib discontinuation, the hyponatremia improved significantly within one week. The patient was started on second-line erlotinib without any signs of hyponatremia after treatment initiation., Conclusion: There is a lack of published data from randomized prospective clinical trials of osimertinib-induced SIADH in metastatic NSCLC. Further studies to evaluate the potential underlying mechanisms are warranted., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Comprehensive next-generation sequencing panels are leading to detection of rare gene fusion events. EFGR-RAD51 fusion is a rare oncogenic finding and clinical data for management of this condition is scarce. We report a widely metastatic non-small cell lung cancer in a never-smoker young male patient with sustained near-complete systemic and intracranial response to osimertinib, a third-generation EGFR tyrosine-kinase inhibitor (TKI). We also review the available data of other TKIs in this scenario and underscore the role of comprehensive molecular testing for NSCLC., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Purpose: No large-scale, prospective, randomized study has evaluated the effect of thoracic surgery on patients with unresectable stage IIIB-IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma who received and responded to EGFR tyrosine kinase inhibitor (TKI) treatment. Therefore, we designed a propensity-score-matched, nationwide, population-based, cohort study to investigate the effects of thoracic surgery on patients with EGFR-mutant lung adenocarcinoma., Patients and Methods: We included patients with unresectable stage IIIB-IV EGFR-mutant lung adenocarcinoma and categorized them into two groups according to their treatment modalities and compared their outcomes: the case group consisted of patients who underwent thoracic surgery for lung tumors after receiving and responding to EGFR-TKI treatment and the comparison group consisted of patients who received EGFR-TKI treatment alone until tumor progression. Patients in both groups were matched at a ratio of 1:4., Results: The matching process yielded a final cohort of 1395 patients (279 and 1,116 in the case and comparison groups, respectively) who were eligible for further analysis. According to multivariable Cox regression analyses, the adjusted hazard ratio (aHR; 95% confidence interval [CI]) for thoracic surgery for lung tumors after EGFR-TKI use and tumor response (group 2) compared with EGFR-TKI treatment alone (group 1) was 0.445 (0.351-0.564)., Conclusions: Thoracic surgery prolonged overall survival in patients with unresectable stage IIIB-IV EGFR-mutant lung adenocarcinoma who received and responded to EGFR-TKI treatment., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: The echinoderm microtubule-associated protein-like 4 gene (EML4) and anaplastic lymphoma kinase gene (ALK) fusion is the most common ALK rearrangements in non-small cell lung cancer (NSCLC). Herein, we firstly report that coexistence of a novel Neurobeachin (NBEA)-ALK, EML4-ALK double-fusion is sensitive to alectinib., Materials and Methods: Hematoxylin-eosin staining (HE), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) was performed on the biopsy sample., Results: The patient responded to alectinib as a second-line treatment and achieved stable disease for 11 months, without significant symptoms of toxicity. Significantly, the liquid biopsy also validated clinical benefit, with the disappearance of NBEA-ALK and EML4-ALK fusion variants. We also provided a comprehensive review of all 50 ALK fusion genes in NSCLC., Conclusion: This is the first report on one patient with a novel NBEA-ALK, EML4-ALK double-ALK fusion beneficial from alectinib. Alectinib may be a viable therapeutic option for NSCLC patients with double-ALK fusion, and liquid biopsy could dynamically monitor clinical curative effect., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The genomic mutation and immune feature landscape of ERBB2 exon 20 insertion (ERBB2-ex20ins)-driven non-small cell lung cancer and the features associated with the response to chemoimmunotherapy are currently unknown., Methods: The genomic landscape of ERBB2-ex20ins lung adenocarcinoma (LUAD) patients was characterized by next-generation sequencing (NGS) of 1021 cancer genes. The clinical outcomes of chemoimmunotherapy were evaluated