Lung Cancer Research Articles

β-blockers and statins: exploring the potential off-label applications in breast, colorectal, prostate, and lung cancers

Despite advances in cancer treatment, current cancer incidence and prevalence still demand multimodal treatments to enhance survival and clinical outcomes. Drugs used in cardiology, such as β-blockers and statins have gained attention for their potential roles in oncology. This review focused on their possible complementary use in solid tumors, including breast, colorectal, lung, and prostate cancers. The involvement of the autonomic nervous system in promoting tumor growth can be disrupted by β-blockers, potentially hindering cancer progression. Statins, known for their pleiotropic effects, may also inhibit cancer growth by reducing cholesterol availability, a key factor in cell proliferation. We will provide an update on the impact of these therapies on cancer treatment and surveillance, discuss the underlying mechanisms, and explore their effects on the heart, contributing to the growing field of cardio-oncology.

Lung cancer mortality attributable to residential radon in Germany.

The radioactive gas radon is one of the most important risk factors for lung cancer after smoking. This article aims to estimate the annual number of lung cancer deaths attributable to residential radon exposure in Germany and its federal states using updated data and an advanced calculation method. Data on lung cancer mortality (2018-2022), smoking behavior (2017), and on the estimated distribution of radon concentration based on a radon residential study (2019-2021) in Germany are used. The risk model employed is derived from the pooled European residential radon study, indicating that excess relative risk for lung cancer increases by 16% per 100 becquerels per cubic meter (Bq/m ) of corrected long-term radon concentration. It is estimated that a total of around 2800 lung cancer deaths per year (95% confidence interval (CI) 900-5100) are attributable to residential radon in Germany. This represents a population attributable fraction of 6.3% (95% CI 2.1-11.4%). Notably, radon-attributable lung cancer deaths occur not only among current (41%) but also significantly among former smokers (41%) and those who have never smoked (19%). The results confirm that radon in homes is an important risk factor for lung cancer, highlighting the need for protective measures against radon for all population groups in Germany.

Multi-center study on the application potential of Siaα-2,6Gal in early and differential diagnosis of lung cancer.

This study aimed to investigate the application potential of the abnormal glycan structure Siaα-2,6Gal in the early and differential diagnosis of lung cancer. Clinical data and serum samples from 730 patients and 120 healthy individuals participating in clinical trials on Siaα-2,6Gal were collected at three medical centers between January 2022 and June 2023. The levels of Siaα-2,6Gal, carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen (CYFRA21-1), squamous cell carcinoma antigen (SCC), neuron-specific enolase (NSE), and pro-gastrin-releasing peptide (ProGRP) in serum were measured. The application potentials of these markers in the early and differential diagnosis, classification, and staging of lung cancer were explored. (1) Serum Siaα-2,6Gal levels in the lung cancer group were 2,606 (1,970-3,458) U/mL, significantly higher than those in the benign lung disease, miscellaneous malignant tumor, miscellaneous benign disease, and healthy individual groups at 1,359 (950-1,528), 1,252 (903-1,532), 1,196 (850-1,490), and 1,210 (1,100-1,287) U/mL (P < 0.0001). (2) Serum Siaα-2,6Gal levels in the early-stage lung cancer (stages 0-II) group were 2,576 (1,929-3,338) U/mL, significantly higher than those in the benign pulmonary nodule group at 1,419 (1,105-1,820) U/mL (P < 0.0001). (3) Receiver operating characteristic curves showed that Siaα-2,6Gal had a high diagnostic efficiency for lung cancer (area under the curve (AUC) = 0.9217), significantly superior to CEA, CYFRA21-1, SCC, NSE, and ProGRP (AUCs of 0.6618, 0.6605, 0.5783, 0.5985, and 0.6381). Siaα-2,6Gal is a promising biomarker for lung cancer diagnosis and may offer superior differential diagnosis of early-stage lung cancer from benign pulmonary nodules compared to traditional tumor markers.

Abstract A006: Development of a circulating tumor cell-derived cancer organoid platform for drug screening against metastatic tumors and longitudinal monitoring of drug resistance

