bluuebunny/crossref_metadata_2025_split huggingface dataset:
Survey of actionable driver mutations KRAS and EGFR in non–small cell lung cancer to evaluate coexisting splicing gene and pathway mutations: A CBioportal database analysis.
Authors: Arter Zhaohui , Nagasaka Misako , Ou Sai-Hong Ignatius 
Published: June 2024

8561 Background: Molecularly targeted therapies have advanced treatment for certain cancers, such as lung cancer with specific EGFR or KRAS mutations. However, oftentimes the tumor becomes eventually treatment resistant. This may be partly because cancers driven by EGFR/KRAS mutations may also harbor additional co-occurring genetic alterations. In non-small cell lung cancer (NSCLC), aberrations in RNA splicing pathways have shown substantial implications for tumor behavior and therapeutic responsiveness. Our study focuses on elucidating the interplay between RNA splicing defects and prominent NSCLC mutations. Methods: In this retrospective, cross-sectional study, we analyzed data from 20,719 NSCLC patients enrolled in participating institutions between 2017 and 2022. The data were sourced from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange (version 13.0). EGFR L858R, EGFR E746_750del, KRAS G12C, KRAS G12D and other KRAS G12 mutations cases were identified and individually analyzed to abstract co-occurring RNA splicing genomic alterations. Results: Among 20,719 patients with NSCLC, we identified 1309 patients with EGFR L 858R mutation, 1121 patients with EGFR E746_750del mutation, 2446 with KRAS 12C, 852 with KRAS G12D, 1107 with KRAS G12V, 452 with KRAS G12A, 173 with KRAS G12F, and 109 with KRAS G12S. RBM 10 was the most common co-occurring RNA splicing gene for EGFR L 858R (178, 13.6%), followed by CDK12 (31, 2.3%) and SPEN (27, 2 %). Similarly, the most prevalent co-occurring RNA splicing genes with EGFR E746_750del were RBM 10 (38, 3.4%) and SPEN (23, 2 %). RBM 10 was the most prevalent co-existing RNA splicing gene for KRAS G12C (211, 8.6 %), KRAS G12D (63, 7.4 %), KRAS G12V (80, 7.2%), KRAS G12A (59, 13.1%), KRAS G12F (12, 7.0%), KRAS G12S (11, 10.1%) and KRAS G12R (6, 8%). Conclusions: Our study uncovers a crucial link between EGFR and KRAS mutations in NSCLC and RNA splicing gene dysregulation, particularly involving RBM10. Further research in this field is warranted as targeting RNA splicing, alone or alongside existing targeted inhibitors, could substantially enhance treatment efficacy for EGFR+ or KRAS+ NSCLC patients. [Table: see text]
Real-world outcomes of osimertinib (Osi) vs. afatinib or erlotinib in patients with classical vs. atypical EGFR-mutated metastatic non-small cell lung cancer (mNSCLC).
Authors: Barsouk Adam , Elghawy Omar , Heidlauf Alec , Yu Connie , Yang David , Kurian Martin , Goel Keshav , Rushkin Lynn , Huang Anran , Voruganti Teja , Sun Lova , Singh Aditi Puri , Cohen Roger B. , Aggarwal Charu , Marmarelis Melina Elpi , Langer Corey J. 
