Early-Stage Small-Cell Lung Cancer Research Articles

The role of adjuvant chemotherapy (CT) for early stage resectable node negative small cell lung cancer with size of ≤ 2 cm post-surgical resection: A SEER plus based statistical analysis.

e20643 Background: Small cell lung cancer (SCLC) is a poorly differentiated neuroendocrine tumor accounting for 15% of all lung cancers. Surgical resection followed by adjuvant platinum-etoposide is recommended for patients with limited-stage SCLC (T1 N0M0). In this study, we sought to evaluate the survival benefit of adjuvant chemotherapy for patients with ≤2 cm size SCLC following surgical resection. Methods: We utilized Surveillance, Epidemiology and End Results (SEER) plus 18 registries to identify adult patients (≥18 years) diagnosed with small cell cancer of the lung with tumor size of ≤ 2 cm from 2010 to 2018. The study population comprised of patients who underwent surgical resection followed by adjuvant chemotherapy and patients who received surgical resection alone. Kaplan-Meier and long rank tests were used to compare overall survival between the two groups. Multivariate survival analysis was done using the Cox proportional hazards regression model. Results: 419 patients were identified, with 203 (48%) receiving adjuvant CT while 216 (52%) not receiving adjuvant CT. The population who received adjuvant chemotherapy was younger than those who did not (Median years: 67 years vs 71 years, p < 0.001). The 5-year overall survival rate was significantly higher for those receiving adjuvant CT (49% vs 40.9%, P value < 0.001). On multivariate analysis after adjusting for age, gender, race, and origin, adjuvant chemotherapy was associated with better overall survival (HR:0.67; 95% CI 0.54 - 0.88, p = 0.003). Conclusions: Our study demonstrates that adjuvant CT should be used for early-stage small cell lung cancer irrespective of tumor size following surgical resection.

Heterogeneous distribution pattern of CD3+ tumor-infiltrated lymphocytes (TILs) and high combined positive score (CPS) favored the prognosis of resected early stage small-cell lung cancer

PurposeThis study aimed to illustrate the heterogeneity of immune features in small cell lung cancer (SCLC). MethodsImmunohistochemistry (IHC) staining of CD3, CD4, CD8 and PD-L1 were performed with 55 SCLC FFPE samples from radical resections. Quantitative assessment of CD3+ tumor-infiltrated lymphocytes (TILs) to present the heterogeneity in the tumor and the stroma areas. Hotspots of TILs were evaluated to illustrate the potential relationship between TIL-density and its immune competence. Programmed death ligand-1 (PD-L1) expressed on both tumor TILs (t-TILs) and stroma TILs (s-TILs) was evaluated and quantitatively described as values of tumor positive score (TPS) and combined positive score (CPS). The clinical value of TPS and CPS were further identified according to their relationship with disease-free survival (DFS). ResultsMore abundant CD3+ TILs were observed in the tumor stroma than that within the parenchyma (15.02±2.25% vs. 1.58±0.35%) . The amount of CD3+ s-TILs were positively correlated with DFS. The CD3+/CD4+ subset of the TILs was found more favorable to DFS compared to the CD3+/CD8+ subset. Hotspots of CD3+ TILs were observed in tumor regions and patients with more Hotspots of CD3+ TILs have better outcomes. CPS were more reliable than TPS to describe PD-L1 expression in SCLC and it was found positively correlated with tumor size and DFS. ConclusionsThe immune microenvironment of SCLC was heterogeneous. Hotspots, the amount of CD3/CD4+ TILs and the CPS value were found valuable in determine the anti-tumor immunity and predicting the clinical outcome of SCLC patients.

Surgery vs. radiotherapy in a population-based cohort of elderly patients with early-stage small-cell lung cancer: an IPTW propensity-score analysis.