Abstract Metastatic disease remains the primary cause of cancer-related deaths, presenting a significant challenge in oncology drug development. Current drug screening efforts often rely on cell lines or primary tumor-derived models, which may not adequately mimic the behavior of metastatic tumors. To address this, we aimed to develop a system that more accurately reflects metastatic tumors for improved drug screening. We leveraged a specialized culture platform featuring patented coated plates and proprietary media developed by AcroCyte (Taiwan) to cultivate circulating tumor cells (CTCs) into cancer organoids without pre-selection or enrichment. Building on our previous work, where we successfully cultivated CTCs from fresh blood and cryopreserved peripheral blood mononuclear cells (PBMCs) from renal, colon, and lung cancer patients into cancer organoids, we have now demonstrated the ability to freeze these CTC- derived organoids and thaw them for new culture when needed. We also present new data extending this success to breast and prostate cancers. CTCs from five frozen PBMC samples from breast cancer patients and three from prostate cancer patients formed visible colonies, with positive immunostaining for EpCAM, cytokeratin, and CD44. The immune cells in the PBMC samples gradually died off within three weeks of culture, as confirmed by the absence of CD45- positive cells. Interestingly, CTC-derived organoids from breast and prostate cancers did not form the spheroids observed in renal, colon, and lung cancer models. Instead, they appeared as colonies or clusters of CTCs. After 6-8 weeks of active growth, these clusters exhibited a slower growth rate, although they remained viable in the proprietary culture system. We are actively evaluating various culture media supplements, tailored to breast and prostate cancers, to extend the active growth period of these CTC-derived organoids for longer durations. Importantly, these CTC-derived colonies retained drug sensitivity, demonstrating the system's potential for effective drug screening against metastatic tumors. Our platform now supports organoid development from renal, colon, lung, breast, and prostate cancers, and we are actively expanding to include all major solid tumors. Since this technology uses blood, which can be obtained non-invasively, it enables longitudinal monitoring of CTCs as a functional liquid biopsy. Additionally, frozen PBMCs can be used as a source material for CTCs, and the resulting organoids can be utilized for drug sensitivity testing. This platform could be instrumental in oncology drug development and holds promise for monitoring emerging drug resistance in clinical trials by analyzing PBMC samples collected before and after treatment, offering a functional liquid biopsy-based approach to aid in developing therapies targeting metastatic disease. Citation Format: Yi-chun Han, David Hsieh, Ruobo Zhang, Emily Miyashita-Lin, Shian-Jiun Shih. Development of a circulating tumor cell-derived cancer organoid platform for drug screening against metastatic tumors and longitudinal monitoring of drug resistance [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A006.

Spatial Analysis of Lung Cancer Patients and Associated Influencing Factors from the Perspective of Urban Sustainable Development: A Case Study of Jiangsu Province, China

With global environmental changes, lung cancer has become one of the most common types of cancer worldwide, posing a significant public health challenge. Jiangsu Province, located in the eastern part of China, is an economically and socially developed region. According to the latest cancer registration data in Jiangsu Province, lung cancer ranks first in both incidence and mortality of cancer in the province. Thus, studying the spatiotemporal distribution of lung cancer cases and analyzing the influence of various factors on this distribution are crucial for the effective prevention and control of the disease in Jiangsu Province. This study takes the statistical data of lung cancer patients in Jiangsu Province in 2020 as the research object, uses Geographic Information System (GIS) visualization and spatial analysis to study the spatial distribution characteristics of lung cancer patients in Jiangsu Province, and employs the geographical detector to numerically express the impact of various environmental factors on the distribution of lung cancer patients in Jiangsu Province. The results reveal a notable spatial clustering of lung cancer cases, with high-incidence areas concentrated in Suzhou, Nanjing, and Xuzhou cities. Among the seven environmental factors examined, PM2.5, SO2, and PM10 concentration exert the most significant influence. This study employs multifactorial spatial analysis to elucidate the intricate relationships between people’s health and air quality, medical resource distribution, and lung cancer incidence in the process of pursuing sustainable development in cities and provides an important reference for the improvement in lung cancer prevention and control strategies.

Abstract A075: Circulating T-cell receptor repertoire analysis improves cancer early detection

Abstract Introduction: Cancer screening by liquid biopsy promises to detect cancer early when it can be cured. However, current ctDNA-based approaches detect only a minority of early-stage cancers. For liquid biopsy to realize its full potential for cancer early detection, sensitivity for earliest stage disease must be improved. Methods: We set out to improve sensitivity of liquid biopsy by exploiting tumor recognition by T cells through sequencing of the circulating T-cell receptor repertoire. Using gDNA extracted from blood buffy coats, we studied a cohort of 471 lung cancer patients (85% stage I) and 600 subjects without cancer enriched for older individuals with a history of smoking. We performed TCR beta chain sequencing to yield a median of 101,899 TCR clonotypes per sample (median 81,602 cancer / 112,966 controls) and built a TCR sequence similarity graph to cluster clonotypes into TCR repertoire functional units (RFUs). The TCR frequencies of RFUs were tested for association with cancer status and significantly associated RFUs were combined using an SVM model into a cancer score. Cancer RFU levels were also correlated to imputed subject HLA types for 32 HLA Class I and 38 Class II alleles. The model was evaluated by 10-fold cross-validation and compared to a ctDNA panel of 237 mutation hotspots in 154 lung cancer driver genes and to 17 lung cancer related protein biomarkers in 86 subjects. Results: We identified 372 cancer-associated TCR RFUs at FDR≤0.1, including 198 enriched in cancer samples (fold-change range 1.03 to 3.13) and 174 enriched in controls (fold- change 0.96 to 0.30). Levels of 265/372 (71%) RFUs were correlated to presence of an HLA allele at FDR ≤ 0.1. Of the total 2,770 significant HLA-RFU associations, 479 (17%) involved an HLA Class I allele, while 2,291 (83%) involved an HLA Class II allele, highlighting a potential role for CD4 helper or regulatory T cell antigen recognition in the cancer RFUs found. The RFU cancer score achieved a cross-validated test ROC AUC of 0.71 for cancer status prediction (0.71 Stage I / 0.70 Stage II-IV) with 49% of Stage I cancers detected at a specificity of 80%. Importantly, the cancer score was not dependent on sample source site, technical or biological variation in TCR repertoire depth, or lung cancer histology subtype. The TCR RFU score also distinguished lung cancer patients from control subjects with other conditions such as benign lung nodules and COPD. We observed an up to ∼20%-point gain in sensitivity for stage I cancer when TCR RFUs were added to ctDNA and proteins in a potential multi-analyte cancer screening test. By contrast, TCR analysis did not provide additional sensitivity for stage II-IV disease. Conclusion: We demonstrate detection of a significant fraction of early lung cancer cases from blood by analyzing the circulating TCR repertoire and show that this signal is complementary to established analytes such as proteins and ctDNA. A similar study for the detection of early colorectal cancer and advanced adenomas is under way. Citation Format: Yilong Li, Michelle Nahas, Dennis Stephens, Kate Froburg, Emma Hintz, Devin Champagne, Amaneet Lochab, Markus Brown, Jasper Braun, María Antonia Fortuño, María-del-Mar Ocón, Andrea Pasquier, Inés María Luque, Christopher W. Seder, Jeffrey A. Borgia, Luis Miguel Seijo, Luis M Montuenga, Roman Yelensky. Circulating T-cell receptor repertoire analysis improves cancer early detection [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A075.