among 13 patients with stage IV ERBB2-ex20ins LUAD, and potential biomarkers of the response to chemoimmunotherapy were explored using NGS and T cell receptor sequencing., Results: Among 8247 LUAD patients, 207 (2.5%) had ERBB2-ex20ins, of whom 181 (87.4%) harbored more than one comutation. The most common comutations were in TP53. Patients with ERBB2-ex20ins had a low tumor mutational burden (TMB; median, 4.2 mutations/Mb), and most (66.7%) were PD-L1 negative. Thirteen of the 207 patients received chemoimmunotherapy, for whom the objective response rate, disease control rate, and median progression-free survival were 31%, 77%, and 8.0 months, respectively. Responders exhibited a higher TMB and a trend toward lower clonality in tumors compared with nonresponders (p = 0.0067 and p = 0.085, respectively). A high TMB combined with mutations in DNA damage repair pathways and SWI/SNF chromatin remodeling complexes was associated with a benefit from chemoimmunotherapy., Conclusions: The efficacy and outcome of chemoimmunotherapy were encouraging among ERBB2-ex20ins LUAD patients, who were characterized by low TMB and negative PD-L1 expression. The combination of TMB and comutations is a potential biomarker to identify patients who will benefit from chemoimmunotherapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown a high response rate and long progression-free survival in primary treatment of ALK-positive non-small-cell lung cancer (NSCLC). De novo resistance or refractory subtype is rare event. Herein, we identify the first case with serial next-generation sequencing (NGS) results that harboured a rare echinoderm microtubule associated protein like 4 gene (EML4) -ALK (breaking site at exon 19) fusion in a lung adenocarcinoma (LUAD) patient who acquired alectinib resistance rapidly (less than 3 months), followed by multi-drug resistance and short survival time., (Copyright © 2021 Elsevier B.V. All rights reserved.)

EGFR-mutant adenocarcinomas represent 12% of unselected lung adenocarcinomas and 44% of never smoker adenocarcinomas in the Caucasian population. Activating mutations like exon19 deletion or exon21 Leu858Arg point mutations are predictive of tumor response to EGFR tyrosine kinase inhibitors. Unfortunately, acquired resistance inevitably occurs by the development of novel EGFR mutations, mutations in other genes, gene amplification, gene fusion or tumor transformation. The management of tumors presenting multiple targetable mutations is unclear. We present the case of a patient developing a BRAF V600 mutation as acquired resistance mechanism to osimertinib, who responded favorably to the combination of dabrafenib, trametinib and osimertinib., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Abnormal expressions of ion channel genes are associated with the occurrence and progression of tumors. At present, their roles in the carcinogenesis of lung adenocarcinoma (LUAD) are not clear., Materials and Methods: Differentially expressed (DE) genes in the tumorigenesis were identified from 328 ion channel genes in 102 LUAD and paired adjacent normal samples. Similar analyses were performed between 177 metastatic and 286 non-metastatic LUAD samples to identify DE ion channel genes in the progression of LUAD. Independent prognostic factors selected from DE ion channel genes were used to construct a prognostic model. Correlation analysis and drugs-drug targets interaction network were used to screen the potential drugs for LUAD patients stratified by GJB2 or SCNN1B., Results: Six ion channel genes (GJB2, CACNA1D, KCNQ1, SCNN1B, SCNN1G and TRPV6) were continuous differentially expressed in the tumorigenesis and progression of LUAD. The survival analysis in four datasets with 522 LUAD samples showed that GJB2 and SCNN1B were independent prognostic biomarkers. Patients with overexpression of GJB2 or underexpression of SCNN1B had shorter overall survival. Moreover, multi-omics analysis showed that hypomethylation of GJB2 and hypermethylation of SCNN1B in the promoter region may contribute to their aberrant expressions. KEGG enrichment analysis showed that the overexpressed genes in the group with high GJB2 or low SCNN1B were enriched in cancer-related pathways, while the underexpressed genes were enriched in metabolism-related pathways. The prognostic model with GJB2 and SCNN1B can