Early-stage Non-small Cell Lung Cancer Research Articles

Exploring the molecular and immune-landscape of lung cancer associated with cystic airspaces

To explore the molecular biological characteristics of lung cancer associated with cystic airspaces (LCCA) and its potential roles on prognosis. A total of 165 LCCAs and 201 non-LCCAs were enrolled in this study. Bulk RNA sequencing was implemented in eight LCCAs and nine non-LCCAs to explore the differentially expressed genes. TCGA data were used to analyze LCCA-specific genes that associated with overall survival (OS). The median age was 60 (IQR 53 to 65) years in LCCA cohort. We found LCCA were predominant in men and had less visceral pleura invasion (VPI) or lympho-vascular invasion (LVI). Moreover, LCCA presented with higher histological heterogeneity. Kaplan-Meier analysis showed that patients of age more than 60 and positive VPI had significantly less PFS in LCCA. Cox regression suggested that LCCA, micropapillary subtype proportion and VPI were the independent risk factors for PFS. LCCA had up-regulated pathways associated with EMT, angiogenesis and cell migration. In addition, LCCA displayed higher levels of immunosuppressor infiltration (M2 macrophages, CAFs and MDSCs) and distinct cell death and metabolic patterns. BCR/TCR repertoire analysis revealed less BCR richness, clonality and high-abundance shared clonotypes in LCCA. Finally, Cox regression analysis identified that four cystic-specific genes, KCNK3, NRN1, PARVB and TRHDE-AS1, were associated with OS of lung adenocarcinoma (LUAD). And cystic-specific risk scores (CSRSs) were calculated to construct a nomogram, which performance well. Our study for the first time indicated significantly distinct molecular biological and immune characteristics between LCCA and non-LCCA, which provide complementary prognostic values in early-stage non-small cell lung cancer (NSCLC).

Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.

In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay. This retrospective cohort study included patients with stage I-III NSCLC. Recruited patients received standard-of-care management (surgical resection with or without adjuvant chemotherapy, followed by surveillance). Whole-exome sequencing of NSCLC resected tissue and matched germline DNA was used to design patient-specific mPCR assays (Signatera, Natera, Inc) to track up to 16 single-nucleotide variants in plasma samples. The overall cohort with analyzed plasma samples consisted of 57 patients. Stage distribution was 68% for stage I and 16% each for stages II and III. Presurgery (i.e., at baseline), ctDNA was detected in 15 of 57 patients (26%). ctDNA detection presurgery was significantly associated with shorter recurrence-free survival (RFS; hazard ratio [HR], 3.54; 95% confidence interval [CI], 1.00-12.62; p=.009). In the postsurgery setting, ctDNA was detected in seven patients, of whom 100% experienced radiological recurrence. ctDNA positivity preceded radiological findings by a median lead time of 2.8 months (range, 0-12.9 months). Longitudinally, ctDNA detection at any time point was associated with shorter RFS (HR, 16.1; 95% CI, 1.63-158.9; p<.0001). ctDNA detection before surgical resection was strongly associated with a high risk of relapse in early-stage NSCLC in a large unique Asian cohort. Prospective studies are needed to assess the clinical utility of ctDNA status in this setting.

Effect of Preoperative Nutritional Status on Clinical Outcome After Surgery for Early-Stage Non-Small Cell Lung Cancer

Effect of Preoperative Nutritional Status on Clinical Outcome After Surgery for Early-Stage Non-Small Cell Lung Cancer

Invasive Nodal Staging via Endobronchial Ultrasound and Outcome in Patients Treated with Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer – Results from a Single Institution Study

