bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic assessment of tumor mutational burden calculation across different sequencing platforms and cancer types and its implication in clinical decision-making.
Authors: Sun Daqiang , Tang Hongzhen , Luo Haitao
Published: June 2022

2631

Background: Tumor mutation burden (TMB) has been validated as a biomarker to predict the response of immune checkpoint inhibitors (ICIs) treatment in various cancers. However, the effects of different sequencing platforms, cancer types and calculation methods on TMB as well as its cut-off value for predicting immunotherapy efficacy are still need to be further investigated. Methods: 4140 tumor samples were performed with targeted panel sequencing or whole exome sequencing (WES) in different platforms such as illumina and MGI. Public sequencing data from 3680 samples which contained targeted panel sequencing, WES and whole genome sequencing were obtained. The impact of different sequencing platforms, sequencing methods and calculation methods on the calculation of TMB were assessed. Further, targeted panel sequencing data from 71 sample of lung cancer patients treated with ICIs were used to determine the best cut-off value of TMB for predicting immunotherapy response. Results: TMB values calculated by different platforms and different sequencing methods were similar and there was no significant difference. The distribution of TMB at different sequencing depths and tumor purity were analyzed. We found that there was no significant difference in the distribution of TMB when the sequencing depth was greater than 500´, the HE purity was greater than 0.1 or NGS purity was greater than 0.3. In addition, the correlation of TMB calculated from single-sample and paired-sample is 0.95. Further, the optimal cut-off value of TMB in lung cancer treated with ICIs was determined to be 8 through ROC curve analysis, and patients with TMB ≥ 8 had better outcomes than patients with TMB < 8. Conclusions: This study systematically analyzed the factors which influenced the TMB calculation, and verifies the feasibility of TMB calculation from single-sample. More importantly, the cut-off value of TMB for predicting immunotherapy efficacy in lung cancer was defined as 8 in East Asian populations, which can help in clinical decision-making.
Promising clinical benefit rates in advanced cancers alongside potential biomarker correlation in a phase I/II trial investigating bexmarilimab, a novel macrophage-guided immunotherapy.
Authors: Bono Petri , Pasanen Annika , Verlingue Loic , de Jonge Maja J.A. , de Miguel Maria J. , Skytta Tanja , Iivanainen Sanna , Shetty Shishir , Ma Yuk Ting , Graham Donna M. , Arora Sukeshi Patel , Jaakkola Panu , Yap Christina , Jalkanen Sirpa , Hollmen Maija , Koivunen Jussi , Minchom Anna Rachel
Published: June 2022

2645

Background: Clever-1 is an immunosuppressive scavenger receptor expressed on tumor associated macrophages. High levels of Clever-1 are associated with poor survival and immunotherapy resistance. Bexmarilimab (FP-1305) is a novel humanized anti-CLEVER-1 IgG4-antibody capable of inducing a phenotypic M2 to M1 immune switch of tumor-associated macrophages. Methods: MATINS (Macrophage Antibody To INhibit immune Suppression) trial is a first-in-human phase I/II study (NCT03733990) to assess safety and preliminary efficacy of Bexmarilimab in patients with refractory advanced solid tumours. Part I has been completed with initial good safety profile of the IMP, preliminary signs of efficiency, and recommended dose of 1mg/kg Q3W for part II (ESMO 2020). In Part II (ESMO 2021), 10 distinct solid tumour types were enrolled to assess preliminary efficacy (overall survival (OS), progression free survival (PFS), and clinical benefit rate (CBR). Clever-1 IHC in pre-treatment biopsies with Ventana platform using a primary antibody 4G9 (Santa Cruz) was scored by % of positive cells compared to the viable tumor cells. Results: At the Jan 2022, a total of 193 patients have been enrolled to the study. In the completed cohorts, 138 patients have received 1-21 doses (median 3) of Bexmarilimab Q3W. Bexmarilimab was well tolerated, and no new safety signals were detected. Part I and Part II fully enrolled 11 cancer cohorts, the median PFS was 2.0 months (95% CI 1.9 – 2.0) and the median OS was 5.2 months (95% CI 4.3 – 6.4). CBR for Part II was 17.3% (19/110) at cycle 4 of treatment (by RECIST v.1.1). Notably, 30-40% CBR at cycle 4 was seen in cutaneous melanoma (30%), gastric cancer (30%), cholangiocarcinoma (30%), hepatocellular cancer (40%), and ER+ breast cancer (40%). Six-month survival rates (landmark analysis) were 70.1% for CBR compared to 34.7% for non-CBR patients, with a similar duration of prior therapy in both groups. Preliminary biomarker analysis (n = 77) demonstrated positive trend (p = 0.038) between CBR and higher intratumoral Clever-1 positivity (median of 15% positivity (range 0-25) in CBR and 3% (range 0-85) in non-CBR patients) Conclusions: Bexmarilimab continues to demonstrate promising anti-tumour activity as a monotherapy in several refractory solid tumours. Furthermore, preliminary biomarker analysis suggests a possibility for patient selection based on tumour Clever-1 expression. Further expansion of the study will investigate optimal dosing and biomarkers of efficacy. Clinical trial information: NCT03733990.
Landscape of tumor mutation burden and correlation to clinical outcomes in 1,744 solid cancers.
Authors: Jung Jaeyun , Park Sehhoon , Lee Jeeyun , KIM Seung
Published: June 2022

