bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using multiomics analysis to examine prognostic biomarkers for patients with squamous cell lung carcinoma treated with neoadjuvant therapy of camrelizumab combined with Apatinib.
Authors: Wang Jinliang , Lu Di , Zhai Jinzhao , Zhang Zhibo , Yan Xiang , Zhang Fan , Wang Lijie , Haitao TAO , Yuan Fang , Li Xiaoyan , Zhi Xiaoyu , Ge Xiangwei , Hu Yi , Zhou Wenhao , Luo Haitao 
Published: June 2022

e20563 Background: Immune checkpoint inhibitor (ICI) combined with targeted therapy as a neoadjuvant therapy has been applied to the treatment of squamous cell lung carcinoma (SCLC). However, biomarkers to predict the response are unclear. Methods: 26 SCLC patients treated with neoadjuvant therapy of camrelizumab combined with apatinib were enrolled. Pretreatment samples of these patients were performed with whole-exome sequencing, RNA sequencing, TCR sequencing and IHC of PD-L1 expression. Peripheral blood at different timepoints were collected and analyzed with ctDNA sequencing. Results: At baseline, tumor mutation burden was found to be associated with clinical benefit. For patients with HLA intact, tumor neoantigen burden are significantly increased in the benefited group compared with non-benefited group. Transcriptome analysis revealed that regulatory T cells were significant higher in non-benefited group. In addition, diversity of dominate T-cell receptor repertoire was found to be associated with clinical benefit. Post-treatment, the levels of ctDNA decreased in the benefited group. Conclusions: In this study, we comprehensively analyzed the genomic, tumor microenvironment and serum biomarkers in SCLC patients treated with ICI combined with targeted therapy, and found that TMB, regulatory T cells and change of ctDNA levels were associated with the clinical benefit. In addition, the combination of HLA status and TNB could further distinguish responders.
Multi-omics analysis uncovers prognostic biomarkers and tumor ecosystem dynamics during sequential neoadjuvant treatment of dose-limiting chemotherapy combined with sintilimab for non-small cell lung cancer.
Authors: Yang Bo , Song Qi , Li Jie , Xiong Qi , Liang Chaoyang , Zhou Wenhao , Luo Haitao 
Published: June 2022

e20564 Background: Patients with non-small cell lung cancer (NSCLC) can benefit from the treatment of preoperative neoadjuvant chemotherapy combined with immunotherapy. However, the selection in concurrent or sequential neoadjuvant treatment is still controversial. Therefore, the effective form of sequential neoadjuvant treatment as well as predictive biomarkers are still need to be further investigated. Methods: We carried out a multi-omics study on 12 enrolled NSCLC patients who received sequential neoadjuvant and adjuvant treatments. The responses to therapy were rigorously evaluated. Biopsies pre and post neoadjuvant therapy were performed with whole-exome sequencing, transcriptome sequencing. Plasma at the different timepoints during therapy were collected and sequenced with TCR sequencing and ctDNA sequencing. Results: After neoadjuvant therapy, 10 were major pathological responses (MPR) and 2 were non major pathological responses (non-MPR). The analysis of TCR sequencing showed that high diversity along with the increase of dominance of T-cell receptor repertoire were observed after chemotherapy. At baseline, tumor mutational burden (TMB) and tumor neoantigen burden (TNB) were higher in MPR group when compared with non-MPR group. Furthermore, tumor infiltrating CD8+ naïve T cells, Tregs and monocytes were associated with clinical benefit and patients with high ratio of CD8+ naïve T cells and monocytes have better pathological response. Conclusions: In this study, sequential neoadjuvant treatment of dose-limiting chemotherapy combined with sintilimab showed a promising antitumor activity in patients with resectable NSCLC. The changes of genomic, transcriptome and TCR repertoire were comprehensively analyzed and correlated with clinical outcomes. TMB, TNB and TCR repertoire are associated with the clinical benefit. The sequential therapy would also impact the immune microenvironment. These result indicate that sequential neoadjuvant treatment of chemotherapy combined with immunotherapy could be a potential treatment for a defined group of patients with NSCLC.
Retrospective study to examine prognostic value of c-reactive protein (CRP) in patients with surgically resected non-small-cell lung cancer (NSCLC).
Authors: Azzoli Christopher G. , Huynh Lynn , Yi Denise , Cai Beilei , Duh Mei Sheng 
Published: June 2022

