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...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.展开更多
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 ...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.展开更多
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 ...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.展开更多
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 g...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.展开更多
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,whi...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.展开更多
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 ...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.展开更多
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)....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.展开更多
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 LSC...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.展开更多
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 ar...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.展开更多
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....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.展开更多
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 fea...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.展开更多
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...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.展开更多
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 resis...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.展开更多
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 tr...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.展开更多
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 standar...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.展开更多
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-activatin...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.展开更多
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...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.展开更多
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...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.展开更多
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 epide...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.展开更多
Background:Human epidermal growth factor receptor(EGFR)is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.Although there are many reports for some individual cancers,co...Background:Human epidermal growth factor receptor(EGFR)is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.Although there are many reports for some individual cancers,comprehensive profiling of EGFR mutations,overexpression,amplification,DNA methylation,and their clinical associations across many different cancers simultaneously was not available.This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications.Methods:The Cancer Genome Atlas(TCGA)datasets for 32 cancer types involving 11,314 patients were analyzed for alterations(mutations and amplification/deletion),abnormal expression and DNA methylation in EGFR gene.Mutation frequency,genomic location distribution,functional impact,and clinical targeted therapy implication were compared among different cancer types,and their associations with patient survival were analyzed.Results:EGFR alteration frequency,mutation sites across functional domains,amplification,overexpression,and DNA methylation patterns differed greatly among different cancer types.The overall mutation frequency in all cancers combined was relatively low.Targetable mutations,mainly in lung cancer,were primarily found in the Pkinase_Tyr domain.Glioblastoma multiforme had the highest rate of alterations,but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.Colon and pancreatic adenocarcinoma had very few EGFR mutations;however,high EGFR expression was significantly associated with short patient survival.Squamous cell carcinoma regardless of their sites(the head and neck,lung,or esophagus)exhibited similar characteristics with an alteration frequency of about 5.0%,was dominated by gene amplification,and had increased EGFR expression generally associated with short patient survival.DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.Conclusions:EGFR aberration type,frequency,distribution in functional domains,and expression vary from cancer to cancer.While mutations in the Pkinase_Tyr domain are more important for treatment selection,increased expression from amplification or deregulation affects more tumor types and leads to worse outcome,which calls for new treatment strategies for these EGFR-driven tumors.展开更多
文摘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.
文摘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.
基金funded by National Key Scientific & Technology Support Program: Collaborative innovation of Clinical Research for chronic obstructive pulmonary disease and lung cancer (NO. 2013BAI09B09)
文摘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.
基金financial support from the National Natural Science Foundation of China (No. 82073402)the Key R&D Plan of Hubei Province (No. 2020BCA060)。
文摘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.
基金supported by the National HighTech R&D Program of China(No.2015AA020408)National Natural Science Foundation of China(No.61204118,81500900 and21503054)+1 种基金Beijing Municipal Science and Technology Project(No.Z171100002017013)Key Research Program of the Chinese Academy of Sciences,Grant NO.KFZD-SW-210
文摘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.
基金supported by the National Key Research&Development Program of China(No.2016YFC1303800)Innovation Project of Health and Technology in Jilin Province(No.2017J064)+1 种基金Special Project of Development and Reform Commission in Jilin Province(No.2017C022)Key Laboratory Construction Project of Department of Science and Technology of Jilin Province(No.20170622011JC)。
文摘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.
基金The authors thank all 48 participants.This study was funded by the Innovation of Science and Technology Commission of Shenzhen(Grant No:KQJSCX2017033116-0008397,JCYJ20170412155231633,JCYJ20170307171034705 and JCYJ20170816105345191).
文摘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.
基金supported by grants from National Natural Sciences Foundation Distinguished Young Scholars(81025012)National Natural Sciences Foundation General Program (81172235)+2 种基金the Capital Development Foundation(2007-1023)Beijing Health Systems Academic Leader(2011-2-22)Science and Technology Project of Beijing(Z090507017709015)
文摘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.
文摘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.
基金Supported by the Key Project of Nanjing Health Bureau,No.ZKX16031the Healthcare Project of Nanjing Science and Technology Committee,No.201715020+2 种基金the Medical Key Science and Technology Development Project of Nanjing,No.ZKX18014the Cadre Health Care Project of Jiangsu Province,No.BJ18006the Cancer Research Funding of CSCO-Hausen,No.Y-HS2019-5
文摘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.