IntroductionStereotactic body radiation therapy (SBRT) is an effective treatment for medically inoperable early-stage non-small cell lung cancer (NSCLC). The prognostic value of invasive nodal staging (INS) for patients undergoing SRBT has not been studied extensively. Herein, we report the impact of INS in addition to 18F-FDG-PET on treatment outcome for patients with NSCLC undergoing SBRT. Materials and MethodsPatients with stage I/ II NSCLC who underwent SBRT were included with IRB approval. Clinical, dosimetric, and radiological data were obtained. Overall survival (OS), regional recurrence free survival (RRFS), local recurrence free survival (LRFS), and distant recurrence free survival (DRFS) were analyzed using Kaplan Meyer method. Univariable analysis (UVA) and multivariable analysis (MVA) were performed to assess the relationship between the variables and the outcomes. ResultsA total of 376 patients were included in the analysis. Median follow up was 43 months (IQ 32.6-45.8). Median OS, LRFS, RRFS, DRFS were 40, 32, 32, 33 months, respectively. The 5-year local, regional, and distant failure rates were 13.4%, 23.5% and 25.3%, respectively. The 1-year, 3-year and 5-year OS were 83.8%, 55.6%, and 36.3%, respectively. On MVA, INS was not a predictor of either improved overall or any recurrence free survival endpoints while larger tumor size, age, and adjusted Charleston co-morbidity index (aCCI) were significant for inferior LRFS, RRFS, and DRFS. ConclusionInvasive nodal staging did not improve overall or recurrence free survival among patients with early-stage NSCLC treated with SBRT whereas older age, aCCI, and larger tumor size were significant predictors of LRFS, RRFS, and DRFS.

A signature of enhanced proliferation associated with response and survival to anti-PD-L1 therapy in early-stage non-small cell lung cancer

In early-stage non-small cell lung cancer, the combination of neoadjuvant anti-PD-L1 and subablative stereotactic body radiation therapy (SBRT) is associated with higher rates of major pathologic response compared to anti-PD-L1 alone. Here, we identify a 140-gene set, enriched in genes characteristic of highly proliferating cells, associated with response to the dual therapy. Analysis of on-treatment transcriptome data indicate roles for T and B cells in response. The 140-gene set is associated with disease-free survival when applied to the combined trial arms. This 140-gene set identifies a subclass of tumors in all 7 of The Cancer Genome Atlas tumor types examined. Worse survival is associated with the 140-gene signature in 5 of these tumor types. Collectively, our data support that this 140-gene set, discovered in association with response to combined anti-PD-L1 and SBRT, identifies a clinically aggressive subclass of solid tumors that may be more likely to respond to immunotherapies.

Diagnostic and prognostic value of serum soluble B7-H3 in nonsmall cell lung cancer.

The aim of this study was to investigate the utility of serum soluble B7-H3 (sB7-H3) as a diagnostic marker for early-stage nonsmall cell lung cancer (NSCLC) and its potential for evaluating the prognosis of patients with advanced-stage NSCLC. In this study, an ELISA was employed to detect the expression levels of sB7-H3 in a cohort of patients diagnosed with NSCLC ( n = 122) and a control group ( n = 42) during the same observation period. Comparative analyses were conducted to ascertain the variations in sB7-H3 concentrations between the NSCLC cohort and the healthy control group, as well as across pathological types and the presence and absence of lymph node metastasis. (1) The concentration of sB7-H3 in patients diagnosed with NSCLC exhibited a statistically significant increase compared to that observed in the healthy control group ( P < 0.05). Elevated expression levels of sB7-H3 demonstrated a significant correlation with pathological type, lymph node metastasis, tumor, node and metastasis stage and programmed cell death ligand (PD-L1) expression ( P < 0.05). (2) The diagnostic utility of sB7-H3 for the diagnosis of NSCLC and the heightened expression of PD-L1 demonstrated high levels of sensitivity and specificity. (3) Elevated levels of sB7-H3 emerged as an independent risk factor impacting the overall survival of patients diagnosed with advanced NSCLC. The findings of this study suggest that sB7-H3 holds promise as a diagnostic tool for early-stage NSCLC. The elevated expression of sB7-H3 appears to serve as a reliable indicator for assessing the prognosis of patients diagnosed with advanced NSCLC.

