Brain metastasis in non-small cell lung cancer (NSCLC) patients with uncommon EGFR mutations： a report of seven cases and literature review

Brain metastasis(BM)arising from non-small cell lung cancer(NSCLC)with rare epidermal growth factor receptor(EGFR)mutations is quite rare.The prognosis and therapeutic effects of BM remain enigmatic.To the best of our knowledge,this is the first report to make a separate analysis of BM from NSCLC patients with original uncommon EGFR mutations.We retrospectively reviewed 7 cases of BM arising from 42 cases of uncommon EGFR mutated lung cancer in Tianjin Medical University Cancer Institute and Hospital.We also performed a literature review to assess therapeutic features and outcomes.

Efficacy Differences of First-line EGFR-TKIs Alone vs in Combination with Chemotherapy in Advanced Lung Adenocarcinoma Patients with Sensitive EGFR Mutation and Concomitant Non-EGFR Genetic Alterations

Background and objective:Epidermal growth factor receptor(EGFR)mutations are often associated with non-EGFR genetic alterations,which maybe a reason for the poor efficacy of EGFR tyrosine kinase inhibitors(TKIs).Here we conducted this study to explore whether EGFR-TKIs combined with chemotherapy would benefit advanced lung adenocarcinoma patients with both sensitive EGFR mutation and concomitant non-EGFR genetic alterations.Materials and methods:Cases of advanced lung adenocarcinoma with EGFR mutation combined with concomitant nonEGFR genetic alterations were retrospectively collected.And the patients were required to receive first-line EGFR-TKIs and chemotherapy combination or EGFR-TKIs monotherapy.Demographic,clinical and pathological data were collected,and the electronic imaging data were retrieved to evaluate the efficacy and time of disease progression.Survival data were obtained through face-to-face or telephone follow-up.The differences between the two groups in objective response rate(ORR),disease control rate(DCR),progression-free survival(PFS)and overall survival(OS)were investigated.Results:107 patients were included,including 63 cases in the combination group and 44 cases in the monotherapy group.The ORR were 78%and 50%(P=0.003),and DCR were 97%and 77%(P=0.002),respectively.At a median follow-up of 13.7 mon,a PFS event occurred in 38.1%and 81.8%of patients in the two groups,with median PFS of18.8 mon and 5.3 mon,respectively(P<0.000,1).Median OS was unreached in the combination group,and 27.8 mon in the monotherapy group(P=0.31).According to the Cox multivariate regression analysis,combination therapy was an independent prognostic factor of PFS.Conclusion:In patients with EGFR-mutant advanced lung adenocarcinoma with concomitant non-EGFR genetic alterations,combination of TKIs and chemotherapy was significantly superior to EGFR-TKIs monotherapy,which should be the preferred treatment option.

Efficacy of third-line pemetrexed monotherapy versus pemetrexed combination with bevacizumab in patients with advanced EGFR mutation-positive lung adenocarcinoma

Objective： The purposes of this study were to observe the effects of different treatment strategies, including third-line pemetrexed alone versus its combination with bevacizumab, in patients with advanced epidermal growth factor receptor（EGFR） mutation-positive lung adenocarcinoma, and to analyze the effects of the different medication orders of first- and second-line drugs on third-line efficacy.Patients and methods： One hundred and sixteen cases of patients with EGFR-positive lung adenocarcinoma who had received third-line pemetrexed alone or in combination with bevacizumab between March 2010 and March 2014 at Guangzhou Institute of Respiratory Diseases, the First Affiliated Hospital of Guangzhou Medical University were analyzed retrospectively. Additionally, all the patients were treated with first-line gemcitabine and cisplatin（GP） chemotherapy and second-line EGFR tyrosine kinase inhibitor（TKI） or with first-line EGFR-TKI and second-line GP chemotherapy.Results： The median survival of 61 cases with third-line pemetrexed monotherapy was 36.22 months, the median survival time of 55 cases with third-line pemetrexed plus bevacizumab was 38.76 months, and there was a significant difference in survival time between the two groups（P=0.04）. Subgroup analysis revealed that among the 55 cases with third-line bevacizumab plus pemetrexed treatment, the median survival of 29 patients with first-line GP and second-line EGFR-TKI was 42.80 months, while the median survival of 26 patients with first-line EGFR-TKI and second-line GP was only 34.46 months; additionally, there was a significant difference in the survival time between the two subgroups（P=0.001）. Among 61 cases with thirdline pemetrexed treatment, the median survival of 34 patients with first-line GP and second-line EGFR-TKI was 38.72 months, while the median survival of 27 patients with first-line EGFR-TKI and second-line GP was only 32.94 months; the survival time of the two subgroups was significantly different（P=0.001）.Conclusions： Regardless of the order of the first- and second-line chemotherapy and TKI therapy, the pemetrexed plus bevacizumab regimen was superior to the pemetrexed monotherapy as the third-line therapy in patients with advanced EGFR-positive lung adenocarcinoma. However, this strategy is worth further investigation in prospective studies.