2667

Background: Tumor mutation burden (TMB) has proven clinical utility and efficacy related to immune checkpoint inhibitor (ICI) treatment in different tumor types. However, limited data were available to understand the landscape and matched clinical outcomes to a pan-cancer extent. Methods: Target sequencing results, using TruSight Oncology 500, from 1,744 solid cancer between 2019 and 2021 as a part of real-world clinical practice were collected. Matched clinical and histological outcomes, including PD-L1 expression ( n= 798) and immunotherapy treatment ( n= 400), were analyzed. Results: Among the 33 different cancer types, high TMB was observed in 257 patients (14.7%) with a significantly higher incidence observed in carcinoma of unknown origin (33.3%), bladder cancer (32.3%), and small bowel cancer (30.0%). TMB was positively correlated with the degree of mutation in homologous recombination genes (HRD, 0.76) and microsatellite instability (MSI, 0.51). The predictive value of high TMB to ICI treatment seemed to be enhanced when it was combined with PD-L1 expression, showing higher response rates in the PD-L1 high group (63.3%) than in the low group (22.2%). In the patients with high TMB, both longer overall survival ( p = 0.015) and progression-free survival ( p = 0.020) were observed compared to the patients with low TMB. Conclusions: We examined the landscape of TMB in a different type of cancer using clinical-level target sequencing outcomes. High TMB seems to be a promising predictive biomarker of ICI, showing a positive correlation with alteration in other DNA damage response and repair-related genes and additive value to PD-L1, which needs to be validated through further prospective trials.
First-in-human, phase I study of AK109, an anti-VEGFR2 antibody, in patients (pts) with advanced or metastatic solid tumors.
Authors: Xu Nong , Zheng Yulong , Zhong Haijun , Zhao Fuyou , Zhou Huan , Mao Chenyu , Lv Wangxia , Yuan Meiqin , Qian Jiong , Jiang Haiping , Wang Zishu , Xiao Cheng , Liu Ting , Liu Wei , Li Baiyong , Xia Yu
Published: June 2022

3021

Background: AK109 is a fully-human monoclonal antibody that specifically binds to vascular endothelial growth factor receptor 2 (VEGFR2), thereby block vascular endothelial growth factor (VEGF)/VEGFR2 signaling pathway to inhibit angiogenesis, endothelial cell migration and proliferation of tumor cells. This phase I study is the first-in-human trial of AK109, which was designed to evaluate safety, tolerability of AK109, to determine the maximum tolerated dose (MTD), recommend phase II dose (RP2D) and to gain preliminary data on pharmacokinetics (PK), pharmacodynamics, immunogenicity and clinical activity for AK109 in pts with advanced or metastatic solid tumors resistant to standard therapies (NCT04547205). Methods: This open-label, multi-center, phase I study included a dose escalation phase (part 1) using a 3+3 design to determine MTD and potential RP2D (n = 36 max), with planned dosing of 2, 4, 8, 12 and 18 mg/kg q2w and 15mg q3w, followed by a dose expansion phase (part 2), at 2 potential RP2Ds in q2w or q3w respectively (n = 24-30). The PK characteristics, dose limiting toxicity (DLT), adverse events per CTCAE 5.0 and efficacy (ORR, DCR, DoR, PFS per RECIST v1.1, OS, etc.) of AK109 were evaluated. Results: As of December 30th, 2021 (median follow-up: 6.0 months), 40 pts (median age: 59.5 years) were enrolled, 16 pts in part 1 and 24 pts in part 2. No DLT was observed AK109 in part 1. Tumor types included gastric cancer (n = 9), non-small cell lung cancer (n = 8), hepatocellular carcinoma (n = 8), colorectal cancer (n = 5), pancreatic carcinoma (n = 2) and oesophagus cancer (n = 2), etc. Preliminary PK analyses showed systemic exposure in Cmax and AUClast increased dose proportionally at doses of 8 mg/kg and above, with a mean half-life of 8.5 to 10 days. 12mg/kg q2w and 15mg/kg q3w were selected as RP2Ds. Average exposure of AK109 was 6.9 cycles. Eight pts received over 10 cycles of AK109. Treatment related adverse events(TRAE) occurred in 38 (95%) of all pts. Grade 3 and 4 TRAE occurred in 16 (40%) of all pts. The most common TRAEs were proteinuria (22/40, 55%), hypertension (13/40, 32.5%) and AST increased (11/40, 27.5%). Serious adverse event (SAE) occurred in 11 (27.5%) pts, 2 (5%) of which were AK109 related. ORR and DCR were 10.0% and 62.5%, respectively. The median PFS of non-small cell lung cancer (n = 8) and gastric cancer (n = 9) were 5.6 months (95% CI, 1.3, NE) and 5.5 months (95% CI, 1.4, NE), respectively. Conclusions: AK109 showed manageable safety and promising anti-tumor activity. Two phase II studies of AK109 combined with AK104 (anti PD-1/CTLA-4 bi-specific antibody) are ongoing to evaluate the efficacy of AK109 combined with AK104 in patients with multiple solid tumors (NCT05142423, NCT04982276). Clinical trial information: NCT04547205.
Multicancer early detection with a spectroscopic liquid biopsy platform.
Authors: Baker Matthew , Cameron James Munro , Sala Alexandra , Antoniou Georgios , Butler Holly , Brennan Paul , Conn Justin , Connal Siobhan , Hegarty Mark , Palmer David , Smith Benjamin
Published: June 2022