Radiomics in stereotactic body radiotherapy for non-small cell lung cancer: a systematic review and radiomic quality score study.

Stereotactic body radiotherapy (SBRT) has been widely utilized for curative treatment of early-stage non-small cell lung cancer (NSCLC). It has achieved good local control rate comparable to surgery. Currently, no standard risk model exists for SBRT outcome or complication prediction. Radiomics has the potential to improve clinical outcome prognostication. Here, we reviewed the current literature on the radiomic analyses of thoracic SBRT through the use of radiomic quality score (RQS). Literature search was conducted on PubMed and Embase to retrieve radiomics studies on SBRT for early NSCLC. The literature search included studies up to June 2021. Only full papers published in peer reviewed journals were included. Studies that included metastatic lung cancers or non-lung cancers were excluded. Two independent investigators evaluated each study using the RQS and resolved discrepancies through discussion. A total number of 25 studies were analysed. The mean RQS was 7.76 of a maximum score of 36. This corresponds to 21.56% of the maximum score. Lack of feature reduction strategies, external validation and open data sharing were identified as key limitations of the reviewed studies. Meanwhile, various common radiomic signatures across different studies such as gray level co-occurrence matrix Homogeneity and energy have been identified. Multiple robust radiomic models have also been reviewed that may improve outcome or complication prediction. Radiomics in thoracic SBRT has a very promising future as a prognostication tool. However, larger multicenter prospective studies are required to confirm radiomic signatures. Improvement in future study methodologies can also facilitate its wider application.

Prospective study investigating hypofractionated proton beam therapy in patients with inoperable early stage non-small cell lung cancer.

To report the results of hypofractionated proton beam therapy (PBT) for the treatment of early stage lung cancer in patients not suitable for surgical resection. Data from 27 adult patients, who were diagnosed with inoperable cT1-3N0 non-small cell lung cancer (NSCLC) between March 2018 and August 2020, were analyzed. PBT was prescribed as 64 Cobalt Grey equivalents delivered in 8 fractions (Sumitomo, Japan). The primary endpoint was local control; secondary endpoints included overall survival, quality of life, and grade ≥3 toxicity. The median follow-up was 28.9 months (range, 1.1-62.1 months). During follow-up, 13 (48.1%) patients experienced disease progression, including local progression in 7. Two-year local control rates were 73.5%, 85.7% for T1, and 61.4% for T2-3. The worse local control rate was observed in those with large clinical target volumes (≥ 47.5 cc) and heavy smoking history (≥30 pack-years). The two-year overall survival rate was 76.5%. Grade 3 radiation-related toxicities were observed in 2 (7.4%) patients. In the European Organization for Research and Treatment of Cancer Quality of Life Core 30 results, the global score did not change significantly from baseline. However, dyspnea score increased from 19.8 before PBT to 33.3 at 4 months' post-PBT (p=0.047) and was maintained until 13 months (p=0.028). Hypofractionated PBT was a safe treatment option for inoperable early stage NSCLC and appeared to be appropriate for small tumor volumes. However, local control for larger tumors requires further improvement.

Comparison of postoperative complications in mediastinal lymph node dissection versus mediastinal lymph node sampling for early stage non-small cell lung cancer: Protocol for a systematic review and meta-analysis.

