Human tumors are diverse in their natural history and response to treatment, which in part results from genetic and transcriptomic heterogeneity. In clinical practice, single-site needle biopsies are used to sample this diversity, but cancer biomarkers may be confounded by spatiogenomic heterogeneity within individual tumors. Here we investigate clonally expressed genes as a solution to the sampling bias problem by analyzing multiregion whole-exome and RNA sequencing data for 450 tumor regions from 184 patients with lung adenocarcinoma in the TRACERx study. We prospectively validate the survival association of a clonal expression biomarker, Outcome Risk Associated Clonal Lung Expression (ORACLE), in combination with clinicopathological risk factors, and in stage I disease. We expand our mechanistic understanding, discovering that clonal transcriptional signals are detectable before tissue invasion, act as a molecular fingerprint for lethal metastatic clones and predict chemotherapy sensitivity. Lastly, we find that ORACLE summarizes the prognostic information encoded by genetic evolutionary measures, including chromosomal instability, as a concise 23-transcript assay.

The benefit of adjuvant therapy remains controversial in completely resected (R0) stage IB non-small cell lung cancer (NCLSC) patients. In this study, we aimed to explore potential prognostic factors in stage IB NSCLC patients.

This study included 215 patients with R0 stage IB lung adenocarcinoma (LUAD) (tumor size: 3-4 cm). DNA sequencing was performed with surgical samples of 126 patients using a panel of 9 driver genes. The molecular risk stratification was assessed by a 14-gene quantitative polymerase chain reaction assay.

Among the 215 patients, 67.9% had micropapillary/solid (MIP/SOL)-predominant tumors. Epidermal growth factor receptor (EGFR) mutations were detected in 75 of 126 patients (59.5%). MIP/SOL tumors harbored less common EGFR mutations than the other histologic patterns (50.6% vs. 79.5%, P=0.003). Molecular risk stratification was successfully assessed in 99 patients, of whom 37.4%, 26.3%, and 36.4% were high, intermediate, and low risk, respectively. The MIP/SOL pattern was associated with shorter disease-free survival (DFS) [hazard ratio (HR) =2.16, 95% confidence interval: 1.28-3.67; P=0.01]. The molecular high-risk patients had shorter DFS than the low- (HR =2.93, P=0.01) and intermediate-risk patients (HR =2.35, P=0.06). The prognostic value of molecular risk stratification was also significant in the MIP/SOL subset (median DFS high-risk: 45 months, low and intermediate risk: not reached; P=0.03).

Our study showed that both the MIP/SOL pattern and molecular high-risk category were adverse prognostic factors in stage IB NSCLC patients. Our results suggest that combining histologic classification and molecular risk stratification may help to identify the subset of patients with poor prognosis.

Cure of cancer is a sensitive and multidimensional concept that is challenging to define, difficult to assert at the individual patient level, and often surrounded by controversy. The notion of cure in non-small cell lung cancer (NSCLC) has changed and continues to evolve with improvements in diagnosis and treatment. Targeted and immune therapies have recently entered the treatment landscape of stage I-III NSCLC. While some initial pivotal trials of such agents failed to improve survival, recently approved epidermal growth factor receptor (EGFR) inhibitors (in EGFR-mutated NSCLC) and immune checkpoint inhibitors have shown delays in disease recurrence or progression and unprecedented survival gains compared to previous standards of care. Additional data is now emerging supporting the benefit of treatment strategies based on alternation-matched targeting (anaplastic lymphoma kinase [ALK] inhibition in ALK-altered disease) and immune checkpoint inhibition in stage I-III NSCLC. Similar to previous developments in the treatment of early and locally advanced NSCLC, it is expected that statistically significant and clinically meaningful trial-level benefits will translate into real-world benefits, including improvements in cure measures. Parallel advances in molecular testing (e.g., circulating tumor DNA analyses) are also allowing for a deeper and more comprehensive characterization of disease status and treatment response. Given the impact that curative-intent treatments have on survival, it is critical that various stakeholders, including clinicians and patients, are aware of new opportunities to pursue cure in stage I-III NSCLC.

The ever-growing knowledge regarding NSCLC molecular biology has brought innovative therapies into clinical practice; however, the treatment situation in the non-metastatic setting is rapidly evolving. Indeed, immunotherapy-based perioperative treatments are currently considered the standard of care for patients with resectable NSCLC in the absence of EGFR mutations or ALK gene rearrangements. Recently, data have been presented on the use of tyrosine kinase inhibitors (TKIs) in the adjuvant and locally advanced setting for patients with NSCLC harboring such driver gene alterations. The aim of the current work is to review the available evidence on the use of targeted treatments in the non-metastatic setting, together with a summary of the ongoing trials designed for actionable gene alterations other than EGFR and ALK. To date, 3-year adjuvant osimertinib treatment has been demonstrated to improve DFS and OS and to reduce CNS recurrence in resected EGFR-mutated NSCLC in stage IB-IIIA (TNM 7th edition). The use of osimertinib after chemo-radiation in stage III unresectable EGFR-mutated NSCLC showed the relevant PFS improvement. In the ALK-positive setting, 2-year alectinib treatment was shown to clearly improve DFS compared to adjuvant standard chemotherapy in resected NSCLC with stage IB (≥4 cm)-IIIA (TNM 7th edition). Several trials are ongoing to establish the optimal adjuvant TKI treatment duration, as well as neoadjuvant TKI strategies in EGFR- and ALK-positive disease, and (neo)adjuvant targeted treatments in patients with actionable gene alterations other than EGFR or ALK. In conclusion, our review depicts how the current treatment scenario is expected to rapidly change in the context of non-metastatic NSCLC with actionable gene alterations, hence appropriate molecular testing from the early stages has become crucial to establish the most adequate approaches both in the perioperative and the locally advanced disease.

