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.

右上肺叶切除术中肺支气管和血管不同的解剖顺序与肺癌患者的手术可行性和术后恢复相关

背景与目的不同解剖顺序的肺癌右上肺叶切除术(right upper lobectomy,RUL)涉及十分多变的解剖结构,但仍没有研究分析其对术后恢复的影响。本研究比较了常规手术入路VAB(首先解剖肺血管,然后是支气管)和另一种手术入路aBVA(先解剖后升动脉,然后是支气管和血管),在肺癌患者手术可行性和术后恢复方面的差异。方法根据手术方法,将接受RUL的肺癌患者分为aBVA和VAB两组。并收集他们的临床信息、病理资料和围手术期特征,用以比较围手术期结局。结果 301例患者纳入研究(aBVA组109例和VAB组192例)。aBVA组的平均手术时间短于VAB组(164 min vs. 221 min,P <0.001),aBVA组的出血量比VAB组更少(92 mL vs. 141 mL,P <0.001)。aBVA组行开胸手术的比率低于VAB组(0%vs. 11.5%,P <0.001)。术后胸腔引流的平均持续时间aBVA组比VAB组短(3.6 d vs. 4.5 d,P=0.001)。两组的术后并发症发生率相似(P=0.629)。两组均未达到中位总生存期(P> 0.05)。比较了两组中所有患者的中位无病生存期(未达到vs. 41.97个月)(P> 0.05)和疾病复发患者的中位无病生存期(13.25个月vs. 9.44个月)(P>0.05)。在两组中对复发类型也进行了比较:局部复发率(6.4%vs. 7.8%)、远处转移率(10.1%vs. 8.3%)、局部复发合并远处转移率(1.8%vs. 1.6%)(均P> 0.05)。结论在RUL中采用aBVA方法,在反复翻转肺叶和解剖静脉之前解剖右上支气管,将可提高肺癌患者的手术可行性和促进术后恢复。

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.

PD-L1表达指导的信迪利单抗与帕博利珠单抗联合或不联合含铂双药化疗治疗未经治晚期非小细胞肺癌患者:一项2期随机对照试验(CTONG1901)

No direct comparison has been performed between different programmed cell death-1(PD-1)inhibitors for first-line treatment in patients with advanced non-small cell lung cancer(NSCLC).The feasibility of using PD-L1-expression-guided immunotherapy remains unknown.In this open-label,phase 2 study(NCT04252365),patients with advanced NSCLC without EGFR or ALK alterations were randomized(1:1)to receive sintilimab or pembrolizumab monotherapy(PD-L1 expression≥50%),or sintilimab or pembrolizumab plus platinum-based chemotherapy(PD-L1 expression<50%).The sample size was calculated by optimal two-stage design.The primary endpoint was the objective response rate(ORR).The study included 71 patients(sintilimab arms,n=35;pembrolizumab arms,n=36)and met its primary endpoint,with a confirmed ORR of 51.4%(18/35)in the sintilimab arms.The confirmed ORR(95%confidence interval)was 46.2%(19.2%,74.9%)and 42.9%(17.7%,71.1%)for patients treated with sintilimab and pembrolizumab monotherapy;and 54.5%(32.2%,75.6%)and 45.4%(24.4%,67.8%)for those treated with sintilimab-and pembrolizumab-based combination therapies.The median progression-free survival was6.9 versus 8.1 months for all sintilimab-treated versus all pembrolizumab-treated patients,respectively,in which it was 7.6 versus 11.0 months in monotherapy and 7.4 versus 7.1 months in combination therapies.The median overall survival was 14.9 versus 21.3 months for all sintilimab-treated versus all pembrolizumab-treated patients,respectively,in which it was 14.9 versus 22.6 months in monotherapy and 14.7 versus 17.3 months in combination therapies.Treatment-related adverse events were consistent with safety outcomes of monotherapy and combination therapy in previous phase III studies.However,the incidence of rash was higher with sintilimab than pembrolizumab monotherapy.This is the first prospective phase 2 study to directly compare two anti-PD-1 antibodies as first-line treatment in advanced NSCLC.Sintilimab was efficacious and well-tolerated irrespective of PD-L1 expression level in patients with advanced NSCLC and had similar efficacy and safety to pembrolizumab.