Lung cancer is the primary cause of cancer-related deaths worldwide, with high rates of morbidity and mortality. The most effective treatment for early stage (I-II) non-small cell lung cancer (NSCLC) is surgical resection. However, the extent of mediastinal lymph nodes removal required and the impact of their removal remains controversial. This systematic review and meta-analysis aimed to evaluate the postoperative complications in patients with stage I-II NSCLC who received mediastinal lymph node dissection (MLND) or mediastinal lymph node sampling (MLNS). According to the predefined inclusion criteria, we will conduct a comprehensive search for randomized controlled trials (RCTs) and observational studies examining the postoperative complications of MLND compared to MLNS in patients with stage I-II NSCLC. The search will be performed across multiple databases including PubMed, Embase, the Cochrane Library, CNKI, WanFang, Sinomed, VIP, Duxiu, and Web of Science from inception to February 2024. Additionally, relevant literature references will be retrieved and hand searching of pertinent journals will be conducted. Screening, data extraction, and quality assessment will be performed by two independent reviewers. Review Manager 5.4 will be applied in analyzing and synthesizing. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) will be used to assess the quality of evidence for the whole RCTs and used Newcastle-Ottawa scale to assess the methodologic quality of observational studies. This study did not include personal information. Ethical approval was not required for this study. This study is based on a secondary analysis of the literature, so ethical review approval is not required. The final report will be published in a peer-reviewed journal. This systematic review will contribute to compare the safety and survival benefits of these two surgical techniques for the treatment of early stage NSCLC, to further guide the selection of surgical approaches. The protocol of the systematic review has been registered on Open Science Framework, with a registration number of DOI https://doi.org/10.17605/OSF.IO/N2Y5D.

A deep learning-based framework (Co-ReTr) for auto-segmentation of non-small cell-lung cancer in computed tomography images.

Deep learning-based auto-segmentation algorithms can improve clinical workflow by defining accurate regions of interest while reducing manual labor. Over the past decade, convolutional neural networks (CNNs) have become prominent in medical image segmentation applications. However, CNNs have limitations in learning long-range spatial dependencies due to the locality of the convolutional layers. Transformers were introduced to address this challenge. In transformers with self-attention mechanism, even the first layer of information processing makes connections between distant image locations. Our paper presents a novel framework that bridges these two unique techniques, CNNs and transformers, to segment the gross tumor volume (GTV) accurately and efficiently in computed tomography (CT) images of non-small cell-lung cancer (NSCLC) patients. Under this framework, input of multiple resolution images was used with multi-depth backbones to retain the benefits of high-resolution and low-resolution images in the deep learning architecture. Furthermore, a deformable transformer was utilized to learn the long-range dependency on the extracted features. To reduce computational complexity and to efficiently process multi-scale, multi-depth, high-resolution 3D images, this transformer pays attention to small key positions, which were identified by a self-attention mechanism. We evaluated the performance of the proposed framework on a NSCLC dataset which contains 563 training images and 113 test images. Our novel deep learning algorithm was benchmarked against five other similar deep learning models. The experimental results indicate that our proposed framework outperforms other CNN-based, transformer-based, and hybrid methods in terms of Dice score (0.92) and Hausdorff Distance (1.33). Therefore, our proposed model could potentially improve the efficiency of auto-segmentation of early-stage NSCLC during the clinical workflow. This type of framework may potentially facilitate online adaptive radiotherapy, where an efficient auto-segmentation workflow is required. Our deep learning framework, based on CNN and transformer, performs auto-segmentation efficiently and could potentially assist clinical radiotherapy workflow.

Molecular alterations and clinical prognostic factors in resectable non-small cell lung cancer

BackgroundEGFR 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.MethodsMedical 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.ResultsTotal 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).ConclusionThe 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.

LINAC-based SBRT in treating early-stage NSCLC patients-single institution experience and survival data analysis.

