Lung Cancer Outcomes Research Articles

Single organ metastatic sites in non-small cell lung cancer: Patient characteristics, treatment patterns and outcomes from a large retrospective Canadian cohort

BackgroundThere is a paucity of information about the characteristics, treatment patterns, and outcomes of non-small cell lung cancer (NSCLC) patients with single organ metastasis (SOM). MethodsThis retrospective cohort study includes all patients with a diagnosis of stage IV NSCLC diagnosed from 2014 to 2016 and treated at Princess Margaret Cancer Centre. We compared baseline characteristics and patterns of metastatic sites between patients with SOM versus multiple (M)OM. Additionally, we identified treatment modalities and outcomes for patients with SOM. Cox multivariable models (MVA) were utilized to evaluate differences in overall survival (OS) between the SOM and MOM cohorts. ResultsOf 893 pts analyzed, 457 (51 %) had SOM, while 436 (49 %) had MOM at initial diagnosis. Demographics were comparable between the two groups. Brain was the most common site of metastasis for SOM patients. When compared to the MOM group, the SOM group had lower percentages of liver and adrenal metastases. Amongst SOM patients, 54 % received single modality treatment, and 20 % did not receive any treatment for their SOM. In MVA, patients with liver (HR 2.4), bone (HR 1.8), and pleural (HR 1.7) metastasis as their SOM site had the worst outcomes, with median OS of 6.8 months, 12.1 months, and 13.0 months respectively. Patients with SOM had a significantly improved median OS compared to those with MOM (15.9 months vs. 10.6 months; HR 0.56, 95 % CI 0.47–0.66, p < 0.001). ConclusionIn NSCLC patients who presented with SOM, survival correlated with the initial organ involved and was better overall compared to patients with MOM. SOM NSCLC may benefit from specific management strategies and SOM patients could be considered as a specific subgroup for survival analyses in observational and non-randomized interventional studies. In clinical trials, SOM can be considered as a stratification factor in the future.

Primary lung cancer in children and adolescents

PurposePrimary lung cancer is extremely rare in children and adolescents. The aim of this study is to clarify clinical features and outcomes of primary lung cancer in children and adolescents.MethodsYoung patients (aged ≤ 20 years) diagnosed as primary lung cancer between 2012 and 2023 were retrospective reviewed. According to radiological appearance of the nodules, they were divided into solid nodule (SN) group and ground glass opacity (GGO) group.ResultsA total of 74 patients were identified, with a median age at diagnosis of 18 years old (range: 11–20), including 7 patients in SN group and 67 patients in GGO group. In the GGO group, none of the nodules enlarged or changed during an average surveillance period of 10.8 months before surgery, except one. Wedge resection was the most common procedure (82.1%), followed by segmentectomy (16.4%) and lobectomy (1.5%). Histopathological analysis revealed that 64.2% of GGO nodules were adenocarcinoma in situ and minimally invasive adenocarcinomas, while the remaining 35.8% were invasive adenocarcinomas. Mutational analysis was performed in nine patients, with mutations identified in all cases. After a mean follow-up period of 1.73 ± 1.62 years, two patients in the SN group died due to multiple distant metastases, while all patients in the GGO group survived without recurrence. The overall survival (100%) of the GGO group was significantly higher than SN group (66.7%).ConclusionsPrimary lung cancer in children and adolescents are rare and histopathological heterogeneous. Persistent GGO nodules may indicate early-stage lung adenocarcinoma in children and adolescents.