Published: June 2024

8566 Background: Limited data are available on the efficacy of osi for mNSCLC with atypical EGFR mutations (AM) such as L861Q, G719X, S768I, and exon20 insertions. Afatinib is FDA approved for mNSCLC harboring L861Q, G719X, and S768I. Real-world analyses comparing osi to afatinib and erlotinib for AM have yielded mixed results. Methods: We performed a single-institution retrospective analysis of patients with EGFR-mutated mNSCLC treated from 2007-2023 with EGFRTKIs. Clinical trial patients were excluded. Patients with classical EGFRmutations (CM) were compared to those with AM. Baseline demographics, disease characteristics, treatment history, toxicity, and clinical outcomes were abstracted from the EMR. Median PFS and OS were estimated and compared via Kaplan-Meier log-rank analysis. Independent sample t-tests and chi-square analyses were used for univariate comparisons. P-values<0.05 were considered statistically significant. Results: Among 355 patients with 1L EGFR-mutated mNSCLC, 315 (90%) had CM (exon19 del [N=182; 51%] and L858R [N=119; 34%]), while 36 (10%) harbored AM in G719X (N=21; 6%), Exon 20 (N=11; 3%), L861Q (N=7; 2%), and S768I (N=4; 1%). Patients with CM vs AM had similar median age at diagnosis (63, p=0.406), gender (65% F; p=0.213), racial composition (p=0.653), and history of smoking (44%, p=0.167). At diagnosis, 45% vs 48% of patients had CNS involvement (p=0.434). 52% vs 41% received osi, 36% vs 20% patients received erlotinib, and 11% vs 37% received afatinib (p<0.001). Patients with CM had superior mPFS (29 vs 15m; p=0.021) and mOS (49 vs 13m; p<0.001) vs AM (Table). In AM patients (N=36), osi had superior mPFS (15m [7-23]) vs afatinib (11m [8-15]; p=0.005) or erlotinib (8m [6-10]; p=0.001). mOS was likewise superior for osi (29m [6-50]) vs afatinib (13m [9-17]; p<0.001) or erlotinib (14m [6-21]; p<0.001). 121 CM and 7 AM patients were rechallenged with a TKI; mPFS2 for AM was 13m for osi (N=4) vs 4m for afatinib (N=3; p=0.114). Dose-reduction due to AE was lower for osi (19%) vs afatinib (24%; p=0.003) or erlotinib (23%; p=0.002). Discontinuation due to AE was lower for osi vs afatinib (1% vs 2%; p<0.001) or erlotinib (2%; p=0.004). Conclusions: Retrospectively, AM were associated withinferior PFS and OS compared to CM. Osi demonstrated superior survival and tolerability compared to afatinib or erlotinib for AM. [Table: see text]
Genomic profiling of non-small cell lung cancer with rare aberrations in EGFR codon L858 and the survival outcome under real-world first-line EGFR tyrosine kinase inhibitor treatment compared to classic EGFRL858R.
Authors: Li Hengyuan , Zhang Jingying , Feng Zhi , Wu Wei , Zhao Xiaotian , Zhu Minyi , Xiao Yao , Pang Jiaohui , Ou Qiuxiang , Zhu Junfei , Qu Hao , Yuan Minchi , Xia Guojie , Shao Youyou , Liu Meng , Lin Peng 
Published: June 2024

8596 Background: Rare genomic aberrations in EGFR codon L858 causing L858R (rare EGFRL858R) or non-L858R mutations have been reported, besides the predominant c.2573T>G genomic mutation leading to classic EGFRL858R. However, molecular features, survival benefit under EGFR tyrosine kinase inhibitors (TKIs), and resistance mechanisms of these rare mutations lack comprehensive investigation in non-small cell lung cancer (NSCLC). Methods: We retrospectively included 489 NSCLCs with treatment-naive tumor tissues/plasma biopsies harboring rare EGFRL858R (N=124), EGFRL858Q/M (N=17), or classic EGFRL858R mutations (N=348). Mutational landscapes, tumor mutation burden (TMB), and chromosome instability (CIN) scores, were investigated using tissue samples subject to a targeted next-generation sequencing panel covering 437 cancer-related genes. Advanced NSCLCs receiving EGFR TKIs as first-line therapy were sub-grouped to study survival benefit and resistance mechanisms. Results: NSCLCs with rare EGFRL858R had less-frequently mutated TP53 (59% vs. 72%, P=0.04) and lower CIN scores (0.29 vs. 0.23, P=0.02) than those with classic EGFRL858R, while age, sex, stage at diagnosis, histology subtype, and TMB were comparable. We also detected the cooccurrence of EGFRL858Q/M with EGFRL861Q ( P<0.01), particularly in patients carrying EGFRL858M (100%). Compared to 233 advanced NSCLCs harboring classic EGFRL858R, 58 patients with rare EGFRL858R exhibited superior first-line progression-free survival (PFS) [median: 13.0 vs. 10.0 months, hazard ratio (HR): 0. 57, 95% confidence interval (CI): 0.41–0.80], with a similar association observed in approximately 80% of included patients who received first-generation EGFR TKIs (median: 12.0 vs. 10.0 months, HR: 0.64, 95% CI: 0.45–0.92). After controlling for age, sex, histological subtype, EGFR TKI category, and anti-vascular therapy, rare EGFRL858R remained associated with improved PFS (adjusted HR: 0.55, 95% CI: 0.39–0.77). Patients with EGFRL858Q/M also had better PFS than those with classic EGFRL858R (adjusted HR: 0.26, 95% CI: 0.10–0.67). Of note, NSCLCs with combined EGFRL858M and EGFRL861Q appeared to have lower progression risks when receiving afatinib than using gefitinib/icotinib as first-line therapy. Furthermore, matched samples at baseline and progression revealed similar resistance mechanisms between NSCLCs with rare and classic EGFRL858R. Conclusions: NSCLCs carrying rare genomic aberrations in EGFR codon L858 were likely to get more survival benefits from first-line EGFR TKI treatment than those with classic EGFRL858R, giving scientific evidence supporting the clinical application of EGFR TKIs in these patients.