Gefitinib combined with γ-ray stereotactic body radiation therapy has better efficacy than gefitinib alone for senile lung adenocarcinoma patients with EGFR mutations as first-line regimen

Objective： The senile lung adenocarcinoma patients harboring an activating epidermal growth factor receptor （EGFR） mutation shows good and rapid response to EGFR tyrosine kinase inhibitors （TKIs）. Whether gefitinib combined with y-ray stereotactic body radiation therapy has better efficacy than gefitinib alone for senile lung adenocarcinoma patients with EGFR mutations as first-line regimen is still under investigation. Methods： The 42 senile lung adenocarcinoma patients with EGFR mutations were divided into 2 groups according to the therapy method. Group A was the 22 patients treated with gefitinib combined with y-ray stereotactic body radiation therapy （SBRT）. Group B was the 20 patients treated with gefitinib alone. All of the patients received gefitinib of 250 mg/d from the first day until disease progression or other reasons. The patients of Group A were treated with y-ray stereotactic body radiation therapy from the second day. Radiation fields included the primary lesions and the integration of lymph nodes. Dose curve of this group was 50%-80%. Encircled dose was 4.0-6.5 Gy per fraction and the range of total dose was 40-52 Gy. We treated the patients 8-12 times and treated five times every week. Results： All the patients were examined by enhanced double helix CT at the second month. The tumor response rate （RR） of group A was 81.8% （18/22）. Disease control rate （DCR） was 90.9% （20/22）. The median overall survival （OS） was 24.2 months （range 8-58 months ） and the progression-free survival （PFS） was 18.6 months. The overall 1-year survival rate was 72.3% （16/22） and 2-year survival rate was 54.5% （12/22）. The main side effects included skin rash and diarrhea. The RR of group B was 50.0 % （10/20）. DCR was 75.0% （15/20）. OS was 17.4 months （range 6-32 months ） and PFS was 12.1 months. The overall 1-year survival rate was 60.0% （12/20） and 2-year survival rate was 40.0% （8/20）. The main side effects included skin rash and diarrhea. The group A who were treated with gefitinib combined with y-ray stereotactic body radiation therapy had a higher short term therapeutic effects （RR） and long term therapeutic effects （OS） than group B who were treated with gefitinib alone respectively （81.8% vs 50.0%, P = 0.029 〈 0.05, x2 = 4.773 and 24.2 vs 17.4, P = 0.024 〈 0.05, X2 = 5.098）. Conclu. sion： Gefitinib combined with y-ray stereotactic body radiation therapy has better efficacy than gefitinib alone for senile lung adenocarcinoma patients with EGFR mutations as first-line regimen. The side affects are acceptable.

Antitumor activity of aumolertinib, a third-generation EGFR tyrosine kinase inhibitor, in non-small-cell lung cancer harboring uncommon EGFR mutations

