Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor(EGFR) activating mutatio...Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor(EGFR) activating mutations and the introduction of its tyrosine kinase inhibitors(TKIs) have expanded the treatment options for patients with non-small cell lung cancer. Nowadays, EGFR mutation testing is now a common routine for newly diagnosed lung cancer. First generation TKIs developed, erlotinib and gefitinib, were reversible ones. After a median of 14 mo, eventually all EGFR mutated patients develop resistance to reversible TKIs. Afatinib, dacomitinib and neratinib, second generation inhibitors, are selective and irreversible TKIs. Finally, third generation phase Ⅰclinical trials were performed, with lower toxicity profiles, and targeting with more precision the driving clone of this heterogeneous disease.展开更多
Objective: To investigate the benefit of epidermal growth factor receptor( EGFR) tyrosine kinase inhibitors( TKIs)with radiotherapy in patients with EGFR mutation-positive metastatic non-small cell lung cancer( NSCLC)...Objective: To investigate the benefit of epidermal growth factor receptor( EGFR) tyrosine kinase inhibitors( TKIs)with radiotherapy in patients with EGFR mutation-positive metastatic non-small cell lung cancer( NSCLC),compared with TKIs alone.Methods: A total of 103 patients with stage Ⅳ EGFR-mutated NSCLC treated from February 2015 to May 2017 at Sichuan Cancer Hospital were analyzed retrospectively. Fifty patients were treated with EGFR-TKIs( gefitinib or erlotinib) plus radiotherapy( the TKI +RT group) and 53 patients received EGFR-TKIs alone( the TKI group). Tumor response,survival and toxicities were compared between the two groups. Results: Median follow-up time was 11. 7 months( 2. 8-36. 3 months). The overall response rate( ORR) and disease control rate( DCR) in the TKI + RT group vs the TKI group were 62% vs 37. 7%( P = 0. 014) and 88% vs 75. 5%( P =0. 101),respectively. The median progression-free survival( PFS) and median overall survival( OS) in the TKI + RT group were superior to those of the TKI group( 18. 87 months vs 12. 80 months,P = 0. 035 and 23. 10 months vs 18. 30 months,P = 0. 011). OS rates in the TKI + RT group and the TKI group were 56. 0% vs 35. 8% at year 1( P = 0. 04) and 16. 0% vs 3. 8% at year 2( P =0. 036). Multivariate Cox model found that TKI + RT related to significantly better OS( hazard ratio = 0. 209;95% CI,0. 066 to0. 661;P = 0. 008) than TKI alone. Adverse events did not differ significantly between the two groups( P > 0. 050). Conclusion:Compared with EGFR-TKIs alone,EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumor response and survival for EGFR mutation-positive metastatic NSCLC patients.展开更多
Objective To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in...Objective To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced lung adenocarcinoma. Methods In this prospective study,adult patients with advanced lung adenocarcinoma were enrolled in our hospital from 1 April 2016 to 1 January 2017. EGFR mutations in tumortissues were detected by ADx-amplification refractory mutationsystem (ADx-ARMS). EGFR mutations of plasmafree tumor DNA were detected by ADx-ARMS and ADxsuperamplification refractory mutation system (ADx-SuperARMS)at the same time. Patients with EGFR-mutantin tumor tissues and receiving EGFR-TKIs were finallyenrolled. Plasma mutation-positive patients with bothmethods were high abundance group. Patients with positivemutations by ADx-SuperARMS but negative of ADx-ARMS were medium abundance group.展开更多
A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor(EGFR)19 del mutation positive.Treatment with icotinib was given,but her disease...A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor(EGFR)19 del mutation positive.Treatment with icotinib was given,but her disease progressed after 6 months remission.CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis,and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction(ARMS-PCR)confirmed EGFR T790M mutation.Treatment with osimertinib was initiated.After 2 months remission,the disease progressed.Re-biopsy was performed for the tumor in the inferior lobe of left lung,and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del.Icotinib was re-challenged,but disease progressed continuously.Bevacizumab was added,and partial response was achieved after 2-cycle of combination therapy.The non-small cell lung cancer(NSCLC)in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment.This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.展开更多