This study aimed to estimate the relative efficacy of neoadjuvant nivolumab in combination with chemotherapy (neoNIVO + CT) compared to relevant treatments amongst resectable non-metastatic non-small-cell lung cancer (rNSCLC) patients.

Treatment comparisons were based on a network meta-analysis (NMA) using randomized clinical trial data identified via systematic literature review (SLR). The outcomes of interest were event-free survival (EFS) and pathological complete response (pCR). NeoNIVO + CT was compared to neoadjuvant chemotherapy (neoCT), neoadjuvant chemoradiotherapy (neoCRT), adjuvant chemotherapy (adjCT), and surgery alone (S). Due to the potential for effect modification by stage, all-stage and stage-specific networks were considered. Fixed-effect (FE) and random-effects Bayesian NMA models were run (EFS = hazard ratios [HR]; pCR = odds ratios [OR]; 95% credible intervals [CrI]).

Sixty-one RCTs were identified (base case = 9 RCTs [n = 1978 patients]). In the all-stages FE model, neoNIVO + CT had statistically significant EFS improvements relative to neoCT (HR = 0.68 [95% CrI: 0.49, 0.94]), S (0.59 [0.42, 0.82]), adjCT (0.66 [0.45, 0.96]), but not relative to neoCRT (HR = 0.77 [0.52, 1.16]). NeoNIVO + CT (5 RCTs) had statistically significant higher odds of pCR relative to neoCT (OR = 12.53 [5.60, 33.82]) and neoCRT (7.15 [2.31, 24.34]). Stage-specific model findings were consistent.

This NMA signals improved EFS and/or pCR of neoNIVO + CT relative to comparators among patients with rNSCLC.

Lung cancer is a leading cause of cancer-related morbidity and mortality worldwide. Metastases in the brain are a common hallmark of advanced stages of the disease, contributing to a dismal prognosis. Lung cancer can be broadly classified as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). NSCLC represents the most predominant histology subtype of lung cancer, accounting for the majority of lung cancer cases. Recent advances in molecular genetics, coupled with innovations in small molecule drug discovery strategies, have facilitated both the molecular classification and precision targeting of NSCLC based on oncogenic driver mutations. Furthermore, these precision-based strategies have demonstrable efficacy across the blood-brain barrier, leading to positive outcomes in patients with brain metastases. This review provides an overview of the clinical features of lung cancer brain metastases, as well as the molecular mechanisms that drive NSCLC oncogenesis. We also explore how precision medicine-based strategies can be leveraged to improve NSCLC brain metastases.

This meta-analysis sought to investigate the effect of neoadjuvant chemotherapy (NACT) combined with surgery in patients with nonsmall cell lung cancer (NSCLC).

With time span from January 2010 to December 2022, PubMed, Web of Science and Embase, China National Knowledge Infrastructure, and WanFang databases were searched for randomized controlled trials on comparison between NACT combined with surgery and surgery alone in patients with NSCLC. Then a meta-analysis was performed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.

A total of 1511 studies were retrieved and 12 were finally included. Meta-analysis results showed that compared with surgery alone, a combination of NACT and surgery was associated with higher treatment response rate (odds ratio, OR = 2.459, 95% confidence interval, CI [1.785, 3.388], P < 0.001), 1-year survival rate (OR = 2.185, 95% CI [1.608, 2.970], P < 0.001), and 3-year survival rate (OR = 2.195, 95% CI [1.568, 3.073], P < 0.001) and lower levels of intraoperative blood loss (standardized mean difference, SMD = -0.932, 95% CI [-1.588, -0.275], P = 0.005) and length of hospital stay (SMD = -0.481, 95% CI [-0.933, -0.028], P = 0.037).

NACT combined with surgery is superior to surgery alone in the treatment of NSCLC and can promote postoperative recovery. Collectively, such combination is a safe and effective treatment for patients with NSCLC.

Circulating tumor DNA (ctDNA) has emerged as a potential novel biomarker to predict molecular residual disease (MRD) in lung cancer after definitive treatment. Herein, we investigated the value of ctDNA in prognosing risk of relapse and monitoring the effect of adjuvant therapy in surgical non-small cell lung cancer (NSCLC).

We enrolled 58 NSCLC patients in a real-world setting, and 58 tumor tissues and 325 plasma samples were analyzed. Tumor tissues and plasma samples were subjected to targeted next-generation sequencing (NGS) of 1021 cancer-related and ultra-deep targeted NGS covering 338 genes, respectively.

ctDNA was detected in 31.0% of cases at the first postoperative time, which was associated with advanced tumor stage, T stage and KEAP1 or GRIN2A mutations in tissues. ctDNA positivity at landmark and longitudinal indicated the shorter disease-free survival. For patients with ctDNA positivity at the first postoperative time, regardless of adjuvant therapy, all patients who were persistently ctDNA positive during postoperative surveillance had disease recurrence. Among the patients who were ctDNA negative, only two patients (15.4%, 2/13) receiving adjuvant therapy relapsed, while one patient (50.0%, 1/2) without adjuvant therapy relapsed. For the first postoperative ctDNA negative patients, the recurrence rate of patients with adjuvant therapy was and higher than without adjuvant therapy (22.6% [7/31] vs. 11.1% [1/9]). The patients who became ctDNA positive may also benefit from intervention therapy.

Postoperative ctDNA is a prognostic marker, and ctDNA-detection may facilitate personalized adjuvant therapy, and applying adjuvant therapy to the patients with detectable ctDNA could bring clinical benefits for them.