Uncommon epidermal growth factor receptor(EGFR) mutations account for 10% 20% of all EGFR mutations in non-small-cell lung cancer(NSCLC). The uncommon EGFR-mutated NSCLC is associated with poor clinical outcomes and generally achieved unsatisfactory effects to the current therapies using standard EGFR-tyrosine kinase inhibitors(TKIs), including afatinib and osimertinib. Therefore, it is necessary to develop more novel EGFR-TKIs to treat uncommon EGFR-mutated NSCLC.Aumolertinib is a third-generation EGFR-TKI approved in China for treating advanced NSCLC with common EGFR mutations. However, it remains unclear whether aumolertinib is effective in uncommon EGFR-mutated NSCLC. In this work, the in vitro anticancer activity of aumolertinib was investigated in engineered Ba/F3 cells and patient-derived cells bearing diverse uncommon EGFR mutations. Aumolertinib was shown to be more potent in inhibiting the viability of various uncommon EGFR-mutated cell lines than those with wild-type EGFR. And in vivo, aumolertinib could also significantly inhibit tumor growth in two mouse allograft models(V769-D770insASV and L861Q mutations) and a patientderived xenografts model(H773-V774insNPH mutation). Importantly, aumolertinib exerts responses against tumors in advanced NSCLC patients with uncommon EGFR mutations. These results suggest that aumolertinib has the potential as a promising therapeutic candidate for the treatment of uncommon EGFR-mutated NSCLC.

Identifying EGFR-Expressed Cells and Detecting EGFR Multi-Mutations at Single-Cell Level by Microfluidic Chip

EGFR mutations companion diagnostics have been proved to be crucial for the efficacy of tyrosine kinase inhibitor targeted cancer therapies. To uncover multiple mutations occurred in minority of EGFR-mutated cells,which may be covered by the noises from majority of unmutated cells, is currently becoming an urgent clinical requirement. Here we present the validation of a microfluidic-chip-based method for detecting EGFR multimutations at single-cell level. By trapping and immunofluorescently imaging single cells in specifically designed silicon microwells, the EGFR-expressed cellswere easily identified. By in situ lysing single cells, the cell lysates of EGFR-expressed cells were retrieved without cross-contamination. Benefited from excluding the noise from cells without EGFR expression, the simple and cost-effective Sanger's sequencing, but not the expensive deep sequencing of the whole cell population, was used to discover multi-mutations. We verified the new method with precisely discovering three most important EGFR drugrelated mutations from a sample in which EGFR-mutated cells only account for a small percentage of whole cell population. The microfluidic chip is capable of discovering not only the existence of specific EGFR multi-mutations,but also other valuable single-cell-level information: on which specific cells the mutations occurred, or whether different mutations coexist on the same cells. This microfluidic chip constitutes a promising method to promote simple and cost-effective Sanger's sequencing to be a routine test before performing targeted cancer therapy.

Correlation of circulating tumor DNA EGFR mutation levels with clinical outcomes in patients with advanced lung adenocarcinoma

Background:Circulating tumor DNA(ctDNA)is a promising biomarker for non-invasive epidermal growth factor receptor mutations(EGFRm)detection in lung cancer patients,but existing methods have limitations in sensitivity and availability.In this study,we used theΔCt value(mutant cycle threshold[Ct]value-internal control Ct value)generated during the polymerase chain reaction(PCR)assay to convert super-amplification-refractory mutation system(superARMS)from a qualitative method to a semi-quantitative method named reformed-superARMS(R-superARMS),and evaluated its performance in detectingEGFRm in plasma ctDNA in patients with advanced lung adenocarcinoma.Methods:A total of 41 pairs of tissues and plasma samples were obtained from lung adenocarcinoma patients who had knownEGFRm in tumor tissue and were previously untreated.EGFRm in ctDNA was identified by using superARMS.Through making use ofΔCt value generated during the detection process of superARMS,we indirectly transform this qualitative detection method into a semi-quantitative PCR detection method,named R-superARMS.Both qualitative and quantitative analyses of the data were performed.Kaplan-Meier analysis was performed to estimate the progression-free survival(PFS)and overall survival(OS).Fisher exact test was used for categorical variables.Results:The concordance rate ofEGFRm in tumor tissues and matched plasma samples was 68.3%(28/41).At baseline,EGFRm-positive patients were divided into two groups according to the cut-offΔCt value ofEGFRm set at 8.11.A significant difference in the median OS(mOS)between the two groups was observed(EGFRmΔCt≤8.11vs.>8.11:not reachedvs.11.0 months;log-rankP=0.024).Patients were divided into mutation clearance(MC)group and mutation incomplete clearance(MIC)group according to whether theΔCt value ofEGFRm test turned negative after 1 month of treatment.We found that there was also a significant difference in mOS(not reachedvs.10.4 months;log-rankP=0.021)between MC group and MIC group.Although there was no significant difference in PFS between the two groups,the two curves were separated and the PFS of MC group tended to be higher than the MIC group(not reachedvs.27.5 months;log-rankP=0.088).Furthermore,EGFRm-positive patients were divided into two groups according to the cut-off of the changes inΔCt value ofEGFRm after 1 month of treatment,which was set at 4.89.A significant difference in the mOS between the two groups was observed(change value ofΔCt>4.89vs.≤4.89:not reachedvs.11.0 months;log-rankP=0.014).Conclusions:DetectingEGFRm in ctDNA using R-superARMS can identify patients who are more likely sensitive to targeted therapy,reflect the molecular load of patients,and predict the therapeutic efficacy and clinical outcomes of patients.

