Stage Non-small Cell Lung Cancer Research Articles

Recent Advancements in Minimally Invasive Surgery for Early Stage Non-Small Cell Lung Cancer: A Narrative Review.

Introduction: Lung cancer remains a global health concern, with non-small cell lung cancer (NSCLC) comprising the majority of cases. Early detection of lung cancer has led to an increased number of cases identified in the earlier stages of NSCLC. This required the revaluation of the NSCLC treatment approaches for early stage NSCLC. Methods: We conducted a comprehensive search using multiple databases to identify relevant studies on treatment modalities for early stage NSCLC. Inclusion criteria prioritized, but were not limited to, clinical trials and meta-analyses on surgical approaches to early stage NSCLC conducted from 2021 onwards. Discussion: Minimally invasive approaches, such as VATS and RATS, along with lung resection techniques, including sublobar resection, have emerged as treatments for early stage NSCLC. Ground-glass opacities (GGOs) have shown prognostic significance, especially when analyzing the consolidation/tumor ratio (CTR). There have also been updates on managing GGOs, including the non-surgical approaches, the extent of lung resection indicated, and the level of lymphadenectomy required. Conclusions: The management of early stage NSCLC requires a further assessment of treatment strategies. This includes understanding the required extent of surgical resection, interpreting the significance of GGOs (specifically GGOs with a high CTR), and evaluating the efficacy of alternative therapies. Customized treatment involving surgical and non-surgical interventions is essential for advancing patient care.

Blood based kinase activity profiling to predict response to immune checkpoint inhibitors in patients with advanced stage non-small cell lung cancer: The IOpener study.

e20576 Background: Treatment with immune checkpoint inhibitors (ICI) has become part of the standard of care for patients with advanced stage non-small cell lung cancer (NSCLC). Unfortunately, its success is limited to a subset of treated patients, while ICI treatment is associated with immune-related adverse events. The predictive value of kinase activity profiling of peripheral blood mononuclear cells (PBMCs) was previously shown in a discovery study (Hurkmans et al., JITC 2020). The aim of the current study was to perform a prospective and blinded validation of the predictive value of kinase activity profiles of PBMCs for response to ICI treatment in patients with NSCLC in a standardized setting. Preliminary results for this study were presented before (De Joode et al. 2022), here we present results for a significantly extended validation cohort with a follow-up of at least 1 year. Methods: PBMCs from patients with advanced stage NSCLC included in this observational multicenter study were collected prior to ICI treatment. Tyrosine kinase activity of PBMCs was profiled using a micro-array with 144 different peptide-substrates (Pamchip). Classification analysis was performed to discriminate between patients with or without progressive disease (RECIST v1.1) within 24 weeks after start of treatment. Only patients treated with first-line pembrolizumab ± chemotherapy were included. Results: A predictive model was first established based on kinase activity profiles, determined in a calibration cohort (N = 61) and subsequently applied to an independent validation cohort (N = 136). The predictive accuracy of the model in the validation cohort was 62% (CI95 = 53-70%). Interestingly, the accuracy improved when the model was combined with PD-L1 expression: for patients with a PD-L1 score < 50%, the accuracy for predicting progressive disease at 24 weeks was 68% (CI95 = 57-78%). Here, significant lower progression free survival (PFS) rates were observed for patients for whom progression was predicted compared to those for whom no progression was predicted (p = 0.0003, hazard ratio = 2.6, CI95 = 1.6-4.3).The 1-year PFS for patients with predicted progression was only 13% (CI95 = 5-31%) which implies a NPV of 87%. PFS rates were also lower for patients with predicted progression in the subgroups with PD-L1 score < 1% (p = 0.03, hazard ratio = 2.2, CI95 = 1.1-4.3) and PD-L1 score 1-49% (p = 0.002, hazard ratio = 5.0, CI95 = 1.8-14). The predictive kinase activity signature appears to be T-cell related, which will be further investigated to improve understanding of the underlying biology. Conclusions: In this prospective validation study the predictive value of kinase activity profiling of PBMCs for response to first-line ICI therapy of patients with advanced NSCLC was confirmed. The final aim is to apply the kinome analysis in clinical practice.

CtDNA-Lung-DETECT: ctDNA outcomes for resected early stage non-small cell lung cancers at 12 months.

8018 Background: ctDNA Lung DETECT is a multicentre investigator initiated prospective study at 3 thoracic surgery centres in the Greater Toronto Area assessing ctDNA detection and association with recurrence free survival (RFS) in patients with early stage non-small cell lung cancer (NSCLC) (NCT05254782). Patients who have ctDNA detected perioperatively are offered ctDNA Lung RCT, a randomized trial investigating the benefit of adjuvant chemo-immunotherapy in patients where the standard of care is observation alone after surgery (NCT04966663). Herein, we report on ctDNA outcomes at 12 months for patients with resected early stage NSCLC. Methods: Patients with stage I (T1-2N0) or multifocal T3-4 < 4cm N0 NSCLC planned for resection at University Health Network consented to plasma ctDNA assessment before and after surgery, and at 12 months post-operatively or relapse using the tumor-informed RaDaR® assay, which detects up to 48 tumor-specific variants in plasma with a Limit of Detection (LoD₉₅) of 0.0011% variant allele fraction. Results: From July 2021 to January 2024, 178 patients were enrolled; 115 had sufficient tissue for assessment. Of these, 68/72 patients have 12 month post-resection ctDNA results available (3 withdrew, 1 sample failed). ctDNA was detected pre-operatively in 18 patients; 99% (71/72) had ctDNA clearance post-operatively, and 93% (62/67) remained ctDNA negative at 12 months. Median follow up time was 18.7 months (range 12.0– 28.3); 8/72 (11%) patients (5 stage I, 3 stage II) experienced lung cancer recurrence. Median time to recurrence was 13.9 months (range 6.2- 24.9). Of these, 3 had ctDNA detected on their preoperative and 12-month or recurrence sample, 1 had ctDNA detected at 12 months prior to relapse, 1 had ctDNA detected at 12 months and recurred around the same time, 2 had negative ctDNA samples and 1 missed sample collection preoperatively. The recurrence rate was 16.7% (3/18, 95% exact CI 3.6-41.4%) in patients with ctDNA detected pre-operatively vs. 7.5% (4/53, CI 2.1-18.2%) in those without. New lung cancers were diagnosed in 5/72 (median time to new primary 15.3 months, range 4.9-14.2) and 2/72 patients had new cancers diagnosed (ovarian/liposarcoma). For those with new lung primaries, 1 had ctDNA detected preoperatively but none had ctDNA detected at time of new primary diagnosis. Of 4 patients who have died, 2 were from recurrent lung cancer and 2 from new primaries (lung/sarcoma). Conclusions: This study represents one of the largest prospective cohorts of ctDNA kinetics in patients with resected lung cancer. Of patients with at least 12 months follow up, 8/72 experienced a lung cancer recurrence with a higher rate in those with pre-operative ctDNA detected (16.7% vs 7.5%). Pre-operative ctDNA detection may help identify patients with resected stage I NSCLC that could benefit from treatment intensification, currently under study in ctDNA Lung RCT (NCT04966663). Clinical trial information: NCT05254782 .