Using digitized data from progression-free survival (PFS) and overall survival Kaplan-Meier curves, one can assess population survival kinetics through exponential decay nonlinear regression analyses. To demonstrate their utility, we analyzed PFS curves from published curative-intent trials of non-small cell lung cancer (NSCLC) adjuvant chemotherapy, adjuvant osimertinib in resected EGFR-mutant NSCLC (ADAURA trial), chemoradiotherapy for inoperable NSCLC, and limited small cell lung cancer (SCLC). These analyses permit assessment of log-linear curve shape and estimation of the proportion of patients cured, PFS half-lives for subpopulations destined to eventually relapse, and probability of eventual relapse in patients remaining progression-free at different time points. The proportion of patients potentially cured was 41% for adjuvant controls, 58% with adjuvant chemotherapy, 17% for ADAURA controls, not assessable with adjuvant osimertinib, 15% with chemoradiotherapy, and 12% for SCLC. Median PFS half-life for relapsing subpopulations was 11.9 months for adjuvant controls, 17.4 months with adjuvant chemotherapy, 24.4 months for ADAURA controls, not assessable with osimertinib, 9.3 months with chemoradiotherapy, and 10.7 months for SCLC. For those remaining relapse-free at 2 and 5 years, the cure probability was 74%/96% for adjuvant controls, 77%/93% with adjuvant chemotherapy, 51%/94% with chemoradiation, and 39%/87% with limited SCLC. Relatively easy population kinetic analyses add useful information.

The treatment landscape of resectable early-stage non-small cell lung cancer (NSCLC) is set to change significantly due to encouraging results from randomized trials evaluating neoadjuvant and adjuvant immunotherapy, as well as adjuvant targeted therapy. As of January 2024, marketing authorization has been granted for four new indications in Europe, and regulatory approvals for other study regimens are expected. Because cost-effectiveness and reimbursement criteria for novel treatments often differ between European countries, access to emerging developments may lead to inequalities due to variations in recommended and available lung cancer care throughout Europe. This Series paper (i) highlights the clinical studies reshaping the treatment landscape in resectable early-stage NSCLC, (ii) compares and contrasts approaches taken by the European Medicines Agency (EMA) for drug approval to that taken by the United States Food and Drug Administration (FDA), and (iii) evaluates the differences in access to emerging treatments from an availability perspective across European countries.

EGFR inhibitor and immunotherapy have been approved for adjuvant treatment in resectable non-small cell lung cancer (NSCLC). Limited reports of molecular and clinical characteristics as prognostic factors in NSCLC have been published.

Medical records of patients with resectable NSCLC stage I-III diagnosed during 2015-2020 were reviewed. Real time-PCR (RT-PCR) was performed for EGFR mutations (EGFRm). Immunohistochemistry staining was conducted for ALK and PD-L1 expression. Categorical variables were compared using chi-square test and Fisher's exact test. Survival analysis was done by cox-regression method.

Total 441 patients were included. The prevalence of EGFRm, ALK fusion, and PD-L1 expression were 57.8%, 1.9%, and 20.5% (SP263), respectively. The most common EGFRm were Del19 (43%) and L858R (41%). There was no significant difference of recurrence free survival (RFS) by EGFRm status whereas patients with PD-L1 expression (PD-L1 positive patients) had lower RFS compared to without PD-L1 expression (PD-L1 negative patients) (HR = 1.75, P = 0.036). Patients with both EGFRm and PD-L1 expression had worse RFS compared with EGFRm and PD-L1 negative patients (HR = 3.38, P = 0.001). Multivariable analysis showed higher CEA at cut-off 3.8 ng/ml, pT4, pN2, pStage II, and margin were significant poor prognostic factors for RFS in the overall population, which was similar to EGFRm population (exception of pT and pStage). Only pStage was a significant poor prognostic factor for PD-L1 positive patients. The predictive score for predicting of recurrence were 6 for all population (63% sensitivity and 86% specificity) and 5 for EGFRm population (62% sensitivity and 93% specificity).

The prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.

Patients with radically resected stage II and III NSCLC are exposed to a high risk of disease recurrence. Thus, adjuvant cisplatin-based chemotherapy is routinely offered to this patient population, although it results in an absolute increase in 5-year survival rate of only 4%. This modest improvement in survival rate makes it challenging to communicate to our patients about the decision to be treated with adjuvant chemotherapy or not. Nowadays, the decision to administer adjuvant chemotherapy or not in resected NSCLC is almost never completely shared with patients because its role is very difficult to explain. The risk-benefit ratio becomes clearly unfavourable in elderly and unfit patients. Recently, the phase III ADAURA trial demonstrated a clinically significant disease-free survival and overall survival benefit with adjuvant osimertinib (with or without adjuvant chemotherapy) versus a placebo in EGFR-mutated stage IB-IIIA resected NSCLC. In this patient population, the decision to administer chemotherapy or not is much more challenging given the great benefit offered by osimertinib alone. Thus, it is time now to improve our communication tools to explain the role of adjuvant chemotherapy to our patients, especially in the EGFR-mutated population, in order to undertake real shared decision making in a clinical context in which the opportunity to administer toxic chemotherapy is debatable and subjective.

Many clinical trials have shown that postoperative adjuvant chemotherapy can provide a survival benefit for patients with stage IB non-small cell lung cancer. However, whether adjuvant chemotherapy should be routinely given after surgery remains controversial. Therefore, we performed a meta-analysis to investigate the efficacy of adjuvant chemotherapy versus surgery alone for stage IB non-small cell lung cancer (NSCLC).

Relevant retrospective studies or randomized controlled trial comparing the efficacy of postoperative adjuvant chemotherapy versus observation on the survival outcomes of NSCLC patients up to October 30, 2023 were searched in PubMed, Web of Science, EMBASE, Cochrane Library, VIP database, Wanfang database, and China National Knowledge Internet database. Patient survival data, population characteristics, and other relevant information were extracted, and data were analyzed using Review Manager 5.4. The primary endpoints included overall survival, disease-free survival, and recurrence-free survival.