Aim: This single institute prospective study aimed to evaluate the feasibility of LINAC-based stereotactic body radiotherapy (SBRT) in treating patients with early-stage non-small cell lung cancer (NSLSC). We focused on the survival data with the local and distant control profiles and the cancer- and non-cancer-specific survival. Treatment-related side effects were also collected and analyzed. Methods: Patients with early-stage NSCLC between January 2018 and October 2021 were included in our prospective study; a total of 77 patients receiving LINAC-based SBRT were analyzed. All patients had pretreatment multidisciplinary tumor board decisions on SBRT. The average patient age was 68.8years (median: 70years, range: 52-82); 70 patients were in ECOG 0 status (91%), while seven patients were in ECOG 1-2 status (9%). 52% of the patients (40) had histologically verified NSCLC, and the other 48% were verified based on PETCT results. We applied the SBRT scheme 8 x 7.5 Gy for central tumors (74%) or 4 x 12 Gy for peripheral tumors (26%). Results: The mean follow-up time was 25.4months (median 23, range 18-50). The Kaplan-Meier estimation for overall survival in patients receiving LINAC-based SBRT was 41.67months. Of the 77 patients treated by SBRT, death was reported for 17 patients (9 cases cancer-specific, 8 cases non-cancer specific reason). The mean local tumor control was 34.25months (range 8.4-41), and the mean systemic control was 24.24months (range 7-25). During the treatments, no Grade I-II were reported; in 30 cases, Grade I non-symptomatic treatment-related lung fibrosis and two asymptomatic rib fractures were reported. Conclusion: In the treatment of early-stage NSCLC, LINAC-based SBRT can be a feasible alternative to surgery. Although we reported worse OS data in our patient cohort compared to the literature, the higher older average age and the initial worse general condition (ECOG1-2) in our patient cohort appear to be the reason for this difference. With the comparable local control and survival data and the favorable side effect profile, SBRT might be preferable over surgery in selected cases.

Accuracy of endobronchial ultrasound-guided transbronchial needle aspiration for staging of non-small cell lung cancer.

Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is routinely performed to confirm a lung cancer diagnosis and/or to clinically stage disease. EBUS-TBNA findings may be used to determine whether patients can be offered potentially curative surgery. In this study, we evaluated the reporting in our service of EBUS-TBNA cytology for early-stage (operable) non-small cell lung cancer (NSCLC), focusing on diagnostic accuracy and analyzing cases with discordant cytologic and post-surgical histopathologic conclusions. Cytology slides and cytopathology reports of 120 NSCLC patients who had undergone EBUS-TBNA and lobectomy in our hospital system between 2015 and 2021 were retrospectively reviewed. Of 290 lymph nodes (110 cases) able to be reviewed, interpretation of 48 lymph nodes was discordant with the original cytopathology report. This included 31 lymph nodes originally reported as adequate, which were found to be non-diagnostic on review. The diagnostic accuracy (benign/malignant) of lymph nodes that were sampled at EBUS-TBNA and excised at surgery was 89%. Specific examination of cases where EBUS-TBNA cytology did not reflect post-surgical findings illustrated important features and limitations of the procedure. These included potential misclassification of lymph node stations, the presence of multiple, variably involved nodes at lymph node stations, and the failure to detect small volume disease. Continuous evaluation of EBUS-TBNA performance identifies technical limitations and areas of improvement for cytopathology reporting. This is increasingly important in an era where lung cancer screening is expected to increase diagnosis of early-stage disease and with the advent of novel treatments, including non-surgical management options.

Wedge Resection Outcomes: A Comparison of Video-Assisted and Robot-Assisted Wedge Resections

BackgroundQuality of oncologic resection for early-stage non-small cell lung cancer (NSCLC) may differ by surgical approach. Minimally invasive surgery has become the standard for surgical treatment of NSCLC. Our study compares quality of wedge resection by video-assisted thoracoscopic surgery (VATS) vs robotic video-assisted thoracoscopic surgery (RVATS). We hypothesized that RVATS would result in higher quality resections and improved patient outcomes. MethodsA retrospective cohort analysis was completed using the National Cancer Database for patients with clinical stage 1 NSCLC with tumor size ≤2 cm who underwent a minimally invasive surgery wedge resection from 2010 to 2019. Wedge resections approached with RVATS were compared with VATS. A 1:1 propensity score matched analysis was performed. ResultsThe cohort included 16,559 patients; 80.4% (13,406) received VATS and 18.9% (3153) received RVATS. Compared with RVATS, a VATS approach was associated with a lower likelihood of lymph nodes being examined (59.0% vs 75.2%; P < .001), fewer nodes dissected (median, 4 vs 5; P < .001), and less adjuvant systemic therapy administered (1.3% vs 2.2%; P < .001). Propensity score matching resulted in 2590 balanced pairs. Statistical significance was maintained for likelihood of lymph nodes examined, number of nodes dissected, and adjuvant systemic therapy administered. There was no significant difference in nodal upstaging after propensity score matching (3.7% vs 4.3%; P = .37). ConclusionsCompared with the VATS approach, wedge resections by RVATS for early-stage NSCLC were more likely to be associated with increased lymph nodes resected. These data may support increased use of RVATS for wedge resections.