e20569 Background: This study evaluated the association between baseline elevated CRP and lung cancer outcomes among adults with NSCLC who underwent surgery in the US. Methods: Optum Clinformatics Data Mart in the US (01/2007-09/2020) was used to identify adults with NSCLC who underwent lung cancer surgery and had at least 1 CRP measurement prior to or > 1 month following the index surgery. Baseline CRP levels were defined as the CRP closest to the index surgery in the pre-surgery cohort, and the CRP at least 1-month after in the post-surgery cohort. The association between elevated CRP (> 10 mg/L) and rate of NSCLC recurrence/risk of death was assessed separately for pre-surgery and post-surgery cohorts using multivariate regressions. The overall trend in CRP measurements over a 5-year period was examined using trend tests among those with persistently elevated CRP. Results: For adults in the pre-surgery cohort who had index lung cancer surgery between 2016-2020 (N = 104), after adjusting for age, sex, National Cancer Institute comorbidity, autoimmune disease, peripheral vascular disease, and smoking status, the adjusted-incidence rate ratio (IRR) for NSCLC recurrence was 2.17 (95% confidence interval [CI]: 1.03, 4.60; p < 0.05) among patients with elevated CRP compared with non-elevated CRP. A similar IRR (2.22 [95% CI: 1.05, 4.70]; p < 0.05) was observed among the 264 patients in the post-surgery cohort. Among the 234 patients in the pre-surgery cohort, there was a near two-fold increase in the risk of all-cause death associated with the elevated than the non-elevated CRP groups (odds ratio [OR]: 1.91 [95% CI: 1.06, 3.42]; p < 0.05), and there was a numerically increased risk associated with elevated baseline CRP for the post-surgery cohort (OR: 1.62 [95% CI: 0.88, 2.97]; p = 0.12). Among those with persistently elevated CRP prior to surgery, we observed a significant overall trend of increased CRP levels over the 5-year period. Conclusions: Using real world data in the US, results suggest that an elevated CRP at baseline is associated with a higher risk of NSCLC recurrence and mortality, for both pre- and post-surgery cohorts. An increasing trend of CRP level within 5 years prior to lung cancer surgery indicates the correlation of CRP (as a marker of inflammation) with tumor development. This study adds to a growing body of literature and may shed light into oncology treatments aimed at suppressing tumor-promoting inflammation.
Absence of CD4+ and CD8+ T cell expansion after primary multimodal treatment predicts early progression in inoperable stage III NSCLC.
Authors: Hofer Thomas Philipp , Nieto Alexander , Käsmann Lukas , Taugner Julian , Pelikan Carolyn , Katanov Dinar , Eze Chukwuka , Guggenberger Julian , Belka Claus , Noessner Elfriede , Manapov Farkhad 
Published: June 2022

e20590 Background: There are no blood-based biomarkers for survival prediction in inoperable stage III NSCLC patients. We propose a method for calculation of novel area under curve (AUC) biomarkers of the dynamic change of multiple leukocyte subpopulations before, during, and after thoracic irradiation (TRT), chemoradiotherapy (CRT), and chemo-radio-immunotherapy (CRT-ICI) in this patient cohort. The extracted biomarkers identify patients with early progression after TRT. Methods: 20 patients (17 male, 3 female), at median age of 65.5 years (range 34 to 79) were enrolled in the study. The median follow-up time was 60 weeks. Eleven patients suffered from adenocarcinoma, 8 squamous cell carcinoma, and 1 undifferentiated NSCLC. They received TRT (2/20, 10%), CRT (11/20, 55%), or CRT-ICI (7/20, 35%). One patient (1/20, 5%) withdrew consent and was excluded from analysis. Primary endpoints were progression free survival (PFS) at 6 and 12 months. Patient blood was analyzed via flow cytometry for 7 circulating leukocyte populations at baseline, twice during radiotherapy, at the end of radiotherapy (RTend), and 10, 20, 35, 48, and 60 weeks after enrollment. We analyzed CD3+ total T cells, CD4+ T cells, CD8+ T cells, CD19+/CD20+ B cells, CD3-CD56+ NK cells, CD56 bright NK cells, and CD56 dim NK cells. Here, we report on CD4+ and CD8+ T cells. The AUC from RTend to zenith of absolute cell counts provided aggregate measures for the time-course data. We performed hierarchical clustering and cluster characterization. Relevant features were selected by stepwise drop-out. Results: Clustering of the AUC between RTend and zenith for CD4+ T cells and CD8+ T cells delineated two prognostic groups. The favorable group was characterized by higher AUC values for CD4+ and CD8+ T cells compared to the unfavorable group. All patients (9/9, 100%) in the favorable group versus 36.4% (4/11) patients in the unfavorable group were progression-free at 6 months (Fisher´s exact test, two-tailed: p-value = 0.00472). This effect was observed as a trend with PFS at 12 months. Here 66.6% (6/9) of patients had PFS at 12 months in the favorable group versus 27.3% (3/11) in the unfavorable group (Fisher´s exact test, two-tailed: p-value = 0.175). There is a directly proportional relationship of the reported AUC values to PFS at 6 months and 12 months. Conclusions: Patients who responded with T cell expansion after immunogenic cell death by TRT, CRT, or CRT-ICI had significantly longer PFS compared to those without increase. Longitudinal monitoring of CD4+ and CD8+ T cells and the AUC from RTend to zenith is a promising biomarker for detecting early progression in the present study which is the subject of validation in an ongoing prospective study (PRECISION, NCT05027165).
Characterizing platinum sensitivity among Medicare FFS patients with limited versus extensive-stage small cell lung cancer receiving NCCN category 1 preferred regimens.
Authors: Cockrum Paul , Dieguez Gabriela , Smith Rebecca A. , Ramirez Robert A. 
Published: June 2022