Over recent years,[18F]-fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography(FDG-PET/CT)has proven its role as a staging modality in patients with non-small cell lung can...Over recent years,[18F]-fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography(FDG-PET/CT)has proven its role as a staging modality in patients with non-small cell lung cancer(NSCLC).The purpose of this review was to present the evidence to use FDG-PET/CT for response evaluation in patients with NSCLC,treated with epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKI).All published articles from 1November 2003 to 1 November 2013 reporting on 18FFDG-PET response evaluation during EGFR-TKI treatment in patients with NSCLC were collected.In total 7studies,including data of 210 patients were eligible for analyses.Our report shows that FDG-PET/CT responseduring EGFR-TKI therapy has potential in targeted treatment for NSCLC.FDG-PET/CT response is associated with clinical and radiologic response and with survival.Furthermore FDG-PET/CT response monitoring can be performed as early as 1-2 wk after initiation of EGFR-TKI treatment.Patients with substantial decrease of metabolic activity during EGFR-TKI treatment will probably benefit from continued treatment.If metabolic response does not occur within the first weeks of EGFR-TKI treatment,patients may be spared(further)unnecessary toxicity of ineffective treatment.Refining FDG-PET response criteria may help the clinician to decide on continuation or discontinuation of targeted treatment.展开更多
BACKGROUND Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute lifethreatening skin reactions.AZD9291 has been developed as a third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase inhib...BACKGROUND Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute lifethreatening skin reactions.AZD9291 has been developed as a third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor(TKI)with activity against T790M mutation.CASE SUMMARY Herein we report a 68-year-old woman who developed a large area of skin necrosis and was diagnosed with toxic epidermal necrolysis after AZD-9291 ingestion.To the best of our knowledge,this is the first case reported in patients with EGFR T790M mutation in non-small cell lung cancer(NSCLC).Cabozantinib combined with erlotinib had clinically meaningful effectiveness,with additional toxicity that was generally manageable.CONCLUSION Treatment with AZD-9261 is effective in regressing the growth of the NSCLC and can bring some hope to despairing patients.We hope that more research will be carried out on the association between severe rashes and EGFR-TKIs,and more safe and effective drugs can be developed.展开更多
BACKGROUND The emergence of secondary drug resistance when treating epidermal growth factor receptor(EGFR)mutated non-small cell lung cancer(NSCLC)using EGFRtyrosine kinase inhibitors(EGFR-TKIs),seriously affects the ...BACKGROUND The emergence of secondary drug resistance when treating epidermal growth factor receptor(EGFR)mutated non-small cell lung cancer(NSCLC)using EGFRtyrosine kinase inhibitors(EGFR-TKIs),seriously affects the therapeutic efficacy and survival of patients.Here,we report a case of advanced NSCLC focusing on the application of multiple biopsy modalities to reveal the development of multiple resistance mechanisms during targeted therapies.CASE SUMMARY A 54-year-old male patient presented with EGFR 19Del-mutated advanced lung adenocarcinoma,and exhibited the development of a T790M mutation during initial TKI treatment.Following 3 mo of Osimertinib treatment,a mixed response was observed.Tissue biopsy of the progressive lesion showed transformation to small cell lung cancer(SCLC)harboring RB1 and TP53 mutations,with loss of the original T790M mutation.A standard chemotherapy regimen with Anlotinib for SCLC was administered.Repeat biopsy revealed adenocarcinoma combined with SCLC after tumor progression.The patient’s overall survival was 24 mo.CONCLUSION Multiple biopsy modalities can reveal the development of multiple resistance mechanisms which help with treatment decision-making.Comprehensive treatment regimens according to the drug resistance mechanism significantly improved the prognosis of such patients.展开更多