Preoperatively predicting survival outcome for clinical stage IA pure-solid non–small cell lung cancer by radiomics-based machine learning

ObjectiveClinical stage IA non–small cell lung cancer (NSCLC) showing a pure-solid appearance on computed tomography is associated with a worse prognosis. This study aimed to develop and validate machine-learning models using preoperative clinical and radiomic features to predict overall survival (OS) in clinical stage IA pure-solid NSCLC. MethodsPatients who underwent lung resection for NSCLC between January 2012 and December 2020 were reviewed. The radiomic features were extracted from the intratumoral and peritumoral regions on computed tomography. The machine-learning models were developed using random survival forest and eXtreme Gradient Boosting (XGBoost) algorithms, whereas the Cox regression model was set as a benchmark. Model performance was assessed using the integrated time-dependent area under the curve (iAUC) and validated by 5-fold cross-validation. ResultsIn total, 642 patients with clinical stage IA pure-solid NSCLC were included. Among 3748 radiomic and 34 preoperative clinical features, 42 features were selected. Both machine-learning models outperformed the Cox regression model (iAUC, 0.753; 95% confidence interval [CI], 0.629-0.829). The XGBoost model showed a better performance (iAUC, 0.832; 95% CI, 0.779-0.880) than the random survival forest model (iAUC, 0.795; 95% CI, 0.734-0.856). The XGBoost model showed an excellent survival stratification performance with a significant OS difference among the low-risk (5-year OS, 100.0%), moderate low-risk (5-year OS, 88.5%), moderate high-risk (5-year OS, 75.6%), and high-risk (5-year OS, 41.7%) groups (P < .0001). ConclusionsA radiomics-based machine-learning model can preoperatively and accurately predict OS and improve survival stratification in clinical stage IA pure-solid NSCLC.

Clinical outcomes associated with neoadjuvant therapy for the treatment of resectable non-small cell lung cancer in real-world practice.

In order to improve survival outcomes in resectable non-small cell lung cancer (NSCLC), strategies for neoadjuvant therapy need to be revisited. We evaluated and compared the efficacy of different neoadjuvant therapeutic modalities in a real-world setting. A total of 258 patients with clinical stage IIA to IIIB NSCLC was included. All the patients underwent surgical resection after one to four cycles of neoadjuvant treatment consisting of chemotherapy (83), immunotherapy (23), and immunotherapy plus chemotherapy (152). The radiologic response rate in the combined immunochemotherapy group was 67.8%, higher than that of 48.2% in the chemotherapy group and 4.3% in the immunotherapy group (p < 0.001). An improved major pathological response (MPR) was also achieved in the combined therapy group compared with the chemotherapy group and the immunotherapy group (53.9% vs. 10.8% vs. 8.7%, p < 0.001). Patients in the combined therapy group had a significant trend toward longer disease-free survival than those in the chemotherapy alone group (3-year disease-free survival [DFS] of 68.79% vs. 50.81%; hazard ratio [HR] for progression or death, 0.477; p = 0.003). Multivariate Cox analysis identified radical surgery (HR, 0.328; p = 0.033), ypN0-1 stage (HR, 0.591; p = 0.038) and MPR result (HR, 0.362; p = 0.007) to be independent prognostic factors for DFS. Neoadjuvant treatment with a combination of immunotherapy plus chemotherapy appears to achieve higher radiological and pathological responses than monotherapy for IIA-IIIB NSCLC. Log-rank analysis showed that a better outcome could be expected in patients with the addition of immunotherapy to neoadjuvant chemotherapy if compared with patients with chemotherapy alone in terms of DFS.

Transforming Lung Cancer Outcomes through Prevention and Early Detection Strategies

Transforming Lung Cancer Outcomes through Prevention and Early Detection Strategies

Peripheral NK cells identified as the predictor of response in extensive-stage small cell lung cancer patients treated with first-line immunotherapy plus chemotherapy.

