IMpower210:A phase Ⅲ study of second-line atezolizumab vs. docetaxel in East Asian patients with non-small cell lung cancer

Objective: IMpower210(NCT02813785) explored the efficacy and safety of single-agent atezolizumab vs.docetaxel as second-line treatment for advanced non-small cell lung cancer(NSCLC) in East Asian patients.Methods: Key eligibility criteria for this phase Ⅲ, open-label, randomized study included age ≥18 years;histologically documented advanced NSCLC per the Union for International Cancer Control/American Joint Committee on Cancer staging system(7th edition);Eastern Cooperative Oncology Group performance status of 0 or 1;and disease progression following platinum-based chemotherapy for advanced or metastatic NSCLC. Patients were randomized 2:1 to receive either atezolizumab(1,200 mg) or docetaxel(75 mg/m^(2)). The primary study endpoint was overall survival(OS) in the intention-to-treat(ITT) population with wild-type epidermal growth factor receptor expression(ITT EGFR-WT) and in the overall ITT population.Results: Median OS in the ITT EGFR-WT population(n=467) was 12.3 [95% confidence interval(95% CI),10.3-13.8] months in the atezolizumab arm(n=312) and 9.9(95% CI, 7.8-13.9) months in the docetaxel arm[n=155;stratified hazard ratio(HR), 0.82;95% CI, 0.66-1.03]. Median OS in the overall ITT population was 12.5(95% CI, 10.8-13.8) months with atezolizumab treatment and 11.1(95% CI, 8.4-14.2) months(n=377) with docetaxel treatment(n=188;stratified HR, 0.87;95% CI, 0.71-1.08). Grade 3/4 treatment-related adverse events(TRAEs) occurred in 18.4% of patients in the atezolizumab arm and 50.0% of patients in the docetaxel arm.Conclusions: IMpower210 did not meet its primary efficacy endpoint of OS in the ITT EGFR-WT or overall ITT populations. Atezolizumab was comparatively more tolerable than docetaxel, with a lower incidence of grade3/4 TRAEs.

Nedaplatin/Gemcitabine Versus Carboplatin/Gemcitabine in Treatment of Advanced Non-small Cell Lung Cancer: A Randomized Clinical Trial

Objective： To evaluate the efficacy and safety of nedaplatin/gemcitabine （NG） and carboplatin/gemcitabine （CG） in the management of untreated advanced non-small cell lung cancer （NSCLC）. Methods： Sixty-two patients with previously untreated advanced NSCLC were recruited between June 2006 and November 2007. Subjects were randomly assigned to the NG arm （n=30） and the CG arm （n=32）. Only patients （24 and 25 in the NG and CG arms, respectively） who completed 〉2 chemotherapy cycles were included in the data analysis. The primary outcome measure was the objective response rate （ORR）. The secondary outcome measures included progression-free survival （PFS）, overall survival （OS） and adverse events. Results： There were no statistically significant differences in the efficacy measures （ORR, P=0.305; median PFS, P=0.298, median OS, P=0.961） or in the major adverse events （grade 3/4 neutropenia, P=0.666; grade 3/4 anemia, P=0.263; grade 3/4 thrombocytopenia, P=0.222） between the two treatment arms. However, there was a trend towards higher ORR （37.5% vs. 24.0%）, longer PFS （6.0 vs. 5.0 months）, and less adverse events in the NG arm. Conclusion： NG regimen seems to be superior over CG regimen for advance NSCLS, but further investigation is needed to validate this superiority.