Prospective validation of in silico clinical trials prediction using an EGFR-mutated NSCLC mechanistic computational disease model.
Authors: Duruisseaux Michaël , Masson Perrine , Nativel Arnaud , Girard Nicolas , Cadranel Jacques , Swalduz Aurélie , Coudron Matthieu , Bouchard Guillaume , Kahoul Riad , Jacob Evgueni , Bosley Jim , Palgen Jean-Louis , L'Hostis Adèle , Monteiro Claudio 
Published: June 2024

8614 Background: Advanced lung adenocarcinoma (aLUAD) is divided into multiple molecularly defined subsets, each with specific biological characteristics and responses to targeted therapy. Consequently, conducting practice-changing and cost-effective randomized trials is challenging. In silico clinical trials, utilizing mechanistic computational models, offer a potential solution, yet their ability to predict clinical trial results has not been proven. Methods: We updated a previously published version of the computational mechanistic model of EGFR-mutated aLUAD, notably by incorporating metastases. Disease model was integrated with physiologically based pharmacokinetic (PBPK) models of cisplatin, pemetrexed, and osimertinib, offering a more comprehensive understanding of the disease's dynamics. These models are founded on causal connections between biological entities and phenomena, establishing a link between the specific biological behaviors of EGFR-mutated aLUAD and the evolution of tumor size and progression over time. We have independently and prospectively simulated the outcomes of the FLAURA2 and MARIPOSA randomized trials dedicated to EGFR-mutated aLUAD. This was achieved by replicating the experimental protocols and generating cohorts of virtual twins of patients using publicly available data. Results: In silico results were released before the actual outcomes of the FLAURA2 and MARIPOSA trials were publicly available. The simulations yielded predictions with overlapping confidence intervals, similar hazard ratios, median survivals, and shapes of curves compared to the actual trial data. Bootstrapped weighted log-rank tests were used to compare the simulated and observed Kaplan-Meier curves for the two arms of FLAURA2 and for the osimertinib arm of MARIPOSA. Between 94 and 98% of the tests were statistically non-significant (α=0.05), confirming the accuracy of the predictions. Conclusions: This first-of-its-kind prediction of clinical trial outcomes demonstrates that in silico trials, when based on robust mechanistic models, can be a reliable tool for enhancing the design of actual trials, particularly for EGFR-mutated aLUAD. They offer a promising avenue for overcoming the challenges of comparator arms in single-arm trials and may serve as a new standard for formulating statistical hypotheses in future studies.
Real-world treatment patterns and outcomes in US patients (pts) with advanced non-small cell lung cancer (NSCLC) after platinum-based chemotherapy (PBC) and anti–PD-(L)1 treatment.
Authors: Velcheti Vamsidhar , Moore Julia , Wang Huifen , Zhu Xinmei , Samyshkin Yevgeniy , Ward Thomas , Christensen Alena , Solem Caitlyn 
Published: June 2024

8627 Background: Effective treatment options for advanced or metastatic NSCLC are limited, especially for pts who progress after treatment with PBC and an anti–programmed cell death 1 protein (PD-1) or ligand 1 (PD-L1) regimen. Examining real-world treatment patterns and long-term outcomes, we report on progression-free survival (PFS) and overall survival (OS) in pts with NSCLC who previously received PBC and anti–PD-(L)1 regimens. Methods: This study used the nationwide Flatiron Health electronic health record–derived deidentified database. Pts included in the analysis were ≥18 years old with an initial diagnosis of advanced or metastatic NSCLC and an ECOG PS of 0 or 1 who had received prior PBC and anti–PD-(L)1 therapy in 1 (in combination) or 2 (in sequence) lines and had initiated ≥1 subsequent line of treatment between 2018 and 2023; the start date of subsequent treatment (defined as the index regimen) was the index date. Pts were followed up until death or last available data through Mar 31, 2023. Pt characteristics, treatment patterns, and outcomes were analyzed for the overall pt group and according to initial treatment cohort (cohort 1: first-line [1L] PBC plus anti–PD-(L)1; cohort 2a: 1L PBC and second-line [2L] anti–PD-(L)1; or cohort 2b: 1L anti-PD-(L)1 and 2L PBC). PFS and OS were estimated using Kaplan-Meier methods. Results: Of 1793 pts, most were in cohort 1 (73.5%), with fewer pts in cohorts 2a (22.5%) and 2b (4.1%). The majority of pts in cohort 2b had PD-L1 ≥50% (n = 57, 78.1%), while the percentage was lower in cohorts 1 (n = 262, 19.9%) and 2a (n = 72, 17.9%). Most pts (n = 1626, 90.7%) had stage IV disease. Median time from advanced diagnosis to index date was 10.5 months (range, 1.1-103.8); median follow-up from index date was 7.8 months (range, 0.0-65.0). A broad range of treatments were used after PBC and anti–PD-(L)1 regimens; among all pts, the most common were docetaxel + ramucirumab and docetaxel monotherapy. Among all pts, median PFS and OS from the time of starting these index regimens were 5.29 and 11.20 months, respectively; PFS and OS were similar across cohorts. Conclusions: A broad range of subsequent treatments were used following PBC and anti–PD-(L)1 regimens, most commonly docetaxel with or without ramucirumab. Short median PFS and OS underscore a significant unmet need among pts previously treated with PBC and anti–PD-(L)1. [Table: see text]
The role of pulmonary metastasectomy for non-primary lung cancer: Umbrella review of meta-analysis.