Although immunotherapy improves outcomes in extensive-stage small-cell lung cancer (ES-SCLC), the search for biomarkers predicting treatment success is crucial. Natural killer (NK) cells are potential indicators in various cancers, however, their precise role in ES-SCLC prognosis remains unclear. In this retrospective study, 33 patients with ES-SCLC treated with first-line immuno-chemotherapy were enrolled. The peripheral NK cell percentage and its longitudinal dynamics were analyzed using flow cytometry. Progression-free survival (PFS) and overall survival (OS) were calculated as hazard ratio (HR) and compared statistically. The median PFS was better in the group with normal baseline NK cell levels than the low group (7.0 vs. 4.6months; HR = 0.17; 95% CI 0.07-0.41; P < 0.0001), but there was no association with OS (14.9 vs. 10.3months; HR = 0.55; 95% CI 0.23-1.31; P = 0.171). Furthermore, the NK cell% for 95.0% of patients increased after immunochemotherapy in the clinical response group (P = 0.0047), which led to a better median PFS (6.3 vs. 2.1months; HR = 0.23; 95% CI 0.05-0.98; P < 0.0001) and OS (14.9 vs. 5.9months; HR = 0.20; 95% CI 0.04-1.02; P < 0.0001). Similar trends were observed with NK cell% changes up to disease progression, improving PFS (6.5 vs. 4.3; HR = 0.41; 95% CI 0.12-0.92; P = 0.0049) and OS (17.4 vs. 9.7; HR = 0.42; 95% CI 0.17-1.02; P < 0.0001). In patients with ES-SCLC, the percentage and changes in peripheral NK cells can predict the response to combined immunotherapy and chemotherapy.

Clinical outcomes in patients with non-small cell lung cancer harboring EGFR Exon20 in-frame insertions in the near-loop and far-loop: Results from LC-SCRUM-Asia

ObjectivesIn this study, we explored the clinical outcomes of non-small cell lung cancer (NSCLC) patients with EGFR Exon20 in-frame insertions (Exon20ins), and the impact of the location of Exon20ins on these clinical outcomes. Materials and methodsThe efficacies of current systemic therapies in NSCLC patients harboring Exon20ins were investigated using a large-scale clinico-genomic database of LC-SCRUM-Asia, and compared with that of amivantamab in the CHRYSALIS trial. ResultsOf the 11,397 patients enrolled in LC-SCRUM-Asia, Exon20ins were detected in 189 patients (1.7 %). Treatment with classical EGFR tyrosine-kinase inhibitors (classical TKIs) was associated with a significantly shorter progression-free survival (PFS) in NSCLC patients with Exon20ins as compared with Exon19 deletions and L858R. Post platinum-based chemotherapy, classical TKIs and immune checkpoint inhibitors (ICIs) were associated with a shorter PFS than with docetaxel in patients with Exon20ins (HR [95 % CI]; TKIs vs docetaxel, 2.16 [1.35–3.46]; ICIs vs docetaxel, 1.49 [1.21–1.84]). Patients treated with amivantamab in the CHRYSALIS trial showed a risk reduction in PFS and overall survival as compared with LC-SCRUM-Asia patients treated with docetaxel, classical TKIs, or ICIs. Among the 189 patients, Exon20ins were classified as near-loop or far-loop insertions in 115 (61 %) and 56 (30 %) patients, respectively. Treatment with osimertinib was associated with a longer PFS in patients with Exon20ins in near-loop as compared with far-loop (median, 5.6 vs. 2.0 months; HR [95 % CI], 0.22 [0.07–0.64]). ConclusionsAfter platinum-based chemotherapy, classical TKIs and ICIs are less effective in NSCLC patients with Exon20ins, and amivantamab may be a promising targeted therapy. There is a possibility that the location of Exon20ins has an impact on the efficacy of TKIs.

5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer.