Due to the lack of treatment outcome data comparing surgical and non-surgical treatment modalities in the era of contemporary staging and treatments, the management of elderly patients with early-stage small cell lung cancer (SCLC) continues to be debated. This study sought to compare surgery and radiotherapy in elderly patients (aged ≥70 years) with early-stage SCLC using data from the Surveillance, Epidemiology, and End Results (SEER) database. The inverse probability of treatment weighting (IPTW) method was used to address the selection bias between the surgery and radiotherapy groups. The Kaplan-Meier method and multivariate Cox proportional hazards regression were used to compare the overall survival (OS) of the treatment cohorts before and after the IPTW adjustment. The competing risk survival analyses used Fine and Gray's method to compare the cancer-specific survival between the groups. Between 2004 and 2018, 685 elderly patients received local treatment for early-stage SCLC. Of these patients, 193 patients (26.6%) received surgery and 492 patients (73.4%) received radiotherapy. Surgery was associated with a longer OS time than radiotherapy (median OS time: 32 vs. 20 months; 5-year OS time: 30.6% vs. 17.6%; P=0.002). The survival advantage of surgery was consistent in the IPTW-adjusted cohort (median OS time: 32 vs. 20 months; 5-year OS time: 30.6% vs. 17.6%; P<0.002). In the multivariate analysis, an increased age (P=0.001), stage T2 (P=0.047), radiotherapy (P<0.001), and no chemotherapy (P=0.034) were associated with unfavorable OS. In the IPTW-adjusted cohort, the multivariate analysis showed a decreased age (P<0.001), stage T1 (P=0.038), and surgery (P<0.001) were associated with superior OS. The competing risk analyses demonstrated that surgery produced a consistent decrease in the cancer-specific mortality rate compared to radiotherapy among the patients aged 70-80 years (53.6% vs. 61.0%, P=0.01), but no difference was observed in the 5-year cumulative incidence rate of cancer-related death between the surgery and radiotherapy groups (66.3% vs. 64.9%; P=0.66) in patients aged ≥80 years. In this population-based study of the optimal local treatment for elderly early-stage SCLC, patients who underwent surgery had superior OS compared to those who underwent radiotherapy.

170 - A UK centre’s experience of stereotactic ablative radiotherapy (SABR) for very early-stage small-cell lung cancer (SCLC)

170 - A UK centre’s experience of stereotactic ablative radiotherapy (SABR) for very early-stage small-cell lung cancer (SCLC)

Clinical Outcome in Patients With Early-Stage Small Cell Lung Cancer Treated With Surgery or Radiation in the Absence of Prophylactic Cranial Irradiation: A Single-Center Retrospective Study

As screening chest computed tomography for patients at high risk for cancer has become more widely accepted, increasing numbers of patients with early-stage small cell lung cancer (SCLC) are being diagnosed. Although surgery is an accepted option for patients with early-stage SCLC, for patients who decline or cannot undergo surgery, stereotactic body radiation treatment (SBRT) is an alternative. Although prophylactic cranial irradiation (PCI) improves survival in patients with limited-stage SCLC, PCI for early-stage SCLC (stage T1-T2) has not been explored. This study defines survival and recurrence patterns in patients with early-stage SCLC who were treated with surgery or SBRT in the absence of PCI. In this single-institution retrospective study, 14 patients diagnosed with early-stage SCLC (stage T1-T2) between July 2015 and May 2021 at a single tertiary care hospital were treated with SBRT or surgery with no PCI. Primary outcomes were locoregional cancer recurrence, distant recurrence, recurrence-free survival, and overall survival. The secondary outcome was development of brain metastasis. Analyses included Cox regression, Kaplan-Meier survival, and log-rank tests. A total of 14 patients (5 women and 9 men) were included in the study: 9 with stage T1 and 5 with stage T2 SCLC. Six patients (43%) received SBRT and 8 (57%) had surgical treatment. All patients except 1 received adjuvant chemotherapy. Median follow-up was 14.3 months (range, 2.4-64.4 months), and the median age at diagnosis was 71.5 years (range, 54-81 years). Cox regression and log-rank tests showed no significant differences in any outcomes between the surgery and SBRT groups, and no patients developed brain metastases during the study period. Data are lacking regarding the benefit of PCI in early-stage SCLC. Although the sample size in this study was too small to draw any conclusions, the findings add to the ongoing dialogue regarding the importance of PCI in this patient population. No difference was identified in survival and cancer recurrence in patients who received either surgery or SBRT in the absence of PCI.

Clinical impact of number of lymph nodes dissected on postoperative survival in node-negative small cell lung cancer.