文摘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.
文摘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.
基金This work was supported by the Shanghai Municipal Key Clinical Specialty(shslczdzk02202)the National Natural Science Foundation of China(81672271).
文摘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.
基金supported by the National Key R&D Program of China(No.2022YFD2401900)the National Natural Science Foundation of China(No.52203163)+4 种基金the High-level Hospital Construction Project(No.DFJH201905)the Natural Science Foundation of Guangdong(No.2021A1515010838)the International Science and Technology Cooperation Program of Guangdong(No.2022A0505050048)the Science and Technology Program of Guangzhou(No.201903010028)Guangdong Provincial People’s Hospital Intermural Program(No.KJ012019447).
文摘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.
基金supported by the National Natural Science Foundation of China(Grant No.81673032).
文摘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.
基金I am thankful to Dr.Anthea Hammond in our department for editing the manuscript.Some of the work done in my lab was supported by the NIH/NCI R01 CA223220,R01 CA245386,UG1 CA233259 awards and Emory University Winship Cancer Institute lung cancer pilot funds.
文摘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.
文摘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.
基金the National Natural Science Foundation of China(Nos.21976155,81802881,and 81773016)the Zhejiang Provincial Natural Science Foundation of China(No.LY18C060001)+1 种基金the Fundamental Research Funds for the Central Universitiesthe Chinese Academy of Medical Sciences(CAMS)Innovation Fund for Medical Sciences(CIFMS)(No.2019-I2M-5-044),China。
文摘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.
基金The study was funded by the National Natural Science Foundation of China(81972796 and 81972863)Radiation Oncology Innovate Unit,Chinese Academy of Medical Sciences(2019RU071)+1 种基金the Academic Promotion Program of Shandong First Medical University(2019ZL002)the Natural Science Foundation of Shandong(ZR2019MH010 and ZR2020MH289).
文摘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.
基金China Scholarship Council,Grant/Award Number:201806015028Chinese National Natural Science Foundation,Grant/Award Numbers:81101998,81872018,81372292+1 种基金Chinese Ministry of Science and Technology,Grant/Award Number:2017YFC0110200Mayo Clinic Center for Individualized Medicine。
文摘Background:Human epidermal growth factor receptor(EGFR)is an oncogenic gene and one of top targets of precision therapy in lung cancer with EGFR mutations.Although there are many reports for some individual cancers,comprehensive profiling of EGFR mutations,overexpression,amplification,DNA methylation,and their clinical associations across many different cancers simultaneously was not available.This study aimed to fill the gap and provide insights to the alteration spectrum of EGFR and its therapeutic and prognostic implications.Methods:The Cancer Genome Atlas(TCGA)datasets for 32 cancer types involving 11,314 patients were analyzed for alterations(mutations and amplification/deletion),abnormal expression and DNA methylation in EGFR gene.Mutation frequency,genomic location distribution,functional impact,and clinical targeted therapy implication were compared among different cancer types,and their associations with patient survival were analyzed.Results:EGFR alteration frequency,mutation sites across functional domains,amplification,overexpression,and DNA methylation patterns differed greatly among different cancer types.The overall mutation frequency in all cancers combined was relatively low.Targetable mutations,mainly in lung cancer,were primarily found in the Pkinase_Tyr domain.Glioblastoma multiforme had the highest rate of alterations,but it was dominated by gene amplification and most mutations were in the Furin-like domain where targeted therapy was less effective.Low-grade glioma often had gene amplification and increased EGFR expression which was associated with poor outcome.Colon and pancreatic adenocarcinoma had very few EGFR mutations;however,high EGFR expression was significantly associated with short patient survival.Squamous cell carcinoma regardless of their sites(the head and neck,lung,or esophagus)exhibited similar characteristics with an alteration frequency of about 5.0%,was dominated by gene amplification,and had increased EGFR expression generally associated with short patient survival.DNA methylation was highly associated with EGFR expression and patient outcomes in some cancers.Conclusions:EGFR aberration type,frequency,distribution in functional domains,and expression vary from cancer to cancer.While mutations in the Pkinase_Tyr domain are more important for treatment selection,increased expression from amplification or deregulation affects more tumor types and leads to worse outcome,which calls for new treatment strategies for these EGFR-driven tumors.