Detecting the spectrum of multigene mutations in non-small cell lung cancer by Snapshot assay

As molecular targets continue to be identified and more targeted inhibitors are developed for personalized treatment of non-small cell lung cancer(NSCLC), multigene mutation determination will be needed for routine oncology practice and for clinical trials. In this study, we evaluated the sensitivity and specificity of multigene mutation testing by using the Snapshot assay in NSCLC. We retrospectively reviewed a cohort of 110 consecutive NSCLC specimens for which epidermal growth factor receptor(EGFR) mutation testing was performed between November 2011 and December 2011 using Sanger sequencing. Using the Snapshot assay, mutation statuses were detected for EGFR, Kirsten rate sarcoma viral oncogene homolog(KRAS), phosphoinositide-3-kinase catalytic alpha polypeptide(PIK3CA), v-Raf murine sarcoma viral oncogene homolog B1(BRAF), v-ras neuroblastoma viral oncogene homolog(NRAS), dual specificity mitogen activated protein kinase kinase 1(MEK1), phosphatase and tensin homolog(PTEN), and human epidermal growth factor receptor 2(HER2) in patient specimens and cell line DNA. Snapshot data were compared to Sanger sequencing data. Of the 110 samples, 51(46.4%) harbored at least one mutation. The mutation frequency in adenocarcinoma specimens was 55.6%, and the frequencies of EGFR, KRAS, PIK3 CA, PTEN, and MEK1 mutations were 35.5%, 9.1%, 3.6%, 0.9%, and 0.9%, respectively. No mutation was found in the HER2, NRAS, or BRAF genes. Three of the 51 mutant samples harbored double mutations: two PIK3 CA mutations coexisted with KRAS or EGFR mutations, and another KRAS mutation coexisted with a PTEN mutation. Among the 110 samples, 47 were surgical specimens, 60 were biopsy specimens, and 3 were cytological specimens; the corresponding mutation frequencies were 51.1%, 41.7%, and 66.7%, respectively(P = 0.532). Compared to Sanger sequencing, Snapshot specificity was 98.4% and sensitivity was 100%(positive predictive value, 97.9%; negative predictive value, 100%). The Snapshot assay is a sensitive and easily customized assay for multigene mutation testing in clinical practice.

Different dissecting orders of the pulmonary bronchus and vessels during right upper lobectomy are associated with surgical feasibility and postoperative recovery for lung cancer patients

Background: Right upper lobectomy(RUL) for lung cancer with di erent dissecting orders involves the most vari?able anatomical structures, but no studies have analyzed its e ects on postoperative recovery. This study compared the conventional surgical approach, VAB(dissecting pulmonary vessels first, followed by the bronchus), and the alter?native surgical approach, a BVA(dissecting the posterior ascending arterial branch first, followed by the bronchus and vessels) on improving surgical feasibility and postoperative recovery for lung cancer patients.Methods: According to the surgical approach, consecutive lung cancer patients undergoing RUL were grouped into a BVA and VAB cohorts. Their clinical, pathologic, and perioperative characteristics were collected to compare periop?erative outcomes.Results: Three hundred one patients were selected(109 in the a BVA cohort and 192 in the VAB cohort). The mean operation time was shorter in the a BVA cohort than in the VAB cohort(164 vs. 221 min, P < 0.001), and less blood loss occurred in the a BVA cohort(92 vs. 141 m L, P < 0.001). The rate of conversion to thoracotomy was lower in the a BVA cohort than in the VAB cohort(0% vs. 11.5%, P < 0.001). The mean duration of postoperative chest drainage was shorter in the a BVA cohort than in the VAB cohort(3.6 vs. 4.5 days, P rvival was n= 0.001). The rates of postoperative complica?tions were comparable(P = 0.629). The median overall suot arrived in both cohorts(P > 0.05). The median disease?free survival was comparable for all patients in the two cohorts(not arrived vs. 41.97 months) and for patients with disease recurrences(13.25 vs. 9.44 months)(both P > 0.05). The recurrence models in two cohorts were also comparable for patients with local recurrences(6.4% vs. 7.8%), distant metastases(10.1% vs. 8.3%), and both(1.8% vs. 1.6%)(all P > 0.05).Conclusions: Dissecting the right upper bronchus before turning over the lobe repeatedly and dissecting veins via the a BVA approach during RUL would promote surgical feasibility and achieve comparable postoperative recovery for lung cancer patients.