A total of 13 randomized controlled trials or cohort studies including 19,442 patients were included. The results of the meta-analysis showed that postoperative adjuvant chemotherapy in patients with stage IB NSCLC had better overall survival (odds ratio [OR] = 1.25, 95% confidence interval [CI] 1.19-1.31, P < .00001) and disease-free survival or recurrence-free survival (OR = 1.57, 95% CI 1.3-1.9, P < .00001) compared with observation; and the 4-year survival rate of patients who received postoperative adjuvant chemotherapy was better than the observation group (OR = 1.52, 95% CI 1.05-2.18, P = .03); and the 8-year survival rate of patients receiving postoperative adjuvant chemotherapy (OR = 1.5, 95% CI 0.94-2.4, P = .09) was comparable to the observation group.

Receiving postoperative adjuvant chemotherapy improved people's survival and prolonged disease-free survival and recurrence-free survival in patients with stage IB non-small cell lung cancer compared with surgery alone.

We aim to molecularly stratify stage IA lung adenocarcinoma (LUAD) for precision medicine.

Twelve multi-institution datasets (837 cases of IA) were used to classify the high- and low-risk types (based on survival status within 5 years), and the biological differences were compared. Then, a gene-based classifying score (IA score) was trained, tested and validated by several machine learning methods. Furthermore, we estimated the significance of the IA score in the prognostic assessment, chemotherapy prediction and risk stratification of stage IA LUAD. We also developed an R package for the clinical application. The SEER database (15708 IA samples) and TCGA Pan-Cancer (1881 stage I samples) database were used to verify clinical significance.

Compared with the low-risk group, the high-risk group of stage IA LUAD has obvious enrichment of the malignant pathway and more driver mutations and copy number variations. The effect of the IA score on the classification of high- and low-risk stage IA LUAD was much better than that of classical clinicopathological factors (training set: AUC = 0.9, validation set: AUC = 0.7). The IA score can significantly predict the prognosis of stage IA LUAD and has a prognostic effect for stage I pancancer. The IA score can effectively predict chemotherapy sensitivity and occult metastasis or invasion in stage IA LUAD. The R package IAExpSuv has a good risk probability prediction effect for both groups and single stages of IA LUAD.

The IA score can effectively stratify the risk of stage IA LUAD, offering good assistance in precision medicine.

The use of adjuvant chemotherapy (ACT) in completely resected stage IB NSCLC is still controversial. This study aims to investigate the efficacy of ACT in pathological stage IB non-small cell lung cancer (NSCLC) with high risk factors.

Patients with pT2aN0M0 stage IB NSCLC who underwent complete resection from 2013 to 2017 were retrospectively analyzed. Univariate and multivariable logistic regression analysis was used to assess potential independent risk factors associated with poor prognosis. To compare survival between patients who received ACT and those who did not.

In univariate and multivariate analyses, adenocarcinomas with predominantly micropapillary (MIP) and solid patterns (SOL), poorly differentiated squamous cell carcinoma (SCC), number of lymph nodes dissected less than 16 and tumor size larger than 36 mm were identified as high-risk factors for recurrence. In patients with high risk factors for recurrence, ACT resulted in significantly longer DFS (HR, 0.4689, 95%CI, 1.193-3.818; p = 0.0108) and OS (HR, 0.4696, 95%CI, 0.6578-6.895; p = 0.2073), although OS failed to reach statistically significance. After propensity score matching (PSM), 67 pairs of patients were 1:1 matched in the two groups and all baseline characteristics were well balanced. The results also demonstrated that ACT was associated with improved DFS (HR, 0.4776, 95%CI, 0.9779-4.484; p = 0.0440) while OS was not significantly different (92.5% vs. 91.0%; HR, 0.6167, 95%CI, 0.1688-2.038; p = 0.7458). In patients with low-risk factors for recurrence, DFS (HR, 0.4831, 95%CI, 0.03025-7.715; p = 0.6068) and OS (HR, 0.969, 95%CI, 0.08364-11.21; p = 0.9794) was not significantly different between those who received ACT and those who did not.

In patients with completely resected stage IB NSCLC, ACT can improve survival in patients with high risk for recurrence. Further large multicenter studies are needed to confirm these findings.

After the successful development of targeted therapy and immunotherapy for the treatment of advanced-stage non-small cell lung cancer (NSCLC), these innovative treatment options are rapidly being applied in the adjuvant setting for early-stage NSCLC. Some adjuvants that have recently been approved include osimertinib for epidermal growth factor receptor-mutated tumors and atezolizumab and pembrolizumab for selected patients with resectable NSCLC. Numerous studies on various targeted therapies and immunotherapy with or without chemotherapy are currently ongoing in the adjuvant setting. However, several questions regarding optimal strategies for adjuvant treatment remain unanswered. The present review summarizes the available literature, focusing on recent advances and ongoing trials with targeted therapy and immunotherapy in the adjuvant treatment of early-stage NSCLC.

Occult nodal metastasis (ONM) plays a significant role in comprehensive treatments of non-small cell lung cancer (NSCLC). This study aims to develop a deep learning signature based on positron emission tomography/computed tomography to predict ONM of clinical stage N0 NSCLC. An internal cohort (n = 1911) is included to construct the deep learning nodal metastasis signature (DLNMS). Subsequently, an external cohort (n = 355) and a prospective cohort (n = 999) are utilized to fully validate the predictive performances of the DLNMS. Here, we show areas under the receiver operating characteristic curve of the DLNMS for occult N1 prediction are 0.958, 0.879 and 0.914 in the validation set, external cohort and prospective cohort, respectively, and for occult N2 prediction are 0.942, 0.875 and 0.919, respectively, which are significantly better than the single-modal deep learning models, clinical model and physicians. This study demonstrates that the DLNMS harbors the potential to predict ONM of clinical stage N0 NSCLC.