AIM: To evaluate the prognostic factors of long-term survival of more than 3 years in patients with advanced non-small cell lung cancer(NSCLC). METHODS: We retrospectively analyzed the records of 474 patients with adv...AIM: To evaluate the prognostic factors of long-term survival of more than 3 years in patients with advanced non-small cell lung cancer(NSCLC). METHODS: We retrospectively analyzed the records of 474 patients with advanced ⅢB/Ⅳ NSCLC who received chemotherapy as initial treatment between September 2002 and March 2007.RESULTS: The median survival time(MST) was 12.5 mo and the 3 year and 5 year survival rates were 14.6% and 5.3%, respectively. Long-term survival of more than 3 and 5 years was observed in 65 and 16 patients, respectively. The MST for the 65 patients was61.5 mo(range, 60.1-81.0 mo). In the 474 patients, a good performance status(PS), female sex, non-smoking status and adenocarcinoma histology were significantly associated with a favorable outcome. Furthermore, female sex, a good PS, non-smoking status and adenocarcinoma histology were significantly correlated with longterm survival of more than 3 years and most of these patients(89.2%, 58/65) received epidermal growth factor receptor-tyrosine kinase inhibitors as any line treatment. Survival analysis of long-term survivors showed that a PS of 0 was an independent prognostic factor for predicting favorable outcomes. CONCLUSION: Our results suggest that a good PS and adenocarcinoma histology play an important role in long-term survival of more than 3 years. A PS of 0 was an independent prognostic factor for predicting favorable outcomes in patients with advanced NSCLC who survived for more than 3 years.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
Background:The synergistic association between metformin and epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)has been confirmed in in vitro studies.It is still controversial which patients can b...Background:The synergistic association between metformin and epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)has been confirmed in in vitro studies.It is still controversial which patients can benefit from metformin plus EGFR-TKIs treatment.Body mass index(BMI)was proved to be independently associated with prolonged progression-free survival(PFS)and overall survival(OS).This study aimed to in-vestigate whether BMI is associated with the synergistic effect of metformin and EGFR-TKIs in advanced EGFR mutation(EGFR m)-positive non-small cell lung cancer(NSCLC)among nondiabetic Asian population.Methods:We performed a post hoc analysis of a prospective,double-blind phase II randomized clinical trial(COAST,NCT01864681),which enrolled 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFR m NSCLC.We stratified patients into those with a high BMI(≥24 kg/m^(2))and those with a low BMI(<24 kg/m^(2))to allow an analysis of the difference in PFS and OS between the two groups.The PFS and OS were analyzed using Kaplan-Meier curves,and the differences between groups were compared using log-rank test.Results:In the univariate analysis,patients who had a high BMI(n=56)in the gefitinib+metformin group(n=28)did not have a better PFS(8.84 months vs.11.67 months;P=0.351)or OS(15.58 months vs.24.36 months;P=0.095)than those in the gefitinib+placebo group(n=28).Similar results were also observed in the low-BMI groups.Strikingly,in the metformin plus gefitinib group,patients who had low BMI(n=69)showed significantly better OS than those with high BMI(24.89 months[95%CI,20.68 months-not reached]vs.15.58 months[95%CI,13.78-31.53 months];P=0.007),but this difference was not observed in PFS(10.78 months vs.8.84 months;P=0.285).Conclusions:Our study showed that nondiabetic Asian advanced NSCLC patients with EGFR mutations who have low BMI seem to get better OS from metformin plus EGFR-TKI treatment.展开更多
Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-profici...Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling cascades.Overexpression of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in patients.Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers.Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to EGFR-TKIs.To date,no HER3-targeted therapy has been approved for cancer treatment.In both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being examined.Recent evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant NSCLC.Herein,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling pathways.We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.展开更多
文摘Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor(EGFR) activating mutations and the introduction of its tyrosine kinase inhibitors(TKIs) have expanded the treatment options for patients with non-small cell lung cancer. Nowadays, EGFR mutation testing is now a common routine for newly diagnosed lung cancer. First generation TKIs developed, erlotinib and gefitinib, were reversible ones. After a median of 14 mo, eventually all EGFR mutated patients develop resistance to reversible TKIs. Afatinib, dacomitinib and neratinib, second generation inhibitors, are selective and irreversible TKIs. Finally, third generation phase Ⅰclinical trials were performed, with lower toxicity profiles, and targeting with more precision the driving clone of this heterogeneous disease.