Small cell lung cancer (SCLC) is a lethal histologic subtype of lung cancer. Although the Commission on Cancer recommends pathological examination of at least 10 lymph nodes dissected (LNDs) for resected early-stage non-small cell lung cancer, its survival benefit of LNDs in patients with early-stage SCLC is unknown. The National Cancer Database was queried for SCLC patients with clinical stage I-II and clinical N0, NX disease per AJCC 7th edition who had undergone lobectomy between 2004 and 2017. Overall survival of SCLC patients by the number of LNDs was compared using Log-rank tests. Univariate and multivariable Cox proportional hazards analyses were performed. In total, 688 (42%), 311 (20%), 247 (16%), 196 (12%), 126 (8%), and 36 (2%) of 1,584 patients with early-stage SCLC had ≥10, 7-9, 5-6, 3-4, 1-2, and 0 LNDs, respectively. The sequential improvement in the HRs was no longer evident if the number of LNDs exceeds 4. Patients with ≥3 LNDs (n = 1,422) had a significantly longer overall survival than those with <3 LNDs (n = 162) (hazard ratio for death: 0.76, 95% confidence interval: 0.62-0.94, P = 0.0087). Multivariate analysis revealed that ≥3 LNDs was an independent factor for predicting overall survival (hazard ratio for death: 0.76, 95% confidence interval: 0.61-0.93, P = 0.0083). Although we are reluctant to recommend a definitive "optimal number" of LNDs, our findings suggest the prognostic and therapeutic roles for performing ≥3 LNDs in patients with early-stage SCLC who undergo lobectomy.

Development and validation of nomogram prognostic model for early-stage T1-2N0M0 small cell lung cancer: A population-based analysis.

Survival outcomes of early-stage T1-2N0M0 small cell lung cancer (SCLC) patients differ widely, and the existing Veterans Administration Lung Study Group (VALSG) or TNM staging system is inefficient at predicting individual prognoses. In our study, we developed and validated nomograms for individually predicting overall survival (OS) and lung cancer-specific survival (LCSS) in this special subset of patients. Data on patients diagnosed with T1-2N0M0 SCLC between 2000 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. All enrolled patients were split into a training cohort and a validation cohort according to the year of diagnosis. Using multivariable Cox regression, significant prognostic factors were identified and integrated to develop nomograms for 1-, 3-, and 5-year OS and LCSS prediction. The prognostic performance of our new model was measured by the concordance index (C-index) and calibration curve. We compared our latest model and the 8th AJCC staging system using decision curve analyses (DCA). Kaplan-Meier survival analyses were applied to test the application of the risk stratification system. A total of 1,147 patients diagnosed from 2000 to 2011 were assigned to the training cohort, and 498 cases that were diagnosed from 2012 to 2015 comprised the validation cohort. Age, surgery, lymph node removal (LNR), and chemotherapy were independent predictors of LCSS. The variables of sex, age, surgery, LNR, and chemotherapy were identified as independent predictors of OS. The above-mentioned prognostic factors were entered into the nomogram construction of OS and LCSS. The C-index of this model in the training cohort was 0.663, 0.702, 0.733, and 0.658, 0.702, 0.733 for predicting 1-, 3-, and 5-year OS and LCSS, respectively. Additionally, in the validation cohort, there were 0.706, 0.707, 0.718 and 0.712, 0.691, 0.692. The calibration curve showed accepted prediction accuracy between nomogram-predicted survival and actual observed survival, regardless of OS or LCSS. In addition, there were significant distinctions in the survival curves of OS and LCSS between different risk groups stratified by prognostic scores. Compared with the 8th AJCC staging system, our new model also improved net benefits. We developed and validated novel nomograms for individual prediction of OS and LCSS, integrating the characteristics of patients and tumors. The model showed superior reliability and may help clinicians make treatment strategies and survival predictions for early-stage T1-2N0M0 SCLC patients.

Evaluation of circulating small extracellular vesicle-derived miRNAs as diagnostic biomarkers for differentiating between different pathological types of early lung cancer

Lung cancer is the leading cause of cancer-related death worldwide. MicroRNAs (miRNAs) in circulating small extracellular vesicles (sEVs) have been suggested to be potential biomarkers for cancer diagnosis. The present study was designed to explore whether plasma-derived sEV miRNAs could be utilized as diagnostic biomarkers for differentiating between early-stage small cell lung cancer (SCLC) and early-stage non-small cell lung cancer (NSCLC). We compared the miRNA profiles of plasma-derived sEVs from healthy individuals, patients with early-stage SCLC and patients with early-stage NSCLC. Next-generation sequencing was used to screen for differentially expressed miRNAs (DEMs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were used to predict the potential functions of these DEMs. Weighted gene coexpression network analysis (WGCNA) was used to identify the different pathology-related miRNA modules. We found that 22 DEMs were significantly different among healthy individuals, patients with early-stage SCLC, and patients with early-stage NSCLC. We selected six representative DEMs for validation by qRT‒PCR, which confirmed that miRNA-483-3p derived from plasma sEVs could be used as a potential biomarker for the diagnosis of early-stage SCLC, miRNA-152-3p and miRNA-1277-5p could be used for the diagnosis of early-stage NSCLC respectively.