stratify all LUAD patients into two groups with significantly different survival. Correlation analysis and drugs-drug targets interaction network suggested that GJB2 and SCNN1B expression might have indicative therapeutic values for LUAD patients. Finally, pan-cancer analysis in other eight cancer types showed that GJB2 and SCNN1B might be also potential prognostic factors for KIRC., Conclusions: GJB2 and SCNN1B were identified as prognostic biomarkers and therapeutic targets for LUAD., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Microtubule inhibitors (MTIs) are widely used as anti-cancer drugs for various types of tumors. Vinorelbine, an MTI, is utilized in postoperative adjuvant chemotherapy, especially for lung adenocarcinoma. However, no molecular markers are able to identify patients for whom MTIs would be effective. In this study, we attempted to identify practical markers to predict the efficacy of MTI-based adjuvant chemotherapy., Materials and Methods: We explored a novel combination of molecular marker candidates, based on gene expression network analysis constructed using an omics panel of 26 lung adenocarcinoma cell lines. We then applied the obtained classification method to predict the efficacy of MTI treatment in patients who received adjuvant chemotherapy. RNA sequencing (RNA-seq) analysis was conducted using surgical specimens from 24 Japanese lung adenocarcinoma patients treated postoperatively with vinorelbine., Results: We identified four modules within the network with module activities that were significantly associated with sensitivity to MTIs. Two modules were associated with high sensitivity to MTIs: genes with low differentiation or transdifferentiation of lung adenocarcinomas. On the other hand, MTI-low sensitivity modules were enriched in common epithelial genes and markers of well-differentiated lung adenocarcinomas. We also classified lung adenocarcinoma cases using the module activities associated with MTI efficacy and stratify the cases with MTI resistance., Conclusion: We demonstrate that the constructed classification method is useful for identifying patients with MTI resistance which results in a high risk of cancer relapse., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Pembrolizumab is a standard treatment for non-small cell lung cancer (NSCLC) with high-PD-L1 expression; however, its effect is dismal in patients with poor physical condition. Additionally, the effect of immunotherapy is generally limited in NSCLC harboring driver mutations such asEGFR, ALK, or RET gene aberrations., Results: We report the beneficial effect of pembrolizumab in a patient with poor performance status and PD-L1+ lung adenocarcinoma with theCCDC6-RET fusion gene and co-occurring NF1/TP53 mutations, complicated by multiple cancer-associated thrombi and respiratory failure., Conclusions: Further studies are warranted to establish the role of co-occurring NF1/TP53 mutations as a positive predictive biomarker for pembrolizumab in NSCLC harboring RET fusion genes., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Transformation to small cell lung cancer (SCLC) is a resistance mechanism to tyrosine kinase inhibitor (TKI) treatment that develops in lung adenocarcinoma. The genomic and treatment outcomes in these populations have not been comprehensively reported in China., Methods: We performed a retrospective study analyzing patients with advanced non-SCLC (NSCLC) from eight sites who were diagnosed with SCLC transformation after receiving epidermal growth factor receptor (EGFR)-TKI treatment including first/second- or third-generation EGFR-TKIs. We assessed the genomic features and clinical prognosis in these patients with EGFR-mutated lung cancer., Results: Thirty-two eligible patients with EGFR mutations were identified, 25 of whom had sufficient tumor tissues for detection of genes by next-generation sequencing. The median progression free survival (mPFS) for first/second-generation TKIs was 14.0 months. The most common mutations identified in samples with transformation to SCLC were in TP53 (17/25, 68.0 %), RB1 (9/25, 36.0 %), and PIK3CA (3/25, 12.0 %), and the incidence rates of RB1 and TP53 mutations were similar between patients receiving first/second-generation and third-generation TKI treatment. The estimated median time to SCLC transformation was 17.0 