e20601 Background: There is limited research evaluating real-world platinum sensitivity and treatment patterns among patients with limited vs. extensive stage small cell lung cancer (SCLC). Methods: We identified patients with SCLC in 2017 using ICD-10 diagnosis (Dx) and drug codes in the 2016-20 Medicare Parts A/B/D 100% Research Identifiable Files. Patients had 1+ lung cancer Dx and continuous enrollment in Parts A/B/D from the month prior to first Dx in 2017 (index) through 2020 or death. Patients with evidence of end-stage renal disease, prior lung or any metastatic cancer Dx within 12 months of index, lung resection/lobectomy, or use of a drug indicated only for non-SCLC or lung neuroendocrine cancer per NCCN guidelines were excluded. Use of systemic therapies cisplatin (ci), carboplatin (ca), etoposide intravenous (etIV), atezolizumab (at), durvalumab (du) and irinotecan (ir) were observed. Patients included in our study were treated with first-line NCCN Category 1 preferred regimens: ca/etIV, ca/etIV/at, ca/etIV/du, ca/ir, ci/etIV, ci/etIV/du, or ci/ir. First line of therapy (LoT1) was defined based on the first claim for a first-line regimen administered within 90 days following or up to 14 days before index. The end of LoT1 was defined as the earliest of death, 32 days after the last administration, or the start of a second line of therapy (LoT2). Patients initially treated with ca/etIV/at, ca/etIV/du, ca/ir, ci/etIV/du, or ci/ir regimens were flagged with extensive stage disease. Patients not receiving these regimens were classified as limited stage disease if they had 15+ days of radiation therapy over a 6-week period during or within 60 days of LoT1. Patients were deemed platinum sensitive (PS) if we did not observe a LoT2, hospice, or death within 6 months of LoT1. Uncategorizable patients were flagged Status Unknown (SU). All other patients were deemed platinum refractory (PR). Results: We identified 3,772 SCLC patients receiving NCCN Category 1 preferred regimens: 43% (1,607) had limited stage, and 57% (2,165) had extensive stage at index. Among patients with extensive stage, 71% (1,541) were PR compared with 34% (548) of patients with limited stage. On average, patients with extensive stage had fewer platinum cycles in LoT1 than those with limited stage. Conclusions: More platinum refractory patterns were observed among Medicare FFS patients with extensive stage SCLC than among patients with limited stage SCLC. Patients with extensive stage SCLC also underwent fewer platinum cycles in their first line of therapy.[Table: see text]
Peripheral blood mononuclear cells (PBMCs), an ideal liquid biopsy approach to evaluate systematic immunity and predict response of neoadjuvant chemo-immunotherapy in resectable NSCLC.
Authors: Zhang Lei , Hou Likun , Wu Junqi , Li Chongwu , Hu Tao , Zhu Changbin , Wu Chunyan , Chen Chang 
Published: June 2022