Authors: Woo Wongi , Park Brandon , Ahadi Awranoos , Chung Liam IL Young , Jung Chan Mi , Bharat Ankit , Chae Young Kwang 
Published: June 2024

8639 Background: Lungs are the most common metastatic area for many cancers. Due to heterogeneous characteristics of primary cancers, the benefit of pulmonary metastasectomy (PM) has not been investigated other than colorectal cancers. Furthermore, well-designed trials in this field are difficult to undertake due to diverse clinical scenarios and therapy related to primary cancers. This study aims to investigate the clinical outcomes of PM for non-primary lung cancer by synthesizing existing literature. Methods: A systematic search for meta-analyses on PM for non-primary lung cancers was conducted, encompassing publications up to January 3, 2024. The analysis included eight primary cancer types: colorectal, renal cell, breast, adrenocortical, head and neck cancers, melanoma, and sarcoma. Primary outcomes, overall survival, and recurrence rates post-PM were assessed using random-effect models to account for study heterogeneity. Subgroup analysis categorized the survival rates based on primary cancer types, and a proportion meta-analysis was performed for comparison. Results: This study included 44 systematic-review articles and 157 individual studies, involving 23,694 patients who underwent PM for non-primary lung cancer. Patients had a mean age of 48.0 [95% CI 43.9-52.0] years, with 68.4% [95% CI 65.0-71.7] being male. About half of patients (47.1% [95% CI 40.8-53.5] had multiple metastatic lesions and 26.6% had bilateral involvement of lung. Sublobar resection was mostly performed (82%), and complete R0 resection was achieved in 87.2% [95% CI 83.0-90.8]. The pooled 5-year overall survival rate after PM was 41.2% [95% CI, 37.1-45.4%], with specific rates for each primary cancer type listed (Table). Patients with germ cell tumor demonstrated significantly higher survival rate than other cancers (p<0.05), while patients with melanoma had worst outcome (p<0.05). During follow-up, 57.6% [95% CI 46.4-68.1] had recurrence: 48% of them had intrathoracic only recurrence and 52% had extra-thoracic recurrence. Conclusions: The findings affirm that PM yields survival benefit. Overall survival rates following PM do not significantly differ based on primary cancer types, except for germ cell tumors and melanoma. Additionally, the recurrence rates are comparable to that of stage 4 advanced cancers other than germ cell tumor and is not significantly influenced by the primary cancer type. This highlights the importance of recognizing and incorporating PM in clinical practice when appropriate. [Table: see text]
Comparing rates of immune checkpoint inhibitor toxicity in different treatment settings (neoadjuvant, adjuvant, and palliative) in non-small cell lung cancer (NSCLC): A meta-analysis of phase III clinical trials.