Insight into early-phase trials for lung cancer in the United States

Introduction:Few data have been published comparing early-phase trials for lung cancer between China and the United States(US).This study was to investigate the differences of phase 1 trials for lung cancer between these two countries.Methods:In 2014,a cross-sectional survey was conducted to compare phase 1 trials for lung cancer between the Guangdong Lung Cancer Institute(GLCI),the University of Wisconsin Carbone Cancer Center(UWCCC),and the University of Texas MD Anderson Cancer Center(MDACC).Results:We found that the GLCI had a lower percentage of phase 1 lung cancer trials than the MDACC in December2014(23.8%[5/21]vs.59.8%[28/47],P = 0.006) and the UWCCC in September 2014(16.7%[3/18]vs.34.8%[8/23],P = 0.345).Descriptive analyses were performed for early-phase trials conducted by the CancerTherapy Evaluation Program at the National Cancer Institute(CTEP/NCI),the MDACC,and the Chinese Thoracic Oncology Group(CTONG).There were 149 ongoing early-phase trials in the Department of Investigational Cancer Therapeutics(Phase 1 program) at the MDACC in October 2014.In contrast,no phase 1 trials had been initiated by the CTONG since its establishment in 2007.Conclusions:These data suggest that a significantly higher percentage of phase 1 trials for lung cancer were conducted in the US than in China.Early-phase oncology trials with robust preclinical data had a higher chance of being approved by the Investigational Drug Branch at the CTEP/NCI.Given the importance of early-phase oncology trials in developing innovative cancer medicines,such studies should be highly encouraged and strategically funded in China.

Comparing overall survival between first generation EGFR-TKIs and chemotherapy in lung cancer patients with Del19/L858R

Objective： Combined overall survival （OS） analysis of Lux-Lung 3 and Lux-Lung 6 demonstrated that patients with epidermal growth factor receptor （EGFR） exon 19 deletions （Del19） would benefit from first-line second generation EGFR tyrosine kinase inhibitors （TKIs） afatinib but not for those with L858R. This study was to investigate the survival difference between first-line first generation EGFR-TKIs and chemotherapy in patients with either Del19 or L858R, and to directly compare OS in these two mutation groups. Methods： Eligibles were all prospective and retrospective studies comparing EGFR-TKIs with conventional chemotherapy or receiving single agent EGFR-TKIs and demonstrating survival analysis based on mutation types. The primary outcome was OS measured as pooled hazard ratios （HRs）. All measures were pooled using random- effects models and 95% confidential interval （95% CI） was calculated. Results： A total of 14 studies incorporating 1,706 patients with either Del19 or L858R were included. Enrolling patients with Del19 or L858R in randomized controlled trials （RCTs）, first-line first generation EGFR-TKIs were associated with no OS benefit, compared with chemotherapy （pooled HR_TKI/Chemo for Del19： 0.82, 95% CI： 0.64- 1.06, P=0.14; pooled HR_TKI/Chemo for L858R： 1.15, 95% CI： 0.85-1.56, P=0.38）. Direct comparison of Del19 with L858R receiving with first-line first generation EGFR-TKIs demonstrated no significant survival difference （pooled HR19/21： 0.88, 95% CI： 0.67-1.16, P=0.37）. Conclusions： Among patients with advanced non-small cell hmg cancer （NSCLC） harboring Del19 and L858R, first-line first generation EGFR-TKIs demonstrated no survival benefit comparing with chemotherapy. Direct comparison between Del19 and L858R revealed no significant survival difference after first-line first generation EGFR-TKIs.