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurately predicting individual patient responses to ICIs remains a challenge. We performed the genome-wide profiling of 5-hydroxymethylcytosine (5hmC) in 85 plasma cell-free DNA (cfDNA) samples from lung cancer patients and developed a 5hmC signature that was significantly associated with progression-free survival (PFS). We built a 5hmC predictive model to quantify the 5hmC level and validated the model in the validation, test, and control sets. Low weighted predictive scores (wp-scores) were significantly associated with a longer PFS compared to high wp-scores in the validation [median 7.6 versus 1.8 months; p = 0.0012; hazard ratio (HR) 0.12; 95% confidence interval (CI), 0.03-0.54] and test (median 14.9 versus 3.3 months; p = 0.00074; HR 0.10; 95% CI, 0.02-0.50) sets. Objective response rates in patients with a low or high wp-score were 75.0% (95% CI, 42.8-94.5%) versus 0.0% (95% CI, 0.0-60.2%) in the validation set (p = 0.019) and 80.0% (95% CI, 44.4-97.5%) versus 0.0% (95% CI, 0.0-36.9%) in the test set (p = 0.0011). The wp-scores were also significantly associated with PFS in patients receiving single-agent ICI treatment (p < 0.05). In addition, the 5hmC predictive signature demonstrated superior predictive capability to tumor programmed death-ligand 1 and specificity to ICI treatment response prediction. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. This study provides proof-of-concept evidence that the cfDNA 5hmC signature is a robust biomarker for predicting ICI treatment response in lung cancer.

Spatially Preserved Multi-Region Transcriptomic Subtyping and Biomarkers of Chemoimmunotherapy Outcome in Extensive-Stage Small Cell Lung Cancer.

Transcriptomic subtyping holds promise for personalized therapy in extensive-stage small cell lung cancer (ES-SCLC). In this study, we aimed to assess intratumoral transcriptomic subtype diversity and to identify biomarkers of long-term chemoimmunotherapy benefit in human ES-SCLC. We analyzed tumor samples from 58 patients with ES-SCLC enrolled in two multicenter single-arm phase IIIb studies evaluating frontline chemoimmunotherapy in Spain: n = 32 from the IMfirst trial and n = 26 from the CANTABRICO trial. We used the GeoMx Digital Spatial Profiler system to perform multi-region transcriptomic analysis. For subtype classification, we performed hierarchical clustering using the relative expression of ASCL1 (SCLC-A), NEUROD1 (SCLC-N), POU2F3 (SCLC-P), and YAP1 (SCLC-Y). Subtype distribution was found to be similar between bothcohorts, except for SCLC-P, which was not identified in the CANTABRICO_DSP cohort. A total of 44% of the patients in both cohorts had tumors with multiple coexisting transcriptional subtypes. Transcriptional subtypes or subtype heterogeneity was not associated with outcomes. Most potential targets did not show subtype-specific expression. Consistently in both cohorts, tumors from patients with long-term benefit (time to progression ≥12 months) contained an IFNγ-dominated mRNA profile, including enhanced capacity for antigen presentation. Hypoxia and glycolytic pathways were associated with resistance to chemoimmunotherapy. This work suggests that intratumoral heterogeneity, inconsistent association with outcome, and unclear subtype-specific target expression might be significant challenges for subtype-based precision oncology in SCLC. Preexisting IFNγ-driven immunity and mitochondrial metabolism seem to be correlates of long-term efficacy in this study, although the absence of a chemotherapy control arm precludes concluding that these are predictive features specific for immunotherapy.

Spatial Architecture of Myeloid and T Cells Orchestrates Immune Evasion and Clinical Outcome in Lung Cancer.

This study provides novel insights into the spatial organization of the lung cancer TME in the context of tumor immunogenicity, tumor heterogeneity, and cancer evolution. Pairing the tumor evolutionary history with the spatially resolved TME suggests mechanistic hypotheses for tumor progression and metastasis with implications for patient outcome and treatment. This article is featured in Selected Articles from This Issue, p. 897.

Surgical outcomes for non-small cell lung cancer in younger adults: A population-based study.