基金supported by Wu Jieping Medical Foundation(NO.320.6750.14273)
文摘Objective: To investigate the benefit of epidermal growth factor receptor( EGFR) tyrosine kinase inhibitors( TKIs)with radiotherapy in patients with EGFR mutation-positive metastatic non-small cell lung cancer( NSCLC),compared with TKIs alone.Methods: A total of 103 patients with stage Ⅳ EGFR-mutated NSCLC treated from February 2015 to May 2017 at Sichuan Cancer Hospital were analyzed retrospectively. Fifty patients were treated with EGFR-TKIs( gefitinib or erlotinib) plus radiotherapy( the TKI +RT group) and 53 patients received EGFR-TKIs alone( the TKI group). Tumor response,survival and toxicities were compared between the two groups. Results: Median follow-up time was 11. 7 months( 2. 8-36. 3 months). The overall response rate( ORR) and disease control rate( DCR) in the TKI + RT group vs the TKI group were 62% vs 37. 7%( P = 0. 014) and 88% vs 75. 5%( P =0. 101),respectively. The median progression-free survival( PFS) and median overall survival( OS) in the TKI + RT group were superior to those of the TKI group( 18. 87 months vs 12. 80 months,P = 0. 035 and 23. 10 months vs 18. 30 months,P = 0. 011). OS rates in the TKI + RT group and the TKI group were 56. 0% vs 35. 8% at year 1( P = 0. 04) and 16. 0% vs 3. 8% at year 2( P =0. 036). Multivariate Cox model found that TKI + RT related to significantly better OS( hazard ratio = 0. 209;95% CI,0. 066 to0. 661;P = 0. 008) than TKI alone. Adverse events did not differ significantly between the two groups( P > 0. 050). Conclusion:Compared with EGFR-TKIs alone,EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumor response and survival for EGFR mutation-positive metastatic NSCLC patients.
文摘Objective To determine whether relative abundance of epidermal growth factor receptor (EGFR) mutations in plasma predicts clinical response to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in patients with advanced lung adenocarcinoma. Methods In this prospective study,adult patients with advanced lung adenocarcinoma were enrolled in our hospital from 1 April 2016 to 1 January 2017. EGFR mutations in tumortissues were detected by ADx-amplification refractory mutationsystem (ADx-ARMS). EGFR mutations of plasmafree tumor DNA were detected by ADx-ARMS and ADxsuperamplification refractory mutation system (ADx-SuperARMS)at the same time. Patients with EGFR-mutantin tumor tissues and receiving EGFR-TKIs were finallyenrolled. Plasma mutation-positive patients with bothmethods were high abundance group. Patients with positivemutations by ADx-SuperARMS but negative of ADx-ARMS were medium abundance group.
文摘A 61-year-old Chinese woman was diagnosed as primary pulmonary adenocarcinoma of left superior lobe with epidermal growth factor receptor(EGFR)19 del mutation positive.Treatment with icotinib was given,but her disease progressed after 6 months remission.CT-guide needle biopsy for the new lesion in inferior lobe of left lung demonstrated intrapulmonary metastasis,and EGFR gene panel by Amplification Refractory Mutation System Polymerase Chain Reaction(ARMS-PCR)confirmed EGFR T790M mutation.Treatment with osimertinib was initiated.After 2 months remission,the disease progressed.Re-biopsy was performed for the tumor in the inferior lobe of left lung,and ARMS-PCR demonstrated no other gene mutation except EGFR 19 del.Icotinib was re-challenged,but disease progressed continuously.Bevacizumab was added,and partial response was achieved after 2-cycle of combination therapy.The non-small cell lung cancer(NSCLC)in this case maintained EGFR activating mutation and lost EGFR T790M mutation was a genetic change after osimertinib treatment.This case suggests the re-challenge of the first-generation EGFR-TKIs combined with bevacizumab may overcome the tumor resistance and prolong survival of NSCLC patient.