Therapeutic revolution for inoperable stage III non-small cell lung cancer in the immune era

The PACIFIC study ushered in a“tsunami-like”therapeutic revolution for stage III inoperable non-small cell lung cancer(NSCLC)In the past,chemoradiotherapy(CRT)has been the standard of care for inoperable stage III NSCLC.Concurrent chemoradiotherapy(cCRT),if tolerable in patients,is the optimal treatment regimen.A meta-analysis has shown that cCRT results in a 5-year survival rate 4.5%longer than that with sequential chemoradiotherapy(sCRT)1.However,within 2 years after cCRT,approximately 30%of patients experience local recurrence,and approximately 40%develop distant metastasis2.Clinicians have explored induction chemotherapy3,consolidation chemotherapy4,and combination use with targeted drugs2,and found that none improve the prognosis.

Establishment and application of a multiplex genetic mutation-detection method of lung cancer based on MassARRAY platform

Objective: This study aims to establish a method for highly parallel multiplexed detection of genetic mutations in Chinese lung cancer samples through Agena i PLEX chemistry and matrix-assisted laser desorption ionization time-of-flight analysis on Mass ARRAY mass spectrometry platform.Methods: We reviewed the related literature and data on lung cancer treatments. We also identified 99 mutation hot spots in 13 target genes closely related to the pathogenesis, drug resistance, and metastasis of lung cancer. A total of 297 primers, composed of99 paired forward and reverse amplification primers and 99 matched extension primers, were designed using Assay Design software. The detection method was established by analyzing eight cell lines and six lung cancer specimens. The proposed method was then validated through comparisons by using a Lung Carta^(TM) kit. The sensitivity and specificity of the proposed method were evaluated by directly sequencing EGFR and KRAS genes in 100 lung cancer cases.Results: The proposed method was able to detect multiplex genetic mutations in lung cancer cell lines. This finding was consistent with the observations on previously reported mutations. The proposed method can also detect such mutations in clinical lung cancer specimens. This result was consistent with the observations with Lung Carta^(TM) kit. However, an FGFR2 mutation was detected only through the proposed method. The measured sensitivity and specificity were 100% and 96.3%, respectively.Conclusions: The proposed Mass ARRAY technology-based multiplex method can detect genetic mutations in Chinese lung cancer patients. Therefore, the proposed method can be applied to detect mutations in other cancer tissues.

A lobe-specific lymphadenectomy protocol for solitary pulmonary nodules in non-small cell lung cancer

Background： We want to establish a lobe-specific mediastinal lymphadenectomy protocol for solitary pulmonary nodules （SPNs） in non-small cell lung cancer （NSCLC）. Methods： We retrospectively analyzed 401 patients with pathological diagnoses of NSCLC who underwent lobectomy, bilobectomy, or pneumonectomy with systematic lymphadenectomy from March 2004 to June 2011 in our hospital. All of the patients enrolled had a SPN preoperatively. Information about the primary tumor location, lymph node metastasis, and other baseline data were collected. Stepwise logistic regression was used to identify the key factors indicating non-regional mediastinal lymph node metastases （NRM）. Results： Of the primary tumors, 117, 39, 74, 104, and 67 were in the right upper lung （RUL）, right middle lung （RML）, right lower lung （RLL）, left upper lung （LUL）, and left lower lung （LLL）, respectively. Stepwise regression showed that #2,4, #10,11, and #10,11 as well as #7 was the key lymph node station for RUL, LUL, and lower lobes： #2,4 [odds ratio （OR）=28.000, 95% confidence interval （CI）： 2.917-268.790, P=0.004] for RUL, #10,11 （OR=31.667, 95% CI： 2.502-400.833, P=0.008） for LUL, #10,11 （OR=19.540, 95% CI： 4.217-90.541, P〈0.001） and #7 （OR=7.395, 95% CI： 1.586-34.484, P=0.011） for lower lobes, respectively. Patients with tumors 〉2 cm rarely had NRM without primary regional mediastinal involvement. Conclusions： With rigid consideration, a lobe-specific lymphadenectomy is feasible in practice. This protocol can be used when the lobe-specific key nodes are negative in intraoperative frozen sections, especially for NSCLC diagnosed as SPN 〈2 cm preoperatively.