e20618 Background: Immune checkpoint inhibitors (ICIs) dramatically improved clinical outcomes of patients with resectable non-small cell lung cancer (NSCLC). However, ICIs are not the scenario of “One-size fits to all”. It is of great importance to explore biomarkers, especially via liquid biopsy-based approach, to predict or monitor treatment response. Besides comprehensive genomic profiling of primary tumor tissue, this study focused on gene expression profile of PBMCs at baseline as well as one week post 1st immunotherapy administration, and its association with major pathological response (MPR) of neoadjuvant chem-immunotherapy in resectable NSCLC patients. Methods: Pre-treatment tumor biopsies and PBMC at baseline (D0) and 7 days after neoadjuvant chem-immunotherapy (D7) were collected from 27 patients with stage IB-IIIB NSCLC from two prospective clinical trials (NCT04422392 and NCT04762030) between Aug 2019 and July 2021. Tumor biopsies were subjected for comprehensive genomic profiling by an NGS panel covering 571 cancer related genes, and RNA from PBMC was subjected to an RNA sequencing panel covering transcripts of 2660 genes. (Amoy Diagnostics, Xiamen, China). Single sample gene set enrichment analysis (ssGSEA) was used to assess enrichment of inflammatory-related gene sets. CIBERSORT and in-housed established DAISM-DNN algorithm were applied to estimate immune cell populations from PBMC-derived gene expression profile. Results: Patients received chemo-immunotherapy achieved 59.3% of MPR. Stronger signatures including effector T cell and IFN-γ/Effector T-cell were significantly enriched in baseline PBMC samples in MPR patients (p = 0.028, p = 0.042 respectively). In parallel, significant increasing Naïve CD8 positive T cells was observed in PBMC at D7 in MPR patients by both CIBERSORT (p = 0.047) and DAISM-DNN algorithm (p = 0.018). Interestingly, at D7, signature of M0 macrophage was enriched in PBMC from patients with non-MPR. In addition, comprehensive genomic profiling indicated a numerically higher level of tumor mutation burden (TMB) in pretreatment tumor samples in MPR patients (Median TMB, MPR 11.51 mut/Mb vs Non-MPR 7.19 mut/Mb, p = 0.074). Conclusions: Expression profile of baseline PBMC as well as dynamics of PBMC profile in a short period (7 days) may predict the clinical efficacy of neoadjuvant chemo-immunotherapy. More patients are being enrolled into this study. Moreover, to validate these findings, large-scale and prospective investigations are warranted. Clinical trial information: NCT04422392 and NCT04762030.
Efficacy of anlotinib for advanced SCLC patients: A real-world study.
Authors: Yao Yu , He Xiaopeng , Hou Xinli , Liao Hehe 
Published: June 2022

e20621 Background: Anlotinib is a novel small molecule multi-target tyrosine kinase inhibitor, which has been approved as a third-line therapy for patients with advanced small cell lung cancer (SCLC) by NMPA in Aug 2019. ALTER 1202 trial has demonstrated that anlotinib significantly prolonged progress-free survival (PFS) and improved disease control rate (DCR) of advanced SCLC patients. Since the efficacy of patients in real clinical practice is affected by many factors, the objective of this study was to assess the efficacy of anlotinib for patients with advanced SCLC in real world. Methods: This is a multi-center, non-interventional, prospective real-world study and all registered data are collected from real clinical practice cases. Patients diagnosed as advanced SCLC and treated with anlotinib were included. The primary endpoint was PFS, and secondary endpoints included overall survival (OS), objective response rate (ORR), DCR and safety. Results: Until Dec 2021, a total of 44 eligible patients were included, with a median age of 62 years, including 34 males (77.3%) and 10 females (22.7%). Among them, 38 patients (86.4%) were diagnosed as a limited stage SCLC and 6 patients (13.6%) diagnosed extensive stage. All patients have not received other targeted therapies before. The median PFS was 6.0 months (95%CI 2.4-5.8), and the median OS was 15.9 months (95%CI 9.1-18.83). At the data cut-off date, 1 patient was assessed as CR, 22 patients were assessed as PR, 15 patients were assessed as SD and 4 patients were assessed as PD. The ORR was 52.3% and the DCR was 86.4%. Conclusions: Significant improvement in OS and PFS were found for advanced SCLC patients in this real-world study. This exhibited that anlotinib has a potential efficacy over previous treatment models. Of course, safety must be further observed subsequently.
MET kinase mutations in lung cancer patients.
Authors: Kalmuk Louise , Descarpentries Clotilde , Mascaux Celine , Munck Camille , Kherrouche Zoulika , Wasielewski Eric , Ulmer Lucie , Farchi Olivier , Escande Fabienne , Beau-Faller Michele , Cortot Alexis B 
Published: June 2022