months. After SCLC transformation, platinum-etoposide was the most common treatment regimen, and the mPFS after platinum-etoposide treatment was 3.5 months. Anlotinib showed good efficacy in these patients (overall response rate, 66.7 %; mPFS, 6.2 months). The median overall survival after the initial diagnosis of metastatic lung cancer was 34.5 months, and patients with small cell transformation after third-generation TKI treatment had better prognosis than patients with transformation after first/second-generation treatment (49.4 months vs. 20.0 months, P = 0.013)., Conclusion: We observed that TP53 and RB1 mutations were common in Chinese patients with SCLC transformation, regardless of whether first/second-generation or third-generation EGFR-TKI treatments were used. Earlier occurrence of small cell transformation after EGFR-TKI treatment was associated with poorer prognosis of patients. After the standard chemotherapy regimens for the management of primary SCLC, anlotinib may be a therapeutic option., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Wild type RAS (RAS WT ) suppresses the function of oncogenic RAS mutants (RAS MUT ) in laboratory models. Loss of RAS WT , which we termed loss of heterozygosity (LOH) for any RAS (LAR) or LAKR in the context of KRAS (LOH at KRAS), is found in patients with RAS MUT cancers. However, the incidence and prognostic significance of LAR has not been studied in modern patient cohorts. LAR or LAKR in RAS MUT cancers is attractive as a potential biomarker for targeted therapy., Materials and Methods: We evaluated for associations between LAKR and cancer mortality in patients with KRAS MUT lung adenocarcinoma (LUAD). We also evaluated for associations between LAKR and the metabolic state of cancer cell lines, given that KRAS has been shown to regulate fatty acid synthesis. In line with this, we investigated fatty acid synthase (FASN) inhibitors as potential therapies for KRAS MUT LAKR, including combination strategies involving clinical KRAS G12C and FASN inhibitors., Results: 24 % of patients with KRAS MUT LUAD showed LAKR. KRAS MUT LAKR cases had a median survival of 16 vs. 30 months in KRAS MUT non-LAKR (p =  0.017) and LAKR was independently associated with death in this cohort (p =  0.011). We also found that KRAS MUT LUAD cell lines with LAKR contained elevated levels of FASN and fatty acids relative to non-LAKR cell lines. KRAS MUT LUAD cells with LAKR showed higher sensitivity to treatment with FASN inhibitors than those without. FASN inhibitors such as TVB-3664 showed synergistic effects with the KRAS G12C inhibitor MRTX849 in LUAD cells with KRAS G12C and LAKR, including an in vivo trial using a xenograft model., Conclusions: LAKR in KRAS MUT cancers may represent an independent negative prognostic factor for patients with KRAS MUT LUAD. It also predicts for response to treatment with FASN inhibitors. Prospective testing of combination therapies including KRAS G12C and FASN inhibitors in patients with KRAS G12C LAKR is warranted., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Patients with ALK rearranged non-small-cell lung cancer (NSCLC) show survival benefits from tyrosine-kinase inhibitor (TKI). Widely application of DNA sequencing revealed various rearrangement pattern in addition to single EML4-ALK fusion. Here, we retrospectively analyzed the distribution and coexistence of ALK rearrangement and therapeutic outcome of patients with ALK rearranged NSCLC., Method: ALK positive NSCLC patients were screened at West China Hospital. NGS was performed on pre-treatment samples. Clinical characteristics and therapeutic outcomes were collected to retrospectively analyzed., Results: Among the 89 patients with 22 ALK rearrangements, fusions of intergenic sequences with ALK were found in 15 (16.85 %). Non-EML4-ALK fusions were present in 18 patients (20.22 %). Coexistence of rearrangements were present in 16 patients (17.98 %). Intergenic sequence-ALK and non-EML4-ALK fusions occurred at higher rates in patients with at least two fusions (62.5 % versus 6.85 % for intergenic sequence-ALK, 62.5 % versus 10.96 % for non-EML4-ALK). There were 40 ALK-rearranged NSCLC patients receiving the first-line crizotinib. The median progression-free survival (PFS) was 9.7 months when excluding three lost patients. In the seven patients who had at least