Associations of radiotherapy receipt with lung cancer risk by histological subtype among breast cancer survivors in the United States.

Radiotherapy for breast cancer has been associated with an increased risk of secondary malignancies, including primary lung cancer. Whether this association varies by histological subtype of lung cancer remains unknown. Based on the data from 12 Surveillance, Epidemiology, and End Results registries, we examined the association between radiotherapy receipt and the risk of subtype-specific subsequent primary lung cancer (SPLC) among female first primary breast cancer cases diagnosed between ages 20 and 84 from 1992 to 2020. More than half (53%) of the 550,007 breast cancer survivors identified had undergone radiotherapy as part of their initial breast cancer treatment. Over an average follow-up of 9.7 years, 8014 survivors developed SPLCs. For small-cell carcinoma, the standardized incidence ratio (SIR) compared with the general population was higher for survivors who received radiotherapy (SIR = 1.15, 95% confidence interval [CI] = 1.06-1.25) but similar for those who did not receive radiotherapy (SIR = 1.00, 95% CI = 0.91-1.09), with the difference in SIRs being statistically significant (p = .003). Similar associations were found for squamous cell carcinoma (SIRyes = 1.16, 95% CI = 1.08-1.24 vs. SIRno/unknown = 1.06, 95% CI = 0.98-1.15; p = .07). The increased risks were confined to ipsilateral SPLC, with the greatest SIRs for small-cell carcinoma occurring 5-10 years since breast cancer diagnosis (SIR = 1.83, 95% CI = 1.53-2.19) and for squamous cell carcinoma with a latency of 10 years or more (SIR = 1.64, 95% CI = 1.42-1.88). In contrast, the risk of developing adenocarcinoma did not vary by radiotherapy receipt (SIRyes = 1.23, 95% CI = 1.18-1.28 vs. SIRno/unknown = 1.17, 95% CI = 1.12-1.22; p = .18), indicating additional risk factors in play. The findings suggest a distinct carcinogenic pathway of radiation-induced lung cancer across histological subtypes and may inform risk-stratified surveillance guidelines for SPLC.

Efficacy and safety of CalliSpheres drug-eluting bead bronchial arterial infusion chemoembolization vs. bland embolization in advanced lung cancer with hemoptysis: A multicenter retrospective study.

Massive hemoptysis is a life-threatening complication in patients with advanced primary lung cancer, and effective, safe treatments are crucial. This study aimed to investigate the efficacy and safety of CalliSpheres drug-eluting bead bronchial arterial infusion chemoembolization (DEB-BACE) for managing this condition. A retrospective analysis included 144 patients with advanced primary lung cancer and massive hemoptysis treated at multiple hospitals from January 2019 to January 2023. Patients undergoing bronchial artery embolization were divided into two groups: the observation group (n=76) received CalliSpheres DEB-BACE with epirubicin, and the control group (n=68) received 8spheres blank embolization. Both groups achieved successful hemostasis, with no statistically significant difference in success rates (observation group: 88.16%, control group: 86.76%). However, the observation group had a significantly longer median duration without hemoptysis (96 days vs. 50 days). Two months post-therapy, the observation group showed higher objective response rates (82.89% vs. 38.24%) and disease control rates (92.11% vs. 66.18%) compared to the control group. Adverse reactions were manageable and similar between groups, with no serious complications observed. By January 31, 2024, the observation group had significantly longer median overall survival (11 months vs. 7 months). The DEB-BACE treatment demonstrates safety and efficacy in managing massive hemoptysis in patients with advanced lung cancer. However, the superiority of this approach over bland embolization remains to be established through well-designed prospective studies. Future research is anticipated to provide a definitive comparison and further validate the role of DEB-BACE in clinical practice.