The surgical outcomes for younger patients with non-small cell lung cancer (NSCLC) remain uncertain. The aim of this study was to investigate the clinical features long-term survival outcomes in younger individuals with NSCLC following surgery. We queried the Surveillance, Epidemiology, and End Results database from 2010 to 2017, selecting all pathologically confirmed NSCLC cases that underwent cancer-directed surgery. Younger patients were defined as those aged 18-50 years, while older patients were 51-80 years. Propensity score matching (PSM) was implemented to mitigate selection bias. Overall survival (OS) and lung cancer-specific survival (LCSS) were compared using the Kaplan-Meier method. Among the 33 586 treated surgically patients, 2223 (6.6%) were young. Compared to the older group, younger patients had a higher frequency of female gender, non-white ethnicity, carcinoid tumors, stage IV disease, pneumonectomy, and postoperative adjuvant therapies. The 5-year OS rates were significantly higher for younger patients (79.3% vs. 62.0%; p < 0.001), as were the 5-year LCSS rates (82.4% vs. 71.8%; p < 0.001). Post-PSM, younger patients consistently demonstrated significantly better OS and LCSS. Further stage-specific analysis revealed significantly improved 5-year OS rates at each stage and superior 5-year LCSS for stages I-II among younger patients. However, there was no statistically significant difference in LCSS for stages III-IV. Overall, younger patients with NSCLC treated surgically exhibit superior OS and LCSS compared to their older counterparts, although no statistically significant difference in LCSS for stages III-IV was observed between the two age groups.

Trajectory patterns and cumulative burden of CEA during follow-up with non-small cell lung cancer outcomes: A retrospective longitudinal cohort study.

Previous studies of non-small cell lung cancer (NSCLC) focused on CEA measured at a single time point, ignoring serial CEA measurements. This retrospective cohort included 2959 patients underwent surgery for stage I-III NSCLC. CEA trajectory patterns and long-term cumulative CEA burden were evaluated using the latent class growth mixture model. Four CEA trajectory groups were identified, named as low-stable, decreasing, early-rising and later-rising. Compared with the low-stable group, the adjusted hazard ratios associated with death were 1.27, 4.50, and 3.68 for the other groups. Cumulative CEA burden were positively associated with the risk of death in patients not belonging to the low-stable group. The 5-year overall survival (OS) rates decreased from 62.3% to 33.0% for the first and fourth quantile groups of cumulative CEA burden. Jointly, patients with decreasing CEA trajectory could be further divided into the decreasing & low and decreasing & high group, with 5-year OS rates to be 77.9% and 47.1%. Patients with rising CEA trajectory and high cumulative CEA were found to be more likely to develop bone metastasis. Longitudinal trajectory patterns and long-term cumulative burden of CEA were independent prognostic factors of NSCLC. We recommend CEA in postoperative surveillance of NSCLC.

High CASC expression predicts poor prognosis of lung cancer: A systematic review with meta-analysis.

The long non-coding RNA cancer susceptibility candidate (CASC) has abnormal expression in lung cancer tissues and may correlate with lung cancer prognosis. This study aimed to comprehensively evaluate the association between CASC expression and the cancer prognosis. PubMed, Embase, Web of Science, Google Scholar, Cochrane Library, and China National Knowledge Infrastructure databases were searched until April 1, 2023, to obtain the relevant literature. Studies that met the predefined eligibility criteria were included, and their quality was independently assessed by 2 investigators according to the Newcastle-Ottawa Scale (NOS) score. Detailed information was obtained, such as first author, year of publication, and number of patients. Hazard ratio (HR) with a 95% confidence interval (CI) was extracted and grouped to assess the relationship between CASC expression and cancer prognosis. The dichotomous data was merged and shown as the odds ratio (OR) with a 95% CI was extracted to assess the relationship between CASC expression and clinicopathological parameters. A total of 12 studies with 746 patients with lung cancer were included in the meta-analysis. The expression levels of lncRNA CASC2 and CASC7 were decreased, while those of CASC9, 11, 15, and 19 were induced in lung cancer tissues compared with paracancerous tissues. In the population with low CASC expression (CASC2 and CASC7), high CASC expression indicated a good lung cancer prognosis (HR = 0.469; 95% CI, 0.271-0.668). Conversely, in the population with high CASC expression (CASC9, 11, 15, and 19), high CASC expression predicted a poor lung cancer outcome (HR = 1.910; 95% CI, 1.628-2.192). High CASC expression also predicted worse disease-free survival (DFS) (HR = 2.803; 95% CI, 1.804-6.319). Combined OR with 95% CI revealed an insignificant positive association between high CASC expression and advanced TNM stage (OR = 1.061; 95% CI, 0.775-1.454), LNM (OR = 0.962; 95% CI, 0.724-1.277), tumor size (OR = 0.942; 95% CI, 0.667-1.330), and histological grade (OR = 1.022; 95% CI, 0.689-1.517). The CASC expression levels negatively correlate with lung cancer prognosis. Therefore, CASC expression may serve as a prognostic marker and a potential therapeutic target for lung cancer.