Authors: Moloney Carolyn , Demir Tarik , Chung Liam IL Young , Oh Youjin , Chae Young Kwang 
Published: June 2024

8645 Background: Immunotherapy has created a paradigm shift in the treatment of NSCLC. There is growing interest in the utility of immunotherapy alone or in combination with chemotherapy for NSCLC in the peri-operative setting with practice changing results demonstrated in several pivotal phase III clinical trials. Nevertheless, immune related adverse events (irAEs) are the main barrier in the care of patients treated with immune checkpoint inhibitors (ICIs) with grade ≥ 3 irAEs seen in 10-15% of patients. The present meta-analysis aims to compare rates of irAEs across different treatment settings in NSCLC to aid in individual patient treatment decisions. Methods: We extracted data from selected published phase III clinical trials which have led to the approval of PD-1/PDL-1 ICIs in the neoadjuvant, adjuvant, peri-operative and in the palliative setting. We excluded trials which did not have supplemental data on irAEs included with published results and trials of CTLA-4 inhibitors. A sensitivity analysis was performed to assess whether number of cycles correlated with toxicity rates. Results: Pooled data from 15 published phase III NSCLC clinical trials including 5918 patients were included. This included 1 neoadjuvant, 2 peri-operative, 3 adjuvant, and 9 palliative studies. One of the peri-operative trials included data on irAEs which occurred during the neoadjuvant/surgery phase only and this data was pooled within the neoadjuvant group. The ICI drugs included nivolumab, pembrolizumab, atezolizumab, durvalumab, cemiplimab +/- chemotherapy. This included a total of 2523 stage 1B-3C and 3395 stage IV patients. We found a 9.5% rate of grade 3-5 and 35.8% rate of all grade irAEs in palliative trials (n=3395). In contrast, neoadjuvant ICI (n=572) had a 3.5% rate of grade 3-5 and 16.8% of all grades irAEs. Peri-operative ICI (n=797) had a 5.4% rate of grade 3-5 and 24.47% all grades irAEs. Adjuvant ICI (n=1550) had a 7% rate of grade 3-5 and 38.52% rate of all grade irAEs. The relative risk (RR) between the palliative and the neoadjuvant setting of a grade 3-5 irAE is 2.35 (95% CI:1.54 to 3.59; p = 0.0001) and the RR of any irAE is 2.03 (95% CI: 1.69 to 2.43; p=0.0001). The following median number of ICI cycles was seen: neoadjuvant = 3.5, adjuvant = 18, peri-operative = 18, palliative = 10. Lower number of cycles did correlate with lower toxicity in the neoadjuvant setting but this was not seen in other treatment settings. Conclusions: Neoadjuvant, peri-operative and adjuvant ICI’s are associated with a lower rate of irAEs than that seen in palliative trials. A neoadjuvant-only approach is associated with the lowest rates of irAEs and this may be due to the lower number of cycles received. These findings have implications for individual patient treatment decisions and support the use of neoadjuvant immunotherapy in NSCLC.
Assessing gender disparities in oncology: Less talk, more action.
Authors: Olazagasti Coral , Villa Celi Claudia , Velazquez Manana Ana I. , Sridhar Arthi , Horiguchi Miki , Mahtani Arun , Dizman Nazli , Gonzalez Nororis Mariana , Bernabe Carolina , Florez Narjust 
Published: June 2024

9011 Background: 'Gender disparities' is a familiar term in medicine. Only 35.2% of oncologists in the U.S. self-identified as women in 2021. Women in medicine are undercompensated and underpromoted. Little is known of the experiences of non-U.S. female physicians in the U.S. We created the first cross-sectional study to assess gender disparities in IMGs and Puerto Rican medical graduates (PRMGs) in oncology in the U.S. Methods: An anonymous online survey was created and distributed via Survey Monkey. Eligible participants were non-U.S. IMGs and PRMGs who trained and/or practiced independently in the U.S. Participants were recruited through email and social media from Sept-Dec 2023. Bivariate association analyses were performed using the two-sample Wilcoxon test for ordered categorical variables and Fisher’s exact test for nominal categorical variables. Results: 97 IMGs and PRMGs in oncology completed the survey. As shown in the table, women were more likely to move to the U.S. for family (22.4% vs 6.2%, p=0.040), whereas men did more for financial gains (20.8% vs 6.1%, p=0.040). culture, particularly to the traditions (65.3% vs 43.8%;p=0.042) and dress code (44.9% vs 20.8%, p=0.017). Women experienced higher rates of gender discrimination during training (53.2% vs 4.5%, p <0.001) and independent practice (57.6% vs 3.6%, p<0.001) than men. Women were also more likely than men to face ethnic/racial discrimination during training (69.6% vs 38.1%; p=0.005). Despite lack of statistical significance, higher trends of ethnic/racial discrimination during independent practice were reported by women (table). More women reported no plans on returning home (68.8% vs 38.3%), whereas more men planned to return home at some point (38.3% vs 16.7%). 18.8% of men vs 0% of women elected leadership opportunities as the reason for returning to their home country (p=0.001). Conclusions: Our study reveals the unfortunate reality that many IMG and PRMG women face in oncology in the U.S. Despite national efforts to reduce the gap in gender disparities, minority women continue to experience racial/ethnic and gender discrimination at higher rates than men. To overcome inequities and achieve gender equity pay transparency, diversity in selection committees is necessary. Further, efforts should be across all settings, academia, private practice, and industry. The time for gender equity in oncology is now. [Table: see text]