Assessing quality of care in early stage resected stage non-small cell lung cancer (NSCLC): An evaluation of epidermal growth factor receptor (EGFR) testing and adjuvant (adj) therapy (tx).

8072 Background: In December 2020, the FDA approved the use of osimertinib in the treatment of stage IB-IIIA (ES) NSCLC patients (pts) with EGFR exon 19 deletions and exon 21 L858R mutations (EGRFm) following tumor resection. Using real-world data, we sought to understand EGFR testing rates among ES pts and whether pts received osimertinib in the adjuvant setting based on EGFRm. Methods: We used the Integra Connect PrecisionQ real-world de-identified database of over 3 million cancer pts across 500 sites of care. From this database, we identified Stage IB – IIIA pts evaluated via medical chart curation who underwent lung cancer resection (R) between 12/1/2021 to 7/31/2023 (N = 803). We assessed adj treatment by stage, EGFR testing rates overall and by stage, EGFR testing rates by adjuvant treatment and non-adj treatment pts, timing of EGFR testing, and treatment rates with an EGFR TKI among EGFRm pts. Descriptive analyses were used and proportions were compared using a chi-squared test. Results: The mean age of the 803 ES R pts in the sample was 69 (SD = 8.3), 53.3% of the pts were female, , and 12% never smoked. We found adj treatment rates among ES R pts to be 56%; these were highest among stage IIIA (N = 245) pts at 70.2%, compared to stage IIB (N = 241) at 68.8%, stage IIA (N = 69) at 53.6% and stage IB (N = 240) at 31.7% (p < 0.001). Among ES R pts, 70% (N = 563) were tested for EGFR; this rate was 78% (N = 455) among ES pts who were R and received adj treatment, compared to 59% (N = 348) among ES R pts who did not receive adj treatment (p < 0.001). EGFR testing rates were highest among stage IIB pts at 76%, compared to stage IIIA pts at 73%, stage IIA pts at 72%, and stage IB pts at 60% (p < .001). Among ES pts who were R and tested for EGFR (N = 563), 14% were tested before surgery, 38% were tested after surgery but before adj treatment, and 48% were tested after initiating adjuvant therapy. EGFRm was found in 10.4% of EGFR tested pts. Among EGFRm ES R pts (N = 59), 54% were treated with an EGFR TKI. EGFRm ES R pts treated with an adj EGFR TKI were highest among stage IIB pts (N = 14) at 93%, compared to stage IIA pts (N = 5) at 60%, stage IB pts (N = 20) at 45%, and stage IIIA pts (N = 20) at 35% (p < 0.01). However, only 69% (N = 41) of EGFRm ES R pts received adj treatment (either chemotherapy or EGFR TKI) and among those pts, 78% (N = 32) received an EGFR TKI. Conclusions: Based on our findings using real-world data for EGFR testing and adjuvant osimertinib use, and in light of the published results from the ADAURA trial which showed disease free survival benefit (HR 0.2) and overall survival benefit (HR 0.49) of adjuvant osimertinib in ES NSCLC, we have identified an opportunity to improve patient outcomes following resection of ES NSCLC by increasing EGFR testing and encouraging treatment with EGFR TKI in exon 19 deletion or exon 21 L858R mutated pts.

Development of a serum miRNA panel for detection of early stage non-small cell lung cancer.

3058 Background: Lung cancer remains the leading cause of cancer deaths, largely due to late-stage diagnosis. Early detection significantly improves survival rates, but current methods like chest X-rays and low-dose CT (LDCT) scans face limitations in sensitivity and specificity. MicroRNAs (miRNAs) are small non-coding RNAs whose dysregulation has been widely observed in different stages of cancer. Evidence suggests that circulating miRNAs could be promising biomarkers for early diagnosis of lung cancer. In this study, we developed and validated a 15-miRNA panel as a blood-based minimally invasive test for early detection of non-small cell lung cancer (NSCLC) using the proprietary multiplex quantitative real-time PCR (qPCR). Methods: 332 serum samples (182 Stage I&II NSCLC, 150 healthy controls) were divided into training (n=266) and validation (n=66) cohorts. Differentially expressed serum miRNAs were screened with Miseq sequencing followed by qPCR validation. The multi-miR panel was developed with a logistic regression model and validated using an independent cohort. Receiver operating characteristic curves were constructed to evaluate the diagnostic accuracy of the panel. A stem-loop quadruplex qPCR assay was invented for concurrent detection of 4 miRs in a single reaction. Results: 15 differentially expressed miRNAs were selected for logistic model construction based on their Ct values (Ct<35) and high diagnostic accuracy of stage I&II NSCLC (AUC>0.7). The 15-miRNA panel model achieved 88.4% sensitivity, 81.7% specificity (AUC = 0.912) in the training cohort (Table), and was validated with 94.4% sensitivity, 73.3% specificity (AUC = 0.892) in the validation cohort. Quantification of 15 miRs and 1 internal control was performed in 4 reactions tubes via quadruplex qPCR assay. Conclusions: The serum 15-miR panel developed and validated in this retrospective study exhibited robust performance for detection of early stage NSCLC. The panel demonstrates potential diagnostic applications and clinical utility to be implemented together with LDCT in current lung cancer screening program as a blood biomarker to reduce false positive results. In addition, the proposed stem-loop quadruplex qPCR system offers an efficient and promising approach for miRNA profiling in future clinical applications. [Table: see text]