3034

Background: A rapid, low-cost, sensitive, multi-cancer early detection (MCED) test would be transformational in the diagnostics field. Earlier cancer detection and instigation of treatment can increase survival rates. An effective test must accurately identify the small proportion of patients with typically non-specific symptoms who actually have cancer. Such symptoms don’t easily segregate by organ system, necessitating a multi-cancer approach. Methods: In this large-scale study ( n = 2094 patients) we applied the Dxcover Cancer Liquid Biopsy to differentiate cancer against non-cancer, as well as organ specific tests to identify cancers of the brain, breast, colorectal, kidney, lung, ovary, pancreas, and prostate. The test uses Fourier transform infrared spectroscopy to analyze all macromolecules in a minute volume of patient serum, and machine learning to build a classifier of the resultant spectral profiles for calling the likelihood of cancer. Results: For the overall cancer classification, our model achieved 90% sensitivity with 61% specificity when tuned for sensitivity, with detection rates of 93% for stage I, 84% for stage II, 92% for stage III and 95% for stage IV. We also tuned for maximum sensitivity or specificity, whilst the other statistic was fixed above a minimum value of 45%. This resulted in 94% sensitivity with 47% specificity, and 94% specificity with 48% sensitivity, respectively. For organ specific cancer classifiers area under the curve values were calculated for all cancers: brain (0.90), breast (0.74), colorectal (0.91), kidney (0.91), lung (0.90), ovarian (0.85), pancreatic (0.81) and prostate (0.85). Conclusions: Cancer treatment is often more effective when given earlier and this low-cost strategy can facilitate the requisite earlier diagnosis. With further development, the Dxcover MCED test could have a significant impact on early detection of cancer, which is vital in the quest for improved survival and quality of life.
Test performance and clinical validity of circulating tumor DNA (ctDNA) in predicting relapse in solid tumors treated with curative intent therapy.
Authors: Mittal Abhenil , Molto Consolacion , Tamimi Faris , Di Iorio Massimo , Al-Showbaki Laith , Cescon David W. , Amir Eitan
Published: June 2022

3036

Background: Studies have explored the prognostic value of ctDNA in predicting relapse in solid tumors treated with curative intent. These studies have evaluated ctDNA at specific ‘landmark’ timepoint or over numerous ‘surveillance’ time points. However, variable results have led to uncertainty about the clinical validity of this tool. Here, we quantify the predictive and discriminatory accuracy of ctDNA and explore sources of heterogeneity at both landmark and surveillance time points across different tumor sites. Methods: A search of MEDLINE (host: PubMed) identified studies evaluating ctDNA after curative intent therapy in solid tumors. Odds ratios (OR) for disease recurrence at both landmark and surveillance time points for each study were calculated and pooled in a meta-analysis using the Peto method. Pooled sensitivity and specificity weighted by individual study inverse variance were estimated and meta-regression utilizing linear regression weighted by inverse variance was performed to explore associations between patient and tumor characteristics and the OR for disease recurrence. Results: Of 23 studies identified; 16 (750 patients) and 14 studies (853 patients) reported on landmark and surveillance time points respectively. The median time from completion of definitive therapy to landmark testing was 51.5 days (range 3-120). The pooled OR for recurrence at landmark was 22.22 (95% CI 14.82-33.30) and at surveillance was 27.51 (95% CI 19.1-39.63). The pooled sensitivity for ctDNA at landmark and surveillance time points were 59.9% and 73.2%. The corresponding specificities were 90.9% and 86.6%. Subgroup results are shown in the table. There was lower predictive accuracy with the use of tumor site specific panels, in patients receiving adjuvant chemotherapy and in lung cancer. Meta-regression showed that longer time to landmark and higher number of surveillance blood draws were associated with higher prognostic accuracy, as was a history of smoking. Conclusions: Although ctDNA at both landmark and surveillance time points shows high prognostic accuracy, it has low sensitivity, suboptimal specificity and therefore weak discriminatory accuracy to predict relapse in patients with solid tumors treated with curative intent. Testing methodology, time points and patient populations need to be optimized before it can be incorporated routinely in clinical practice.[Table: see text]
Increasing targeted therapy options for patients with relapsed cancer with broader somatic gene panel analysis from the primary tumor: The Profiler02 randomized phase II trial.
Authors: Tredan Olivier , Pouessel Damien , Penel Nicolas , Chabaud Sylvie , Gomez-Roca Carlos A. , Pannier Diane , Brahmi Mehdi , Fabbro Michel , Garcia Marie-Eve , Larrieu-Ciron Delphine , Ray-Coquard Isabelle Laure , Viala Marie , Italiano Antoine , Cassier Philippe Alexandre , Dufresne Armelle , Attignon Valéry , Treilleux Isabelle , Viari Alain , Pérol David , Blay Jean-Yves
Published: June 2022

3130

Background: PROFILER-02 is a multicenter randomized prospective study comparing the proportion of metastatic cancer patients (pts) with Targeted Agent (TA) recommendation provided by large NGS panel (FOne panel, 324 genes) vs home 87-gene NGS panel (CTRL) (PMID 30865223). Methods: Adult pts with advanced/metastatic cancer during 1st or 2nd line of therapy without known targetable gene alteration were eligible and randomized (1:1) to FOne vs CTRL panel. Both panels were performed for each patient. The randomization arm defined the first panel reviewed by dedicated Molecular Tumor Board (MTB) at disease progression while the 2nd panel remained blinded. The primary objective was the pts rate with at least one TA recommendation by the MTB using either FOne or CTRL panel. The study was designed in order to detect difference in proportions of 10% between the two panels. A sample size of 289 pts with both panels were requested to show this difference with an expected proportion of discordant pairs of 20% using a McNemar's test with 98% power and 5% two-sided significance level. Secondary endpoints included number of pts receiving at least one TA, progression free survival (PFS) and overall survival (OS). Results: From June 2017 to June 2019, among the 339 included pts 171 and 168 pts were randomized in FOne or CTRL panels’ first use, respectively. Median age was 57 years [19.0 - 85.0]; 54.9% were female. The median time from randomization to first MTB was 7.62 months [range 0.80 - 48.1]. Among the 339 pts, 147 pts (43.4%) had no TA recommendation, 108 pts (31.9%) had at least one TA recommendation according to both panels, 67 pts (19.8%) had one or more TA recommendation according to FOne panel only and 17 pts (5%) according to CTRL panel only (McNemar p < 0.001). At the time of the analysis, 51/339 (15%) pts started recommended treatment: 27 pts (8%) with TA recommendation from both panels, 21 pts (6.2%) from FOne only and 3 pts (0.3%) from CTRL only. Main initiated TA were PARP inh. (FOne n = 12; CTRL n = 9), PI3K/AKT/mTOR inh. (FOne n = 10; CTRL n = 9) and immunotherapy (ICI) (FOne n = 7; CTRL n = 0). Median PFS following first MTB were 3.2 months (95% CI 2.5-3.8) and 2.6 months (95% CI 2.0-3.8), median OS were 8.7 months (95% CI 6.6-10.8) and 8.4 months (95% CI 6.4-9.7), in the FOne and CTRL arm, respectively. Conclusions: Larger NGS panel including Tumor Mutational Burden increased the number of recommended options (TA and ICI), as well as the number of treatment initiation. Clinical trial information: NCT03163732.
Pan-cancer landscape of CD274 (PD-L1) and PDCD1LG2 (PD-L2) structural variations.
Authors: Hoskins Emily Louise , Samarodnitsky Eric , Wing Michele , Reeser Julie , Hopkins Julia , Murugesan Karthikeyan , Kuang Zheng , Stein Leah , Risch Zachary , Vella Raven , Abedola Serifat , Yu Lianbo , Paruchuri Anoosha , Huang Richard S.P. , Albacker Lee A. , Roychowdhury Sameek
Published: June 2022