two fusions, the median PFS was 11.9 months, compared with 9.0 months among those with single (p = 0.336). No significant difference in median PFS was found between patients with and without intergenic-ALK fusion (12.0 months versus 9.6 months, p = 0.989). The median PFS was 9.0 months in patients harboring a single EML4-ALK fusion versus 13.0 months in those with other ALK alterations (P = 0.890). The PFS of patients with single intergenic sequence-ALK fusion reached to 2.9 months, 27 months, and 28.9 months respectively., Conclusion: Our study reports the distribution of intergenic sequence-ALK and coexisting fusions in ALK-rearranged NSCLC. Intergenic sequence-ALK and non-EML4-ALK are prone to coexist with other fusions. Neither intergenic sequence-ALK nor coexistence of fusions had a significant effect on the therapeutic benefit of treatment with crizotinib., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Lung cancer is the leading cause of cancer death worldwide. In the past decade EGFR, ALK and ROS1 TKIs lead to an unprecedented survival improvement of oncogene-addicted NSCLC patients, with better toxicity profile compared to chemotherapy. In recent years the implementation of high-throughput sequencing platforms led to the identification of uncommon molecular alterations in oncogenic drivers, such as BRAF, MET, RET, HER2 and NTRK. Moreover, newly developed drugs have been found to be active against hard to target drivers, such as KRAS. Specific TKIs targeting these genomic alterations are currently in clinical development and showed impressive activity and survival improvement, leading to FDA-accelerated approval for some of them. However, virtually all patients develop resistance to TKIs by on-target or off-target mechanisms. Here we review the clinicopathological features, the emerging targeted therapies and mechanisms of resistance and strategies to overcome them of KRAS, BRAF, MET, RET, HER2 and NTRK-addicted advanced NSCLCs., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The FAM179A gene has recently been screened as a new fusion partner fusing to the anaplastic lymphoma kinase gene (ALK) in plasma cell-free DNA (cfDNA) of patients with non-small-cell lung cancer (NSCLC). However, the response of patients with NSCLC harboring the FAM179A-ALK fusion to ALK inhibitors remains unknown. In this study we report a novel FAM179A-ALK rearrangement variant (F1, A19) identified by next-generation sequencing in an NSCLC patient with multiple brain metastases (M1c). This patient responded sensitively to lorlatinib as evaluated by brain MRI and chest CT, followed up using plasma cfDNA. The conclusion is that we found a novel FAM179A-ALK rearrangement variant (F1, A19) and provided evidence of its sensitivity to ALK inhibitors., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Currently, the main treatment for non-small cell lung cancer (NSCLC) is surgery and chemotherapy. Although major progress has been made in targeted treatment and immunotherapy, the survival rates for this disease are still low and associated with resistance to chemotherapy. Previous studies have shown that histone acetylation and microRNAs (miRNAs) might play an important role in chemotherapy resistance. The aim of this study was to identify candidate miRNAs related to cisplatin (DDP) resistance in lung adenocarcinoma., Methods: We used 5-aza-2'-deoxycytidine and trichostatin A to reverse the drug resistance of A549/DDP cells in vitro, and miRNA expression profiling was performed by microarrays to identify candidate miRNAs. In addition, we investigated the correlations between miR-320a expression and clinical characteristics through data collected from Gene Expression Omnibus (GEO) microarrays, and The Cancer Genome Atlas (TCGA) to determine the clinical role of miR-320a in lung adenocarcinoma. Furthermore, we investigated the biological function of miR-320a. TargetScanHuman, PicTar2005 and miRanda v5.1. were used to predict the target genes of miR-320a; then, the function of these genes were suggested from the enrichment of GO categories items and KEGG analyses., Results: Treatment with 5-Aza-dc significantly inhibited cellular proliferation, and increased apoptosis in the A549/DDP cells compared with the untreated cells. TSA did not reverse cisplatin resistance. MiR-320a was up-regulated during reversal