Trends and Projections of Mortality Attributed to Occupational Neoplasms and Occupational Tracheal, Bronchus, and Lung Cancer in the World, G7 Countries and Turkey

Background: The most important and remarkable aspect of occupational neoplasms is that they are preventable. We aimed to examine the trends and projections of mortality rates attributed to occupational neoplasms (MAON) and occupational tracheal, bronchus, and lung cancer (MAOLCa) in the world, G7 countries, and Turkey from 1990 to 2040. Methods: The study was ecological one. Data for the study were obtained from the Global Burden of Disease (GBD) Foresight Visualization. For the study, time points were set every five years. For each time point, the age-standardized MAON, MAOLCa, and their 95% confidence intervals (CIs) were recorded. Rates were analyzed by joinpoint regression analysis. Results: Globally, MAON was projected to decrease from 3.81% in 1990 to 2.83% in 2040. According to the joinpoint regression analysis, the joint year for the world was 2020. In Germany, the US, the UK, Italy, Canada and Turkey, the trend for MAON showed a decrease, similar to the global trend. However, MAON was stable in France and increased in Japan. Globally, MAOLCa was expected to decline gradually from 19.44% to 16.82% from 1990 to 2040. In the US, France and Turkey, the trend for MAOLca decreased, similar to the global trend. However, it was stable in the UK, Italy, and Canada and increased in Germany and Japan. Conclusion: MAON tended to decrease worldwide and in the six countries, except France and Japan. MAOLCa tends to decrease worldwide, in the US, France, and Turkey, increase in Germany and Japan, and remain stable in the UK, Italy, and Canada.

Abstract A057: Cancer-induced epigenomic changes in circulating immune cells enable breast, colorectal and lung cancer detection

Abstract Background: Epigenomic changes via the measurement of 5-hydroxymethylation cytosine (5hmC) in DNA have been shown to enable detection in a variety of cancers including pancreatic and ovarian cancer in plasma-derived cell-free DNA (cfDNA). Here, we investigated whether blood-based 5hmC profiling of genomic DNA (gDNA) derived from cells of the buffy coat (BC) possess signals that enable the detection of breast, colorectal and lung cancers. Method: Blood samples collected in Streck tubes from cancer patients or non-cancer controls were processed to obtain buffy coat and plasma samples. gDNA and cfDNA was isolated from buffy coat and plasma, respectively. gDNA or cfDNA was then subjected to 5hmC enrichment by click chemistry followed by preparation of sequencing libraries. Sequencing was performed to obtain genome-wide 5hmC profiles of buffy coat gDNA and cfDNA samples. Results: Differential hydroxymethylation analysis of BC gDNA revealed increased 5hmC over genes associated with myeloid lineage in breast, colorectal and lung cancers relative to non-cancer controls. Flow cytometry analysis confirmed increases in myeloid cells in cancer samples relative to non-cancer controls. 5hmC patterns in BC gDNA showed a larger number of cancer-associated changes compared to cfDNA, in particular this was found in early-stage disease. 5hmC features from BC gDNA or plasma-derived cfDNA were used to build prediction models that yielded cancer classification with overall sensitivity of 51.3% and 52.6% at 98% specificity, for BC or cfDNA, respectively. For early-stage cancer, the sensitivity at 98% specificity was 46.5% for the BC and 28.2% for cfDNA model. A final prediction model incorporating features from both tissue sources achieved superior classification (65.8% sensitivity) at 98% specificity, compared with using features from either tissue source alone, particularly for early-stage cancer which achieved 53.5% sensitivity of cancer detection. Conclusion: Our results demonstrate that cancer impacts the 5hmC profiles of buffy coat cells which can be leveraged for cancer detection using blood. Citation Format: Gulfem D Guler, Giuliana P Mognol, Yuhong Ning, Carolina Fraire, David Haan, Michael Kesling, Roger Malta, Melissa Peters, Anna Bergamaschi, Tierney Phillips, Shimul Chowdhury, Wayne Volkmuth, Samuel Levy. Cancer-induced epigenomic changes in circulating immune cells enable breast, colorectal and lung cancer detection [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A057.