Clinical and Therapeutic Characteristics of Hospitalized Patients with Advanced Lung Cancer in Najran, Saudi Arabia: A Retrospective Study.

Lung cancer is one of the top causes of cancer deaths globally, including in Saudi Arabia. Although several prognostic markers have been established, the clinical features and outcomes of lung cancer in Saudi Arabia are not well understood. This study aimed to describe the clinical and therapeutic characteristics of advanced lung cancer in Najran, SaudiArabia. A retrospective chart review of 44 patients diagnosed with advanced lung cancer between June 2018 and September 2021 and treated at the Oncology Center of King Khalid Hospital in Najran City, Saudi Arabia. The clinicopathological features, treatment used, response, and survival outcomes were collected and analyzed. The mean age was 69.3 ± 10.7 years, most of them (n = 35, 79.5%) were male and older than 70 years (n = 24, 54.5%). Adenocarcinoma was the most observed cancer (n = 35, 79.5%), followed by squamous cell carcinoma in six (13.6%). Most cases (n = 42, 95.5%) were in stage IV. Epidermal growth factor receptor (EGFR) mutations were positive in two (4.5%) cases and ALK mutation was positive in two (4.5%) cases. Metastasis to pleura with pleural effusion was the common presentation (n = 41, 93%). Chemotherapy was administered as the first line in 19 cases (43.2%) while 25 cases (56.8%) received chemoimmunotherapy. The commonest chemoimmunotherapy regimen used was carboplatin-pemetrexed-pembrolizumab in 16 (36.4%), followed by carboplatin-paclitaxel-pembrolizumab in 9 (20.5%) cases. The response to initial systemic therapy was as follows disease progression, stable disease, and complete remission in 10 (22.7%), 33 (75.0%), and 1 (2.3%), respectively. Median progression-free survival was 8.7 months (interquartile range (IQR): 5.7-11.4), and the median overall survival was 12.3 months (IQR: 11.1-13.4). Among the total documented 36 (81.8%) dead cases, disease progression was the main cause of death in 25 cases (56.8%). Using chemoimmunotherapy as the first-line therapy was associated with numerical survival improvement compared to using chemotherapy alone (HR: 0.75; 95% CI: 0.39-1.46) however, it was not statistically significant (p = 0.397). In this study, the majority of lung cancer patients were male and over 70 years old. Adenocarcinoma was the most common histological type. Metastasis to pleura with pleural effusion was the common presentation. The most common treatment used was chemoimmunotherapy with a regimen of carboplatin-pemetrexed-pembrolizumab. Addressing the possible causes of delayed diagnosis of lung cancer is crucial for improved survival outcomes.