P067: A pilot of lung cancer screening for survivors of Hodgkin lymphoma

Background: Alkylating agents and thoracic radiation put survivors of Hodgkin lymphoma (HL) at excess risk of lung cancer (30-year cumulative incidence 6.4%). Lung cancer screening (LCS) using low-dose CT thorax (LDCT) scans reduces lung cancer mortality in ever smokers in the general population by detecting early-stage lung cancers. We ran an LCS pilot in HL survivors, who are generally ineligible for LCS programmes aimed at the general population. Methods: 218 5+ year survivors of HL treated with mustine or procarbazine and/or thoracic radiation were identified from a follow-up database (ADAPT) hosted at The Christie NHS Foundation Trust and sent a letter of invitation. Participants underwent a baseline LDCT scan. Scans were reported as negative/indeterminate/positive in accordance with lung nodule guidelines. Indeterminate nodules required a further LDCT scan 3-months later. Participants with a positive scan were referred to lung cancer services. Results: Of the 218 invited to the study 54% were female, median age was 53 (range 25–80), median years since treatment 21 (6–45). 12 were ineligible. 127 (59%) expressed interest in participating. The uptake among eligible responders was 83% (102/123). Participation was not influenced by age or gender. Baseline LDCT scan results in 102 participants were: 90 (88.2%) negative, 10 (9.8%) indeterminate, 2 (2.0%) positive. 3-month surveillance LDCT scan results (n=9) were: positive (2), stable (5), with 2 pending. Among 4 participants with positive baseline or 3-month scans, 1 has been diagnosed with early-stage small-cell lung cancer and treated with curative intent, 1 is undergoing tests for presumed lung cancer and 2 are undergoing further surveillance. Coronary artery calcification was detected in 36.3%. Clinically significant incidental findings including emphysema, bronchiectasis, pulmonary inflammation/infection, metastatic breast cancer and vertebral insufficiency fractures were seen in 20 (19.6%). Notably, 3/35 participants who were ever smokers met the age and risk criteria for LCS through the programme aimed at the general population. Conclusion: LDCT scanning protocols tested in the general population are appropriate for use in the HL survivor population in a future targeted LCS programme. The feasibility of such a programme is contingent on developing methods to identify and contact long-term survivors of HL at risk of lung cancer and on investigating and addressing barriers to uptake.

The role of surgery in older patients with T1-2N0M0 small cell lung cancer: A propensity score matching analysis.

BackgroundSurgical resection could improve the survival of patients with early-stage small cell lung cancer (SCLC). However, there is a lack of dedicated studies concentrating on surgical treatment in older patients with T1-2N0M0 SCLC. Thus, we performed this population-based study to investigate whether older patients with T1-2N0M0 SCLC could benefit from surgery.MethodsWe collected the data of patients with SCLC between 2000 and 2015 from the Surveillance, Epidemiology, and End Results Program database. Older patients (≥ 65 years) with T1-2N0M0 SCLC were included, and we converted the staging information into those of the eighth edition. The propensity score matching (PSM) was used to balance the distribution of clinical characteristics between surgery and no-surgery groups.ResultsBefore PSM, the distribution proportions of clinical characteristics in 1,229 patients were unbalanced. The Kaplan–Meier curves of overall survival (OS) and cancer-specific survival (CSS) showed that the patients in the surgery group were better than those in the non-surgery group (all P < 0.001). After 1:2 PSM, the distribution proportions of clinical characteristics in 683 patients were balanced (all P > 0.05). The OS and CSS of patients in the surgery group were still better than that of patients in the no-surgery group (all P < 0.001), and subgroup analysis showed that the surgery was a protective factor for OS and CSS in all clinical characteristics subgroups (almost P < 0.001). The multivariate Cox analysis further confirmed this result (OS: HR, 0.33; 95% CI, 0.27–0.39; P < 0.001; CSS: HR, 0.29; 95% CI, 0.23–0.36; P < 0.001). The result of subgroup analysis based on age, T stage, and adjuvant therapy showed that surgery was related to better OS and CSS compared with non-surgery group (almost P < 0.001) and that lobectomy exhibited the longer survival than sublobectomy. Age, sex, and race were the independent prognostic factors for OS in patients undergoing surgery, whereas only the factor of age affects the CSS in patients with surgery.ConclusionsOlder patients with T1-2N0M0 SCLC can benefit significantly from surgical treatment, and lobectomy provides better prognosis than sublobectomy.