Abstract B043: Molecular profiling of serially collected cerebrospinal fluid uncovers therapy-resistant subclones in recurrent leptomeningeal metastatic disease

Abstract Leptomeningeal metastatic disease (LMD) is the spread of cancer cells to the cerebrospinal fluid (CSF)-filled spaces surrounding the central nervous system. After symptom onset, LMD patients survive for only weeks to months while enduring devastating neurologic symptoms. Current clinical tools to diagnose LMD, such as CSF cytology and magnetic resonance imaging, do not detect mutations susceptible to treatment, quantitatively monitor response to therapy, or identify mutation-based resistance mechanisms. Here, we sought to profile LMD using next-generation sequencing by studying CSF-derived cell-free DNA (CSF-cfDNA) from 9 breast cancer and 5 lung cancer patients with LMD and 4 LMD-negative controls. To conduct an unbiased search for somatic mutations, we used a custom-designed gene panel and our validated True2 sequencing workflow with a specificity of &amp;lt;1 false positive per 100kb panel positions and a 97.6% sensitivity for detecting single nucleotide variants (SNVs) with a variant allele frequency (VAF) ≥0.1%. Although CSF-cfDNA quantity ranged widely (&amp;lt;1 to 91 ng), genomic alterations were observed in 100% of LMD patients vs. none in the controls. In 13 patients with a SNV, an average of 4.5±3.3 variants were detected with a VAF ranging from 0.051% (HER2 p.S1151L associated with a 12-fold amplification and read depth of 25,542X) to 98.7% (PTEN p.Q733X associated with a loss of heterozygosity). Importantly, subclones in cancer driver genes were detected in 10 of 13 (76.9%) samples consistent with a high prevalence in LMD. Somatic mutations in genes common to both cancers were discovered (e.g., TP53, KMT2D, and EGFR), while other affected genes segregated based on cancer type (e.g., PIK3CA, ATM, and CDH1 in breast cancer; PTEN, MTOR and PDGFRA in lung cancer). An amplification or deletion was detected in 10 of 14 patients (71.4%), a subset of which segregated by cancer type (e.g., HER2 and ESR1 amplifications in breast cancer; CDKN2A and TP53 codeletions in lung cancer). Using serially collected CSF samples, we observed: (1) loss of subclones in response to therapy followed by resurgence at clinical recurrence showing suppression of disease but not eradication; (2) multiple subclones in the same gene supporting evidence of convergent evolution; and (3) emergence of new subclones at clinical recurrence consistent with mutation evolution in response to therapy. For example, in a breast cancer patient with a known HER2 amplification receiving intrathecal Trastuzumab, a previously absent HER2 p.V777L mutation was present at the end of therapy with a VAF of 18.6% which increased at clinical recurrence to 94.8% in association with a 2.4-fold HER2 amplification indicating the mutated HER2 subclone was already therapy-resistant. Our findings support a panel-based approach to detect and monitor LMD-derived somatic mutations using CSF-cfDNA. Moreover, the untargeted search for somatic mutations via True2 has the potential to guide personalized, adaptive therapeutics for LMD patients which may prove essential in improving patient survival. Citation Format: Yingqi Zhang, Rachna Malani, Charlie S Dean, Laura A Boatz, Brion E Harrison, Mei Wei, Wallace Akerley, Mary P Bronner, Hunter R Underhill. Molecular profiling of serially collected cerebrospinal fluid uncovers therapy-resistant subclones in recurrent leptomeningeal metastatic disease [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B043.

Two-Year Experience of a Center of Excellence for the Comprehensive Management of Non-Small Cell Lung Cancer at a Fourth-Level Hospital in Bogota, Colombia: Observational Case Series Study and Retrospective Analysis

Background: This study aimed to provide a comprehensive analysis of 56 patients admitted to the Lung Cancer Clinical Care Center (C3) at Fundación Santa Fe de Bogotá (FSFB) between 2 May 2022 and 22 April 2024. The focus was on demographic characteristics, smoking history, comorbidities, lung cancer types, TNM classification, treatment modalities, and outcomes. Methods: This observational case series study reviewed medical records and included patients over 18 years with a confirmed diagnosis of non-small cell lung cancer (NSCLC). Data were collected and analyzed for demographics, comorbidities, treatment types, biomolecular profiling, and survival rates. Ethical approval was obtained, and data were anonymized. Results: The mean age was 71.8 years with a female predominance (53.6%). A history of smoking was present in 71.4% of patients. Adenocarcinoma was the most common type (75.0%), followed by squamous cell carcinoma (19.6%). At admission, the most frequent TNM stages were IA2 (17.9%) and IVA (16.1%). One-year survival was 68.8%, and 94.3% of stage I–IIIA patients underwent PET scans. Biomolecular profiling revealed 69.2% non-mutated EGFR, 90.4% ALK-negative, and various PDL-1 expression levels. Immunotherapy was received by 91.4% of patients, with Alectinib and Osimertinib being common. Grade III–IV pneumonitis occurred in 5.4% of patients. Conclusions: The study’s findings align with existing literature, highlighting significant smoking history, common adenocarcinoma, and substantial use of immunotherapy. Limitations include the observational design, small sample size, and short follow-up period, impacting the generalizability and long-term outcome assessment. Future research should address these limitations and explore longitudinal outcomes and emerging therapies.