3133

Background: PD-1 receptor and PD-L1 ligand interactions are the target of immunotherapies across multiple tumor types. Established biomarkers that predict response to immunotherapy are microsatellite instability, tumor mutational burden, and PD-L1 immunohistochemistry. Structural variations in CD274 (PD-L1) and PDCD1LG2 (PD-L2) have been observed in cancer, but the comprehensive landscape is unknown. Here we describe the genomic landscape of CD274 and PDCD1LG2 structural variations, their potential impact on the tumor microenvironment, and evidence that patients with these alterations can benefit from immunotherapy. Methods: We analyzed sequencing data from 514 cancer cases with CD274 and PDCD1LG2 structural variations across 25 publications and data sources, including large pan-cancer sources: Foundation Medicine, Inc (FMI), The Cancer Genome Atlas (TCGA), and Oncology Research Information Exchange Network. To evaluate immune signature enrichment, we ran the software ImSig on gene expression data. We curated literature reporting clinical outcomes of patients harboring structural variations in CD274 and PDCD1LG2. Results: From 25 studies and datasets, we curated 514 cancer cases with structural variations in PD-L1 and PD-L2, including 158 duplications, 126 deletions, 97 inversions, 178 translocations, and 96 unclassified structural variations, totaling to 655 events. We observed breakpoint ‘hotspots’ in the 3’-untranslated regions (UTRs) of PD-L1 and PD-L2. Leveraging TCGA data, we observed, in CD274-rearranged tumors, significant upregulation in PD-L1 and PD-L2 expression and signatures for interferon signaling, macrophages, monocytes, T cells, and immune cell proliferation (each p < 0.001, compared to CD274 non-rearranged, copy neutral tumors). Furthermore, retrospective review of 12 studies that included patients with structural variations in CD274 or PDCD1LG2, including duplications, inversions and copy number amplifications, revealed a 73% (52/71) response rate to PD-1 immunotherapy with durable responses. Conclusions: Our evaluation of CD274 and PDCD1LG2 structural variations shows that the 3’-UTR is frequently affected and is associated with increased expression of ligands and immune signatures. Enriched interferon signaling in CD274-rearranged tumors is of particular interest, as interferon exposure is known to drive PD-L1 and PD-L2 expression. Retrospective evidence from curated studies suggests that these genomic alterations could identify candidates for PD-1 or PD-L1 immunotherapy. We expect that these findings will better define CD274 and PDCD1LG2 structural variations in cancer and support our pan-cancer prospective clinical trial to target these alterations.
Combining autophagy and immune characterizations to predict prognosis and therapeutic response in lung adenocarcinoma.
Authors: Li Qiaxuan , Zhou HaiYu
Published: June 2022

3140

Background: As a key regulator of programmed cell death, autophagy is critical for maintaining the stability of the intracellular environment. Increasing evidences have found that the clinical importance of the interaction between autophagy and immune status in LUAD. Reliable prognostic signatures based on combination of autophagy and immune status have not been well-established. We aimed to explore the potential autophagy-immune-derived biomarkers to predict prognosis and therapeutic response in lung adenocarcinoma. Methods: Patients from GSE72094 dataset were randomized 7:3 to a training set or an internal validation set. Three independent cohorts, TCGA, GSE31210 and GSE37745, were used as the external verification. Unsupervised hierarchical clustering was used to identify the autophagy-associated and immune-associated molecular patterns for LUAD based on autophagy-genes and immune-genes. The LASSO analysis, univariate and multivariate cox regression analysis were performed to filtrate significant prognostic autophagy-immune-based genes, followed with model construction and patient stratification. Tumor immune microenvironment and functional pathways were investigated. The potential therapeutic responses were explored by GDSC database, TIDE algorithm, and immunotherapy clinical cohorts. Results: We found that autophagy cluster A had the better survival prognosis (p < 0.001) and high immune status (p < 0.001) was identified as favorable factors for patients’ overall survival. We merged autophagy and immune subtype into a two-dimensional index to characterize the combined prognostic classifier 535 genes were defined as autophagy-immune-related DEGs. Four genes (C4BPA, CD300LG, CD96, and S100P) were identified to construct the autophagy-immune-related prognostic risk model. Survival analysis and receiver operating characteristic curve showed significant prognostic efficacy. Through ssGSEA and CIBERSORT analysis, the majority of immune infiltrating cells were shown to be enriched in the low-risk group. What’s more, the expression of crucial immune checkpoint molecules, such as PD-1, PD-L1 and CTLA-4, was observed highest in low-risk group (p < 0.001). TIDE and immunotherapy clinical cohorts’ analysis showed that low-risk group was predicted with more potential responders to immunotherapy. In addition, there are different patterns of autophagy between low- and high- risk patients. GO, KEGG and GSEA function analysis focus on cell cycle, MAPK, apoptosis, MTORC1 and selective autophagy pathway. Docetaxel, rapamycin and sorafenib may be the potential drugs candidate in high-risk group (p < 0.01). Conclusions: In summary, the autophagy-immune-based gene signature represents a promising tool for risk stratification tool in lung adenocarcinoma, which can regard individualized treatment and follow-up scheduling for patients.
Construction of a near-term predictive model for irAEs induced by PD-1 inhibitors.
Authors: Zhang Ying , Zhao Jun , Hu Wenqing , Du Yunyi , Zhang Xiaoling , Ma Ning , Yang Wei , Yang Bo , Gao Yangjun , Wang Yu , Liu Min , Wang Mei , Wang Hui , Feng Tingting , Cai Linlin , Li Weiling , Lu Jing
Published: June 2022