Adjuvant treatment for patients with incidentally resected limited disease small cell lung cancer-a retrospective study.

BackgroundWith the exception of very early-stage small cell lung cancer (SCLC), surgery is not typically recommended for this disease; however, incidental resection still occurs. After incidental resection, adjuvant salvage therapy is widely offered, but the evidence supporting its use is limited. This study aimed to explore proper adjuvant therapy for these incidentally resected SCLC cases.MethodsPatients incidentally diagnosed with SCLC after surgery at the Shanghai Pulmonary Hospital in China from January 2005 to December 2014 were included in this study. The primary outcome was overall survival. Patients were classified into different group according to the type of adjuvant therapy they received and stratified by their pathological lymph node status. Patients’ survival was analyzed using a Kaplan-Meier analysis and Cox regression analysis.ResultsA total of 161 patients were included in this study. Overall 5-year survival rate was 36.5%. For pathological N0 (pN0) cases (n=70), multivariable analysis revealed that adjuvant chemotherapy (ad-chemo) was associated with reduced risk of death [hazard ratio (HR): 0.373; 95% confidence interval (CI): 0.141–0.985, P=0.047] compared to omission of adjuvant therapy. For pathological N1 or N2 (pN1/2) cases (n=91), taking no adjuvant therapy cases as a reference, the multivariable analysis showed that ad-chemo was not associated with a lower risk of death (HR: 0.869; 95% CI: 0.459–1.645, P=0.666), while adjuvant chemo-radiotherapy (ad-CRT) was associated with a lower risk of death (HR: 0.279; 95% CI: 0.102–0.761, P=0.013).ConclusionsPatients who incidentally receive surgical resection and are diagnosed with limited disease SCLC after resection should be offered adjuvant therapy as a salvage treatment. For incidentally resected pN0 cases, ad-chemo should be considered and for pN1/2 cases, ad-CRT should be received.

Impact of Lymph Node Dissection on Survival and Tumor Recurrence for Patients with Resected cT1-2N0 Small Cell Lung Cancer.

The role of lymph node (LN) dissection for early-stage small cell lung cancer (SCLC) remains unclear. Therefore, this study aimed to investigate the impact of LN dissection on patient survival and tumor recurrence for patients with cT1-2N0M0 SCLC. Patients with cT1-2N0M0 SCLC who underwent intent-to-cure surgery at our institution between 2011 and 2019 were retrospectively reviewed. The survival outcomes of patients with systematic LN dissection (n = 112) and LN sampling (n = 35) were compared before and after propensity score-matching (PSM), as were the outcomes for patients with (pN+) and without (pN0) pathologic nodal metastasis. The prognostic impact of LN dissection was evaluated through multivariable analysis. The dissection group displayed significantly better overall survival (66.4% vs. 48.4%; P = 0.009) and recurrence-free survival (RFS) (63.5% vs. 37.6%;, P = 0.003) than the sampling group at 5 years. The rate of local recurrence was significantly lower in the dissection group than in the sampling group (11.6% vs. 42.9%; P < 0.001). After adjustment by multivariable analysis and PSM, LN dissection retained its independent favorable effects. The overall nodal upstaging rate was 37.6%, and the dissection group had a tendency of better RFS in both the pN0 (P = 0.05) and pN+ (P = 0.036) patients. Systematic LN dissection is associated with improved survival of patients who undergo surgery for cT1-2N0 SCLC. Further studies are warranted to verify the necessity of LN dissection in the surgery for SCLC.

Neurological Paraneoplastic Syndromes: the Early Diagnosis of Lung Cancer

Paraneoplastic syndromes of the nervous system are rare disorders, strongly linked with lung cancer. This report aims to explore the challenges in the diagnosis and treatment of a patient with early-stage small cell lung cancer and neurological manifestations as initial clinical symptoms.

Adjuvant therapy for lung neuroendocrine neoplasms.

Pulmonary neuroendocrine neoplasms (NENs) represent a minority of lung cancers and vary from slower growing pulmonary carcinoid (PC) tumors to aggressive small cell lung cancer (SCLC). While SCLC can account for up to 15% of lung cancer, PCs are uncommon and represent about 2% of lung cancers. Surgical resection is the standard of care for early-stage PCs and should also be considered in early stage large cell neuroendocrine carcinoma (LCNEC) and SCLC. Adjuvant treatment is generally accepted for aggressive LCNEC and SCLC, however, less well established for PCs. Guidelines admit a lack of trials to support a high-level recommendation for adjuvant therapy. This manuscript will discuss the role for adjuvant therapy in NENs and review the available literature.