Non-small cell lung cancer (NSCLC) is associated with a poor survival rate, even for patients with early-stage cancer. Identifying patients with pathological N0 NSCLC who may benefit from adjuvant chemotherapy treatment after surgery is essential. We conducted a retrospective cohort study used data from the Surveillance, Epidemiology, and End Results database and included 26,380 patients with pathological N0 NSCLC after surgery between January 2018, and December 2019. Among 26,380 patients, 24,273 patients received surgery alone and the other 2107 patients received surgery plus adjuvant chemotherapy. After 1:1 propensity score matching, both groups contained 2107 patients. Adjuvant chemotherapy did not show significantly better 24-month survival in T2aN0 NSCLC patients (83.41% vs. 82.91%, p = 0.067), although it did for T2bN0 patients (86.36% vs. 81.70%, p = 0.028). Poorly-differentiated NSCLC remained a high-risk factor for pT2N0, and adjuvant chemotherapy provided better 24-month survival after matching (86.36% vs. 81.70%, p = 0.029). In conclusion, when treating pN0 NSCLC, adjuvant chemotherapy had a beneficial effect when the tumor size was larger than 4 cm. The effect when the tumor size was between 3 and 4 cm was not remarkable. Poorly-differentiated NSCLC was a high-risk factor in the pT2N0 stage.

This study aimed to evaluate the effect of lymph node dissection method on staging results, diagnosis of tumor metastasis in single or multiple N1 lymph nodes and survival rates in patients with non-small cell lung cancer (NSCLC).

Patients with NSCLC who underwent anatomic resection between September 2014 and October 2019 were examined prospectively. All patients with similar clinico-demographic characteristics were randomly assigned to either the surgical group (n = 83) or the pathology group (n = 87). Lymph node dissection was performed by the surgeon in the surgical group and by the pathologists after formaldehyde exposure in the pathology group. Data were analyzed according to formaldehyde exposure, N1 positivity, and number of N1 positive lymph nodes.

There were no significant differences in N1 lymph node positivity between the two groups (p = 0.482). On average 9.08 lymph node sampling was performed in the surgical group and 2.39 in the pathology group (p = 0.0001). Multiple lymph node involvement was significantly higher in the surgical group (P = 0.0001) than in the pathology group.

It is easier to detect lymph node involvement without introducing formaldehyde into the sample. We recommend that N1 lymph node dissection be performed on fresh specimens to detect more lymph node involvement.

Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC.

We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment.

From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity.

Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required.

Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

The therapeutic interventions against lung cancer are currently based on a fully personalized approach to the disease with considerable improvement of patients' outcome. Alongside continuous scientific progresses and research investments, massive technologic efforts, innovative challenges, and consolidated achievements together with research investments are at the bases of the engineering and manufacturing revolution that allows a significant gain in clinical setting.

The scope of this review is thus to focus, rather than on the biologic traits, on the analysis of the precision sensors and novel generation materials, as semiconductors, which are below the clinical development of personalized diagnosis and treatment. In this perspective, a careful revision and analysis of the state of the art of the literature and experimental knowledge is presented.

Novel materials are being used in the development of personalized diagnosis and treatment for lung cancer. Among them, semiconductors are used to analyze volatile cancer compounds and allow early disease diagnosis. Moreover, they can be used to generate MEMS which have found an application in advanced imaging techniques as well as in drug delivery devices.

Overall, these issues represent critical issues only partially known and generally underestimated by the clinical community. These novel micro-technology-based biosensing devices, based on the use of molecules at atomic concentrations, are crucial for clinical innovation since they have allowed the recent significant advances in cancer biology deciphering as well as in disease detection and therapy. There is an urgent need to create a stronger dialogue between technologists, basic researchers, and clinicians to address all scientific and manufacturing efforts towards a real improvement in patients' outcome. Here, great attention is focused on their application against lung cancer, from their exploitations in translational research to their application in diagnosis and treatment development, to ensure early diagnosis and better clinical outcomes.

No molecular biomarkers have been proven applicable in clinical practice to identify patients who can benefit from adjuvant chemotherapy in non-small cell lung cancer (NSCLC). In this study, we established a biomarker, RPMB, short for promotor methylation burden of DNA repair genes (DRGs), to identify the subgroup of patients who might benefit from adjuvant chemotherapy in NSCLC. Methylation profiles of 828 NSCLC primary tumors and their clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. The RPMB for each patient after radical resection was calculated and its correlation with the prognosis of NSCLC was extensively investigated. DRGs of NSCLC were much more hypomethylated than the other genes (all p＜0.001). RPMB was defined as the ratio of methylated DRGs to the total number of all the DRGs. Patients with higher RPMB values tended to be nonsmokers, had adenocarcinoma, were female and had peripheral tumors. Subgroup analysis of forest plot among different clinical factors showed that high RPMB was significantly correlated to better disease-free survival (DFS) in pathologic N-positive patients after adjuvant chemotherapy (HR = 0.404, n = 62, p = 0.034). Notably, more superior DFS was exhibited in high RPMB NSCLCs with N1 nodal stage compared with those with low RPMB values (HR = 0.348, n = 47, p = 0.043). High RPMB might be used as a potential predictor to identify suitable N-positive NSCLC patients who can benefit from adjuvant chemotherapy after radical surgery.

According to a nation-based study, we intend to report the data of the patients operated on for lung cancer invading the chest wall, taking into consideration the completion of induction chemotherapy (Ind_CT), induction radiochemotherapy (Ind_RCT) or no induction therapy (0_Ind).

All patients with a primary lung cancer invading the chest wall who underwent radical resection from 2004 to 2019 were included. Superior sulcus tumors were excluded.