3147

Background: Immune checkpoint inhibitors have opened a new chapter in cancer therapy, but the incidence of irAEs caused by them is high, and severe irAEs can be fatal. The current research on irAEs is almost focused on early predictions, and there is a lack of near-term predictions (the cycle before the occurrence of irAEs). Absolute eosinophil count (EO#) has been reported to be associated with immune-related pneumonia, but its association with other systemic irAEs requires further exploration. The aim of this study was to explore the near-term predictive value of neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR), and EO# for PD-1 inhibitor-induced irAEs. Methods: The data are from tumor patients who received PD-1 inhibitor therapy in our department from July 2019 to May 2021. A total of 146 cases were included, of which 56 had irAEs. The data of NLR, PLR and EO# in the cycle before the occurrence of irAEs (the median number of cycles was the second cycle) were collected, and the data of the second cycle was used as the control for patients without irAEs group. Logistic method was used to analyze the correlation between NLR, PLR and EO# and irAEs, and a predictive model was constructed. The sensitivity and specificity of the model were evaluated by ROC curve. This study was registered on Chinese Clinical Trail Registry (ChiCTR2100049849). Results: A total of 146 tumor patients were included, of which 56 developed at least one irAEs. Grade 1-2 irAEs occurred in 39 cases, grade 3-4 in 12 cases (including cardiac, liver, lung and skin toxicity), grade 5 in 2 cases(including cardiac and lung toxicity), and ungraded in 3 cases. The data of the cycle before the occurrence of irAEs were analyzed. Univariate analysis showed that NLR (odds ratio [OR], 1.4, p< 0.05) and EO# (OR, 12.6, p< 0.05) were associated with irAEs, and multivariate analysis suggested NLR (OR, 1.7, p< 0.001) and EO# (OR, 20.4, p< 0.05) were independent risk factors for irAEs. The prediction model composed of NLR, PLR and EO# had a correct rate of 76.7% (AUC = 0.752) in predicting the occurrence of irAEs in the near-term cycle, with a sensitivity of 51.8% and a specificity of 92.2%; the correct rate of predicting irAEs of grade 3 and above was as high as 91.9% (AUC = 0.778), the sensitivity was 14.3% and the specificity was 99.2%. Conclusions: The model composed of NLR, PLR and EO# may predict the occurrence of irAEs in the near-term cycle, especially the prediction of irAEs above grade 3, which can provide early warning for the occurrence of irAEs. Clinical trial information: ChiCTR2100049849.
Combination treatment of radiofrequency ablation and peptide neoantigen vaccination: Promising modality for future cancer immunotherapy.
Authors: Fang Yong , Shou Jiawei , Mo Fan , Zhang Shanshan , Lu Lantian , Han Ning , Liu Liang , Qiu Min , Li Hongsen , Han Weidong , Ma Dongying , Guo Xiaojie , Guo Qianpeng , Huang Qinxue , Zhang Xiaomeng , Ye Shengli , Pan Hongming , Chen Shuqing
Published: June 2022

3151

Background: We previously reported the safety and immunogenicity of a personalized neoantigen-based peptide vaccine, iNeo-Vac-P01, in patients with a variety of cancer types. The current study investigated the synergistic effects between radiofrequency ablation (RFA) and neoantigen vaccination in cancer patients and tumor-bearing mice. Methods: 28 cancer patients were enrolled in this study, including 10 patients who had received RFA treatment within 6 months before scheduled for vaccination, and 18 patients who had not. Individualized neoantigen peptide vaccines were designed, manufactured, and delivered for all patients, followed by subcutaneous administration of GM-CSF as an adjuvant. Mouse models were used to validate the synergistic efficacy of combination treatment of RFA and neoantigen vaccination. Results: Longer median progression free survival (mPFS) and median overall survival (mOS) were observed in patients receiving RFA prior to vaccines compared to patients only receiving vaccines (4.42 and 20.18 months vs. 2.82 and 10.94 months). Ex vivo ELISpot assay showed that patients who received both had stronger IFN-γ responses against patient-specific neoantigens at baseline and post vaccination. Mice receiving RFA together with vaccine displayed higher antitumor immune responses than mice receiving single modality; addition of anti-PD-1 further enhanced the antitumor response. Conclusions: Neoantigen vaccination after RFA treatment led to an overall increase in clinical response and immune response among patients of different cancer types. Combination treatment of both modalities in mice further validated their synergistic antitumor potentials, which could be further enhanced by the addition of anti-PD-1. The mechanisms of their synergies require further investigation. Clinical trial information: NCT03662815.
Race, age, and sex differences on the influence of obesity on colorectal cancer (CRC) sidedness and mortality: A national cross-sectional study.
Authors: Ulanja Mark Bilinyi , Beutler Bryce D. , Antwi-Amoabeng Daniel , Rahman Ganiyu A. , Ulanja Reginald N. , Mabrouk Tariq , Alese Olatunji B.
Published: June 2022