文摘Over recent years,[18F]-fluorodeoxyglucose positron emission tomography acquired together with low dose computed tomography(FDG-PET/CT)has proven its role as a staging modality in patients with non-small cell lung cancer(NSCLC).The purpose of this review was to present the evidence to use FDG-PET/CT for response evaluation in patients with NSCLC,treated with epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKI).All published articles from 1November 2003 to 1 November 2013 reporting on 18FFDG-PET response evaluation during EGFR-TKI treatment in patients with NSCLC were collected.In total 7studies,including data of 210 patients were eligible for analyses.Our report shows that FDG-PET/CT responseduring EGFR-TKI therapy has potential in targeted treatment for NSCLC.FDG-PET/CT response is associated with clinical and radiologic response and with survival.Furthermore FDG-PET/CT response monitoring can be performed as early as 1-2 wk after initiation of EGFR-TKI treatment.Patients with substantial decrease of metabolic activity during EGFR-TKI treatment will probably benefit from continued treatment.If metabolic response does not occur within the first weeks of EGFR-TKI treatment,patients may be spared(further)unnecessary toxicity of ineffective treatment.Refining FDG-PET response criteria may help the clinician to decide on continuation or discontinuation of targeted treatment.
基金National Natural Science Foundation of China,No.81974570.
文摘BACKGROUND Toxic epidermal necrolysis and Stevens-Johnson syndrome are acute lifethreatening skin reactions.AZD9291 has been developed as a third-generation epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitor(TKI)with activity against T790M mutation.CASE SUMMARY Herein we report a 68-year-old woman who developed a large area of skin necrosis and was diagnosed with toxic epidermal necrolysis after AZD-9291 ingestion.To the best of our knowledge,this is the first case reported in patients with EGFR T790M mutation in non-small cell lung cancer(NSCLC).Cabozantinib combined with erlotinib had clinically meaningful effectiveness,with additional toxicity that was generally manageable.CONCLUSION Treatment with AZD-9261 is effective in regressing the growth of the NSCLC and can bring some hope to despairing patients.We hope that more research will be carried out on the association between severe rashes and EGFR-TKIs,and more safe and effective drugs can be developed.
文摘BACKGROUND The emergence of secondary drug resistance when treating epidermal growth factor receptor(EGFR)mutated non-small cell lung cancer(NSCLC)using EGFRtyrosine kinase inhibitors(EGFR-TKIs),seriously affects the therapeutic efficacy and survival of patients.Here,we report a case of advanced NSCLC focusing on the application of multiple biopsy modalities to reveal the development of multiple resistance mechanisms during targeted therapies.CASE SUMMARY A 54-year-old male patient presented with EGFR 19Del-mutated advanced lung adenocarcinoma,and exhibited the development of a T790M mutation during initial TKI treatment.Following 3 mo of Osimertinib treatment,a mixed response was observed.Tissue biopsy of the progressive lesion showed transformation to small cell lung cancer(SCLC)harboring RB1 and TP53 mutations,with loss of the original T790M mutation.A standard chemotherapy regimen with Anlotinib for SCLC was administered.Repeat biopsy revealed adenocarcinoma combined with SCLC after tumor progression.The patient’s overall survival was 24 mo.CONCLUSION Multiple biopsy modalities can reveal the development of multiple resistance mechanisms which help with treatment decision-making.Comprehensive treatment regimens according to the drug resistance mechanism significantly improved the prognosis of such patients.
文摘AIM: To evaluate the prognostic factors of long-term survival of more than 3 years in patients with advanced non-small cell lung cancer(NSCLC). METHODS: We retrospectively analyzed the records of 474 patients with advanced ⅢB/Ⅳ NSCLC who received chemotherapy as initial treatment between September 2002 and March 2007.RESULTS: The median survival time(MST) was 12.5 mo and the 3 year and 5 year survival rates were 14.6% and 5.3%, respectively. Long-term survival of more than 3 and 5 years was observed in 65 and 16 patients, respectively. The MST for the 65 patients was61.5 mo(range, 60.1-81.0 mo). In the 474 patients, a good performance status(PS), female sex, non-smoking status and adenocarcinoma histology were significantly associated with a favorable outcome. Furthermore, female sex, a good PS, non-smoking status and adenocarcinoma histology were significantly correlated with longterm survival of more than 3 years and most of these patients(89.2%, 58/65) received epidermal growth factor receptor-tyrosine kinase inhibitors as any line treatment. Survival analysis of long-term survivors showed that a PS of 0 was an independent prognostic factor for predicting favorable outcomes. CONCLUSION: Our results suggest that a good PS and adenocarcinoma histology play an important role in long-term survival of more than 3 years. A PS of 0 was an independent prognostic factor for predicting favorable outcomes in patients with advanced NSCLC who survived for more than 3 years.