of cisplatin resistance. The lung adenocarcinoma groups had a significantly lower level of miR-320a expression than the control groups. For the bioinformatics analyses, we found some target genes involved in cell cycle progression, tumor progression, the MAPK signaling pathway, and the ErbB signaling pathway. The promising target genes were highly enriched in various pathways in cancer., Conclusions: The current study confirmed miR-320a was up-regulated during the revering of cisplatin resistance. The results of bioinformatics analyses may present a new method for investigating the pathogenesis of lung adenocarcinoma., (Copyright © 2020. Published by Elsevier B.V.)

Objective: Patient-derived xenografts (PDX) are useful preclinical models to study cancer biology and mechanisms of drug response/resistance, particularly in molecularly targetable tumors. However, PDX engraftment may not be stochastic. We investigated clinical, histological and molecular features associated with PDX engraftment in a large cohort of EGFR-mutated lung adenocarcinoma (LUAD)., Material and Methods: Samples were collected by different methods from patients at various disease stages and phases of treatment. PDX engraftment was defined as an ability to passage tumors twice in NOD-SCID mice. Uni- and multivariate logistic regression evaluated factors associated with engraftment., Results: Among 138 EGFR-mutated LUAD implanted into NOD-SCID mice, the overall engraftment rate was only 10% (14/138). However, engraftment was significantly higher in specimens from surgical resections or core-needle biopsies collected from metastatic sites (5/5; 100%) or from patients who had progressed on EGFR-inhibitors (7/10; 70%). Engrafted tumors usually showed poor histological differentiation, a solid morphologic pattern, and presence of either EGFR T790 M and/or TP53 mutations., Conclusions: Population level analyses of mutant EGFR-PDX show that these models might not fully recapitulate the inter-patient heterogeneity of EGFR-LUAD. However, mutant EGFR-PDXs may be useful to address key clinical questions, notably development of resistance to EGFR-inhibitors and disease progression to distant metastases., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Somatic chromosomal rearrangements resulting in ALK fusion oncogenes are observed in 3-7 % of lung adenocarcinomas. ALK tyrosine kinase inhibitors (ALKi) induce initially response, however, various resistance mechanisms limit their efficacy. Novel therapeutic approaches are of utmost importance to tailor these targeted therapies., Materials and Methods: A synchronous ALK-rearranged and mutated lung cancer cell line pair was established from malignant pleural effusion (PF240-PE) and carcinosis (PF240-PC) at time of ALKi resistance. Immunohistochemistry, FISH and sequencing were performed in pre- and post-treatment tumors and in both cell lines. Differentiation markers were measured by immunoblot. Viability was tested following treatment with ALKi and/or a pan-HDAC inhibitor. Additionally, a novel treatment-naïve ALK-rearranged cell line served as control. In vivo tumorigenicity was evaluated in subcutaneous xenografts., Results: Two distinct resistance mutations were identified in different carcinosis tissues at time of resistance, the previously described resistance mutation L1152R and the hitherto uncharacterized E1161K. Strikingly, PF240-PC cells carried E1161K and PF240-PE cells harbored L1152R. Immunohistochemistry and immunoblot identified epithelial-to-mesenchymal transition markers upregulated following ALKi resistance development both in carcinosis tissues and cell lines. While both lines grew as xenografts, they differed in morphology, migration, in vivo growth and sensitivity to ALKi in vitro. Strikingly, the combination of ALKi with SAHA yielded strong synergism., Conclusion: Using a patient-derived ALKi resistant lung cancer model we demonstrated the synergism of HDAC and ALK inhibition. Furthermore, our findings provide strong evidence for intratumoral heterogeneity under targeted therapy and highlight the importance of site-specific mutational analysis., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: Targeted therapies in the management of patients with lung cancer provide significantly better outcome compared to chemotherapy. Detection of the anaplastic