Neoadjuvant nivolumab with or without platinum-doublet chemotherapy based on PD-L1 expression in resectable NSCLC(CTONG1804):a multicenter open-label phase II study

This prospective multicenter phase II study evaluated the clinical efficacy of neoadjuvant nivolumab-exclusive(N)and nivolumab–chemotherapy(N/C)combinations based on PD-L1 expression.Eligible patients exhibited resectable clinical stage IIA–IIIB(AJCC 8th edition)NSCLC without EGFR/ALK alterations.Patients received either mono-nivolumab(N)or nivolumab+nabpaclitaxel+carboplatin(N/C)for three cycles based on PD-L1 expression.The primary endpoint was the major pathological response(MPR).Key secondary endpoints included the pathologic complete response(pCR),objective response rate(ORR),and event-free survival(EFS).Baseline PD-L1 expression and perioperative circulating tumor DNA(ctDNA)status were correlated with pCR and EFS.Fifty-two patients were enrolled,with 46 undergoing surgeries.The MPR was 50.0%(26/52),with 25.0%(13/52)achieving pCR,and 16.7%and 66.7%for patients with PD-L1≥50%in N and N/C groups,respectively.Thirteen(25.0%)patients experienced grade 3 or higher immune-related adverse events during neoadjuvant treatment.Patients with post-neoadjuvant ctDNA negativity was more likely to have pCR(39.1%)compared with those remained positive(6.7%,odds ratio=6.14,95%CI 0.84-Inf,p=0.077).With a median follow-up of 25.1 months,the 18-month EFS rate was 64.8%(95%CI 51.9–81.0%).For patients with ctDNA–vs.ctDNA+,the 18m-EFS rate was 93.8%vs 47.3%(HR,0.15;95%CI 0.04,0.94;p=0.005).Immunochemotherapy may serve as an optimal neoadjuvant treatment even for patients with PD-L1 expression≥50%.ctDNA negativity following neoadjuvant treatment and surgery could help identify superior pathological and survival benefits,which requires further confirmation in a prospective clinical trial(NCT04015778).

Erlotinib versus gemcitabine plus cisplatin as neoadjuvant treatment of stage IIIA-N2 EGFR-mutant non-small-cell lung cancer:final overall survival analysis of the EMERGING-CTONG 1103 randomised phase II trial

EMERGING-CTONG 1103 showed improved progression-free survival(PFS)with neoadjuvant erlotinib vs.chemotherapy for patients harbouring EGFR sensibility mutations and R0 resected stage IIIA-N2 non-small cell lung cancer(NSCLC)(NCT01407822).Herein,we report the final results.Recruited patients were randomly allocated 1:1 to the erlotinib group(150 mg/day orally;neoadjuvant phase for 42 days and adjuvant phase to 12 months)or to the GC group(gemcitabine 1250 mg/m2 plus cisplatin 75 mg/m2 intravenously;2 cycles in neoadjuvant phase and 2 cycles in adjuvant phase).Objective response rate(ORR),complete pathologic response(pCR),PFS,and overall survival(OS)were assessed along with safety.Post hoc analysis was performed for subsequent treatments after disease recurrence.Among investigated 72 patients(erlotinib,n=37;GC,n=35),the median follow-up was 62.5 months.The median OS was 42.2 months(erlotinib)and 36.9 months(GC)(hazard ratio[HR],0.83;95%confidence interval[CI],0.47-1.47;p=0.513).The 3-and_(5-y)ear OS rates were 58.6%and 40.8%with erlotinib and 55.9%and 27.6%with GC(p_(3-y)=0.819,p_(5-y)=0.252).Subsequent treatment was administered in 71.9%and 81.8%of patients receiving erlotinib and GC,respectively;targeted therapy contributed mostly to OS(HR,0.35;95%CI,0.18-0.70).After disease progression,the ORR was 53.3%,and the median PFS was 10.9 months during the EGFR-TKI rechallenge.During postoperative therapy,grade 3 or 4 adverse events(AEs)were 13.5%in the erlotinib group and 29.4%in the GC group.No serious adverse events were observed.Erlotinib exhibited clinical feasibility for resectable IIIA-N2 NSCLC over chemotherapy in the neoadjuvant setting.

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.

Neoadjuvant immune checkpoint inhibitor plus chemotherapy in rare tracheal tumors

Dear Editor,Primary malignant tumors of the trachea account for 0.01%-0.4%of all cancer cases[1].Due to their locally aggressive growth,surgical resection including carinal resection and airway reconstruction was most frequently applied for these diseases[2].However,tracheal surgery is technically challenging and is associated with high rates of operative morbidity and mortality.Effective neoadjuvant treatment is expected to reduce the tumor load and lessen the extent of resecting primary tracheal tumors.However,evidence regarding neoadjuvant treatment for tracheal tumors remains relatively scarce and platinumbased doublet chemotherapy remains the standard in this setting.Immune checkpoint inhibitors are a promising approach to neoadjuvant treatment.

Genomic Evolution of Lung Cancer Metastasis:Current Status and Perspectives

INTRODUCTION Lung cancer is one of the cancers with the highest morbidity and mortality worldwide.Over the two past decades,although the treatment of non-small cell lung cancer(NSCLC)has been revolutionized by the use of tyrosine kinase inhibitor(TKI)and immune treatments,metastatic disease remains largely incurable and presents a 5-year survival rate of approximately 10%[1].