Plasma Based Protein Signatures Associated with Small Cell Lung Cancer.

Simple SummarySmall-cell lung cancer (SCLC) typically presents at an advanced stage and is associated with high mortality. When diagnosed at an early stage with localized disease, long-term survival can, however, be achieved. In this study, we report a comprehensive proteomic profiling of case plasmas collected at the time of diagnosis or preceding diagnosis of SCLC with the objective of identifying blood-based markers associated with disease pathogenesis. Our study reveals the occurrence of circulating protein features centered on signatures of oncogenic MYC and YAP1 that were elevated in plasmas of cases at and before the time-of-diagnosis of SCLC. We further report several proteins, particularly inflammatory markers, that were identified as elevated in plasma several years prior to the diagnosis of SCLC and that may indicate increased risk of disease. In summary, our study identifies several novel circulating proteins associated with SCLC development that may offer utility for early detection.Small-cell-lung cancer (SCLC) is associated with overexpression of oncogenes including Myc family genes and YAP1 and inactivation of tumor suppressor genes. We performed in-depth proteomic profiling of plasmas collected from 15 individuals with newly diagnosed early stage SCLC and from 15 individuals before the diagnosis of SCLC and compared findings with plasma proteomic profiles of 30 matched controls to determine the occurrence of signatures that reflect disease pathogenesis. A total of 272 proteins were elevated (area under the receiver operating characteristic curve (AUC) ≥ 0.60) among newly diagnosed cases compared to matched controls of which 31 proteins were also elevated (AUC ≥ 0.60) in case plasmas collected within one year prior to diagnosis. Ingenuity Pathway analyses of SCLC-associated proteins revealed enrichment of signatures of oncogenic MYC and YAP1. Intersection of proteins elevated in case plasmas with proteomic profiles of conditioned medium from 17 SCLC cell lines yielded 52 overlapping proteins characterized by YAP1-associated signatures of cytoskeletal re-arrangement and epithelial-to-mesenchymal transition. Among samples collected more than one year prior to diagnosis there was a predominance of inflammatory markers. Our integrated analyses identified novel circulating protein features in early stage SCLC associated with oncogenic drivers.

Clinical utility of circulating genetically anormal cells in stage I small-cell lung cancer diagnosis.

e20581 Background: Small-cell lung cancer (SCLC) is an aggressive disease with rapid progression rate and high metastatic potential that accounts for 15% of all lung cancers. Early-stage SCLC is usually asymptomatic; therefore, the majority of the SCLC patients were diagnosed in advanced stages. Although some radiological features were reported with advanced stages SCLC by CT scans, diagnosis of early stages SCLC from CT images has remained challenging since the radiological features are not distinct. Neuron-specific enolase (NSE) is commonly used in the clinical setting as a biomarker for SCLC, but the sensitivity of the test did not meet the needs. Here, we proposed a study using Circulating Genetically Abnormal Cells (CAC) to improve the diagnosis rate of SCLC in the early stages. Methods: A series of 26 stage I SCLC patients were enrolled from October 2019 to October 2020. All participants were having newly discovered pulmonary nodules ≤ 30mm when enrolled in the study, with no previous cancer history. Before the histopathological examination, 10 ml of peripheral blood were collected from each patient for CAC test, by using a 4 color FISH–based assay to detect the genetic abnormalities of 3p22.1, 3q29, 10q22.3, and CEP10 in the chromosome. Besides, NSE was performed on all participants. Both tests were intended to evaluate the malignant risk of lung nodules. Results: Confirmed by histopathological exam, 69% patients were diagnosed with SCLC located on the central part of the lung, and 31% patients were found to have peripheral-type SCLC. 88% of the patients in the overall cohort were smokers or past smokers, and only 12% participants had a family history of cancer. For Immunohistochemistry tests, the numbers of participants with positive CD56, TTF-1, CgA, CK, Syn and Ki-67 ≥ 60% are 65%, 58%, 12%, 42%, 50% and 69%, respectively. For diagnostic performance, the sensitivity of CAC in the over-all cohort is 73.08% (95%CI: 52.21%-88.43%), compared with 50.00% (95%CI: 29.93%- 70.07%) for NSE. CAC has achieved 77.78% (95%CI: 52.36% - 93.59%) and 62.5% (95%CI：24.49% - 91.48%) sensitivity in the centra and peripheral group. For NSE, the sensitivity of these two groups were 55.56% (95%CI: 30.76% - 78.47%) and 37.5% (95%CI: 8.52% - 75.51%). Conclusions: Compared with NSE, CAC is more sensitive to stage I SCLC, especially for SCLC that arising in central locations. This non-invasive method can be a complementary diagnostic tool with LDCT for smokers aged ≥65 with newly discovered pulmonary nodules. Clinical trial information: ChiCTR1900026233.