Single nucleotide polymorphisms of MAGE-A3 gene and its clinical implications in Chinese patients with non-small cell lung cancer(NSCLC)

Background： Available study revealed advanced tumors have a higher expression rate of MAGE-A3 gene which has a lot of single nucleotide polymorphism（SNP） loci with polymorphisms. This study aimed to analyze the allele frequency of SNP loci in MAGE-A3 gene and investigate the relationship between MAGE-A3 gene polymorphisms and clinical factors.Methods： Tumor samples of a cohort of 191 NSCLC patients were collected. EGFR m RNA expression were detected by q RT-PCR. SNPs in whole length of MAGE-A3 gene were detected by direct sequencing. Frequencies of the SNPs were correlated to gene expression, mutation status of EGFR and clinical factors.Results： Sequencing analysis confirmed that allele frequencies of genotypes on SNP loci rs5970360, rs5925210, rs5970361, rs5925211 and rs35123853 were CC（0.681）/CT（0.319）, CC（0.660）/CG（0.340）, CC（0.681）/CA（0.319）, AA（0.984）/AT（0.016） and GG（1.000）/GA（0.000）, respectively, which were different from the frequencies and genotypes of MAGE-A3 in SNP database. Chi-square tests showed the EGFR mR NA expression level had significant correlation with the genotypes of SNP loci rs5970360 and rs5925210. But all frequencies of each MAGE-A3 SNPs were not found significantly different between EGFR mutant and wild type patients. MAGE-A3 gene polymorphisms had no significant effects on survival of NSCLC patients.Conclusions： Chinese patients with NSCLC had different SNP patterns of MAGE-A3 in comparison with those in international SNP database. These MAGE-A3 SNP loci might have not prognostic significance. MAGE-A3 SNP loci rs5970360 and rs5925210 might be predictive for EGFR m RNA expression levels and helpful to the selection of patients for epidermal growth factor receptor（EGFR） targeted immunotherapy.

Mutation and polymorphism in the tyrosine kinase domain of KDR in Chinese human lung cancer patients

Objective： Although the kinase insert domain-containing receptor （KDR） gene play an very important role in the metastasis of cancer and is also as one of the molecular targets used in cancer therapy, mutation in the tyrosine kinase （TK） domain of the KDR gene has not been reported. Here we detected the mutations and polymorphisms in the TK domain of KDR gene in human lung cancer patients and to give the basic evidence and clue for cancer prevention and target therapy. Methods： The entire sequence of exons 21, 22, 23 and 27 （which contain the coding sequence of tyrosine phosphorylation） in the TK domain of KDR gene in the patients with lung cancer and control healthy individuals were assayed by PCR and DNA sequencing. We also analyzed one non-coding single nucleotide polymorphisms （SNPs） in the KDR gene. Results： No mutations were found in exon 22, 23 and 27. One heterozygous mutation of c.＋2837 in exon 21 was found at a frequency of 2.08% （2/96） in the patients with lung cancer and none were detected in the healthy control individuals. The mutation was from a G to a A resulting in substitution of arginine with histidine residue. Conclusion： Our data suggested that we should focus on the mutation or SNP in the other regions or the expression levels of KDR gene, and the function of c.＋2837 mutation of KDR .qene may be needed further study in the future.

Elevated expression level of laminin 5 may be a negative predictive factor for the response to gefitinib in lung cancer patients

Objective: To investigate whether laminin 5 (LN5) might be a predictor in lung cancer patient treated with gefitinib and estimate the underlying mechanisms. Methods: LN5 and epidermal growth factor receptor (EGFR) mRNA expression level were detected in the tumor tissues of lung cancer patients who underwent surgery resection prior to gefitinib treatment. EGFR exon 19 and 21 mutation status was also detected in these specimens. The association between LN5, EGFR mRNA expression level, EGFR mutation and gefitinib treatment response were evaluated. In vitro study were carried by adding exog- enous LN5 and gefitinib to A549 lung cancer cell line, and Western-blotting was performed to investigate the phosphorylation level of EGFR,Ak, and Erk. Results: The disease control rate according to LN5 mRNA level was 52.9% for the below cut- point group, and 17.6% for the above cut-point (P = 0.009). The in vitro study showed that exogenous LN5 can neutralize the inhibition of phosphor-Akt by gefitinib. Conclusion: Patients with lower LN5 mRNA level would likely benefit from gefitinib. In vitro study indicated that the inhibition of Akt induced by gefitinib might be reversed by LN5. These results provide important insights into the molecular mechanisms underlying sensitivity to gefitinib in lung cancer patients.