lymphoma kinase (ALK) gene rearrangement has great predictive value for treatment with small molecule tyrosine kinase inhibitor (crizotinib and alectinib commonly). Fluorescent in situ hybridisation (FISH) assay is a basic diagnostic test designed for detecting ALK gene rearrangements. Although being considered as gold standard method by IASLC's guideline, it is often regarded as difficult and error prone. Our aim was to examine a unique atypical ALK FISH pattern, revealed during a systematic large-scale monitoring, which carries the great risk of misinterpretation, hence may result in loss of patients eligible for targeted therapy., Materials and Methods: Tissue and cytology samples from nearly one thousand patients with advanced stage non-small cell lung cancer (NSCLC, n = 996) were routinely examined by ALK FISH and immunohistochemistry (Ventana ALK-D5F3-CDx assay). Anchored Multiplex PCR based Next Generation Sequencing (AMP-NGS) was used to detect fusion gene transcripts in ambiguous cases., Results: Fifty-nine (5,9%) of the cases were positive with ALK FISH test. Three cases showed atypical pattern with a significantly reduced sized red (3') signal and complete loss of green signals. Digital signal measurement confirmed this finding, showing consistent attenuation of 3' signals throughout the tumours. In all three cases AMP-NGS and ALK IHC verified the presence of a fusion gene and expressed oncoprotein, respectively., Conclusion: Approximately 5% of the 59 ALK positive cases exhibited atypical attenuated isolated 3' signal pattern. The immunohistochemistry and AMP-NGS examinations helped to clarify the presence of oncoprotein and the fusion gene, respectively. Our results emphasize the importance of extensive exploration of the genetic background of any unexpected FISH finding to avoid false diagnosis. This enables clinicians to indicate the adequate therapy with higher efficiency for patients suffering from NSCLC., Competing Interests: Declaration of Competing Interest The authors declare that there is no business relationship resulting in conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: In non-small cell lung cancer patients with acquired resistance to first- or second-generation EGFR-TKIs, osimertinib is approved in the presence of the T790 M resistance mutation. We assessed the efficacy of osimertinib in both T790M-positive and T790M-negative patients., Materials and Methods: The TREM-study is an investigator-initiated, multi-centre, single-arm, phase 2 clinical trial conducted in five Northern European countries. Patients with progression on at least one previous EGFR-TKI were assigned to treatment with 80 mg of osimertinib daily until radiological progression or death. Patients were included regardless of the presence of T790 M. The primary endpoint was objective response rate (ORR)., Results: Of 199 included patients, 120 (60 %) were T790M-positive, 52 (26 %) were T790M-negative and 27 (14 %) had unknown T790M-status. 24 % had brain metastases and 15 % had an ECOG performance status of 2. Overall ORR was 48 % (95 % CI, 41 %-55 %), 60 % (51 %-69 %) for T790M-positive patients and 28 % (15 %-41 %) for T790M-negative patients, p < 0.001. ORR for patients with co-occurring del19 vs L858R was 61 % vs 32 %, p = 0.001. Duration of response was similar between the T790M-positive and -negative groups (11.8 vs 10.7 months, p = 0.229). Overall median progression-free survival (PFS) was 8.9 months (95 % CI, 7.4-10.5), and 10.8 vs 5.1 months for T790M-positive vs -negative patients (HR 0.62, p = 0.007). Median overall survival (OS) was 17.9 months (95 % CI, 14.4-21.3). For T790M-positive vs -negative median OS was 22.5 vs 13.4 months, (HR 0.55, p = 0.002)., Conclusions: This study confirms the efficacy of osimertinib for T790M-positive patients. There was also clinically significant activity of osimertinib in a proportion of T790M-negative patients., Clinical Trial Registration: This trial is registered with ClinicalTrials.gov (NCT02504346)., Competing Interests: Declaration of Competing Interest IJZE, ÅH, SE and SC have nothing to disclose. AM has received grants from AstraZeneca. KHH has received honoraria for lectures or advisory boards for Takeda, Roche, MSD, AstraZeneca, Pierre Fabre and BMS. JK has received honoraria for lectures or advisory boards from