126 Exploring Real-World Treatment Patterns and Outcomes in Stage IIIA N2 Non-Small Cell Lung Cancer (NSCLC)

126 Exploring Real-World Treatment Patterns and Outcomes in Stage IIIA N2 Non-Small Cell Lung Cancer (NSCLC)

94 Clinical outcomes in advanced Non-Small Cell Lung Cancer (NSCLC) with METexon 14 skipping mutation

94 Clinical outcomes in advanced Non-Small Cell Lung Cancer (NSCLC) with METexon 14 skipping mutation

131 Early stage lung cancer outcomes – a 10 year review of surgery and radiotherapy in patients with performance status 0-1 and Stage I and II NSCLC lung cancer

131 Early stage lung cancer outcomes – a 10 year review of surgery and radiotherapy in patients with performance status 0-1 and Stage I and II NSCLC lung cancer

Down-regulated HHLA2 enhances neoadjuvant immunotherapy efficacy in patients with non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD)

BackgroundEmerging data suggested a favorable outcome in advanced non-small cell lung cancer (NSCLC) with chronic obstructive pulmonary disease (COPD) patients treated by immunotherapy. The objective of this study was to investigate the effectiveness of neoadjuvant immunotherapy among NSCLC with COPD versus NSCLC without COPD and explore the potential mechanistic links.Patients and methodsPatients with NSCLC receiving neoadjuvant immunotherapy and surgery at Shanghai Pulmonary Hospital between November 2020 and January 2023 were reviewed. The assessment of neoadjuvant immunotherapy’s effectiveness was conducted based on the major pathologic response (MPR). The gene expression profile was investigated by RNA sequencing data. Immune cell proportions were examined using flow cytometry. The association between gene expression, immune cells, and pathologic response was validated by immunohistochemistry and single-cell data.ResultsA total of 230 NSCLC patients who received neoadjuvant immunotherapy were analyzed, including 60 (26.1%) with COPD. Multivariate logistic regression demonstrated that COPD was a predictor for MPR after neoadjuvant immunotherapy [odds ratio (OR), 2.490; 95% confidence interval (CI), 1.295–4.912; P = 0.007]. NSCLC with COPD showed a down-regulation of HERV–H LTR-associating protein 2 (HHLA2), which was an immune checkpoint molecule, and the HHLA2low group demonstrated the enrichment of CD8+CD103+ tissue-resident memory T cells (TRM) compared to the HHLA2high group (11.9% vs. 4.2%, P = 0.013). Single-cell analysis revealed TRM enrichment in the MPR group. Similarly, NSCLC with COPD exhibited a higher proportion of CD8+CD103+TRM compared to NSCLC without COPD (11.9% vs. 4.6%, P = 0.040).ConclusionsThe study identified NSCLC with COPD as a favorable lung cancer type for neoadjuvant immunotherapy, offering a new perspective on the multimodality treatment of this patient population. Down-regulated HHLA2 in NSCLC with COPD might improve the MPR rate to neoadjuvant immunotherapy owing to the enrichment of CD8+CD103+TRM.Trial registrationApproval for the collection and utilization of clinical samples was granted by the Ethics Committee of Shanghai Pulmonary Hospital (Approval number: K23-228).

Abstract 1141: Spatial-specific gene signatures to predict immunotherapy outcomes in lung cancer