3527

Background: CRC sidedness has recently been recognized as a significant prognostic factor for survival; left-sided colorectal cancer (LCRC) is associated with superior outcomes as compared to right-sided colon cancer (rCC). Although obesity has long been recognized as a risk factor for CRC, the influence of obesity on CRC sidedness remains to be elucidated. To evaluate the effect of obesity on CRC sidedness and determine how race, age, and sex affect mortality among individuals with obesity and CRC. Methods: A survey-weighted analysis was conducted using data obtained from the National Inpatient Sample (NIS) between 2016 and 2019. Results: Of the 24,549 patient discharges included in the cohort with a diagnosis of CRC and a reported body mass index (BMI), 52.6% were LCRC and 47.5% were rCC. The race distribution was 67.7% White, 17.6% Black, 10.0% Hispanic, and 4.8% Other (American Indian, Asian, Pacific Islander, or Alaskan Native). Overweight and obese individuals were more likely to have rCC as compared to normal weight patient discharges [adjusted OR (aOR) = 1.28; 95% CI:1.17 – 1.39 and aOR = 1.45; 95% CI:1.37 –1.54, respectively). In addition, among the obese population, Blacks were more likely to have rCC as compared to Whites (aOR = 1.23; 95% CI: 1.09 – 1.38). Normal weight, overweight, and obese individuals in the “Other” race category had increased odds of death as compared to all other races (aOR=1.18; 95% CI:1.13-1.22; aOR=1.09 95% CI: 0.99-1.19; and aOR=1.19; 95% CI: 1.13-1.25, respectively). Overweight and obese patient discharges over the age of 65 years were more likely than their younger counterparts to present with rCC. As compared to males, females had a higher likelihood of presenting with rCC irrespective of weight, but lower mortality across all weight categories (Table). Conclusions: Obesity is associated with an increased risk of rCC. Racial disparities in CC sidedness and outcomes are particularly pronounced among the overweight and obese population. Investigation into causes of these disparities may help improve outcomes among all individuals with CRC. [Table: see text]
Trends in ethnic-specific colorectal cancer mortality in patients with and without diabetes in the United States: A CDC database population-based study 2011-2019.
Authors: Al Armashi Abdul Rahman , Al Zubaidi Anas , Hammad Faris , Elantably Dina , Patell Kanchi , Somoza-Cano Francisco , Krishna Chandar Apoorva , Ravakhah Keyvan , Alkrekshi Akram
Published: June 2022

3545

Background: Colorectal cancer (CRC) is the third most frequent type of cancer and the second most lethal in both sexes combined. CRC is strongly associated with both environmental and genetic risk factors. Previous studies reported an increased mortality in CRC patients with diabetes mellitus, however, the interplay between ethnicity and diabetes mellitus was not explored. This study analyzes trends in mortality across ethnic groups and assess the impact of diabetes mellitus. Methods: We queried the Multiple Cause of Death database (International Classification of Diseases, 10th revision) between 2011 and 2019, we identified all patients (Hispanic and non-Hispanic origin) who died of a malignant neoplasm of the colon, rectosigmoid junction, and rectum {Codes C18.x to C20.x reported as the underlying cause of death (UCD)}. Then we identified the same group (UCD) among individuals with diabetes (Insulin-dependent diabetes mellitus and non-insulin-dependent diabetes mellitus) (Codes E10.x to E11.x reported as multiple causes of death). Age-adjusted mortality rates per million persons (PMP) were estimated, standardized to US census data from 2000, and stratified by Hispanic origin. Results: In the general population, a total of 464,058 deaths from CRC were identified, with an overall age- adjusted mortality rate of 137.9 PMP (Hispanic: 109.3, Non-Hispanic: 141.1). Overall, age-adjusted mortality declined by 13% among Hispanic, from 118.1 PMP in 2011 to 102.9 PMP in 2019, and by 8% among non-Hispanic, from 153.3 PMP in 2011 to 141.1 PMP in 2019. In the diabetic population, a total of 8679 CRC death were identified, with an overall age-adjusted mortality rate of 2.6 PMP (Hispanic: 3.6, Non-Hispanic: 2.5). Age-adjusted mortality increased by 32% in Hispanic from 3.1 PMP in 2011 to 4.1 PMP in 2019 and by 13% in non-Hispanic from 2.4 PMP in 2011 to 2.7 PMP in 2019. Conclusions: This study concludes that between 2011 and 2019, the CRC mortality was reduced in both Hispanic and non-Hispanic in the general population. Notably, this tendency was not observed in the diabetic population, where mortality increased, particularly among Hispanic. Additional studies are warranted to determine the causes of the rise among diabetics and strategies for minimizing the disparity between Hispanic and non-Hispanic. [Table: see text]
Effects of liver metastases on efficacy of immune checkpoint blockade in treatment refractory, metastatic colorectal cancer (CRC): CCTG CO.26.
Authors: Chen Eric Xueyu , Loree Jonathan M. , Tu Dongsheng , O'Callaghan Christopher J. , Kennecke Hagen Fritz , Jonker Derek J. , Chaudhary Ahmad , Colwell Bruce , Harb Mohammed , Aucoin Nathalie , Couture Felix , Samimi Setareh , Kavan Petr , Aubin Francine , Samson Benoit , Goffin John R. , Berry Scott , Abbas Tahir , Koski Sheryl L. , Wei Alice Chia-chi
Published: June 2022

