tbuckley/cabot-search huggingface dataset:
Smoking and pathogenic germline variants in patients with lung cancer.
Authors: Ed Esplin, Sarah M. Nielsen Young, Emily M. Russell, Rachel Ellsworth, Brandie Heald, Alexander S Watson, Dara L. Aisner, W. Michael Korn
Journal: Journal of Clinical Oncology (2024)

8040 Background: Few studies have investigated the correlation of smoking history with pathogenic germline variants (PGVs) in patients diagnosed with lung cancer. With emerging opportunities for PGVs in DNA damage-repair (DDR) genes to inform precision therapies, we investigated the prevalence of PGVs in patients with lung cancer, stratified by smoking status. Methods: Germline genetic testing (GGT) (Invitae Corp.) and insurance claims (Komodo Healthcare MapTM) data were reviewed for 14,317 patients with an ICD code for lung cancer from 2015-2023 and hereditary cancer GGT of ≥ 10 genes. PGV rates were assessed overall, in DDR genes and in lung cancer related genes. Smoking history was defined by ICD codes. Number of genes tested varied per ordering clinician preference. Clinically actionable PGVs were defined as those associated with clinical management recommendations or trial eligibility per current standard of care guidelines. Chi-square tests were used with significance set to p &lt; 0.05. Results: The cohort was predominantly female (70.9%), white (65.7%), and over half had a history of smoking (57.1%). PGVs in 73 known cancer-risk genes were identified in 1,804/14,317 (12.6%) patients. Frequencies of PGV were 12.6% (1,026/8,175) in patients with smoking history compared to 12.7% (778/6,142) in those with no reported smoking history. There was no statistically significant difference in DDR gene, TP53, or EGFR PGV rates for patients with or without smoking history (p &gt; 0.05). Mean (SD) age of lung cancer diagnosis was significantly younger for patients with a history of smoking and DDR PGVs (61 (11)) compared to those with negative results (62 (12), p = 0.005). There was no significant difference in age of diagnosis between patients with no smoking history and DDR PGVs (60 (12)) and those with negative results (59 (13), p = 0.888). PGV rates by clinician-reported ancestry: Black/African-American, 9%; Asian or Pacific Islander, 11%; Hispanic, 12%; White, 13%. Among genes with &gt; 1,000 patients tested, PGVs were most common in BRCA2 (2.2%), CHEK2 (2.0%), ATM (1.6%), SPINK1 (1.6%), and BRCA1 (1.2%). Conclusions: In 14,317 patients with lung cancer, 12.6% had PGVs. There was no significant difference in enrichment of PGVs in DDR genes when patients were stratified by reported smoking history, suggesting the enrichment of these genes is independently associated with lung cancer. The age of onset for patients with DDR gene PGVs varied with smoking history, suggesting that risk conferred by these PGVs could be additive to smoking risk. These data reinforce prior studies supporting consideration of GGT for all patients with lung cancer, independent of age or reported smoking history.
Neoadjuvant and perioperative immunotherapy in resectable non-small cell lung cancer (NSCLC): A systematic review and extracted individual patient data meta-analysis.