Ultrasensitive circulating tumor DNA (ctDNA) minimal residual disease (MRD) detection in early stage non-small cell lung cancer (NSCLC).

8078 Background: Translation of ctDNA MRD in NSCLC has been hampered by suboptimal sensitivity of 1st-generation assays. Here, we explore how improvements in analytical sensitivity can drive improved clinical sensitivity for MRD after surgery in NSCLC. Methods: To understand MRD kinetics, we analyzed longitudinal ctDNA in early stage NSCLC using data from the TRACERx study. Patient-specific mathematical models were generated to predict MRD levels at the postsurgical landmark and estimate the impact of an assay’s 95% limit of detection (LOD95) on clinical sensitivity. To test these predictions, tumor-informed ctDNA testing was performed using an SNV-based assay (CAPP-Seq) and a phased variant-based assay (PhasED-Seq, Foresight Diagnostics) on 269 samples from 46 patients. We also assessed MRD performance for predicting 1) patient outcomes at the landmark timepoint and 2) the effect of adjuvant treatment. Results: ctDNA MRD dynamics were assessed in 23 patients from TRACERx with ≥3 consecutive samples with detectable ctDNA without intervening therapy. MRD kinetics strongly correlated with exponential growth, with a median ctDNA doubling time of 51 days. Extrapolating MRD levels to the postsurgical landmark predicted that improving MRD assay LOD95 from 100 ppm (0.01%) to 1 ppm could increase clinical sensitivity by 2.1-fold. We then evaluated 46 NSCLC cases using two assays. The median LOD95 was 1 ppm for PhasED-Seq and 84 ppm for CAPP-Seq. Twelve cases were MRD+ by PhasED-Seq, all of whom recurred (100%), with MRD levels as low as 0.19 ppm. In contrast, 6 cases were MRD+ by the SNV-based approach, of whom 5 (83%) recurred. Accordingly, PhasED-Seq had a higher clinical sensitivity than the SNV-based method (12/18 [67%] vs. 5/18 [28%], P = 0.022). Kaplan Meier analysis for freedom from recurrence revealed significantly worse outcomes for patients with detectable MRD regardless of the method used; however, outcomes were better stratified using PhasED-Seq (HR 3.1 vs. 11.4). Patients who were MRD- after surgery by both assays had similar outcomes regardless of adjuvant therapy (chemotherapy and/or radiotherapy). However, MRD+ patients by PhasED-Seq receiving adjuvant therapy had significantly better outcomes than those who did not (HR 8.2, P = 0.00035). A similar benefit for adjuvant therapy was not observed with the SNV-based assay. Using PhasED-Seq, 80% (4/5) of MRD+ patients receiving adjuvant therapy cleared their MRD, compared to 0% (0/3) without adjuvant treatment. Conclusions: Ultrasensitive ctDNA detection improved the clinical sensitivity of MRD at key landmarks in early stage NSCLC. PhasED-Seq detected MRD at levels below 1 ppm and was associated with significantly better outcomes, revealing potential benefits of adjuvant therapy in MRD+ patients. This suggests that ultrasensitive MRD detection is promising for use in risk-adapted trials in early stage NSCLC.

Ensuring precision medicine for veterans with lung cancer: A randomized clinical trial.

1501 Background: National guidelines recommend molecular testing for patients with non-small cell lung cancer, yet this is not routinely completed in practice. In prior work, we identified barriers to testing in the Veterans Affairs. First, physicians are unaware if and when testing has occurred. Second, patients are unaware of testing and the implications on treatment and clinical outcomes. In response, in collaboration with a Veteran and Caregiver Advisory Board, we created a multilevel intervention led by a peer volunteer who: 1) provides tailored education of molecular testing for 1 month for Veterans newly diagnosed with lung cancer and, 2) alerts clinicians via secure messaging if tumor samples have not been tested. We conducted this randomized clinical trial to assess whether the intervention improves patient knowledge of molecular testing and patient activation and increases receipt of molecular genomic testing compared with usual care. Methods: All veterans >18 years old with a new diagnosis of any stage non-small cell lung cancer were eligible. Exclusions included inability to consent. All participants completed baseline assessments at randomization and at 1-month follow-up comprised of a 3-question validated precision medicine knowledge questionnaire and a 13-question validated patient activation measure. Genomic testing was assessed by chart review at 6-months followup. We used regression models to assess differences in mean knowledge and activation scores over time between groups and compared rates of genomic testing. Results: 75 Veterans were screened with 46 eligible. All 46 consented to participate, with 23 in each group. All were male (100%), had mean age of 76.3+/-5.54 years; 31 (67.4%) were Latinx; 2 (4.4%) Asian; 11 (23.9%) Black; 1 (2.2%) Native Hawaiian; 32 (69.6%) White; 32 (69.6%) had Stage 4 disease. At 1 month follow-up mean knowledge scores increased over time in the intervention group and remained stable in the control group (mean score 2.30 +/- 0.97 versus 1.16 +/- 1.15, p=0.014). At 1-month follow-up, patient activation increased for the intervention group more than the control group (46.7 +/- 11.3 versus 37.6 +/- 9.26, p=0.002). There were no significant differences in tumor testing between groups (intervention: 95.6% versus control: 86.9%, p=0.62). Conclusions: A volunteer led effort improved patient education regarding precision medicine and patient activation among Veterans as compared with usual care alone. Interventions that include volunteers and other support can enhance care and clinical outcomes among veterans with lung cancer. Clinical trial information: NCT05795959 .