Abstract The widespread use of immunotherapy in lung cancer, and its more recent approval for early stages, underscores the need for biomarkers that can identify the most responsive patients. Spatial transcriptomics, which maps gene expression in its spatial tissue context, offers a unique approach over bulk transcriptomics. By incorporating spatial information, the predictive power of the signature can be enhanced. Here, we aim to develop spatially informed gene signatures that could be translated into clinical RNA in situ assays, distinguishing patients unlikely to benefit from immunotherapy and thereby sparing them unnecessary side effects. We utilized the NanoString GeoMX Whole Transcriptome Atlas for spatially resolved transcriptomic profiling of retrospectively collected lung cancer tissue samples from patients treated with immunotherapy in an advanced-stage setting (N=60). By targeting 18,190 genes within distinct areas of interest (AOIs)—including stromal (macrophages/CD68+ and leukocytes/CD45+) and tumor (cytokeratin, CK+) cells—we developed AOI-specific gene signatures to predict objective responses. These were derived from a robust computational framework employing LASSO logistic regression on a split-sample approach, yielding predictive models for treatment outcome.We achieved high predictive accuracy on the training set, with the area under the curve (AUC) exceeding 0.86 for all AOI-specific spatial signatures, indicating strong potential for clinical application. Validation against an independent cohort (N=42) corroborated the efficacy of these signatures. Our 6-gene tumor signature was validated with an AUC of 0.73 (95% CI: 0.67-0.89, p = 0.009**), while the CD45 5-gene signature showed an AUC of 0.75 (95% CI: 0.53-0.97, p = 0.022*). Our 18-gene CD68 signature trended towards validation but lacked statistical significance. A combined CD68 and CD45 signature predicted outcomes with greater accuracy, achieving an AUC of 0.79 (95% CI: 0.62-0.98, p = 0.0088*). Following gene set enrichment analysis on our differentially expressed and signature genes, we identified genes with positive coefficients in both tumor and stroma signatures that were associated with glucocorticoid response and glycolytic processes linked to T-cell homeostasis, while genes with negative coefficients were associated with epithelial cell differentiation and cytokine production. These associations are concordant with the observation that genes with positive coefficients are predictors of treatment response, while those with negative coefficients indicate resistance.Our findings indicate that AOI-specific signatures predict the immunotherapy outcome in lung cancer with high accuracy, suggesting that spatial assessment can provide substantial predictive information. The high performance of these signatures indicates their potential for prospective clinical applications. Citation Format: Thazin N. Aung, Myrto Moutafi, Ioannis Trontzas, Arutha Kulasinghe, James Monkman, Niki Gavrielatou, Ioannis Vathiotis, Jonathan H. Warrell, David L. Rimm. Spatial-specific gene signatures to predict immunotherapy outcomes in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1141.

Abstract 3634: Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer

Abstract Deleterious mutations in STK11/LKB1, KEAP1, and SMARCA4 have been shown to be associated with adverse response to immunotherapy in several lung cancer cohorts. However, the biological and clinical implications of deletions of these genes, which all reside on chromosome 19p (chr19p), has not been extensively described. We sought to first characterize the association between immune infiltration and these copy number changes in chr19p. To do this, we analyzed mutation, copy number, and gene expression data from non-small cell lung cancer cohorts in the Cancer Genome Atlas (TCGA). Chr19p is frequently deleted across cancers in the TCGA dataset, with higher rates in lung adenocarcinoma. In both lung adenocarcinoma and squamous cell carcinoma, nearly half of TCGA tumors have deletion of chr19p including STK11, KEAP1, and SMARCA4, and these tumors are enriched for STK11 mutation. Immune infiltrate (estimated by methylation patterns) was not significantly associated with STK11 mutation but was significantly reduced in tumors with chr19 deletion when controlling for tumor type and overall copy number load. In addition, low-level deletion of any of these genes correlated with decreased expression of immune signaling pathways. Based on these findings, we next wanted to characterize the association between chr19p copy number and immunotherapy response. We previously reported that low-level deletion of STK11 correlated with an immunosuppressive, treatment-refractory phenotype in samples collected from non-small cell lung cancer (NSCLC) patients with resectable disease in a phase II study of neoadjuvant atezolizumab + chemotherapy. To confirm these findings in a larger cohort, we examined the AACR GENIE NSCLC biopharma collective (BPC) dataset. A subset of this cohort included patients treated with immunotherapy (atezolizumab, nivolumab, and/or pembrolizumab) and with copy number data available or GISTIC analysis of individual genes (n = 204). Here, deletion of any of these three genes correlated with worse overall survival, and this was statistically significant for STK11 deletion. Overall, our data suggests that a broader set of patients, defined by copy number changes in these genes, may experience this adverse immunobiology. Further study to elucidate the mechanistic implications of this association is warranted. Citation Format: Brian S. Henick, Yohanna Georgis, Benjamin O. Herzberg, Carla P. Concepcion-Crisol, Alison M. Taylor. Copy number alterations in chromosome 19 genes associate with reduced immune infiltrate and adverse outcomes in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3634.