Effect of autologous NK cell immunotherapy on advanced lung adenocarcinoma with EGFR mutations

This study investigated the efficiency of natural killer(NK)cell immunotherapy on non-small cell lung cancer with and without EGFRmutations in order to evaluate the response rate(RR)and progression-free survival(PFS).Among the 48 patients recruited,24 were clinically confirmed to be EGFR mutation positive.The study group was treated with autologous NK cell immunotherapy.Comparisons of the lymphocyte number,serum tumourrelated biomarkers,circulating tumour cells(CTC),Karnofsky Performance Status(KPS)and survival curves were carried out before and after NK cell immunotherapy.The safety and short-term effects were evaluated,followed by median PFS and RR assessments.The serum CEA and CA125 values were found lower in the NK cell therapy group than that of the non-NK treatment group(p<0.05).Theχ2 test showed a 75%RR of the study group A,significantly higher than that of the control group B(16.7%;p<0.01).The RR of groups C(58.3%)and D(41.7%)were not statistically significant.The p values of the 4 groups were 0.012,0.012,0.166 and 1 from group A to group D,respectively.The median PFS was 9 months in EGFR mutation positive group undergoing NK cell infusion interference.By evaluating the changes in immune function,tumour biomarkers,CTC,KPS and PFS,we demonstrated that NK cell therapy had better clinical therapeutic effects on EGFR mutation-positive lung adenocarcinoma.

PIK3CA mutation in Chinese patients with lung squamous cell carcinoma

Objective： To investigate PIK3CA mutation in Chinese patients with lung squamous cell carcinoma （LSCC） and explore their relationship with clinicopathological profiles. Methods： Tumor samples from 123 cases of LSCC were included in this study. PIK3CA mutations in exon 9 and 20 were screened by pyrosequencing and confirmed by clone sequencing or amplification refractory mutation system （ARMS）. Denaturing performance liquid chromatography （DHPLC） was employed for evaluation of EGFR mutation in exon 19, 21 and KRAS mutation. Results： PIK3CA mutations were found in 3 （2.4%） patients. The mutation type included E545K, E452Q and H1047R. Of these three patients, one coupled with EGFR mutation, and the other two coupled with PIK3CA amplification. All the three patients shared the same clinicopathologic characteristics： male, less than 60 years old, had smoke history, stage III and carried wild-type KRAS. Conclusions： The frequency of PIK3CA mutation is low in Chinese patients with LSCC. The mutational status of PIK3CA is not mutually exclusive to EGFR mutation.

Response to dacomitinib in advanced non-small-cell lung cancer harboring the rare delE709_T710insD mutation:A case report

BACKGROUND Tyrosine kinase inhibitors(TKI)have been the standard first-line therapy for advanced non-small cell lung cancer(NSCLC)of epidermal growth factor receptor(EGFR)sensitive mutations.Uncommon EGFR mutations are increasingly reported with the development of next-generation sequencing.However,their sensitivity to TKIs is variable with limited clinical evidence.CASE SUMMARY Here,we report a patient with the rare delE709_T710insD mutation,who showed the favorable efficacy of dacomitinib and achieved a partial response with a progression-free survival of 7.0 mo.CONCLUSION To our knowledge,this is the first report displaying the clinical efficacy of dacomitinib for patients with delE709_T710insD,which may help to provide alternatives in non-classical variant NSCLC patients.Further studies are warranted to make the optimal choice of EGFR-TKI for rare mutations.