Temporal trends in clinical and pathologic stage discordance in resectable non-small cell lung cancer.

e20068 Background: Neoadjuvant chemoimmunotherapy is increasingly utilized in patients with resectable non-small cell lung cancer (NSCLC), with treatment decisions based on clinical (cTNM) rather than pathologic (pTNM) stage. Therefore, the accuracy of cTNM needs to be better defined. We evaluated the correlation between cTNM and pTNM stage in NSCLC using the National Cancer Database (NCDB), which captures approximately 72% of all patients with cancer cases in the United States. Methods: The NCDB was queried for patients with surgically resected NSCLC diagnosed between 2004 and 2020 with complete clinical (c) and pathological (p) staging information on tumor (T) and lymph nodes (N). Patients with clinical stage IV, cN3, no lymph node examined during surgery, and those who received neoadjuvant therapy were excluded. The discrepancies of cTNM and pTNM were evaluated for all patients, by histological subtype, and year of diagnosis. The histology was subdivided into lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LSCC) and others. Upstaging and downstaging were defined as discrepancies between cTNM and pTNM stages. Pearson’s correlation coefficient (r) was used to assess the correlation between year of surgery and changes in upstaging and downstaging. Results: Among the 325,794 eligible patients, most had cT1 (63.7%), cN0 (88.9%). The median number of lymph nodes examined was 9 with an interquartile range from 5 to 15. The median number of regional lymph nodes examined in patients with cN1 increased from 9 in 2004 to 14 in 2020 (r = 0.89, p < 0.0001). Tumor upstaging was seen in 63,241 (19.4%) patients and downstaging in 14,237 (4.4%), whereas N upstaging was seen in 42,406 (13%) patients and downstaging in 9,552 (2.9%). Upstage in cN0 and cN1 was 13.4% and 15.4% respectively, and downstage in cN1 and cN2 was 21% and 36.1% respectively. The percentage of unsuspected pN2 was 5.3% for the entire cohort, 4.7% in patients with cN0 and 15.2% in patients with cN1. Over time, there was a small variation in the cN0 to pN2, ranging from 3.8% to 5.2% (r = 0.5478, p = 0.02). However, cN1 to pN2 upstaging continuously increased from 8.5% to 20% (r = 0.98, p < 0.001). The percentage of patients with N upstage increased from 12.3% in 2004 to 13.8% in 2020 (r = 0.8892, p < 0.0001). The N downstage decreased from 4.1% in 2004 to 1.9% in 2020 (r = -0.95, p < 0.0001). N upstage was seen in 13.6% of LUAD and 12.4% of LSCC, whereas N downstage was seen in 2.2% of LUAD and 4.6% of LSCC. Conclusions: Although there is a good correlation between cTNM and pTNM stages, a discrepancy between cT and pT stages occurs in 23.8%, and a discrepancy between cN and pN stages occurs in 15.9% of cases. The percentage of unsuspected pN2 increase may be related to the higher number of lymph nodes examined. Clinical decisions on the treatment of resectable NSCLC, especially with the use of neoadjuvant therapy, should consider the discordances between cTNM and pTNM stages.

Prospective “common arm” comparison of US SWOG S0424 and Japanese JME studies in early-stage non-small cell lung cancer (NSCLC): Survival differences in the context of race, gender and smoking.

8036 Background: In NSCLC, overall frequencies and subtype distribution of EGFR and KRAS mutations differ significantly between Japanese and US patients. In many NSCLC clinical trials, Japanese patient outcomes appear superior to those in western populations. Since 2009, SWOG and Japanese investigators have used the “Common Arm” analytic method to interpret globally-conducted lung cancer clinical trials, providing a mechanism for direct patient-level comparisons in matching trials performed in the US and Japan. S0424 and the Japanese Molecular Epidemiology Study (JME) are large prospective molecular epidemiology studies conducted by SWOG and Japanese investigators and prospectively planned for “Common Arm” analysis. We investigated the effects of mutation distribution on overall survival in early stage NSCLC using data from JME and S0424. Methods: Both studies were designed to accrue representative proportions of ever-smokers (ES) versus never-smokers (NS) in male and female cohorts. Accrual to S0424 was completed in 2011 with 981 pts enrolled (Cheng et al JNCI 2018); JME was completed in 2012 with 957 pts (Kawaguchi et al JCO 2016). A comprehensive questionnaire was used to capture lifestyle, carcinogenic exposures, demographic and clinical data. Five years of follow-up was completed for each study. The association between baseline characteristics and mutation types were analyzed using multivariate logistic regression. The product-limit method was used to estimate overall survival and Cox regression models were fit to estimate hazard ratios. p-values were two-sided and p-values < 0.05 were considered significant. Results: Evaluable pts: 876 for JME; 957 for S0424. Demographic distribution: S0424: 87% Caucasian, 5% Asian, 4% Black; JME: 100% Japanese. As expected, multivariate logistic models adjusting for age, smoking status, gender and BMI showed JME were more likely to have EGFR mutations (p < 0.0001) and less likely to have KRAS mutations (p = 0.02). EGFR mutations were associated with never-smoking (p < 0.0001) and female sex (p < 0.0001); KRAS was associated with smoking (p < 0.0001). Adjusting for age, smoking status and gender, overall survival was greater in JME patients (p < 0.0001,HR = 0.49 (95% CI: 0.40-0.60)). In the subset of pts without an EGFR mutation, survival still favored the JME cohort (p < 0.001, HR = 0.68 (0.53-0.86). Conclusions: Patient level comparison of US (SWOG) and Japanese (JME) patients with early stage NSCLC demonstrated longer survival in Japanese patients even after adjusting for EGFR mutation frequency. Identification of factors that contribute to this finding are under investigation. Female sex remained a risk factor for EGFR mutation-driven disease in both populations. This analysis forms the basis for applying this population-related model in other clinical settings.