Multiomic, plasma-only ctDNA NGS assay for minimal residual disease (MRD) detection in solid tumors.

3045 Background: Detection of minimal residual disease (MRD) by circulating tumor DNA (ctDNA) post-curative intent treatment is predictive of recurrence in many solid tumors. Due to biological challenges with low ctDNA shed in early-stage disease and potential to detect non-tumor derived alterations in plasma (e.g. CHIP), most ctDNA MRD assays are dependent on a priori knowledge of genomic alterations from tumor tissue to achieve high sensitivity and specificity. Tissue-dependent methods limit the clinical application of a MRD assay, especially in cancer types where tissue biopsy is challenging, neoadjuvant therapy (NAT) is standard of care, and/or rapid turnaround times are needed for clinical decision making. We previously validated an assay (Guardant Reveal) that combines somatic and epigenomic analysis to detect ctDNA from early-stage colorectal tumors without tumor tissue or peripheral blood cells. Here we describe the expansion of this assay to detect MRD across multiple tumor types. Methods: Cell-free DNA (cfDNA) fragments are extracted from patient plasma, partitioned based on methylation fraction, enriched using a panel to target informative genomic and epigenomic regions, barcoded, and pooled for sequencing. Methylation status is determined non-destructively and with minimal loss of molecules, allowing sensitive genomic and epigenomic analysis of the same cfDNA fragments. A single assay with a total panel size of 5.3 Mb was developed for MRD analysis in multiple cancer types, including CRC, Lung and Bladder. A “ctDNA detected” result is defined by the de novo identification of tumor-derived somatic variants and/or the observation of a tumor-specific methylation profile exceeding predefined thresholds. Results: The assay performance was tested using 163 pre-treatment clinical samples from patients with early-stage non small cell lung cancer (NSCLC) and bladder cancer and 133 self-declared healthy donors. Sensitivity for pre-treatment detection in NSCLC was 68.9% at 95% specificity (20/42 Stage I: 47.6%, 25/30 Stage II: 83.3%, 19/21 Stage III: 90.5%). Sensitivity for bladder cancer was 44.2% at 95% specificity (13/43 NMIBC: 30.2%, 18/27 MIBC: 66.7%). Additional development from larger cohorts and other tumor types is ongoing and data will be presented as available. Conclusions: Using cancer-specific genomic and epigenomic signals combined with learning-based classifiers, we developed a highly specific method for detecting the presence of ctDNA in early-stage NSCLC and bladder cancer patients from plasma without the need for tumor tissue but with comparable sensitivities to tissue-dependent approaches. A plasma-only MRD assay will allow for greater clinical impact by overcoming the challenges of tissue procurement, particularly following NAT, and enabling faster time to results.

Surgery in Small-Cell Lung Cancer

Simple SummarySmall-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers and is one of the most aggressive tumors, with poor prognosis and limited therapeutic options. This review summarizes the main results observed with surgery in SCLC, discussing the critical issues related to the use of this approach. Following two old randomized clinical trials showing no benefit with surgery, several prospective, retrospective, and population-based studies have demonstrated the feasibility of a multimodality approach including surgery in addition to chemotherapy and radiotherapy in patients with selected stage I SCLC. Currently, the International Guidelines recommend a surgical approach in selected stage I SCLC patients, after adequate staging within a multimodal approach and after a multidisciplinary evaluation.Small-cell lung cancer (SCLC) is one of the most aggressive tumors, with a rapid growth and early metastases. Approximately 5% of SCLC patients present with early-stage disease (T1,2 N0M0): these patients have a better prognosis, with a 5-year survival up to 50%. Two randomized phase III studies conducted in the 1960s and the 1980s reported negative results with surgery in SCLC patients with early-stage disease and, thereafter, surgery has been largely discouraged. Instead, several subsequent prospective studies have demonstrated the feasibility of a multimodality approach including surgery before or after chemotherapy and followed in most studies by thoracic radiotherapy, with a 5-year survival probability of 36–63% for patients with completely resected stage I SCLC. These results were substantially confirmed by retrospective studies and by large, population-based studies, conducted in the last 40 years, showing the benefit of surgery, particularly lobectomy, in selected patients with early-stage SCLC. On these bases, the International Guidelines recommend a surgical approach in selected stage I SCLC patients, after adequate staging: in these cases, lobectomy with mediastinal lymphadenectomy is considered the standard approach. In all cases, surgery can be offered only as part of a multimodal treatment, which includes chemotherapy with or without radiotherapy and after a proper multidisciplinary evaluation.