Durable response to pulsatile icotinib for central nervous system metastases from EGFR-mutated non-small cell lung cancer: A case report

BACKGROUND Central nervous system(CNS) metastases are a catastrophic complication of nonsmall cell lung cancer(NSCLC), including brain and leptomeningeal carcinomatosis, and are always accompanied by a poor prognosis. Despite the continuous development of existing treatments, the therapy of CNS metastases remains challenging.CASE SUMMARY We report a patient who was definitively diagnosed with brain and leptomeningeal metastases from NSCLC with a targeted mutation in epidermal growth factor receptor(EGFR). A standard dosage of icotinib(125 mg three times daily) was implemented but ineffective. CNS lesions developed despite stable systemic control, so pulsatile icotinib(1125 mg every 3 d) was administered. This new strategy for administration has lasted 25 mo so far, and resulted in complete remission of neurological symptoms, almost vanished lesions, and longer survival with no notable side effects.CONCLUSION This is the first successful example of pulsatile icotinib for treating isolated CNS progression from EGFR mutation-positive NSCLC, providing a new alternative for the local treatment of CNS metastases.

Epidermal growth factor receptor mutation analysis in cytological specimens and responsiveness to gefitinib in advanced non-small cell lung cancer patients

Background： Epidermal growth factor receptor（EGFR） mutation is the key predictor of EGFR tyrosine kinase inhibitors（TKIs） efficacy in non-small cell lung cancer（NSCLC）. We conducted this study to verify the feasibility of EGFR mutation analysis in cytological specimens and investigate the responsiveness to gefitinib treatment in patients carrying EGFR mutations.Methods： A total of 210 cytological specimens were collected for EGFR mutation detection by both direct sequencing and amplification refractory mutation system（ARMS）. We analyzed EGFR mutation status by both methods and evaluated the responsiveness to gefitinib treatment in patients harboring EGFR mutations by overall response rate（ORR）, disease control rate（DCR） and progression free survival（PFS）.Results： Of all patients, EGFR mutation rate was 28.6%（60/210） by direct sequencing and 45.2%（95/210） by ARMS（P〈0.001） respectively. Among the EGFR wild type patients tested by direct sequencing, 26.7% of them were positive by ARMS. For the 72 EGFR mutation positive patients treated with gefitinib, the ORR, DCR and median PFS were 69.4%, 90.2% and 9.3 months respectively. The patients whose EGFR mutation status was negative by direct sequencing but positive by ARMS had lower ORR（48.0% vs. 80.9%, P=0.004） and shorter median PFS（7.4 vs. 10.5 months, P=0.009） as compared with that of EGFR mutation positive patients by both detection methods. Conclusions： Our study verified the feasibility of EGFR analysis in cytological specimens in advanced NSCLC. ARMS is more sensitive than direct sequencing in EGFR mutation detection. EGFR Mutation status tested on cytological samples is applicable for predicting the response to gefitinib. Abundance of EGFR mutations might have an influence on TKIs efficacy.

Bladder metastasis from epidermal growth factor receptor mutant lung cancer:A case report

BACKGROUND Bladder metastasis from lung cancer with epidermal growth factor receptor(EGFR)mutation is extremely rare.Here,we report a case of bladder metastasis from lung adenocarcinoma with EGFR mutation.CASE SUMMARY A 53-year-old female patient was diagnosed with advanced lung adenocarcinoma with EGFR exon 19 deletion.Multiple nodules on the bladder wall were found by regular examination of the pelvic cavity through computed tomography during targeted therapy.Further cystoscopy and histological examination of bladder biopsy tissues confirmed the bladder metastasis from lung adenocarcinoma.In addition,genetic analysis of the bladder metastasis revealed EGFR T790M mutation.The patient achieved a good response to a third-generation EGFR tyrosine kinase inhibitor.CONCLUSION During routine follow-up of lung cancer patients,imaging examination of the pelvic cavity should be performed to avoid missing bladder metastasis.The ultimate diagnosis of bladder metastasis sill depends on the pathological result of biopsy tissues.