Overall, 688 patients were included: 522 operated without induction therapy, 101 with Ind_CT and 65 with Ind_RCT. Postoperative 90-day mortality was 10.7% in the 0_Ind group, 5.0% in the Ind_CT group, 7.7% in the Ind_RCT group (p = 0.17). Incomplete resection rate was 14.0% in the 0_Ind group, 6.9% in the Ind_CT group, 6.2% in the Ind_RCT group (p = 0.04). In the 0_Ind group, 70% of the patients received adjuvant therapies. Overall survival (OS) analysis disclosed the best long-term outcomes in the Ind_RCT group (5-year OS probability: 56.5% versus 40.0% and 40.5% for 0_Ind and Ind_CT groups, respectively; p = 0.035). At multivariable analysis, Ind_RCT (HR = 0.571; p = 0.008), age > 60 years old (HR = 1,373; p = 0.005), male sex (HR = 1.710; p < 0.001), pneumonectomy (HR = 1.368; p = 0.025), pN2 status (HR = 1.981; p < 0.001), ≥3 resected ribs (HR = 1.329; p = 0.019), incomplete resection (HR = 2.284; p < 0.001) and lack of adjuvant therapy (HR = 1.959; p < 0.001) were associated with OS. Ind_CT was not associated with survival (HR = 0.848; p = 0.257).

Induction chemoradiation therapy seems to improve survival. Therefore, the present results should be confirmed by a prospective randomized trial testing the benefit of induction radiochemotherapy for NSCLC invading the chest wall.

There is scant evidence-based information about survival benefits of postoperative chemotherapy in elderly patients with early-stage non-small cell lung cancer (NSCLC). The purpose of this study is to compare the overall survival (OS) and cancer-specific survival (CSS) rates of surgery alone versus postoperative chemotherapy in patients aged ≥70 years with stage I-II NSCLC.

Elderly patients aged ≥70 years diagnosed with stage I-II NSCLC were selected from the Surveillance, Epidemiology, and End Results (SEER) database from January 1, 2010 to December 31, 2015. OS and CSS were compared between the two groups utilizing overlap weighting analysis, inverse probability of treatment weight (IPTW), and propensity score matching (PSM).

Of the 7193 included patients with stage I-II NSCLC who are more than 70 years old, 681 patients (9.5%) received postoperative chemotherapy and 6512 patients (90.5%) received surgery-alone. Median OS was 77 months in postoperative chemotherapy group versus 79 months in surgery-alone group (p = 0.89). The result of IPTW analysis showed the similar results. The probability of patients choosing chemotherapy increased with the AJCC stage and Grade increasing (p < 0.001) and decreased with the growth of age (p < 0.001). The results of subgroup analysis showed that the survival rate of stage IA patients decreased significantly after postoperative chemotherapy (p < 0.01) while the survival rate of stage IB-II patients increased significantly (p < 0.01). At the same time, we found that patients in the postoperative chemotherapy group tended to have better OS than those in the surgery-alone group with the grade and tumor size increasing.

The results of this study indicated that postoperative chemotherapy could significantly improve the survival of stage IB-II NSCLC patients aged ≥70 years, and decrease the survival of stage IA patients.

Lung cancer is one of the most common solid malignancies. Tissue biopsy is the standard method for accurately diagnosing lung and many other malignancies over decades. However, molecular profiling of tumors leads to establishing a new horizon in the field of precision medicine, which has now entered the mainstream in clinical practice. In this context, a minimally invasive complementary method has been proposed as a liquid biopsy (LB) which is a blood-based test that is gaining popularity as it provides the opportunity to test genotypes in a unique, less invasive manner. Circulating tumor cells (CTC) captivating the Circulating-tumor DNA (Ct-DNA) are often present in the blood of lung cancer patients and are the fundamental concept behind LB. There are multiple clinical uses of Ct-DNA, including its role in prognostic and therapeutic purposes. The treatment of lung cancer has drastically evolved over time. Therefore, this review article mainly focuses on the current literature on circulating tumor DNA and its clinical implications and future goals in non-small cell lung cancer.

Off-label use of medicines is generally discouraged. However, several off-patent, low-cost cancer medicines remain off-label for indications in which they are commonly used in daily practice, supported by high-level evidence based on results of phase III clinical trials. This discrepancy may generate prescription and reimbursement obstacles as well as impaired access to established therapies.

A list of cancer medicines that remain off-label in specific indications despite the presence of high-level evidence was generated and subjected to European Society for Medical Oncology (ESMO) expert peer review to assess for accountability of reasonableness. These medicines were then surveyed on approval procedures and workflow impact. The most illustrative examples of these medicines were reviewed by experts from the European Medicines Agency to ascertain the apparent robustness of the supporting phase III trial evidence from a regulatory perspective.

A total of 47 ESMO experts reviewed 17 cancer medicines commonly used off-label in six disease groups. Overall, high levels of agreement were recorded on the off-label status and the high quality of data supporting the efficacy in the off-label indications, often achieving high ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scores. When prescribing these medicines, 51% of the reviewers had to implement a time-consuming process associated with additional workload, in the presence of litigation risks and patient anxiety. Finally, the informal regulatory expert review identified only 2 out of 18 (11%) studies with significant limitations that would be difficult to overcome in the context of a potential marketing authorisation application without additional studies.

We highlight the common use of off-patent essential cancer medicines in indications that remain off-label despite solid supporting data as well as generate evidence on the adverse impact on patient access and clinic workflows. In the current regulatory framework, incentives to promote the extension of indications of off-patent cancer medicines are needed for all stakeholders.

The combination of immunotherapy and chemotherapy has shown great efficacy in stage IV non-small cell lung cancer (NSCLC) and is now widely used in clinical treatment strategy. This study retrospectively analyzed the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy for resectable NSCLC in real world.