Evaluation of molecular residual disease in operable non-small cell lung cancer with gene fusions,MET exon skipping or de novo MET amplification

Gene fusions and MET alterations are rare and difficult to detect in plasma samples.The clinical detection efficacy of molecular residual disease(MRD)based on circulating tumor DNA(ctDNA)in patients with non-small cell lung cancer(NSCLC)with these mutations remains unknown.This prospective,non-intervention study recruited 49 patients with operable NSCLC with actionable gene fusions(ALK,ROS1,RET,and FGFR1),MET exon 14 skipping or de novo MET amplification.We analyzed 43 tumor tissues and 111 serial perioperative plasma samples using 1021-and 338-gene panels,respectively.Detectable MRD correlated with a significantly higher recurrence rate(P<0.001),yielding positive predictive values of 100%and 90.9%,and negative predictive values of 82.4%and 86.4%at landmark and longitudinal time points,respectively.Patients with detectable MRD showed reduced disease-free survival(DFS)compared to those with undetectable MRD(P<0.001).Patients who harbored tissue-derived fusion/MET alterations in their MRD had reduced DFS compared to those who did not(P=0.05).To our knowledge,this is the first comprehensive study on ctDNA-MRD clinical detection efficacy in operable NSCLC patients with gene fusions and MET alterations.Patients with detectable tissue-derived fusion/MET alterations in postoperative MRD had worse clinical outcomes.

Application of next-generation sequencing technology to precision medicine in cancer: joint consensus of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology

Next-generation sequencing(NGS) technology is capable of sequencing millions or billions of DNA molecules simultaneously.Therefore, it represents a promising tool for the analysis of molecular targets for the initial diagnosis of disease, monitoring of disease progression, and identifying the mechanism of drug resistance. On behalf of the Tumor Biomarker Committee of the Chinese Society of Clinical Oncology(CSCO) and the China Actionable Genome Consortium(CAGC), the present expert group hereby proposes advisory guidelines on clinical applications of NGS technology for the analysis of cancer driver genes for precision cancer therapy. This group comprises an assembly of laboratory cancer geneticists, clinical oncologists, bioinformaticians,pathologists, and other professionals. After multiple rounds of discussions and revisions, the expert group has reached a preliminary consensus on the need of NGS in clinical diagnosis, its regulation, and compliance standards in clinical sample collection. Moreover, it has prepared NGS criteria, the sequencing standard operation procedure(SOP), data analysis, report, and NGS platform certification and validation.

Characteristics of tumor microenvironment and novel immunotherapeutic strategies for non-small cell lung cancer

Immune checkpoint inhibitor-based immunotherapy has revolutionized the treatment approach of non-small cell lung cancer(NSCLC).Monoclonal antibodies against programmed cell death-1(PD-1)and PD-ligand 1(PD-L1)are widely used in clinical practice,but other antibodies that can circumvent innate and acquired resistance are bound to undergo preclinical and clinical studies.However,tumor cells can develop and facilitate the tolerogenic nature of the tumor microenvironment(TME),resulting in tumor progression.Therefore,the immune escape mechanisms exploited by growing lung cancer involve a fine interplay between all actors in the TME.A better understanding of the molecular biology of lung cancer and the cellular/molecular mechanisms involved in the crosstalk between lung cancer cells and immune cells in the TME could identify novel therapeutic weapons in the old war against lung cancer.This article discusses the role of TME in the progression of lung cancer and pinpoints possible advances and challenges of immunotherapy for NSCLC.