EGFR/BRAF/MEK co-inhibition for EGFR-mutated lung adenocarcinoma patients with an acquired BRAF^(V600E) mutation: a case report and review of literature

Despite the promising initial anti-tumor efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors(EGFR-TKIs),most advanced non-small-cell lung cancers(NSCLCs)progress eventually due to therapeutic resistance.V-Raf murine sarcoma viral oncogene homolog B1(BRAF)^(V600E) mutation has been considered as an uncommon mutation that contributes to acquired resistance for EGFR-TKIs.In the presented case,BRAF^(V600E) mutation was detected as an acquired resistance-mediated mutation in a patient treated with osimertinib(a third-generation EGFR-TKI).The presented patient achieved partial regression and ongoing PFS of four months after the co-inhibition of osimertinib plus dabrafenib(BRAF inhibitor)and trametinib(MEK inhibitor).Our case further enriches the clinical evidence of the efficacy of EGFR/BRAF/MEK co-inhibition in patients with an acquired BRAF^(V600E) mutation,consistent with the review of the literature(eight cases).Additionally,our case highlights the important role of sample type,method,and platform of gene detection in patient management,life quality,and prognosis,as well as the understanding of acquired resistance mechanism.

A homologous and molecular dual-targeted biomimetic nanocarrier for EGFR-related non-small cell lung cancer therapy

The abnormal activation of epidermal growth factor receptor(EGFR)drives the development of non-small cell lung cancer(NSCLC).The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR mutation.However,free osimertinib administration exhibits an inadequate response in vivo,with only~3%patients demonstrating a complete clinical response.Consequently,we designed a biomimetic nanoparticle(CMNP^(@Osi))comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery,thereby supporting a dual-target strategy for enhancing osimertinib efficacy.After intravenous injection,CMNP^(@Osi)accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous targeting.Osimertinib is subsequently released into the cytoplasm,where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC cells.Thus,this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.

T790M mutation in stage IV EGFR-mutated NSCLC patient with acquired resistance reverted to original 19Del mutation after administration of a series of precision treatments:a case report

Existing studies have yet to elucidate clearly the mechanisms of secondary resistance to third generation epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),neither is there any established standard therapy for patients resistant to third generation EGFR-TKIs.This case report demonstrates a rare mutation pattern in a male patient with a pathologic diagnosis of non-small cell lung cancer(NSCLC)harboring an EGFR exon 19 deletion(19Del)mutation,who then acquired an EGFR-T790M mutation after developing resistance to the first generation EGFR-TKI(gefitinib).The mutation reverted to the original EGFR-19Del mutation after the patient developed secondary resistance against the third generation TKI(osimertinib).This patient eventually achieved partial response(PR)with second generation TKI(afatinib)as a fourth-line treatment.

Taking early preventive interventions to manage the challenging issue of acquired resistance to third-generation EGFR inhibitors

Although the clinical efficacies of third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase in-hibitors(TKIs)such as osimertinib in the treatment of non-small cell lung cancer(NSCLC)with EGFR-activating mutations are promising,drug-acquired resistance inevitably occurs whether they are used as first-line or second-line treatment.Therefore,managing the acquired resistance to third-generation EGFR-TKIs is crucial in the clinic for improving patient survival.Great efforts have been made to develop potentially effective strategies or regimens for the treatment of EGFR-mutant NSCLC patients after relapse following these TKIs therapies with the hope that patients will continue to benefit from treatment through overcoming acquired resistance.Although this approach,which aims to overcome drug-acquired resistance,is necessary and important,it is a passive practice.Taking pre-ventive action early before disease progression to manage the unavoidable development of acquired resistance offers an equally important and efficient approach.We strongly believe that early preventive interventions using effective and tolerable combination regimens that interfere with the process of developing acquired resistance may substantially improve the outcomes of EGFR-mutant NSCLC treatment with third-generation EGFR-TKIs.Thus,this review focuses on discussing the scientific rationale and mechanism-driven strategies for delaying and even preventing the emergence of acquired resistance to third-generation EGFR-TKIs,particularly osimertinib.