Cardiac substructure radiation dose study of conventional radiotherapy for stage N2-3 non-small cell lung cancer.

e20071 Background: There has been widespread reporting on predictive dose parameters for cardiac substructures in radiotherapy for non-small cell lung cancer (NSCLC). However, most advanced NSCLC patients are staged as N2-3, and there is a lack of research on the dose distribution, dose contribution and prognosis of the heart in conventional radiotherapy for N2-3 stage NSCLC. Methods: Retrospective analysis of 274 patients of stage N2-3 NSCLC treated with radiotherapy (RT) of prescription dose from 60Gy to 70Gy. Experienced radiation oncologists delineated the cardiac substructures. All patients were categorized according to different lymph node irradiation and tumor spatial locations. Spearman and linear regression were used for variation of dose-volume parameters, as well as the impact of different primary tumor locations and irradiated lymph nodes on the parameters of the entire heart and substructures. Receiver operating characteristic (ROC) curves, Kaplan-Meier, and Cox regression were performed on the influencing factors of adverse cardiac events after radiotherapy and prognosis analysis. Results: There are significant differences in the dose-volume parameters of the whole heart and its substructures. Mean heart doses (MHD),and the mean doses (Dmean) for the left atrium, right atrium, right ventricle, left ventricle and the left anterior descending coronary artery (LAD) were 15.7Gy (range 0.2-30.0Gy), 19.7Gy (range 0.3-55.0Gy), 9.7Gy (range 0.3-59.8Gy), 7.9Gy (range 0.1-48.2Gy), 6.4Gy (range 0.1-52.6Gy) and 5.2Gy (range 0.1-45.0Gy), respectively. The left atrium Dmean has the most significant impact on MHD compared to other substructures (B = 0.418, P < 0.05). Dose-volume parameters of the whole heart and the left atrium were positively correlated with the irradiation of the 7th lymph node region (P < 0.05). MHD and left atrium Dmean for tumors located in the lower region were significantly higher than those in the upper region (P < 0.001). Patients with LAD V30 ≥ 26.9% had a significantly higher risk of mortality compared to those with LAD V30 < 26.9% (P = 0.003, HR = 2.883, 95% CI = 1.436-5.788). Conclusions: With the dose distribution differences among the whole heart and its substructures. We observed the base of the heart received the highest dose, the dose to the left atrium is particularly required attention. The irradiation of different lymph nodes and different primary lesions has an impact on the dose variations of different cardiac structures. LAD V30 is an independent influencing factor of overall survival (OS) for N2-3 stage NSCLC. This study provides considerable information for the dose optimization of cardiac substructure in radiotherapy planning for N2-3 stage NSCLC.

Assessing the value of repeat next generation testing in patients with non-small cell lung cancer: A retrospective review.

3071 Background: Analyzing a tumor’s molecular profile in non-small cell lung cancer (NSCLC) by next generation sequencing (NGS) has been essential in the advancement of precision medicine and has led to development of several targeted therapeutic agents. While their use significantly improves patients’ outcomes, patients will inevitably develop progression of disease. Tumor sequencing at the time of progression, whether tissue or liquid biopsy, is important to identify the mechanism of resistance. We sought to investigate which patients benefit from repeat NGS testing which ultimately allowed for changes in their therapeutic management based on its updated molecular profile. Methods: We performed a single institution retrospective study of patients with NSCLC between 2014-2023 who have undergone two or more NGS sequencing. Testing was performed through Foundation One tissue CDx or liquid CDx. Data obtained through chart review included NSCLC stage, NGS dates and results, and treatments received. We evaluated clinically meaningful results from repeat testing if patients were continued on their targeted therapy, were switched to or received additional targeted therapy, detected a target when prior tests were negative, had a change in their systemic therapy, or confirmed recurrence or a second primary. Results: A total of 277 subjects with NSCLC were identified to have had more than one NGS sequencing. The average number of NGS obtained was 2.90. The average number of liquid NGS was 2.15 and tissue based NGS was 0.75. Out of the 277 patients, repeat testing was clinically meaningful in 134 (48%) patients. Of the 134 patients, 67 (50%) harbored EGFR, 16 (11.9%) ALK, 9 (6.7%) KRAS, 6 (4.5%) ROS1, 6 (4.5%) MET exon 14 skipping, 3 (2.2%) ERBB2, 1 (0.7%) BRAF, and 1 (0.7%) RET as their primary driver alteration upon initial testing. 25 patients (18.7%) had other alterations or no alterations. NGS was repeated for early stage localized recurrence in 8 patients (6%), stage I-III who developed new metastasis in 18 patients (13.4%), and recurrent metastasis in 108 patients (80.6%). Of the patients who clinically benefited from repeat testing, 77 patients (57.5%) were continued or resumed on their targeted therapy, 19 (14.2%) were switched to or received additional targeted therapy, 12 (9%) detected a target when prior tests were negative, and 3 (2.2%) had a change in their chemotherapy or immunotherapy. In 23 patients (17.1%), repeat NGS either confirmed recurrence (n=14) or second primary (n=9). Conclusions: Repeat NGS testing in NSCLC can be clinically meaningful to guide management, such as in detecting a target when prior tests were negative, allowing for switch in, continuation of or addition of targeted therapy, or providing confirmation of a recurrence or a second primary. Further research is warranted in this field to evaluate if repeat NGS can ultimately improve clinical outcomes in these patients.

Multiplex analysis of the immune environment before and after neoadjuvant durvalumab as a prognostic factor in resectable non-small cell lung cancer (NSCLC) in the IFCT-1601 IONESCO phase 2 trial.