Protein Glycopatterns in Bronchoalveolar Lavage Fluid as Novel Potential Biomarkers for Diagnosis of Lung Cancer.

Lung cancer is one of the most prevalent and life-threatening neoplasias worldwide due to the deficiency of ideal diagnostic biomarkers. Although aberrant glycosylation has been observed in human serum and tissue, little is known about the alterations in bronchoalveolar lavage fluid (BALF) that are extremely associated with lung cancer. In this study, our aim was to systematically investigate and assess the alterations of protein glycopatterns in BALF and possibility as biomarkers for diagnosis of lung cancer. Here, lectin microarrays and blotting analysis were utilized to detect the differential expression of BALF glycoproteins from patients with 80 adenocarcinomas (ADC), 77 squamous carcinomas (SCC), 51 small cell lung cancer (SCLC), and 73 benign pulmonary diseases (BPD). These 281 specimens were then randomly divided into a training cohort and validation cohort for constructing and verifying the diagnostic models based on the glycopattern abundances. Moreover, an independent test was performed with 120 newly collected BALF samples enrolled in the double-blind cohort to further assess the clinical application potential of the diagnostic models. According to the results, there were 15 (e.g., PHA-E, EEL, and BPL) and 14 lectins (e.g., PTL-II, LCA, and SJA) that individually showed significant variations in different types and stages of lung cancer compared to BPD. Notably, the diagnostic models achieved better discriminate power in the validation cohort and exhibited high accuracies of 0.917, 0.864, 0.712, 0.671, and 0.781 in the double-blind cohort for the diagnosis of lung cancer, early stage lung cancer, ADC, SCC, and SCLC, respectively. Taken together, the present study revealed that the abnormally altered protein glycopatterns in BALF are expected to be novel potential biomarkers for the identification and early diagnosis of lung cancer, which will contribute to explain the mechanism of the development of lung cancer from the perspective of glycobiology.

Prognostic significance of OX40+ lymphocytes in tumor stroma of surgically resected small-cell lung cancer

ABSTRACT OX40 (CD134) is a co-stimulatory molecule mostly expressed on activated T lymphocytes. Previous reports have shown that OX40 can be an immuno-oncology target and a clinical biomarker for cancers of various organs. In this study, we collected formalin-fixed paraffin-embedded tumor samples from 124 patients with small-cell lung cancer (SCLC) who had undergone surgery. We analyzed the expression profiles of OX40 and other relevant molecules, such as CD4, CD8, and Foxp3, in tumor stroma and cancer nest using immunohistochemistry and investigated their association with survival. High infiltration of OX40+ lymphocytes (OX40high) in tumor stroma was positively associated with relapse-free survival (RFS) and overall survival (OS) compared with low infiltration of OX40+ lymphocytes (OX40low) (RFS, median, 26.0 months [95% confidence interval (CI), not reached (NR)–NR] vs 13.2 months [9.1–17.2], p = .024; OS, NR [95% CI, NR–NR] vs 29.8 months [21.3–38.2], p = .049). Multivariate analysis revealed that OX40high in tumor stroma was an independent indicator of prolonged RFS. Moreover, RFS of patients with OX40high/CD4high in tumor stroma was significantly longer than that of patients with OX40low/CD4low. The RFS of patients with tumor stroma with OX40high/CD8high was significantly longer than that of patients with tumor stroma with OX40low/CD8high, OX40high/CD8low, or OX40low/CD8low. These findings suggest that OX40+ lymphocytes in tumor stroma play a complementary role in regulating the relapse of early-stage SCLC. Reinforcing immunity by coordinating the recruitment of OX40+ lymphocytes with CD4+ and CD8+ T cells in tumor stroma may constitute a potential immunotherapeutic strategy for patients with SCLC.