Authors: Mateus Trinconi Trinconi Cunha, Rubens Copia Sperandio, Kelvin K. Chan, Ines B. Menjak
Journal: Journal of Clinical Oncology (2024)

8045 Background: Neoadjuvant and perioperative immunotherapy are emerging approaches for resectable NSCLC. However, survival outcomes are still immature and subgroup analyses are underpowered. We report extracted individual patient (pt) data (eIPD) and trial-level (TL) meta-analyses of phase II and III randomized controlled trials (RCTs) in this setting. Methods: The systematic review included Cochrane, Embase, and major oncology conferences (ASCO annual meetings, ESMO meetings, WCLC meetings). Primary objectives were eIPD event-free survival (EFS) and overall survival (OS). Secondary objectives included eIPD and TL meta-analysis of subgroups. Kaplan-Meier plots of time-to-event outcomes were reconstructed with WebPlotDigitizer (v4.6, 2022), and eIPD was estimated with IPDfromKM (v0.1.10, 2020) stratified by study. Comparisons between arms were made in a 1-stage model with a Cox Proportional Hazards model stratified by study. The difference of restricted mean survival time (D-RMST), a quantification of the postponement of an event during a specified interval, was used to compare survival when the proportional hazard assumption (PHA) was violated, tau being the shortest follow-up time of the available trials. TL meta-analysis was performed with a random effects model. This meta-analysis was registered in the PROSPERO database under CRD42024502150. Results: Seven RCTs (AEGEAN, CM816, CM77T, KN671, NADIM II, NeoTorch, and Lei et al. [ESMO IOTECH 2022, #56O]) were identified, comprising 2995 pts. EFS analysis included all pts, with HR of 0.58 (0.52-0.65; p&lt;0.01). OS analysis (1645 evaluable pts from 4 trials) showed a D-RMST of 5.17 mo. (p&lt;0.01) due to PHA violation. Full eIPD analysis in the table. TL meta-analysis showed benefit in all subgroups, including PD-L1 expression, histology, stage, smoking status, sex, and age. TL EFS and OS results were comparable to results obtained from eIPD analysis, with low heterogeneity measures. Conclusions: This meta-analysis provides robust and nuanced insights into the positive impact of immunotherapy in resectable NSCLC. While evidence supports its efficacy, uncertainty surrounding the benefit in stage &lt; III disease highlights the need for additional research and more mature results to guide clinical decision-making effectively. [Table: see text]
Artificial intelligence-based prediction model of malignant lung nodules for preoperative planning.
Authors: Di Lu, Yupeng Cai, Liuyin Chen, Xing Yuan, Zhiming Chen, Zhizhi Wang, Yu Tong, Kaican Cai
Journal: Journal of Clinical Oncology (2024)

8034 Background: The histopathological prediction of malignant lung nodules is crucial for preoperative planning, but it always remains not precise until the detailed pathological evaluation is performed after the surgery. Thus, to define the histology types (in situ adenocarcinoma (AIS), microinvasive adenocarcinoma (MIA), and invasive adenocarcinoma (IA)) of pulmonary adenocarcinoma appearing as lung nodules before the operation and reduce unnecessary invasive diagnosis and treatment operations, we developed a classification model of based on CT images. Methods: Patients who were diagnosed with pulmonary adenocarcinoma (tumor diameter ≤ 3cm) at Nanfang Hospital, Southern Medical University, China, were retrospectively enrolled, including detailed pathology results, computed tomography (CT) images, and basic information. Through training the model proposed in our previous study, we proposed a new model for defining histopathological types. Then, we used this data to train and compare the diagnostic efficacy of our model with another previously reported deep learning (DL) model (that was a segmentation - classification model with the 3D Unet++ - ResNet-50 combined model) and machine learning (ML) model (that was a traditional model Grey Level Co-occurrence Matrices (GLCM) as the feature extractor and the support vector machine (SVM) as the classifier) in the same method. Results: A total of 2061 patients (with 395 of AIS, 334 of MIA and 1332 of IA) were retrospectively enrolled from January 2019 to April 2022. The data from 2/3 of the patients were randomly selected for training and another 1/3 for verifying. Through training and verifying, our model shows much better diagnostic efficacy, with areas under receiver operating characteristic (ROC) curves with 95% confidence interval (CI) of 0.97(0.96, 0.98), comparing with those of the ML model of 0.77(0.73, 0.81) and the DL model of (0.90(0.88, 0.92). The heatmap visualization of the proposed model shows the classification ability with prediction probabilities of our model clearly and understandably. Conclusions: In this study, we developed a novel artificial intelligence multi-task learning model to precisely predict the pathology type of malignant lung nodules with satisfying diagnostic efficacy, which might provide a new and reliable way for preoperative planning of lung nodules. Further external verifying should be done in the future. In addition, prediction of the growth patterns of pulmonary adenocarcinoma could be more helpful in addition to predicting histopathological types.
The association between osimertinib and nutritional deficiency among patients with non-small cell lung cancer.