8022 Background: Immune checkpoint inhibitors (ICI) are currently included in the peri-operative standard of care for NSCLC with the objective of a curative strategy. In early stages of NSCLC, biomarkers predicting ICI efficacy should be more stringent than PD-L1 tumoral expression in order to improve the benefit-toxicity ratio. We deeply analyzed the tumor microenvironment of patients included in the IONESCO multicenter phase 2 trial (stage IB > 4cm–IIIA, non N2 resectable NSCLC). Diagnostic biopsies and surgical resection specimen after 3 cycles of Durvalumab were available. We previously showed that the % of residual viable tumor cells (RVT) was associated with disease free survival (DFS) and overall survival (OS). PD-L1 tumor positive score was not correlated to RVT nor survival. Methods: 46 patients were included in the IONESCO trial. Among them, diagnostic biopsy (n = 32), surgical resection specimen post durvalumab (n = 39) and paired tumor samples (n = 31) were analyzed. Immune environment was assessed using 7 quantitative 7-plex immunofluorescence panels generating 349 different cellular phenotypes in 3 different compartments (whole tumor, intra cytokeratin and stroma), focusing on T and B lymphocytes, macrophages, immune checkpoint, NK cells, apoptosis, innate and adaptive immunity, dendritic cells. Densities of cells were quantified using Fluorescent Multiplex immunohistochemistry performed on Leica Bond RX, using OpalTM technology. A fisher's exact test or chi2 test was used for demographics variables and RVT. HRs and 95% CIs were estimated using a Cox model. NCT number: NCT03030131. Results: With median follow-up of 4.5 years, 16/31 patients had a disease recurrence. Histology, sex, stage and survival were significantly associated with intra-tumor densities of CD3, CD8, PD1, TIM3, and CD163 cells in the diagnostic biopsy, and with the delta of CD3, FoxP3, CD4, CD163PD1, TIM3, PDL1 on immune cells and TIM3PDL1 cells, between biopsy and surgical specimen. DFS was significantly associated with high density of CD8+TIM3+ in biopsies (HR = 0.25 [0.09-0.71], p = 0.0092) and with the high density of CD20+ cells in surgical specimen (HR = 0.36 [0.13-0.97], p = 0.04). The RVT was significantly associated with CK+Caspase3- cells and CK+PDL1+ cells in the surgical specimen. No biomarker was associated with OS. Conclusions: Multiparameter analysis of the immune NSCLC environment of patients treated with neoadjuvant anti-PDL1 allows identification of markers associated with clinical, pathological parameters and DFS. Our findings highlight the substantial impact of high CD8+TIM3+ cell density pre-durvalumab and of high CD20+ cell density post-durvalumab on DFS. These findings deserve to be assessed in patients treated with neoadjuvant combined immunotherapy chemotherapy. Clinical trial information: NCT03030131 .

Lower dose radiotherapy did not alter cardiac function and was not pro-arrhythmic: results of the small prospective HALO trial

Abstract Background Stereotactic arrhythmia radiotherapy (STAR) is a highly promising bail-out treatment for patients with therapy-refractory ventricular tachycardia (VT). Despite precise, noninvasive targeting of the pro-arrhythmic area, surrounding healthy cardiac tissue inadvertently receives low-dose radiation. There is a historical notion that collateral cardiac damage from radiation of extra-cardiac structures can cause heart failure and arrhythmias. In the HALO trial, where non-small cell lung cancer (NSCLC) patients treated with stereotactic ablative radiotherapy (SABR) received relatively low-dose radiotherapy to the heart, detailed cardiac safety after radiotherapy was therefore evaluated. Objective The aim of this study was to prospectively evaluate cardiac function after collateral radiotherapy on the heart in patients with NSCLC treated with SABR. Methods The HALO trial was a prospective observational trial evaluating cardiac adverse effects in patients treated with SABR for early stage NSCLC. Patients with a tumour within 3cm of the pericardium were eligible to participate. The mean radiotherapy dose per segment was calculated by semi-automated angulation and segmentation using an in-house developed tool. The heart was segmented according to the AHA 17-segment model. Patients underwent cardiac magnetic resonance imaging (CMR) pre-treatment, 3 and 12 months after treatment. CMR strain-analysis was conducted by two independent observers using cvi42 software. Longitudinal, radial and circumferential strain were measured both globally and segmentally and evaluated for dose-dependent effects. Results Ten patients were included in this study. Two patients dropped out before first follow-up and were not included in this analysis. Median age was 66 years (range 58-81) and four were male (50%). Median distance between the tumour and pericardium was 0.46cm (range 0.00-2.80). Patients were treated with 8 fractions of 7.0-7.5 Gy (n=6), 5 fractions of 11.0 Gy (n=1) or 3 fractions of 18.0 Gy (n=1). Median global cardiac radiotherapy dose was 6.7 Gy (range 0.1-17.9). Pre-treatment, median left ventricular ejection fraction as measured on CMR was 65% (range 40-75), global longitudinal strain was -15% (-20 - -9), global circumferential strain was -17% (-26 - -9) and global radial strain was 28% (11-60). These did not significantly change comparing 3 months and 12 months after treatment with pre-treatment. As can be appreciated from Table 1, there were no dose-dependent effects on segmental longitudinal, radial and circumferential strain both 3 months or 12 months after SABR. There were no ventricular arrhythmias observed during follow-up. Conclusion In this small study, collateral radiotherapy in patients with NSCLC treated with SABR did not significantly alter cardiac function as measured on CMR, and no relevant pro-arrhythmic effects were observed during short term follow-up. Extending the research into a larger dataset is warranted.