We retrospectively analyzed patients with NSCLC who received neoadjuvant immunotherapy plus chemotherapy and underwent complete tumor resection in Zhejiang Cancer Hospital between January 2019 and January 2021. Tumor staging was based on the eighth TNM classification system of the American Joint Committee on Cancer staging criteria. The safety and toxicity (including operative and postoperative complications) and the efficacy [including objective response rate (ORR), disease control rate (DCR), tumor major pathological remission (MPR), and pathological complete response (pCR)] were evaluated.

In total, 368 patients with NSCLC were administered with neoadjuvant immunotherapy. Of them, 211 patients were included in this retrospective study. Most patients had stage II-III disease, with 75 (35.5%) and 88 (41.7%) patients diagnosed with clinical stages IIB and IIIA, respectively. A total of 206 patients (97.6%) received at least two doses of neoadjuvant immunotherapy plus chemotherapy. In addition, 121 patients (57.3%) have achieved MPR, and 80 patients (37.9%) have achieved pCR, with ORR at 69.2% and DCR at 97.7%. Treatment-related adverse events occurred in 46.4% of patients, and the incidence rate of grade 3 or 4 treatment-related adverse events was 13.3% (13/98). Moreover, adverse events of any grade of surgical complication occurred in 15.6% of patients. One-year disease-free survival was 80.6% (170/211).

Neoadjuvant immunotherapy plus chemotherapy has significant efficacy with a high pCR and tolerable adverse effects for patients with resectable stage II-III NSCLC in real world.

The effect of postoperative tegafur-uracil on overall survival (OS) after resection of stage I adenocarcinoma has been shown in clinical trials. The purpose of this study was to investigate whether findings from randomized trials of adjuvant tegafur-uracil are reproducible in a real-world setting.

A retrospective cohort study was performed using a multi-institutional database that included all patients who underwent complete resection of pathological stage I adenocarcinoma between 2014 and 2016. Survival outcomes for patients managed with and without tegafur-uracil were analyzed using the Kaplan-Meier method and a Cox proportional hazards model for the whole patient cohort and in a selected cohort based on eligibility criteria of a previous randomized trial. Propensity score matching was used to adjust for confounding effects.

After propensity score matching, the hazard ratios for OS were 0.57 (95% confidence interval (CI) 0.29-1.14, P = 0.11) in the whole cohort and 0.69 (95% CI 0.32-1.50, P = 0.35) in the selected cohort.

The effects of tegafur-uracil in this retrospective study appear to be consistent with those found in randomized clinical trials. These effects may be maximized in patients aged from 45 to 75 years.

For patients with T2aN0 stage IB lung adenocarcinoma, benefits of adjuvant chemotherapy remain controversial. Here, we aimed to evaluate such benefits.

This retrospective cohort study was conducted on the database of the National Taiwan Cancer Registry. We analyzed patients with T2aN0 stage IB lung adenocarcinoma (re-classified by AJCC 8th edition) diagnosed during the period from January 2011 to December 2017. They were divided into two groups: (1) group 1: tumor <=3 cm with visceral pleural invasion (VPI); (2) group 2: tumor >3 cm, but <=4 cm. Overall survival (OS) and cancer specific survival (CSS) were evaluated. Risk factors for survival were determined.

A total of 2,100 patients with T2aN0 stage IB lung adenocarcinoma (1,265 in group 1 and 835 in group 2) were enrolled for study. The proportions of patients receiving adjuvant chemotherapy in group 1 and 2 were 39.1% and 68.6%, respectively. Amongst group 1 patients, adjuvant chemotherapy was not an independent risk factor for OS and CSS. Amongst group 2 patients, high-grade histologic findings and receiving sublobar resection were two risk factors for poorer survival. Adjuvant chemotherapy was also associated with an OS (adjusted hazard ratio (aHR), 0.52; 95% confidence interval (CI), 0.38-0.72; P<0.001) and CSS (aHR, 0.54; 95% CI, 0.37-0.78; p=0.001) benefit regardless of the presence or absence of risk factors.

For patients with T2aN0 stage IB lung adenocarcinoma, adjuvant chemotherapy improved OS and CSS in those with tumors >3 cm, but <=4 cm.For patients with tumors <=3 cm with VPI, adjuvant chemotherapy had no survival benefit.

The benefit of adjuvant chemotherapy for IB/IIA non-small cell lung cancer (NSCLC) patients remains uncertain. This study aimed to develop a prognostic model to predict overall survival in resected NSCLC patients with T1-2N0-1M0 stage and identify optimal candidates for postoperative chemotherapy among those with stage IB or IIA disease.

We conducted a retrospective study using the SEER 18 database (2000-2018, November 2020 submission) of patients who underwent radical surgery for T1-2N0-1M0 NSCLC. The patients not receiving adjuvant chemotherapy were randomly divided into training and validation cohorts. A prognostic nomogram was established and evaluated using calibration and receiver operating characteristic curves. Based on the nomogram, stage IB and IIA patients were categorized into two prognostic groups, each further divided into cohorts based on adjuvant chemotherapy status. Kaplan-Meier analysis and log-rank tests were used to compare overall survival between these groups.

A total of 14 789 patients were enrolled and randomly assigned to the training cohort (n = 10 352) and validation cohort (n = 4437). Ten independent prognostic factors were identified and integrated into the prognostic model. The area under the receiver operating characteristic curve was .706, .699, and .705 in the training cohort, and .700, .698, and .695 in the validation cohort at 1, 3, and 5 years, respectively. Among stage IB and IIA patients, only those in the high-risk group showed a significant benefit from adjuvant chemotherapy, with a 16.4% absolute increase in 5-year overall survival.

The nomogram developed in the study may help physicians choose the most appropriate management strategy for each patient.