3600

Background: Immune checkpoint blockade has limited activity in microsatellite-stable (MSS) or mis-match repair proficient (pMMR) CRC. Recent findings suggest that immunotherapy efficacy may be modulated by the presence of liver metastases. We conducted a retrospective analysis of the Canadian Cancer Trials Group (CCTG) CO.26 study to investigate the relationship between the presence of liver metastases and activity of immune checkpoint blockade. Methods: The CCTG CO.26 study was a randomized phase II study (NCT02870920). Pts with treatment refractory CRC were randomized to durvalumab, tremelimumab and best supportive care (BSC) or BSC alone in a 2:1 fashion. Treatment consisted of durvalumab (1500 mg) q 28 days and tremelimumab (75 mg) q 28 days for the first 4 cycles. The primary endpoint was overall survival (OS) and a two-sided p-value <0.10 was considered significant. Results: Between 08/20106-06/2017, 180 pts were enrolled and 179 treated as randomized. Pt baseline characteristics were balanced between groups. With a median follow-up of 15.2 months, the median OS was 6.6 months for durvalumab and tremelimumab and 4.1 months for BSC (p = 0.07; Hazard ratio (HR): 0.72, 90% confidence interval (CI): 0.54 – 0.97). Progression free survival (PFS) was 1.8 months and 1.9 months respectively (HR 1.01, 90% CI: 0.76 – 1.34). Disease control rate (DCR) was 22.6% for durvalumab and tremelimumab and 6.6% for BSC (p = 0.006). At study entry, liver metastases were absent in 29.4% pts. Pts without liver metastases had improved OS compared to those with liver metastases, irrespective of treatments. PFS was significantly longer in those without liver metastases on durvalumab and tremelimumab (HR: 0.55, 90% CI: 0.31 – 0.97, p = 0.08, interaction p = 0.02). DCR was 49% in patients without liver metastases with durvalumab and tremelimumab, compared to 10% in those with liver metastases (Odds Ratio: 0.12, 90% CI: 0.05 – 0.26). Conclusions: Pts without liver metastases had improved OS and PFS, and higher DCR. Absence of liver metastases may be an indicator for improved efficacy of immune checkpoint blockade and should be investigated in future studies. [Table: see text]
Effect of adjuvant chemotherapy in patients with stage III colon cancer based on the Multi-Institutional Registry of Large Bowel Cancer in Japan.
Authors: Yamada Yasuhide , Kobayashi Hirotoshi , Nagashima Kengo , Sugihara Kenichi
Published: June 2022

3610

Background: A fluoropyrimidine plus oxaliplatin is the standard of care for stage III colon cancer but a fluoropyrimidine alone is also recommended for stage III patients in Japanese and other practice guidelines. We assessed efficacy of adjuvant fluoropyrimidine with or without oxaliplatin across a population of stage III colon patients in the Multi-Institutional Registry of Large Bowel Cancer in Japan. Methods: 7,024 of stage III colorectal cancer patients in this registry were analyzed. Endpoints were relapse-free survival (RFS) and overall survival (OS). Results: All patients received adjuvant chemotherapy between 2008 and 2011.Patient characteristics except lymph node metastases were well balanced across groups. The RFS of fluoropyrimidine with or without oxaliplatin show comparable efficacy for stage III, even for stage IIIc patients, less than 70 years old, and T4 or N2b. Median follow-up was 74.9 months in oxaliplatin combined therapy and 74.7 months in fluoropyrimidine monotherapy. The additive efficacy of oxaliplatin was not shown for RFS and OS. Conclusions: Adjuvant fluoropyrimidine monotherapy and fluoropyrimidine plus oxaliplatin show comparable efficacy benefits for the treatment of stage III of Japanese colon cancer patients; supporting fluoropyrimidine alone as standard options for the adjuvant therapy of stage III in Japan. [Table: see text]
Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade for patients with pMMR, high-risk, and locally advanced middle to low rectal cancer.
Authors: WU Aiwen , Li Yingjie , Ji Dengbo , Zhang Li , Zhang Xiaoyan , Cai Yong , Zhang Yangzi , Yao Yunfeng , Wang Lin , Leng Jiahua , Zhan Tiancheng , Sun Ying-Shi , Li Zhongwu , Cui Xiaoli , Luo Haitao
Published: June 2022

3611

Background: Total neoadjuvant therapy (TNT) with chemotherapy and chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal cancer patients, especially for those with high risk factors. And the effects of immune checkpoint inhibitors (ICIs) on rectal cancer with defect mismatch repair (dMMR) have been demonstrated. However, the efficacy of TNT combined with PD-1 blockage for rectal cancer patients with proficient mismatch repair (pMMR) is unknown. The purpose of this study is to evaluate the clinical safety and efficacy of neoadjuvant PD-1 blockade combined with TNT in locally advanced rectal cancer with pMMR. Methods: We designed a prospective, single-arm, phase II study on stage II and III dMMR rectal cancer with high risk factors. Patients received neoadjuvant POC regimen (PD-1 inhibitor, camrelizumab, also called SHR01210, 200mg d1, Oxaliplatin 130mg/m2 d1 and Capecitabine 1250mg/m2 bid1-14, q3wks) for three cycles, then with long course chemoradiation (IMRT, 1.8Gy/f*25f). If there were no disease progression occurs, patients would be treated with another two cycles of CapeOx. The primary endpoint was pathological complete response rate (pCR rate), and the secondary outcome include adverse events and surgical complication. Biopsies and plasma pre-neoadjuvant therapy were collected and performed with whole-exome sequencing (WES), and ctDNA sequencing, respectively. Results: 27 patients were screened, of whom 25 patients were enrolled. All patients have completed the TNT. After neoadjuvant treatment, 21 patients underwent TME surgery. 7 (33.3%) patients were pCR, 3 (14.3%) achieved clinical complete or near complete response and 7 (33.3%) had a major pathological response. No progressive disease was found. WES and ctDNA sequencing analysis showed that tumor mutation burden (TMB) and level of ctDNA did not differ significantly between responders and non-responders. However, 3 responders with TMB high were found to be defective in other DNA damage repair pathways. Conclusions: Total neoadjuvant chemoradiation combined with neoadjuvant PD-1 blockade can achieve high pathological response rate, demonstrating its antitumor efficacy in pMMR locally advanced rectal cancer patients with high risk factors.
Adiposity in resectable colorectal cancer.
Authors: Hopkins Jessica , Bigam David , Baracos Vickie , Eurich Dean , Reif Rebecca , Sawyer Michael B.
Published: June 2022