A novel neoadjuvant therapy for early-stage non-small cell lung cancer in a mouse model.

Lung cancer is the common malignancy with high mortality rate in the world. Even with curative resection for early-stage lung cancer patients, the rate of postoperative recurrence and metastasis is still high. Neoadjuvant nivolumab combined with chemotherapy leads to improved pathological complete response rate and event-free survival in resectable non-small cell lung cancer (NSCLC) patients. However, the neoadjuvant therapy is not only accompanied by grade 3 or above adverse events which resulting in the potential missing out on the window for curative surgery for the patients, but also has low efficacy especially in patients with low programmed death ligand 1 (PD-L1) expression. Hence, it is particularly important to explore innovative ways to inhibit tumour recurrence and metastasis. In the present study, we investigated whether neoadjuvant therapy with intralesional Rose Bengal (RB) elicited specific immune responses compared with control group, and then the lung cancer mouse model was used to evaluated the immunological mechanism. The secondary Lewis lung cancer cells (LLCs) tumour growth was significantly suppressed by RB intralesional injection into subcutaneous tumour; the formation rate of secondary tumours induced by the B16 melanoma cell injection was 100%. Intralesional RB neoadjuvant therapy before surgical resection exhibited effectively enhanced T central memory cells (Tcm) and T memory stem cells (Tscm) + naïve T cells (Tn) infiltration, elicited stronger cytotoxic T lymphocyte (CTL) responses against LLCs, and displayed markedly higher proportions of splenic lymphocytes that produce tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) upon restimulation in a lung cancer mouse model. Based on our preclinical data, neoadjuvant therapy with intralesional RB injection generated immune memory and prevented the recurrence and metastasis of tumour in a lung cancer mouse model, which provides a new strategy for neoadjuvant treatment of early-stage NSCLC.

Abstract PR011: Comprehensive longitudinal tracking of lung cancer evolutionary clonal dynamics during therapy using circulating tumour DNA