Abstract A025: Tumor fraction (TF) is associated with real-world progression-free survival (rwPFS) in advanced non-small-cell lung cancer (aNSCLC) patients treated with chemotherapy (chemo)

Abstract Background: Genomic ctDNA molecular response (gMR) predicts clinical benefit from immune checkpoint inhibitors, but associations with benefit from chemo are inconsistent. gMR may predict benefit from chemo after filtering to tissue-confirmed somatic variants, suggesting interference from clonal hematopoiesis (CH) mutations. Using methylation tumor fraction (TF) for MR assessment may mitigate the risk of CH interference without tissue and with higher sensitivity. Here, we report a retrospective study assessing the feasibility of using methylation- based TF from the Guardant Infinity platform to predict clinical benefit from chemo in a real- world cohort of patients (pts) with aNSCLC. Methods: Plasma samples were analyzed from pts (n=67) with aNSCLC, undergoing treatment with chemo only in 1st line or later setting, who had serial methylation TF results from tissue-free genomic and epigenomic ctDNA NGS. The present analysis included 27 pts with a baseline sample (T1) within 105 days prior to treatment start and an on-treatment timepoint (T2) 2-15 weeks after treatment start and &amp;gt;10 days prior to treatment end. gMR was based on the % change in mean variant allele fraction (VAF) T2/T1. TF % change was defined as TF (T2) / TF (T1). Relationships between time-to-next- treatment (TTNT; proxy for progression-free survival) and gMR or TF % change from T1 to T2 were explored using Cox proportional hazards (CPH) analysis. Multiple cutpoints were evaluated to label pts as molecular responders or non-responders for outcomes analysis. Gender, age, and therapy line were included as covariates for all analyses. Results: A ctDNA change from T1 to T2 was quantifiable in 85% of pts (18/27) by TF change versus 67% of pts by gMR due to improved limit of quantification for TF relative to somatic variants. CPH revealed that gMR defined by any ctDNA % change threshold was not associated with TTNT (p=(0.182- 0.862)). However, pts with a ≥95% decrease in TF from T1 to T2 had a significant association with improved TTNT (HR 0.14; 95% CI (0.03, 0.80); p=0.027). Furthermore, molecular responders defined by any decrease cutpoint &amp;gt;70% were significantly associated with improved TTNT (p≤0.033). Conclusions: A decrease in TF &amp;gt;70% early during chemotherapy was significantly associated with improved TTNT, even in this small cohort. The change in ctDNA was quantifiable in more patients by TF change than by gMR and included patients with no somatic variants detected. In contrast, gMR defined by any ctDNA % change threshold was not associated with TTNT. These results demonstrate feasibility of methylation-based TF to predict benefit from chemo in aNSCLC patients without tissue and with higher sensitivity than gMR, laying groundwork for future studies to address validity of serial TF monitoring in this patient population. Citation Format: Jing Wang, Sean Gordon, Errin Lagow, Tara Dinman, Carin Espenschied, Shile Zhang, Kimberly Banks. Tumor fraction (TF) is associated with real-world progression-free survival (rwPFS) in advanced non-small-cell lung cancer (aNSCLC) patients treated with chemotherapy (chemo) [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A025.

New strategies for lung cancer diagnosis and treatment: applications and advances in nanotechnology.

Lung cancer leads in causing cancer-related mortality worldwide, continually posing a significant threat to human health. Current imaging diagnostic techniques, while offering non-invasive detection, suffer from issues such as insufficient sensitivity and the risks associated with radiation exposure. Pathological diagnosis, the gold standard for confirmation, also faces challenges like invasiveness and high costs. In treatment, surgery, radiotherapy, and chemotherapy are the main modalities, each encountering challenges related to precision, environmental adaptability, and side effects. Nanotechnology's advancement provides new solutions for the diagnosis and treatment of lung cancer, promising to enhance diagnostic accuracy and reduce side effects during treatment. This article introduces the main types of nanomaterials used in the field of lung cancer, offering a comprehensive overview of current research on the application of nanotechnology in early screening, diagnosis, treatment, and monitoring of lung cancer, and summarizing ongoing clinical research findings.

Abstract B025: Monitoring response to immunotherapy in lung cancer using cell-free DNA fragmentomes