Authors: Zhiting Tang, Cho Han Chiang, Yu-Cheng Chang, Xin Ya See, Qian Wang, Afshin Dowlati, Cho Hung Chiang, Kuan-Yu Chi
Journal: Journal of Clinical Oncology (2024)

8031 Background: Osimertinib, a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), is the standard-of-care in EGFR mutation-positive non-small-cell lung cancer (NSCLC) in various settings. Osimertinib commonly causes gastrointestinal adverse effects thereby potentially leading to nutritional deficiencies. Therefore, we aim to evaluate the association between the use of osimertinib and nutritional deficiencies among patients with NSCLC. Methods: We performed a retrospective, propensity score matched study using the TriNetX database, a network comprising deidentified data across more than 120 participating healthcare institutions. We included patients with NSCLC who received either osimertinib or other EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib). The outcomes of interest included vitamin B deficiency, vitamin D deficiency, iron deficiency as well as associated anemia including vitamin B12 deficiency anemia, folate deficiency anemia, and iron deficiency anemia within 5 years of EGFR-TKI initiation. Results: We matched 4264 patients who received osimertinib to patients who received other EGFR-TKIs. In Cox proportional hazard analysis, osimertinib was associated with a 50% higher risk of vitamin B deficiency (Hazard ratio, 1.52 [95% CI: 1.07-2.16]) compared to other EGFR-TKIs. Consistent with this observation, osimertinib was associated with an increased risk of vitamin B12 deficiency anemia and a tendency towards folate deficiency anemia. We also noted a 2-fold higher risk of vitamin D and 5-fold higher risk of iron deficiency in the osimertinib cohort. Consistent with this observation, osimertinib was associated with an increased risk of iron deficiency anemia compared to other EGFR-TKIs. Conclusions: The use of osimertinib is associated with a higher risk of nutritional deficiencies and associated anemias compared to other EGFR-TKIs. One potential explanation is the extended duration of osimertinib therapy, driven by its potent anti-cancer effects. Therefore, it is advisable to consider screening for specific nutritional deficiencies in individuals receiving osimertinib therapy. [Table: see text]
Induction therapy with PD-1 antibody combined with platinum-based doublet chemotherapy for locally-advanced non-small cell lung cancer: A randomised controlled, open-label, phase 2 trial.
Authors: Suyu Wang, Peng Zhang
Journal: Journal of Clinical Oncology (2024)

8044 Background: Chemoradiotherpay plus immunotherapy is recommended for unresectable locally-advanced non-small cell lung cancer (NSCLC) based on PACIFIC trial. However, it is unclear whether surgery can provide survival benefit for patients with tumors initially unresectable transformed into resectable ones after chemoimmunotherapy. This trial aims to investigate the efficacy and safety of the therapeutic regimen of chemoimmunotherapy plus surgery or radiotherapy. Methods: Patients with unresectable stage IIIB-IIIC NSCLC were enrolled to receive 4 cycles (q21d) of PD-1 antibody (Serplulimab, 4.5mg/kg) and platinum-based doublet chemotherapy. After the induction therapy, those with disease downstaged to IIIA or lower stage and resectable were randomized to receive radical surgery or radiotherapy with a ratio of 1:1, and those with stage IIIB or higher stage or unresectable disease after induction therapy were then treated by oncologists. Primary endpoint was event-free survival (EFS). Secondary endpoints included objective response rate (ORR), major pathologic response (MPR), pathologic complete response (pCR), progression-free survival (PFS), disease-free survival (DFS), overall survival (OS), R0 rate of resection, severe adverse event (SAE) rate, and health related quality of life (HRQol). Preliminary short-term results were collected. Results: One hundred patients will be enrolled as planned, and a total of 82 patients were enrolled by the data cutoff date (January 6, 2024). Fifty-four and 28 patients were diagnosed with stage IIIB and IIIC disease, respectively. The percentage of squamous carcinomas, adenocarcinomas, and NSCLCs not otherwise specified were 68.3% (56/82), 15.9% (13/82), and 15.9% (13/82), respectively. ORR in 73 evaluable patients was 74.0% (54/73). Twenty-six of them are still in induction therapy phase, and the other 47 and 9 patients received 4 cycles and 1-3 cycles of induction therapy, respectively. Thirty-one patients had downstaged and resectable disease after 4 cycles of induction therapy, and 26 of them were randomized to arm A (n = 13) and arm B (n = 13), and 5 refused randomization (3 received surgery). One patient received surgery after 2 cycles of induction therapy. In 56 patients finished 1-4 cycles of induction therapy, the rate of conversion to resectability was 57.1% (32/56). In total, 17 patients received surgery, and the MPR and pCR rate in 16 evaluable patients were 62.5% (10/16) and 31.3% (5/16), respectively. The grade 3-5 adverse event rate in 56 patients finished induction therapy was 50.0% (28/56). One patient died of immune-related pneumonia. Conclusions: Induction therapy with PD-1 antibody (Serplulimab) and chemotherapy could transform half of unresectable stage IIIB-IIIC NSCLC into resectable, and the efficacy and safety were satisfactory. Clinical trial information: NCT05766800 .