e21014 Background: Although mutations in the kinase domain of MET are well described in papillary renal cell carcinoma, they are rare and poorly studied in lung cancer, but could constitute a new therapeutic target given the availability of potent MET inhibitors. The characteristics of patients with MET kinase mutation in lung cancer are still unknown. Our objective was to describe the demographic, clinical and biological characteristics of these patients, and analyze their survival. Methods: We conducted a multicenter retrospective study including patients with lung cancer harboring a MET kinase mutation. Patients who had already received treatment with a MET TKI before the MET kinase mutation was found were excluded. Results: We identified 37 patients with a MET kinase mutation. Among them, 2 had already received a MET inhibitor and in 8 cases, the data were not accessible. A total of 27 patients were included in the final analysis, including 17 males (63%) and only 2 (8%) never smokers. The median age was 64 (range 43-86). Most patients had adenocarcinoma (n = 25, 93%). 19 patients were diagnosed at an advanced stage. The main metastatic sites were brain (n = 8, 42%), bones (n = 7, 37%) and lungs (n = 5, 19%). PDL1 expression level was available for 21 patients, and was < 1%, 1-49% and ≥50% in 4 (19%), 5 (24%) and 12 (57%) patients respectively. MET kinase mutations involved exon 15, 16, 17, 18 or 19 in 6 (22%), 7 (26%), 7 (26%), 3 (11%) and 4 (15%) patients respectively. The 2 most common mutations were H1112Y (4 patients) and H1097R (3 patients). 18 patients (67%) had a concurrent alteration by NGS including TP53 mutations (n = 11, 41%), KRAS mutations (n = 6, 22%) and NRAS mutations (n = 3, 11%). Overall, co-alterations involving known driver oncogenes were detected in 13 patients (48%). 19 patients received a first-line systemic treatment for advanced disease. Median progression-free survival with chemotherapy and immunotherapy was 10.5 and 6.4 months, respectively (p = 0.55). Median overall survival was 12.2 months. No patient received a MET inhibitor. Conclusions: MET kinase mutations are not associated with specific clinical characteristics and frequently occur together with other oncogene mutations. These results suggest that these mutations may not be sufficient to drive carcinogenesis by themselves.
Molecular characteristics and treatment strategy in advanced, EGFR-mutant non-small cell lung cancer with concomitant BRAF variations.
Authors: Wei Xue-Wu , Deng Jia-Yi , Xu Chongrui , Chen Zhihong , Zhu Dongqin , Wu Qian , Zhang Xuchao , Shao Yang , Wu Yi-Long , Zhou Qing 
Published: June 2022

e21021 Background: BRAF variants were reported resistant mechanisms to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). However, concomitant somatic variations other than BRAF variants and efficacy of subsequent treatment remained unclear. Methods: From October 2016 to May 2020, advanced NSCLC patients who underwent next-generation sequencing and were detected with co-mutation of BRAF and EGFR activating mutations are retrospectively included. Since June 2020, EGFR-mutant patients with acquired BRAF V600E after progression from previous Osimertinib are prospectively arranged to explore efficacy of the EGFR-BRAF co-inhibition. Results: Fifty-eight patients were retrospectively identified and five patients were prospectively included. BRAF variants was acquired after a median time of 22.7 months from initial diagnosis. Variations of TP53, PIK3CA, RB1, MET, LRP1B, APC, CDKN2A, MYC, ERBB2 and SMAD4 were over 10%, which were enriched in cell cycle/p53 pathway, EGFR downstream and bypass pathway. Subsequently, median progression-free survival was 5.0 months for chemotherapy and 2.1 months for TKI treatment without targeting both EGFR and BRAF respectively (p = 0.019). Osimertinib plus vemurafenib (n = 4) or dabrafenib + trametinib (n = 1) was prospectively administrated in five patients. Median PFS was 7.8 months. Grade 3 rash was observed in one patient. Upon disease progression, activation of RAS signaling was observed. Conclusions: Variations of EGFR downstream or bypass pathway were also frequent in patient with co-mutation of EGFR and BRAF. Efficacy of subsequent TKI without targeting both EGFR and BRAF was inferior to chemotherapy. EGFR-BRAF co-inhibition showed improved efficacy. More treatment strategy should be explored in the future.