Risk factors of immune checkpoint inhibitor-related pneumonitis after neoadjuvant immunochemotherapy for resectable NSCLC

BackgroundThe incidence of checkpoint inhibitor-associated pneumonitis (CIP) in advanced non-small cell lung cancer (NSCLC) has been substantiated through large-scale clinical trials or real-world studies. However, reports on CIP incidence within the context of neoadjuvant immunotherapy for resectable NSCLC remain scarce. This study endeavors to investigate the incidence, risk factors, and outcomes of CIP in patients with resectable NSCLC receiving neoadjuvant immunochemotherapy.MethodsA retrospective, case-control study was conducted on patients diagnosed with NSCLC stages IIA–IIIB who received neoadjuvant immunochemotherapy between January 2018 and September 2022. Patients were stratified into two groups based on the presence or absence of CIP, facilitating a comparative analysis of clinical characteristics, treatment modalities, physiological indicators, and prognostic outcomes .ResultsThe study cohort comprised 245 patients, with 11.4% (28/245) experiencing CIP. The median period of CIP onset was 70 (range, 40–221) days. The incidence of severe CIP (grade 3–4) was 3.7% (9/245). Patients with CIP showed a higher all-cause mortality rate of 21.4% (6/28) compared to that of patients without CIP. Those who developed CIP exhibited elevated body mass index (BMI) values (p = 0.028) and increased fibrinogen (FIB) levels (p < 0.001), alongside a significant decrease in both diffusing capacity for carbon monoxide (DLCO)% pred (p = 0.001) and DLCO/VA% pred (p = 0.021) after neoadjuvant therapy compared to pre-indicators. Receiver operating characteristic curve (ROC) analysis showed that the area under the ROC curve of three assessed variables (FIB levels, BMI, DLCO) reached 0.806 in predicting CIP occurrence at an early stage.ConclusionsThis cohort demonstrated that elevated BMI, increased FIB levels, and decreased pulmonary diffusion function after neoadjuvant therapy are risk factors of CIP occurrence. Early assessment and continuous monitoring of these indicators are imperative for the predictive identification of CIP, enhancing patient management and outcomes.

Study on the difference and regularity of tongue images in 309 patients with different pathological stages of non-small cell lung cancer.

Tongue diagnosis is a crucial traditional Chinese medicine (TCM) inspection method for TCM syndrome differentiation and treatment. The primary research focus was on tongue image characteristic parameters of patients with non-small cell lung cancer (NSCLC). Analysis of the tongue image parameters of various pathological stages of NSCLC provides technical support for establishing an integrated Chinese and Western auxiliary diagnosis and efficacy evaluation medicine system for lung cancer that integrates tongue image features. Tongue image characteristics of 309 patients with NSCLC and 206 controls were collected and analyzed clinically. The T-test or rank sum test and logistic regression analysis were applied to analyze the characteristics of tongue image indicators of different pathological stages of NSCLC. There were differences in tongue image characteristics in the NSCLC group compared to the control group. The tongue quality and brightness of the tongue coating in the NSCLC group increased, the red component was reduced, the tongue coating thickened, and the yellow component increased compared to the healthy control group. A comparison of tongue image indexes of NSCLC in different pathological stages showed that stage IV had lower TB-b and higher TB-a than stage I. In addition, stage IV had lower TB-b than stage II + III, showing an increase in the blue and red components of the tongue in stage IV and the appearance of cyanotic tongue features. The tongue image characteristics of NSCLC patients differed from those of the control group. Tongue imaging indicators can reflect the characteristics of tongue images of patients with NSCLC. The tongue image characteristics of patients with stage IV lung cancer are bluish and purple compared with those with stage I, II, and III. It is suggested that the tongue's image characteristics can be used as a reference for the pathological classification of NSCLC and judgment of the disease process.

Construction of An Orthotopic Xenograft Model of Non-small Cell Lung Cancer Mimicking Disease Progression and Predicting Drug Activities.

Non-small cell lung cancer (NSCLC) is a highly lethal disease with a complex and heterogeneous tumor microenvironment. Currently, common animal models based on subcutaneous inoculation of cancer cell suspensions do not recapitulate the tumor microenvironment in NSCLC. Herein we describe a murine orthotopic lung cancer xenograft model that employs the intrapulmonary inoculation of three-dimensional multicellular spheroids (MCS). Specifically, fluorescent human NSCLC cells (A549-iRFP) were cultured in low-attachment 96-well microplates with collagen for 3 weeks to form MCS, which were then inoculated intercostally into the left lung of athymic nude mice to establish the orthotopic lung cancer model. Compared with the original A549 cell line, MCS of the A549-iRFP cell line responded similarly to anticancer drugs. The long-wavelength fluorescent signal of the A549-iRFP cells correlated strongly with common markers of cancer cell growth, including spheroid volume, cell viability, and cellular protein level, thus allowing dynamic monitoring of the cancer growth in vivo by fluorescent imaging. After inoculation into mice, the A549-iRFP MCS xenograft reliably progressed through phases closely resembling the clinical stages of NSCLC, including the expansion of the primary tumor, the emergence of neighboring secondary tumors, and the metastases of cancer cells to the contralateral right lung and remote organs. Moreover, the model responded to the benchmark antilung cancer drug, cisplatin with the anticipated toxicity and slower cancer progression. Therefore, this murine orthotopic xenograft model of NSCLC would serve as a platform to recapitulate the disease's progression and facilitate the development of potential anticancer drugs.

Implementation of Artificial Intelligence in Personalized Prognostic Assessment of Lung Cancer: A Narrative Review.