Abstract Background: Outgrowth of resistance cancer cell populations is a common mechanism of therapy failure in oncology. Effective personalised medicine relies on targeting of ubiquitous aberrations; however, tumours are highly heterogenous. Liquid biopsies have the potential to provide representative tumour sampling at regular intervals through disease course, but extensive interrogation of longitudinal clonal evolution through therapy has been lacking, particularly for patients on a curative disease pathway. Methods: We analysed 1102 plasma samples from 202 early-stage non-small cell lung cancer patients who underwent multiregional whole exome sequencing of primary tumour, relapse and, where available, comprehensive post-mortem samples. We designed personalised panels targeting a median of 200 mutations for each patient and sequenced cell-free DNA (cfDNA) around these variant sites to saturation. For four patients we designed personalised panels including all clonal and subclonal mutations discovered (up to 600). One of these four patients received a personalised neoantigen vaccine. We used ECLIPSE to determine the clonal composition of low tumour fraction ctDNA. Results: We found a directly proportional correlation between the cancer cell fraction (CCF) of subclones estimated in plasma and multiregional tissue samples at surgery. Lower plasma CCFs were observed for clonal illusion mutations from randomly selected single samples, one for each TRACERx patient, when compared to truly clonal mutations (P &amp;lt; 0.001, OR = 0.44), distinguishing appropriate therapeutic targets without multiregional sampling. In 24 patients with both cfDNA and tissue available at relapse we detected 28/29 relapse tissue subclones in the cfDNA with an additional 8 cfDNA unique subclones. We found a strong bias for cfDNA unique subclones to be present in only subset of cells (P = 0.008, OR = 5.5), consistent with insufficient tissue sampling. We observed longitudinal clonal dynamics which were often, but not always, associated with treatment. Metastatic competent subclones had higher CCFs in the primary tumour, as measured in pre-operative plasma (P &amp;lt; 0.001, OR = 4.5). Upon receiving a personalised neoantigen vaccine a patient had regression of clones harbouring a targeted EGFR mutation. However, copy number loss of the targeted EGFR mutation occurred in a liver lesion which grew over the treatment period on surveillance radiology alongside a novel ctDNA subclone. Upon cessation vaccine treatment the resistance-associated subclone and liver lesion underwent regression. EGFR mutant clones become dominant in the tumour thereafter suggesting a fitness cost associated with vaccine resistant EGFR mutation loss in this patient, measured using ctDNA. Conclusions: We find evidence that comprehensive tracking of subclonal mutations in plasma can accurately profile the clonal structure of tumours over time, revealing clonal dynamics in response to treatment and biological determinants of metastasis with the potential to guide personalised medicine. Citation Format: Alexander M. Frankell, Christopher Abbosh, Kristiana Grigoriadis, Emilia Lim, Selvaraju Veeriah, Sophia Ward, Tak Karasaki, James R. M. Black, Mariam Jamal-Hanjani, Nicholas McGranahan, Charles Swanton. Comprehensive longitudinal tracking of lung cancer evolutionary clonal dynamics during therapy using circulating tumour DNA [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR011.

Gut microbes as medical signature for the effectiveness of immunotherapy in patients with advanced non-small cell lung cancer.

Lung cancer (LC) is the most common cause of cancer-related death worldwide and poses a severe threat to public health. Immunotherapy with checkpoint blockers has improved the outlook for advanced non-small cell lung cancer (NSCLC) therapy. For the treatment of patients with advanced NSCLC, antibodies such as anti-programmed death 1 (anti-PD1), anti-programmed death ligand 1 (anti-PD-L1), and anti-cytotoxic T lymphocyte-associated antigen 4 (anti-CTLA-4) are of paramount importance. Anti-PD-1 and anti-PD-L1 monoclonal antibody therapies are used to block the PD-1/PD-L1 pathway and identify cancerous cells to the body's defenses. Antibodies directed against CTLA-4 (anti-CTLA-4) have also been shown to improve survival rates in patients with NSCLC. Currently, other immunotherapy approaches like neoadjuvant immune checkpoint inhibitors (NAICIs) and chimeric antigen receptor T-cell (CAR-T) therapies are applied in NSCLC patients. NAICIs are used for resectable and early stage NSCLC and CAR-T is used to find more useful epitope sites for lung tumors and destroy cancer cells. A patient's gut microbiota might influence how their immune system reacts to NSCLC immunotherapy. The majority of intestinal microbes stimulate helper/cytotoxic T cells, induce natural killer (NK) cells, activate various toll-like receptors (TLR), build up cluster of differentiation 8 (CD8), increase PD-1 production, and attract chemokine receptors towards cancer cells. Thus, they serve as immune inducers in NSCLC immunotherapy. Nonetheless, certain bacteria can function as immune suppressors by inhibiting DC proliferation, stopping CD28 trafficking, restoring CD80/CD86, increasing immunological tolerance, and upsetting Th17 cells. Therefore, they are prevalent in non-responders with NSCLC immunotherapy.

Commentary: is segmentectomy curative in patients with early-stage ground glass opacity predominant non-small cell lung cancer?