Retrospective analysis of change in frequency of STK11 mutation in lung adenocarcinomas over a 10-year period.
Authors: Deevyashali Parekh, Alina Basnet, Dean Pavlick, Jeffrey S. Ross, Stephen L. Graziano
Journal: Journal of Clinical Oncology (2024)

8032 Background: Previous studies have linked the presence of inactivating mutations in the tumor suppressor gene STK11 with reduced efficacy of immune checkpoint inhibitor (ICI) treatments in lung adenocarcinoma (LA). We queried whether there has been a change in the STK11 mutation frequency over the last 10-year period that could potentially reflect the emergence of additional acquired resistance mutations. Methods: Over a 10-year period from 2013 through 2022, 109,763 clinically advanced LA underwent hybrid capture based comprehensive genomic profiling (CGP) to assess all classes of genomic alterations (GA) at a single reference laboratory (Foundation Medicine). MSI-high status and tumor mutational burden (TMB) were determined from the sequencing data. PD-L1 status was measured by immunohistochemistry (IHC) using the Dako 22C3 kit with TPS scoring. Statistical comparisons utilized the 2-tailed Chi Square method with the Yates’ correction. Results: The frequency of STK11 inactivating GA in all cases of LA significantly increased during the study period from 2013 to 2022 (16.1% vs 20.1%; p=0.0005). This increase appeared to be predominantly in KRAS wild type LA (10.1% vs 15.5%; p&lt;0.0001). The STK11 GA frequency slightly declined in the KRAS mutated LA over the 10-year period (29.9% vs o 27.0%, P=0.25). During the same time period, the KEAP1 GA frequency increased from 12.6% to 14.9% (p= 0.076) and the frequency of combined STK11 and KEAP1 GA increased from 4.8% to 8.0% (p=.0006). The frequencies of MSI-high status, TMB and PD-L1 expression did not significantly change over the observation period. Conclusions: The continuously increasing approved indications for ICI-based treatments for both early stage and clinically advanced LA appears to be accompanied by a significant increase in the frequency of inactivating STK11 GA predominantly in the KRAS mutation negative LA population. This inactivation is associated with an attenuated response rate and progression-free survival in this population. Given the development of novel therapies focused on potential restoration of STK11 function by HDAC/CoREST inhibition, further study of the STK11 GA distribution in LA appears warranted. [Table: see text]
Differentially expressed microRNAs in prediagnostic serum linked to lung cancer up to eight years before diagnosis in prospective, population-based cohorts: A HUNT study.