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.
基金This work was supported by the National Natural Science Foundation of China(NSFC)(Nos.81972189,82172623,81802293,and 81902343)Chongqing Science and Technology Commission(No.cstc2021jcyj-msxmX0014).
文摘Background:The synergistic association between metformin and epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)has been confirmed in in vitro studies.It is still controversial which patients can benefit from metformin plus EGFR-TKIs treatment.Body mass index(BMI)was proved to be independently associated with prolonged progression-free survival(PFS)and overall survival(OS).This study aimed to in-vestigate whether BMI is associated with the synergistic effect of metformin and EGFR-TKIs in advanced EGFR mutation(EGFR m)-positive non-small cell lung cancer(NSCLC)among nondiabetic Asian population.Methods:We performed a post hoc analysis of a prospective,double-blind phase II randomized clinical trial(COAST,NCT01864681),which enrolled 224 patients without diabetes with treatment-naïve stage IIIB-IV EGFR m NSCLC.We stratified patients into those with a high BMI(≥24 kg/m^(2))and those with a low BMI(<24 kg/m^(2))to allow an analysis of the difference in PFS and OS between the two groups.The PFS and OS were analyzed using Kaplan-Meier curves,and the differences between groups were compared using log-rank test.Results:In the univariate analysis,patients who had a high BMI(n=56)in the gefitinib+metformin group(n=28)did not have a better PFS(8.84 months vs.11.67 months;P=0.351)or OS(15.58 months vs.24.36 months;P=0.095)than those in the gefitinib+placebo group(n=28).Similar results were also observed in the low-BMI groups.Strikingly,in the metformin plus gefitinib group,patients who had low BMI(n=69)showed significantly better OS than those with high BMI(24.89 months[95%CI,20.68 months-not reached]vs.15.58 months[95%CI,13.78-31.53 months];P=0.007),but this difference was not observed in PFS(10.78 months vs.8.84 months;P=0.285).Conclusions:Our study showed that nondiabetic Asian advanced NSCLC patients with EGFR mutations who have low BMI seem to get better OS from metformin plus EGFR-TKI treatment.
基金We are grateful to Dr.Shi-Yong Sun(Emory University School of Medicine and Winship Cancer Institute)for his critical reading of the manuscript.This work was supported in part by a translational research grant from METAvivor Research and Support Inc.and a start-up fund provided by the Stanley S.Scott Cancer Center at Louisiana State Uni-versity(LSU)Health Sciences Center(to BL).
文摘Human epidermal growth factor receptor 3(HER3)is a unique member of the human epidermal growth factor receptor(HER/EGFR)family,since it has negligible kinase activity.Therefore,HER3 must interact with a kinase-proficient receptor to form a heterodimer,leading to the activation of signaling cascades.Overexpression of HER3 is observed in various human cancers,including non-small cell lung cancer(NSCLC),and correlates with poor clinical outcomes in patients.Studies on the underlying mechanism demonstrate that HER3-initiated signaling promotes tumor metastasis and causes treatment failure in human cancers.Upregulation of HER3 is frequently observed in EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors(TKIs).Increased expression of HER3 triggers the so-called EGFR-independent mechanism via interactions with other receptors to activate“by-pass signaling pathways”,thereby resulting in resistance to EGFR-TKIs.To date,no HER3-targeted therapy has been approved for cancer treatment.In both preclinical and clinical studies,targeting HER3 with a blocking an-tibody(Ab)is the only strategy being examined.Recent evaluations of an anti-HER3 Ab-drug conjugate(ADC)show promising results in patients with EGFR-TKI-resistant NSCLC.Herein,we summarize our understanding of the unique biology of HER3 in NSCLC refractory to EGFR-TKIs,with a focus on its dimerization partners and subsequent activation of signaling pathways.We also discuss the latest development of the therapeutic Abs and ADCs targeting HER3 to abrogate EGFR-TKI resistance in NSCLC.