Abstract BACKGROUND: Immune checkpoint inhibition (ICI) continues to be a promising area of research with treatments continuing to show efficacy in late-stage cancers. The detection of disease progression for patients undergoing treatment with this modality remains challenging however given the lack of reliable biomarkers for which to monitor disease. Current methods including imaging can be challenging to evaluate as they do not always capture the timing and nature of clinical responses. Liquid biopsies may offer a solution by allowing for minimally invasive tumor monitoring during therapy. We previously reported on the DELFI Tumor Fraction (DELFI-TF) algorithm, as a tumor- and mutation-naive approach to monitoring using cell-free DNA (cfDNA) fragmentomes (Alipanahi et al., AACR 2023). In this study we examine the performance of DELFI-TF in a cohort of patients with metastatic NSCLC treated with ICI. METHODS: Longitudinal blood samples (n=323) were collected from NSCLC patients (n=109) which received ICI therapy. Whole genome sequencing at low coverage (∼4x) was performed following cfDNA extraction. DELFI-TF scores, predicted using fragmentome features, were used to monitor changes in circulating tumor DNA (ctDNA) levels and associated variations in disease burden. Predictions from DELFI-TF were compared to maximum observed mutation allele frequencies (maxMAF) from a targeted sequencing gene panel for the same samples. In order to determine the prognostic performance of DELFI-TF we evaluated ctDNA changes at baseline and within 3 to 9 weeks of ICI initiation. The presence of undetectable DELFI-TF, defined as below the observed limit of blank (LOB) within 3 to 9 weeks of ICI initiation, indicated a molecular response (mR). In contrast, the persistence of DELFI-TF within this interval signified molecular disease progression (mPD). RESULTS: We observed a strong correlation between DELFI-TF predictions and maxMAF (r=0.93, p&amp;lt;0.001). Further, changes in ctDNA predictions from baseline to the first post-treatment timepoint showed a high correlation between DELFI-TF and maxMAF (r=0.94, p&amp;lt;0.001). Patients with a higher disease burden prior to immunotherapy, as predicted by DELFI-TF and maxMAF, had shorter overall survival (OS) compared to patients with a lower disease burden (DELFI-TF: 11.4 v 33.0 months, p=0.006; maxMAF: 7.82 vs low 33.0 months, log-rank p=0.001). Among 79 patients evaluable for molecular response, 28 (35%) were classified as mPD and 51 (65%) were classified in the mR category. Patients with mR attained longer progression free survival (PFS;16.04 v 2.70 months, log-rank p&amp;lt;0.001) compared to those in the mPD group. Furthermore, assessment of landmark PFS at 6 months revealed a significant association between ctDNA molecular response and durable clinical benefit (DCB; p &amp;lt; 0.001, Fisher’s exact test). CONCLUSIONS: DELFI-TF is a low-cost, tumor and mutation naive approach that accurately monitors longitudinal dynamic changes in tumor burden and captures durable therapeutic responses in patients with metastatic NSCLC receiving immunotherapy. Citation Format: Lavanya Sivapalan, Bahar Alipanahi, Jamie E Medina, Bridget Tripp, Zachary L Skidmore, Paola Ghanem, Gavin Pereira, Nisha Rao, Kavya Velliangiri, Caitlin Schonewolf, Noushin Niknafs, Bryan Chesnick, Jennifer Tom, Stephen Cristiano, Peter Bach, Nicholas C Dracopoli, Robert B Scharpf, Victor Velculescu, Lorenzo Rinaldi, Valsamo Anagnostou. Monitoring response to immunotherapy in lung cancer using cell-free DNA fragmentomes [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B025.

Chemiluminescent Fe3O4@Nickel-Cobalt Double Hydroxide Magnetic Core-Shell Nanomaterial as an Analytical Interface for Label-Free CYFRA21-1 Immunosensing.

Cytokeratin 19 fragment (CYFRA21-1) is considered to be a potential marker for the diagnosis and of classification of lung cancer. It is highly desired to develop rapid and highly sensitive label-free chemiluminescence (CL) immunosensors for the detection of CYFRA21-1. In this work, magnetic core-shell nanocomposite Fe3O4@nickel-cobalt double hydroxide (Fe3O4@DH) was used for the first time as a carrier to synthesize N-(4-aminobutyl)-N-ethylisoluminol (ABEI) and gold and silver nanocluster (AuAgNC) bifunctionalized magnetic nanomaterials Fe3O4@DH/AuAgNCs-ABEI. The resulting Fe3O4@DH/AuAgNCs-ABEI demonstrated excellent CL performance, attributed to the exceptional catalytic capability of nickel-cobalt double hydroxide (NiCo-DH) and AuAgNCs, as well as the large specific surface area of NiCo-DH for AuAgNCs and ABEI enrichment. Moreover, Fe3O4@DH/AuAgNCs-ABEI exhibited superior stability compared to Fe3O4-based CL-functionalized magnetic nanomaterials, owing to the presence of NiCo-DH shells. On this basis, a label-free CL immunosensor using CYFRA21-1 antibody-modified Fe3O4@DH/AuAgNCs-ABEI as an analytical interface was constructed for the detection of CYFRA21-1 in the range from 1.0 × 10-13 to 1.0 × 10-8 g/mL. The detection limit of this CL immunosensor was 47.7 fg/mL, 4 orders of magnitude lower than existing CL methods. The CL immunosensor was able to accurately detect the concentration of CYFRA21-1 in serum samples, as evidenced by ELISA results. More importantly, it not only distinguished well between healthy persons and lung cancer patients (90.0% sensitivity and 90.0% specificity), but also effectively distinguished between patients with non-small cell lung cancer and small cell lung cancer (80.0% sensitivity and 86.7% specificity).