Authors: Olav Toai Duc Nguyen, Yannis Fotopoulos, Therese Haugdahl Nøst, Maria Markaki, Vincenzo Lagani, Pål Sætrom, Ioannis Tsamardinos, Oluf Dimitri D. Røe
Journal: Journal of Clinical Oncology (2024)

8041 Background: With lung cancer incidence and mortality on the rise, blood biomarkers are increasingly in demand for early detection. The aim of this study is to discover and validate novel biomarkers based on next-generation sequencing performed on blood samples from non-cancer, ever-smokers up to eight years prior to diagnosis. Methods: Initial consideration was given to serum samples from the population-based prospective HUNT2 and HUNT3 cohorts, age &gt; 18 (n = 98,737). Inclusion criteria for cases were ever-smokers, no prior cancer at study entry, and 0–8 years between blood sampling and lung cancer diagnosis in the discovery and 0-4 years in the validation cohort. Among future cases, equal numbers of adenocarcinoma, squamous cell carcinoma and small-cell lung carcinoma were included. Every subsequent case of lung cancer had a matched control, ratio 1:1. The controls were matched for sex, age at study entry, pack-years, smoking cessation duration, comparable HUNT Lung Cancer Model risk score and no cancer diagnosis until the end of the study. The total number of serum samples included in the discovery and validation dataset were 240 (from HUNT2) and 72 (from HUNT3), respectively. The samples were analyzed by genome-wide small RNA seq (Illumina). Results: When we contrasted all cases against all controls, nine differentially expressed microRNAs with AUC &gt; 0.60 (FDR &lt; 0.25) and total raw count of &gt; 0.5 appeared in common in the discovery and validation datasets. Among these, three microRNAs were associated with non-small cell metastatic with mean AUC of 0.65 and 0.76 in the discovery and validation datasets, respectively. Furthermore, the signature of these three microRNAs in combination reached an AUC of 0.75 (discovery) and 0.90 (validation). Conclusions: Up to eight years before diagnosis, a small number of substantially differentially expressed microRNAs were found in serum. These intriguing microRNAs can potentially function as early diagnostic indicators for lung cancer, either alone or in combination. Further investigation and validation of these results in a larger prospective serum dataset are required.
Signatures of early plasticity in the histological transformation of lung cancer.
Authors: Swanand Rakhade, Monica F Chen, Alvaro Quintanal-Villalonga, Amin Sabet, Parvathy Manoj, Ojasvi Chaudhary, Tianhao Xu, Ignas Masilionis, Christina J. Falcon, Jacklynn V. Egger, Tal Nawy, Linas Mazutis, Ronan Chaligne, Helena Alexandra Yu, Dana Pe'er, Charles M. Rudin, Joseph Minhow Chan
Journal: Journal of Clinical Oncology (2024)

8042 Background: Tumor plasticity, especially histological transformation, is an emergent mechanism of therapeutic resistance. Lung adenocarcinoma (LUAD) can transform to small cell lung cancer (SCLC), a more aggressive tumor type of neuroendocrine (NE) histology, leading to EGFR inhibitor resistance and a more aggressive disease phenotype. TP53 and RB1 loss are enriched but insufficient for NE transformation, and it remains unknown what additional molecular changes underlie plasticity. We use single-cell RNA sequencing (scRNA-seq) to profile the intratumoral transcriptional heterogeneity of NE transformation across multiple time points. Methods: We performed 10X scRNA-seq in patient samples to create an atlas of NE plasticity (47 transformed and admixed LUAD-SCLC, 10 EGFR/RB1/TP53 mut LUAD, 17 de novo SCLC, 4 normal lung). Our pipeline performed ambient RNA removal, outlier filtering, normalization, and batch correction. Tumor cells from transformed and admixed LUAD-SCLC tumors were divided into the LUAD compartment prior to transformation (pre-transformed LUAD) and the transformed SCLC compartment based on acquisition of NE marker expression. We performed copy-number inference, pseudotime analysis, and estimation of differentiation potential to establish dynamic changes in phenotypic and subclonal architecture across longitudinal timepoints. Results: We captured 12,105 (9%) pre-transformed LUAD cells from transformed and admixed LUAD-SCLC tumors. Canonical squamous cell carcinoma genes (KRT5, KRT6A, TP63, SERPINB4) were found to be enriched in this pre-transformed LUAD compartment. By projecting a force-directed layout of cells from these samples, we modeled the transition between LUAD, LUSC, and SCLC cell types. Genetic pathways promoting angiogenesis, inflammatory signaling, epithelial-to-mesenchymal transition, and RAS/RAF signaling were highly overexpressed during LUAD-LUSC transformation. Furthermore, we show that macrophages from transforming LUAD-LUSC tumors exhibit a pro-fibrotic phenotype. CNV inference revealed distinct subclonal populations in pre-transformed LUAD tumors. Subclones with high CNV burden and high differentiation potential represented early plastic cells whose lineage could be traced to matched longitudinal post-transformation samples. Conclusions: There is remarkable intratumoral heterogeneity within transforming LUAD. Squamous transformation, mediated by early RAS/RAF signaling, may represent a precursor to SCLC transformation. Identifying early hallmarks of plasticity can help stratify patients at high risk for transformation and reveal therapeutic vulnerabilities.