Artificial Intelligence (AI) has revolutionized the management of non-small-cell lung cancer (NSCLC) by enhancing different aspects, including staging, prognosis assessment, treatment prediction, response evaluation, recurrence/prognosis prediction, and personalized prognostic assessment. AI algorithms may accurately classify NSCLC stages using machine learning techniques and deep imaging data analysis. This could potentially improve precision and efficiency in staging, facilitating personalized treatment decisions. Furthermore, there are data suggesting the potential application of AI-based models in predicting prognosis in terms of survival rates and disease progression by integrating clinical, imaging and molecular data. In the present narrative review, we will analyze the preliminary studies reporting on how AI algorithms could predict responses to various treatment modalities, such as surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. There is robust evidence suggesting that AI also plays a crucial role in predicting the likelihood of tumor recurrence after surgery and the pattern of failure, which has significant implications for tailoring adjuvant treatments. The successful implementation of AI in personalized prognostic assessment requires the integration of different data sources, including clinical, molecular, and imaging data. Machine learning (ML) and deep learning (DL) techniques enable AI models to analyze these data and generate personalized prognostic predictions, allowing for a precise and individualized approach to patient care. However, challenges relating to data quality, interpretability, and the ability of AI models to generalize need to be addressed. Collaboration among clinicians, data scientists, and regulators is critical for the responsible implementation of AI and for maximizing its benefits in providing a more personalized prognostic assessment. Continued research, validation, and collaboration are essential to fully exploit the potential of AI in NSCLC management and improve patient outcomes. Herein, we have summarized the state of the art of applications of AI in lung cancer for predicting staging, prognosis, and pattern of recurrence after treatment in order to provide to the readers a large comprehensive overview of this challenging issue.

Association between postoperative radiotherapy for young-onset nonsmall cell lung cancer and risk of second primary malignancies: comparative study.

The most common form of therapy for nonsmall cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. The authors aimed to quantify the risks of SPM associated with PORT treatment for young‑onset NSCLC in early stage. The authors screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology, and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs. Among the 30308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies [relative risks (RR)=1.31; 95% CI: 1.17-1.46], lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74), and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR=1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60-69 years (RR=1.33), in white race (RR=1.36), diagnosed in 1975-2000 (RR=1.23) and 2001-2015 (RR=1.40), or diagnosed with lung adenocarcinoma (RR=1.55). PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer, as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients.

Durvalumab impacts progression-free survival while high-dose radiation >66 Gy improves local control without excess toxicity in unresectable NSCLC stage III: Real-world data from the Austrian radio-oncological lung cancer study association registry (ALLSTAR)

BackgroundChemo-radioimmunotherapy with total radiation doses of 60–66 Gy in 2 Gy fractions is the standard of care for non-small cell lung cancer (NSCLC) UICC stage III. The Austrian radio-oncological lung cancer study association registry (ALLSTAR) is a prospective multicentre registry intended to document clinical practice at the beginning of the Durvalumab era. Patients and methodsPatients were eligible if they had pathologically verified unresectable NSCLC stage III with a curative treatment option. Chemo-radiation combined with immunotherapy was performed according to local treatment practices. The endpoints were local control (LC), progression-free survival (PFS) and toxicity. ResultsBetween 2020/03 and 2023/04, 12/14 (86 %) Austrian radiation-oncology centres recruited 188 patients (median 17, range: 1–89). PD-L1 testing was performed in 173/188 (93 %) patients. The median interval between the end of chemoradiotherapy and start of Durvalumab was 14 days (range: 1–65). About 40 % (75/188) of the patients received a total radiation dose of > 66 Gy (range: 67.1–100), which improved 2-year LC (86 % versus 60 %, HR = 0.41; 95 %-CI: 0.17–0.98; log-rank p-value < 0.05). Median PFS for patients with Durvalumab was 25.8 months (95 %-CI: 21.9-not reached) compared to 15.7 months (95 %-CI: 13.2–27.8) for those without (HR = 1.88; 95 %-CI: 1.16–3.05; log-rank p-value < 0.01). The rates of esophageal and pulmonary toxicities were 34.6 % and 23.9 %, respectively, including one case of grade 4 pneumonitis. In the subcohort of 75 patients who received > 66 Gy, 19 (25 %) cases of pulmonary toxicity grades 1–3 were observed. ConclusionWhile Durvalumab impacts PFS, LC can be improved by total radiation doses > 66 Gy without excess toxicity.

Survival analysis after stereotactic ablative radiotherapy for early stage non-small cell lung cancer: a single-institution cohort study

BackgroundStereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small cell lung cancer (ES-NSCLC), but which patients benefit from stereotactic radiotherapy is unclear. The aim of this study was to analyze prognostic factors for early mortality.MethodsFrom August 2010 to 2022, 617 patients with medically inoperable, peripheral or central ES-NSCLC were treated with SABR at our institution. We retrospectively evaluated the data from 172 consecutive patients treated from 2018 to 2020 to analyze the prognostic factors associated with overall survival (OS). The biological effective dose was > 100 Gy10 in all patients, and 60 Gy was applied in 3–5 fractions for a gross tumor volume (GTV) + 3 mm margin when the tumor diameter was < 1 cm; 30–33 Gy was delivered in one fraction. Real-time tumor tracking or an internal target volume approach was applied in 96% and 4% of cases, respectively. In uni- and multivariate analysis, a Cox model was used for the following variables: ventilation parameter FEV1, histology, age, T stage, central vs. peripheral site, gender, pretreatment PET, biologically effective dose (BED), and age-adjusted Charlson comorbidity index (AACCI).ResultsThe median OS was 35.3 months. In univariate analysis, no correlation was found between OS and ventilation parameters, histology, PET, or centrality. Tumor diameter, biological effective dose, gender, and AACCI met the criteria for inclusion in the multivariate analysis. The multivariate model showed that males (HR 1.51, 95% CI 1.01–2.28; p = 0.05) and AACCI > 5 (HR 1.56, 95% CI 1.06–2.31; p = 0.026) were significant negative prognostic factors of OS. However, the analysis of OS showed that the significant effect of AACCI > 5 was achieved only after 3 years (3-year OS 37% vs. 56%, p = 0.021), whereas the OS in one year was similar (1-year OS 83% vs. 86%, p = 0.58).ConclusionSABR of ES-NSCLC with precise image guidance is feasible for all medically inoperable patients with reasonable performance status. Early deaths were rare in our real-life cohort, and OS is clearly higher than would have been expected after best supportive care.