Tumor resection could increase treatment efficacy of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). This study aimed to retrospectively analyze patients with advanced EGFR-mutant NSCLC from a Taiwanese tertiary center and receiving EGFR-TKI treatment with or without tumor resection. A total of 349 patients were enrolled. After propensity score matching, 53 EGFR-TKI treated patients and 53 EGFR-TKI treated patients with tumor resection were analyzed. The tumor resection group showed improved progression-free survival (PFS) (52.0 vs. 9.8 months; hazard ratio [HR] = 0.19; p < 0.001) and overall survival (OS) (not reached vs. 30.6 months; HR = 0.14; p < 0.001) compared to the monotherapy group. In the subgroup analysis of patients with newly-diagnosed NSCLC, the tumor resection group showed longer PFS (52.0 vs. 9.9 months; HR = 0.14; p < 0.001) and OS (not reached vs. 32.6 months; HR = 0.12; p < 0.001) than the monotherapy group. In conclusion. the combination of EGFR-TKI and tumor resection provided better PFS and OS than EGFR-TKI alone, and patients who underwent tumor resection within six months had fewer co-existing genomic alterations and better PFS.

Prognostic assessment in patients undergoing cancer treatments is of paramount importance to plan subsequent management. In resectable lung cancer availability of an easy-to use nomogram to predict long-term outcome would be extremely useful to identify high-risk patients in the era of perioperative targeted and immune therapies.

We retrieved clinical, surgical and pathological data of all consecutive patients included in Epithor, the database of French Society of Thoracic and Cardiovascular Surgery, and operated on between 2003 and 2020 for non-small cell lung cancer in a curative intent. The primary endpoint was overall survival up to 5 years. We assessed prognostic significance of available variables using Cox modelling, in the whole dataset, and in men and in women separately, and performed temporal validation. Finally, we constructed two sex-specific nomograms. Survivals by fifths of score were assessed in the development and temporal validation sets.

The study included 62,633 patients (43,551 men and 19,082 women). Median survival time was 9.2 years. Nine factors had strong prognostic impact and were used to construct nomograms. The optimism-corrected c statistic for the prognostic score was 0.689 in the development sample, and 0.726 (95% CI 0.718-0.735) in the temporal validation sample. All differences between adjacent fifths of score were significant (P < 0.0001). Figures of 3-year OS by fifths of score were 92.2%, 83.0%, 74.3%, 64.0%, and 43.4%, respectively, in the development set and 93.3%, 88.4%, 81.0%, 73.7%, 55.7% in the temporal validation set. Performance of score was maintained when stratifying by stage of diseases.

In the present work, we report evidence that long-term overall survival after resection of NSCLC can be predicted by an easy to construct and use composite score taking into account both host and tumour related factors.

Epithor is funded by FSTCVS.

Objectives: A growing body of evidence suggests the important role of chemosensitive gene expression in the prognosis of patients with lung cancer. However, studies on combined gene expression assessments for personalized prescriptions of chemotherapy regimens in patients have not yet been conducted. The aim of this work was to conduct a prospective study on the appointment of personalized chemotherapy in patients with non-small-cell lung cancer. Materials and methods: The present study analyzed 85 patients with lung cancer (stage IIB-IIIB). Within this group, 48 patients received individualized chemotherapy, and 37 patients received classical chemotherapy. In the individualized chemotherapy group, the mRNA expression levels of ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 in lung tissues were measured by quantitative real-time PCR (qPCR), and an individual chemotherapy regimen was developed for each patient according to the results. Patients in the classical chemotherapy group received the vinorelbine/carboplatin regimen. Survival analyses were performed using the Kaplan−Meier method. Prognostic factors of metastasis-free survival (MFS) and overall survival (OS) of patients were identified via Cox’s proportional hazards regression model. Results: MFS and OS were significantly better in the personalized chemotherapy group compared to the classic chemotherapy group (MFS, 46.22 vs. 22.9 months, p = 0.05; OS, 58.6 vs. 26.9 months, p < 0.0001). Importantly, the best metastasis-free survival rates in the group with personalized ACT were achieved in patients treated with the paclitaxel/carboplatin regimen. Based on an assessment of chemosensitivity gene expression in the tumors, the classical chemotherapy strategy also increased the risk of death (HR = 14.82; 95% CI: 3.33−65.86; p < 0.000) but not metastasis (HR = 1.95; 95% CI: 0.96−3.98; p = 0.06) compared to the group of patients with chemotherapy. Conclusions: The use of combined ERCC1, RRM1, TUBB3, TYMS, TOP1, TOP2α, BRCA1, and GSTP1 gene expression results for personalized chemotherapy can improve treatment efficacy and reduce unnecessary toxicity.

In China, lung cancer is a primary cancer type with high incidence and mortality. Risk factors for lung cancer include tobacco use, family history, radiation exposure, and the presence of chronic lung diseases. Most early-stage non-small cell lung cancer (NSCLC) patients miss the optimal timing for treatment due to the lack of clinical presentations. Population-based nationwide screening programs are of significant help in increasing the early detection and survival rates of NSCLC in China. The understanding of molecular carcinogenesis and the identification of oncogenic drivers dramatically facilitate the development of targeted therapy for NSCLC, thus prolonging survival in patients with positive drivers. In the exploration of immune escape mechanisms, programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor monotherapy and PD-1/PD-L1 inhibitor plus chemotherapy have become a standard of care for advanced NSCLC in China. In the Chinese Society of Clinical Oncology's guidelines for NSCLC, maintenance immunotherapy is recommended for locally advanced NSCLC after chemoradiotherapy. Adjuvant immunotherapy and neoadjuvant chemoimmunotherapy will be approved for resectable NSCLC. In this review, we summarized recent advances in NSCLC in China in terms of epidemiology, biology, molecular pathology, pathogenesis, screening, diagnosis, targeted therapy, and immunotherapy.