Risk Factors of Immune-Mediated Hepatotoxicity Induced by Immune Checkpoint Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis

Immune checkpoint inhibitors (ICIs) significantly improve survival, while immune-mediated hepatotoxicity (IMH) has been reported. To evaluate the incidence and potential risk factors of IMH among cancer patients treated by ICIs, PubMed/Medline, Web of Science, Cochrane, and Embase were searched before 30 March 2024 for systematic review and meta-analysis. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated. Quality assessment was completed using the Newcastle–Ottawa scale. Of 1217 articles identified, 24 consisting of 9076 patients were included, with one study being prospective and the rest retrospective. The overall incidence of any grade IMH and grade ≥ 3 secondary to ICIs was 14% and 7%, respectively. The cholestatic pattern was more prevalent than the hepatocellular and mixed patterns. The meta-analysis revealed that ICI treatment was related to reduced risk of IMH in older patients (SMD: −0.18; 95% CI: −0.33 to −0.04), individuals with higher body mass index (WMD: −2.15; 95% CI: −3.92 to −0.38), males (OR: 0.44; 95% CI: 0.27 to 0.72), and patients with lung cancer (OR: 0.58, 95%CI 0.41 to 0.83). On the other hand, patients with liver metastasis (OR: 1.80; 95% CI: 1.47 to 2.20), history of ICI treatment (OR: 3.09; 95% CI: 1.21 to 7.89), diabetes (OR: 2.19; 95% CI: 1.36 to 3.51), chronic HBV (OR: 3.06; 95% CI: 1.11 to 8.46), and concomitant use of ICIs (OR: 8.73; 95% CI: 2.41 to 31.59) increased the risk of developing IMH. This study will provide clinicians with information on potentially high-risk groups for IMH, who need to be cautiously monitored for liver function when receiving immunotherapy.

Abstract IA026: Methods for tumor subtype classification using cell-free DNA

Abstract Accurately diagnosing the tumor histological subtype is crucial for clinical care. Changes in subtype can emerge during treatment resistance. However, obtaining a biopsy to determine the tumor histology presents challenges for patients with advanced cancers. Circulating tumor DNA (ctDNA) is a non-invasive 'liquid biopsy' solution that overcomes this limitation of tissue accessibility. Current ctDNA approaches primarily focuses on detecting genetic mutations, but these alterations alone may not fully delineate tumor histological subtypes or explain treatment resistance. Recent advancements highlight the value of epigenetic information obtained from profiling nucleosome positioning and accessibility in ctDNA. I will discuss how we applied these concepts to develop computational methods for predicting transcriptional activity and classifying tumor subtypes and phenotypes in breast, prostate, and lung cancers. These tools have applications in monitoring treatment-induced phenotype changes and expand on the utility of ctDNA for precision oncology. Citation Format: Gavin Ha. Methods for tumor subtype classification using cell-free DNA [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr IA026.

The molecular features of lung cancer stem cells (LCSCs) in dedifferentiation process-driven epigenetic alterations.

Cancer stem cells (CSCs) may be dedifferentiated somatic cells following oncogenic processes, representing a subpopulation of cells able to promote tumor growth with their capacities for proliferation and self-renewal, inducing lineage heterogeneity, which may be a main cause of resistance to therapies. It has been shown that the "less differentiated process" may have an impact on tumor plasticity, particularly when non-CSCs may dedifferentiate and become CSC-like. Bidirectional interconversion between CSCs and non-CSCs has been reported in other solid tumors, where the inflammatory stroma promotes cell reprogramming by enhancing Wnt signaling through NF-κB activation in association with intracellular signaling, which may induce cells' pluripotency, the oncogenic transformation can be considered another important aspect in the acquisition of "new" development programs with oncogenic features. During cell reprogramming, mutations represent an initial step towards dedifferentiation, in which tumour cells switch from a partially or terminally differentiated stage to a less differentiated stage that is mainly manifested by re-entry into the cell cycle, acquisition of a stem cell-like phenotype and expression of stem cell markers. This phenomenon typically shows up as a change in the form, function, and pattern of gene and protein expression, and more specifically, in CSCs. This review would highlight the main epigenetic alterations, major signaling pathways and driver mutations in which cancer stem cells, in tumors and specifically, in lung cancer, could be involved, acting as key elements in the differentiation/dedifferentiation process. This would highlight the main molecular mechanisms which need to be considered for more tailored therapies.

Enhancing disease risk gene discovery by integrating transcription factor-linked trans-variants into transcriptome-wide association analyses.

Transcriptome-wide association studies (TWAS) have been successful in identifying disease susceptibility genes by integrating cis-variants predicted gene expression with genome-wide association studies (GWAS) data. However, trans-variants for predicting gene expression remain largely unexplored. Here, we introduce transTF-TWAS, which incorporates transcription factor (TF)-linked trans-variants to enhance model building for TF downstream target genes. Using data from the Genotype-Tissue Expression project, we predict gene expression and alternative splicing and applied these prediction models to large GWAS datasets for breast, prostate, lung cancers and other diseases. We demonstrate that transTF-TWAS outperforms other existing TWAS approaches in both constructing gene expression prediction models and identifying disease-associated genes, as shown by simulations and real data analysis. Our transTF-TWAS approach significantly contributes to the discovery of disease risk genes. Findings from this study shed new light on several genetically driven key TF regulators and their associated TF-gene regulatory networks underlying disease susceptibility.