Commentary: is segmentectomy curative in patients with early-stage ground glass opacity predominant non-small cell lung cancer?

Clinical Significance of Preserving Pulmonary Function After Lung Resection in Early-Stage Non–Small-Cell Lung Cancer

IntroductionTo determine the association between changes in pulmonary function before and after surgery, and the subsequent prognosis, of patients with early-stage non–small-cell lung cancer (NSCLC). MethodsA total of 485 patients who underwent lobectomy or segmentectomy for NSCLC with whole tumor size ≤2 cm and clinical stage IA at 2 institutions were retrospectively reviewed. The relationship between the postoperative reduction rate in vital capacity (VC), forced vital capacity (FVC), and forced expiratory volume in 1 second (FEV1) and overall survival (OS) was investigated. OS determined the cut-off value of the reduction rate, according to the reduction rate of every 10% in pulmonary function. ResultsMultivariable Cox regression analysis showed that a reduction rate in VC at 12 months postoperatively was an independent prognostic factor for OS (hazard ratio, 1.05; 95% confidence interval [CI], 1.02-1.07; P < .001) but those in FVC and FEV1 were not. OS was classified into good and poor with 20% reduction rate in VC. OS and recurrence-free survival (RFS) in a higher than 20% reduction rate in VC were worse than those in ≤20% reduction rate in VC (5 year-OS; 82.0% vs. 93.4%; P = .0004. Five year-RFS; 80.3% vs. 89.8%; P = .0018, respectively). Multivariable logistic analysis showed that lobectomy was a risk factor for the higher than 20% reduction rate in VC (odds ratio, 1.61; 95% CI, 1.01-2.56; P = .045). ConclusionsPostoperative decrease in VC was significantly associated with the prognosis. Preserving pulmonary function is important for survival of patients with early-stage NSCLC.

Trends and Disparities in Curative-Intent Treatment for Early-Stage Non-Small Cell Lung Cancer: A Population-Based Analysis of Surgery and SBRT.

Despite the increasing adoption of stereotactic body radiotherapy (SBRT) as a recommended alternative for early-stage non-small cell lung cancer (NSCLC), population-based research on racial/ethnic disparities in curative-intent treatment accounting for SBRT remains limited. This study investigated trends and disparities in receiving curative-intent surgery and/or SBRT in a diverse, retrospective cohort. Early-stage NSCLC cases (2005-2017) from the Florida cancer registry were linked to individual-level statewide discharge data containing comorbidities and specific treatment information. Joinpoint regression assessed trends in treatment receipt. Multivariable logistic regression examined associations between race/ethnicity and treatment type. Among 64,999 patients with early-stage NSCLC, 71.6% received curative-intent treatment (surgery and/or SBRT): 73.1%, 72.4%, and 60.3% among Hispanic, White, and Black patients, respectively (P < 0.01). SBRT use increased steeply from 2005 to 2007 and then by 7.9% annually from 2007 to 2017 (P < 0.01); curative-intent surgery remained stable from 2005 to 2014 before declining by 6.2% annually during 2014-2017 (P = 0.04). The Black-White disparity in receipt of curative-intent treatment was significant [ORadj, 0.65; 95% confidence interval (CI), 0.60-0.71]. Patients with Charlson comorbidity index (CCI)≥3 had 36% (ORadj, 0.64; 95% CI, 0.60-0.69) lower odds of receiving curative-intent surgery and no significant difference for SBRT (ORadj, 1.06; 95% CI, 0.93-1.20) compared with CCI = 0. Racial disparities in receiving curative-intent treatment for early-stage NSCLC persist despite the availability of SBRT, suggesting the full potential of curative-intent treatment for early-stage NSCLC remains unachieved. Addressing disparities in early-stage NSCLC requires addressing differential treatment patterns and enhancing accessibility to treatments like underutilized SBRT, particularly for high-comorbidity populations such as Black patients.