Clinicopathological Characteristics and Prognosis of Patients with Adenosquamous Lung Carcinoma

This study was aimed to characterize clinicopathological features and prognosis of patients with adenosquamous lung carcinoma（ASC）. Among the 2531 patients with lung cancer who underwent surgery between January 2000 and June 2012 in our hospital, 59 were histologically diagnosed as having ASC. The clinicopathological features and follow-up data of ASC patients were collected and analyzed statistically. Superior lobectomy was accomplished in 40 patients, middle and inferior lobectomy in 3, lobectomy plus partial resection of contralateral lung in 5, partial lung resection in 4, and pneumonectomy in 7. Moreover, 22 cases were found to be adenocarcinoma-predominant, and 18 to be squamous cell carcinoma-predominant. The median survival time was 13.6 months, and the 1-, 3-, and 5-year survival rates were 59.9%, 36.4% and 31.2%, respectively. Of the 52 cases with tissue specimens available, 11 had an EGFR mutation（21.2%） and 2 had a KRAS mutation（3.8%）. Multivariate analysis showed that histology subtype, pleural invasion, TNM stage, and postoperative treatment were all independent prognostic factors. The data from the current study demonstrated that SCC-predominant histology represents a better prognosis of ASC. Histology subtype, pleural invasion, TNM stage, and postoperative treatment are independent prognostic factors for ASC and adjuvant therapy may help control the disease.

USH2A mutation and specific driver mutation subtypes are associated with clinical efficacy of immune checkpoint inhibitors in lung cancer

This study aimed to identify subtypes of genomic variants associated with the efficacy of immune checkpoint inhibitors(ICIs)by conducting systematic literature search in electronic databases up to May 31,2021.The main outcomes including overall survival(OS),progression-free survival(PFS),objective response rate(ORR),and durable clinical benefit(DCB)were correlated with tumor genomic features.A total of 1546 lung cancer patients with available genomic variation data were included from 14 studies.The Kirsten rat sarcoma viral oncogene homolog G12C(KRAS^(G12C))mutation combined with tumor protein P53(TP53)mutation revealed the promising efficacy of ICI therapy in these patients.Furthermore,patients with epidermal growth factor receptor(EGFR)classical activating mutations(including EGFRL858Rand EGFRΔ19)exhibited worse outcomes to ICIs in OS(adjusted hazard ratio(HR),1.40;95%confidence interval(CI),1.01-1.95;P=0.0411)and PFS(adjusted HR,1.98;95%CI,1.49-2.63;P<0.0001),while classical activating mutations with EGFR^(T790)Mshowed no difference compared to classical activating mutations without EGFR^(T790)Min OS(adjusted HR,0.96;95%CI,0.48-1.94;P=0.9157)or PFS(adjusted HR,0.72;95%CI,0.39-1.35;P=0.3050).Of note,for patients harboring the Usher syndrome type-2A(USH2A)missense mutation,correspondingly better outcomes were observed in OS(adjusted HR,0.52;95%CI,0.32-0.82;P=0.0077),PFS(adjusted HR,0.51;95%CI,0.38-0.69;P<0.0001),DCB(adjusted odds ratio(OR),4.74;95%CI,2.75-8.17;P<0.0001),and ORR(adjusted OR,3.45;95%CI,1.88-6.33;P<0.0001).Our findings indicated that,USH2A missense mutations and the KRAS^(G12C)mutation combined with TP53 mutation were associated with better efficacy and survival outcomes,but EGFR classical mutations irrespective of combination with EGFR^(T790)Mshowed the opposite role in the ICI therapy among lung cancer patients.Our findings might guide the selection of precise targets for effective immunotherapy in the clinic.

The efficacy and possible mechanisms of immune checkpoint inhibitors in treating non-small cell lung cancer patients with epidermal growth factor receptor mutation

Over the past few years,immune checkpoint inhibitors(ICIs)have greatly improved the survival for patients with non-small cell lung cancer(NSCLC)without driver mutations.Compared with wild-type tumors,tumors with epidermal growth factor receptor(EGFR)mutations show more heterogeneity in the expression level of programmed cell death-ligand 1(PD-L1),tumor mutational burden(TMB),and other immune microenvironment characteristics.Whether ICIs are suitable for NSCLC patients with EGFR mutations is still worth exploring.In previous studies,no significantly improved benefits were observed with immunotherapy monotherapy in NSCLC patients with EGFR mutation.Here,we summarized and analyzed data from the clinical trials of ICIs or combined therapy in NSCLC patients with EGFR mutations.We also focused on the mechanisms affecting the efficacy of ICIs in NSCLC patients with EGFR mutations,the characteristics of potential responders,and provided insights into areas worth further investigations in future studies.