3614

Background: Sarcopenia and myosteatosis affect survival in colorectal cancer (CRC). The role of adiposity is not yet fully elucidated. This study explores visceral and subcutaneous adipose tissue (VAT/SAT) distributions, and how they affect overall (OS), disease-free (DFS) and cancer specific survival (CSS). Methods: This retrospective cohort study, included resected stage I-III CRC in Alberta from January 2007 to December 2009. We excluded recurrent/metastatic disease or no CT scan. This study was approved by the Health Research Ethics Board at the University of Alberta. Body composition parameters were measured from CT scans. Sarcopenia and myosteatosis were defined by cohort-specific cut-off values. Total and visceral fat areas were indexed by height, and cohort-specific cut-offs defined total and visceral obesity (VO). SAT (SC:TFR) and VAT (V:TFR) to total adipose ratios were compared by gender, as described by Fleming. SAT and VAT fat radiodensity (Hounsfield units, HU) was measured and divided into quartiles. Differences between groups were compared with student’s t-test and Fisher Exact test. Cox proportional hazard models were created, adjusting for important covariates, to assess adiposity effects on OS, DFS and CSS. Results: Our cohort included 968 patients with a median follow up of 63.5 months. The majority were stage II (38.6%) and III (51.0%). In total, 67.9% had total obesity and 51.0% had visceral obesity. In males, there was no difference in the incidence of myosteatosis or sarcopenia, regardless of V:TFR or SC:TFR. In women, those with a high V:TFR or SC:TFR had significantly higher incidence of myosteatosis, but not sarcopenia. Men and women with elevated V:TFR had significantly lower VAT and SAT HU (p<0.001, p=0.0113). Those with elevated SC:TFR had significantly higher VAT and SAT HU (p<0.001). VAT and SAT HU was lowest in those with myosteatosis alone (p<0.001; p=0.005). In survival analysis, VO and VAT HU quartiles predicted worse OS in uni-, but not multivariate analysis. SAT HU quartiles predicted worse survival in uni- and multivariate analysis, with the highest quartile of SAT HU predicting increased risk of death (HR 1.35, p=0.037). Adiposity was not predictive of CSS or DFS in uni- or multivariate analysis. Conclusions: This study demonstrated changes in VAT/SAT in relation to well described body composition parameters. SAT HU may have a more important role in OS than visceral adipose characteristics, despite known metabolic characteristics of VAT. True roles of adipose tissue in CRC outcomes remains unclear. VAT/SAT measurements using cross-sectional imaging allows for a detailed analysis and understanding of how adiposity may affect survival. [Table: see text]
Trend of sphincter-preserving surgeries for resectable low rectal cancer: A 20-year experience in China.
Authors: HU Qingqing , Zheng Kuo , Yao Yuting , Zhou Yuan , Meng Ronggui , Wang Hao , Hao Liqiang , Zhang Yongjing , Qiu Hong , Zhang Wei
Published: June 2022

3615

Background: Over the last decades, patients with low rectal cancer have realized better functional, morbidity, and quality-of-life outcomes from improvements in surgical techniques in sphincter preservation. We aimed to quantify the trend in sphincter-preserving surgeries for low rectal cancer over 20 years in China. Methods: Between November 1999 and October 2021, a cohort of patients with pathologically confirmed primary malignant rectal tumor ≤5cm from the anal verge and who received selective surgery at Changhai Hospital, was identified. Demographic and clinical data were extracted from electronic medical records. Survival data were collected from outpatient medical records and follow-up phone interviews. A Joinpoint Regression Model was used to analyze trends in surgical procedures by average annual percentage change (AAPC). A Cox proportional hazards regression model adjusting for demographic and clinicopathological confounders was used to assess the overall survival for patients with sphincter-preserving surgery vs. abdominoperineal resection (APR). Results: Among 19,276 patients with colorectal cancer, 4,072 (21.1%) had a tumor in the low rectum during the study period; 3,025 (74.2%) underwent a sphincter-preserving surgery and 1,047 (25.7%) received APR. Sphincter-preserving surgery increased 3.6% per year (AAPC 3.6, p=.006). Anterior resection was the most performed procedure (86.3%) and maintained a steady trend (AAPC 0.13, p=.49), while intersphincteric resection (including conformal sphincter preservation operation) increased 49.4% annually (AAPC 49.4, p=.003). Laparoscopic techniques increased 15.1% per year (AAPC 15.1, p=.035). Sphincter-preserving surgery increased annually for tumors ≤2cm, 2-3cm and 3-4cm from the anal verge (AAPC 7.08, p=.001; 4.69, p=.001; 2.66, p=.001, respectively). A total of 2,854 patients had sufficient vital status data for inclusion in the survival analysis. The characteristics of those with and without a follow-up encounter were comparable. Patients with sphincter-preserving surgery had a lower risk of death compared to APR (adjusted HR 0.78, 95% CI, 0.65-0.93, p=.01). Conclusions: Utilization of sphincter-preserving surgeries increased significantly over the last 20 years. Patients with low rectal cancer who underwent sphincter preservation had better survival than similar patients who underwent APR.[Table: see text]