AstraZeneca, BMS, Boehringer-Ingelheim, MSD and Roche. BHG has received honoraria for lectures and advisory boards for AstraZeneca. OTB has received grants from Roche and Pfizer., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The metabolic changes associated with cachexia - sarcopenia syndrome might down-regulate antitumor immunity. We hypothesized that this syndrome reduces efficiency of immune checkpoint inhibitors (ICPI) in non-small cell lung cancer (NSCLC)., Methods: The records of 142 consecutive NSCLC patients receiving first- or second-line anti-Programmed cell death protein 1) ICPI were reviewed. Response evaluation according to Response Evaluation Criteria in Solid Tumors 1.1 was performed at the eighth week of immunotherapy. Pretreatment cachexia was defined as a body-weight loss of 5% or more in the previous 6 months. Sarcopenia was estimated with the third lumbar skeletal muscle mass index (mSMI) and was evaluated before immunotherapy and at the eighth week. A decrease by 5% or more of the mSMI was considered as an evolving sarcopenia. The endpoints were disease control rate (DCR), progression-free (PFS) and overall survival (OS).Logistic regression model and Cox model took into account others covariables known to influence ICPI efficiency, particularly Programmed Death -Ligand 1 tumor cell score, Eastern Cooperative Oncology Group performance status and common somatic mutational status., Results: In multivariate analysis, cachexia - sarcopenia syndrome reduced the probability of achieving a disease control and were associated with a shorter survival. Patients without cachexia had a better probability to achieve disease control in comparison with those who did not experience cachexia (59.9 % and 41.1 %, respectively; odds ratio 95 % (confidence interval [95 %CI]): 2.60 (1.03-6.58)). Patients with cachexia had a shorter OS when compared with those without cachexia (hazard ratios [HR] (95 %CI): 6.26 (2.23-17.57)). Patients with an evolving sarcopenia had a shorter PFS and OS, with HR (95 %CI): 2.45 (1.09-5.53) and 3.87 (1.60-9.34) respectively., Conclusion: Cachexia - sarcopenia syndrome negatively influences patients' outcome during anti-PD-1 ICPI therapy., Competing Interests: Declaration of Competing Interest None for the current work., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: ROS1-rearranged non-small cell lung cancer (NSCLC) has demonstrated promising response to lorlatinib; however, no targeted therapy is available after failure of lorlatinib and information on acquired resistance mechanisms mediating lorlatinib resistance among ROS1-rearranged NSCLC patients is limited. We report a ROS1-rearranged NSCLC patient who responded to immunochemotherapy after acquisition of ROS1 G2032K-mediated lorlatinib resistance., Methods: Next-generation sequencing (NGS) was performed on supraclavicular lymph nodes (SLN) and blood samples obtained from the 53-year old male patient with advanced CD74-ROS1-rearranged NSCLC. In vitro experiments with patient-derived SLN tumor cells and in silico homology modeling were performed to investigate mechanisms of G2032K-mediated inhibitor resistance., Results: NGS analysis revealed the detection of an acquired ROS1 G2032 K after failure from lorlatinib. Homology modeling revealed the conformational change in the inhibitor binding site induced by the ROS1 G2032 K that disrupted lorlatinib binding. In vitro experiments using patient-derived cells bearing concurrent CD74-ROS1-rearrangement and ROS1 G2032 K demonstrated half-maximal inhibitory concentration IC50 of 730.2 nM for lorlatinib, 812.1 nM for entrectinib, and 1546 nM for crizotinib, indicating resistance to these inhibitors. With PD-L1 expression of TPS 30 %, nab-paclitaxel plus pembrolizumab was administered as fifth-line treatment and achieved partial response, with sustained response ongoing for 7 months as of January 31, 2020., Conclusion: ROS1 G2032 K is a novel mutation that mediates resistance to lorlatinib. With the lack of targeted therapeutic options after lorlatinib resistance, checkpoint inhibitor plus chemotherapy may be considered as a treatment option in patients with ROS1-rearranged NSCLC., Competing Interests: Declaration of Competing Interest Analyn Lizaso and Xinru Mao are employees of Burning Rock Biotech. The other authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)