SYK-mediated epithelial cell state is associated with response to c-Met inhibitors in c-Met-overexpressing lung cancer

Genomic MET amplification and exon 14 skipping are currently clinically recognized biomarkers for stratifying subsets of non-small cell lung cancer(NSCLC)patients according to the predicted response to c-Met inhibitors(c-Metis),yet the overall clinical benefit of this strategy is quite limited.Notably,c-Met protein overexpression,which occurs in approximately 20–25%of NSCLC patients,has not yet been clearly defined as a clinically useful biomarker.An optimized strategy for accurately classifying patients with c-Met overexpression for decision-making regarding c-Meti treatment is lacking.Herein,we found that SYK regulates the plasticity of cells in an epithelial state and is associated with their sensitivity to c-Metis both in vitro and in vivo in PDX models with c-Met overexpression regardless of MET gene status.Furthermore,TGF-β1 treatment resulted in SYK transcriptional downregulation,increased Sp1-mediated transcription of FRA1,and restored the mesenchymal state,which conferred resistance to c-Metis.Clinically,a subpopulation of NSCLC patients with c-Met overexpression coupled with SYK overexpression exhibited a high response rate of 73.3%and longer progression-free survival with c-Meti treatment than other patients.SYK negativity coupled with TGF-β1 positivity conferred de novo and acquired resistance.In summary,SYK regulates cell plasticity toward a therapy-sensitive epithelial cell state.Furthermore,our findings showed that SYK overexpression can aid in precisely stratifying NSCLC patients with c-Met overexpression regardless of MET alterations and expand the population predicted to benefit from c-Met-targeted therapy.

Circulating tumor DNA(ctDNA)-based minimal residual disease in non-small cell lung cancer

Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related fatalities,with non-small cell lung cancer(NSCLC)accounting for 85%of all lung cancers.Over the past forty years,patients with NSCLC have had a 5-year survival rate of only 16%,despite improvements in chemotherapy,targeted therapy,and immunotherapy.Circulating tumor DNA(ctDNA)in blood can be used to identify minimal residual disease(MRD),and ctDNA-based MRD has been shown to be of significance in prognostic assessment,recurrence monitoring,risk of recurrence assessment,efficacy monitoring,and therapeutic intervention decisions in NSCLC.The level of MRD can be obtained by monitoring ctDNA to provide guidance for more precise and personalized treatment,the scientific feasibility of which could dramatically modify lung cancer treatment paradigm.In this review,we present a comprehensive review of MRD studies in NSCLC and focus on the application of ctDNA-based MRD in different stages of NSCLC in current clinical practice.

Neoadjuvant immunotherapy for non-small cell lung cancer:State of the art

Lung cancer mortality has decreased over the past decade and can be partly attributed to advances in targeted therapy and immunotherapy.Immune checkpoint inhibitors(ICIs)have rapidly evolved from investigational drugs to standard of care for the treatment ofmetastatic non-small cell lung cancer(NSCLC).In particular,antibodies that block inhibitory immune checkpoints,such as programmed cell death protein 1(PD-1)and programmed cell death 1 ligand 1(PD-L1),have revolutionized the treatment of advanced NSCLC,when administered alone or in combination with chemotherapy.Immunotherapy is associated with higher response rates,improved overall survival(OS),and increased tolerability compared with conventional cytotoxic chemotherapy.These benefits may increase the utility of immunotherapy and its combinational use with chemotherapy in the neoadjuvant treatment of patients with NSCLC.Early findings from various ongoing clinical trials suggest that neoadjuvant ICIs alone or combined with chemotherapy may significantly reduce systemic recurrence and improve long-term OS or cure rates in resectable NSCLC.Here we further summarize the safety and efficacy of various neoadjuvant treatment regimens including immunotherapy from ongoing clinical trials and elaborate the role of neoadjuvant immunotherapy in patients with resectable NSCLC.In addition,we discuss several unresolved challenges,including the evaluations to assess neoadjuvant immunotherapy response,the role of adjuvant treatment after neoadjuvant immunotherapy,the efficacy of treatment for oncogenic-addicted tumors,and predictive biomarkers.We also provide our perspective on ways to overcome current obstacles and establish neoadjuvant immunotherapy as a standard of care.

Impact of smoking status and pathologic type on epidermal growth factor receptor mutations in lung cancer

Background Epidermal growth factor receptor （EGFR） responsive to the treatment with tyrosine kinase inhibitors. large series of lung carcinomas. mutations in lung carcinomas can make the disease more We aimed to evaluate the prevalence of EGFR mutations in a Methods We examined 1195 consecutive lung cancer patients for EGFR mutations in exons 18, 19, and 21 using direct sequencing of polymerase chain reaction products. A detailed smoking history was obtained. Patients were categorized as never smokers （〈100 lifetime cigarettes）, former smokers （quit 〉1 year ago）, or current smokers （quit 〈1 year ago）. Results There were EGFR mutations in 9 （4.5%） of 201 squamous carcinomas, in 1 （2%） of 50 large cell carcinomas, and in 1 （2.3%） of 44 small cell carcinomas that were investigated. Three hundred and twenty-seven mutations were found in the series of 858 adenocarcinomas （38.1%）. Among 858 lung adenocarcinomas, we detected EGFR mutations in 250 （48.6%） of 514 never smokers, 39 （33.9%） of 115 former smokers, and 38 （16.6%） of 229 current smokers. Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years （P=-0.0002） or stopped smoking less than 15 years ago （P=0.033） compared with individuals who never smoked. Conclusions Adenocarcinoma is the most frequent EGFR mutation pathologic type in lung cancer. The likelihood of EGFR mutations in exons 18, 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 15 years ago. These data can assist clinicians in assessing the likelihood of exons 18, 19, or 21 EGFR mutations in Chinese patients with lung cancer when mutational analysis is not feasible.

Organ-specific efficacy in advanced non-small cell lung cancer patients treated with first-line single-agent immune checkpoint inhibitors

Background:Response to immune checkpoint inhibitors(ICIs)is affected by multiple factors.This study aimed to explore whether sites of metastasis are associated with clinical outcomes of ICIs in advanced non-small-cell lung cancer(NSCLC)patients.Methods::The data of NSCLC patients with high programmed death-ligand 1 expression and good performance status receiving first-line ICIs monotherapy from Guangdong Provincial People’s Hospital between May 2019 and July 2020 were retrospectively analyzed.Metastatic sites included liver,bone,brain,adrenal gland,pleura,and contralateral lung.Progression-free survival(PFS)and overall survival(OS)were compared between different metastatic sites and metastatic burden by the Kaplan-Meier method.Organ-specific disease control rate(OSDCR)of different individual metastatic sites was evaluated.Results:Forty NSCLC patients meeting the criteria were identified.The presence of liver metastasis was significantly associated with shorter PFS(3.1 vs.15.5 months,P=0.0005)and OS(11.1 months vs.not reached,P=0.0016).Besides,patients with bone metastasis tend to get shorter PFS(4.2 vs.15.5 months,P=0.0532)rather than OS(P=0.6086).Moreover,the application of local treatment could numerically prolong PFS in patients with brain metastasis(15.5 vs.4.3 months,P=0.1894).More metastatic organs involved were associated with inferior PFS(P=0.0052)but not OS(P=0.0791).The presence of liver metastasis or bone metastasis was associated with more metastatic organs(Phi[φ]:0.516,P=0.001).The highest OSDCR was observed in lung(15/17),and the lowest in the liver(1/4).Conclusions:Metastases in different anatomical locations may be associated with different clinical outcomes and local tumor response to ICIs in NSCLC.ICIs monotherapy shows limited efficacy in patients with liver and bone metastasis,thus patients with this type of metastasis might require more aggressive combination strategies.