Chinese Colorectal Cancer Patients Research Articles

Mutational profile evaluates metastatic capacity of Chinese colorectal cancer patients, revealed by whole-exome sequencing

Colorectal cancer (CRC) is the third most common cancer and the prevalence rate of CRC is increasing in the China. In this study, whole-exome sequencing (WES) was performed on primary tissues of 47 CRC Chinese patients including 22 metastatic and 25 non-metastatic patients. By comparison with data from western colorectal cancer patients in the Cancer Genome Atlas (TCGA), we identified a number of genes that are more likely to be mutated in Chinese colorectal cancer patients, such as MUC12, MUC12, MUC2, MUC4, HYDIN and KMT2C. Interestingly, MUC family genes including MUC12, MUC2 and MUC4, have mutation rates of >20%, while the mutation frequency was extremely low in western colorectal cancer patients, which were <3% in TCGA and 0% in Memorial Sloan Kettering Cancer Center (MSKCC). We detected metastasis-specific mutated genes including TCF7L2, MST1L, HRNR and SMAD4, while MUC4, NEB, FLG and RFPL4A alteration is more prevalent in the non-metastasis group. Further analysis reveals mutation genes in metastasis group are more focus in the Wnt and Hippo signaling pathway. APC, SMAD4 and TCF7L2 accounted for the major genetic abnormalities in this pathway. In conclusion, this study identified the unique characteristics of gene mutations in Chinese patients with colorectal cancer, and is a valuable reference for personalized treatment in Chinese CRC patients.

Clinical-Molecular characteristics and Post-Translational modifications of colorectal cancer in north China: Implications for future targeted therapies

This study delineated the elucidate molecular changes and their post-translational modifications (PTMs) in heterogenetic colorectal cancer (CRC) for a deeper understanding of the CRC pathophysiology and identifying potential therapeutic targets. In this retrospective study, the profiles of 13 hot spot gene mutations were analyzed and the microsatellite instability (MSI) status was determined.Employing the Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) assay, the clinical-pathological features of CRC were characterized in 249 Chinese patients. PTMs were quantified online.Among the patients with CRC, the mutation frequencies of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC genes were 47.8%, 3.6%, 4.8%, 13.7%, 55.8%, and 36.9%, respectively. The proportion of MSI-high (MSI-H) was 7.8%.Subsequent multiple logistic regression analysis showed significant associations including a link between lung metastasis and KRAS mutation, between liver metastasis and lymph node metastasis, between MSI-H and early-onset CRC (EOCRC) and KRAS mutation, between right-sided colon cancer and peritoneal metastasis, and between PIK3CA mutation and PTEN mutation. Patients with KRAS mutation presented with MSI-H, lung metastasis, and PIK3CA mutation. MSI-H, BRAF mutation, and PTEN mutation were more frequent in EOCRC. Phosphorylation and ubiquitylation were found in KRAS, BRAF, PTEN, and SMAD4; SUMOylation and ubiquitylation were observed in HRAS and NRAS; while phosphorylation was obvious in APC, P53, and MLH1. Notably, Phosphorylation and ubiquitylation were the two most common PTMs. The biological characteristics of CRC in Chinese patients have some unique clinical features, which can be explained by the genetic mutation profile, correlations among gene mutations and clinical characteristics. These distinctions set the Chinese patient population apart from their Western counterparts.

Expert consensus on the early diagnosis and treatment of colorectal cancer in China (2023 edition)

Colorectal cancer (CRC) has been a common malignant tumor in China. Through the great effort in cancer prevention and treatment, the 5-year survival rate of patients with CRC in China has been largely improved. However, insufficient early diagnosis and treatment have seriously impeded the prognosis of Chinese CRC patients. The Early Diagnosis and Treatment Group of the Chinese Medical Association, Oncology Branch organized experts in the area of CRC to write the Expert Consensus on the Early Diagnosis and Treatment of Colorectal Cancer in China and issued it publicly (2020 edition). The 2020 edition of expert consensus has been meaningful to the early diagnosis and standardized treatment of CRC. Based on the prior edition, the Early Diagnosis and Treatment Group of the Chinese Medical Association, Oncology Branch revise the consensus focused on the early screening and diagnosis protocols for colorectal cancer, endoscopic/surgical management of early colorectal tumor, as well as adjuvant treatment and remedial measures and follow-up monitoring protocols. The 2023 edition of the consensus not only synthesized the latest evidence from China and combined it with the specific national condition and clinical practice, but also referred to the international guidelines. This 2023 edition consensus, developed for clinicians working on the screening, early diagnosis and treatment for CRC, would further promote the standardization and advances in the diagnosis and treatment of CRC at the early stage in China, and improve the survival and prognosis of CRC.

Prevalence and influencing factors of probiotic usage among colorectal cancer patients in China: A national database study.

Probiotics have become increasingly popular among cancer patients. However, there is limited data from a real-world setting. This study aims to conduct a retrospective analysis to understand the trend of probiotic prescriptions in Chinese colorectal cancer patients. The Mann-Kendall and Cochran-Armitage trend test was applied to estimate the trend significance. Gephi software identified the combination of probiotic strains. The binary logistic regression investigated influence factors, and Spearman's rank correlation coefficient calculated correlations between probiotics and antitumor drug usage. The probiotic prescription percentage increased from 3.3% in 2015 to 4.2% in 2021 (Z = 12.77, p < 0.001). Although 48.3% of probiotic prescriptions had no indication-related diagnosis, diarrhea (OR 10.91, 95% CI 10.57-11.26) and dyspepsia (3.97, 3.82-4.12) included prescriptions most likely to contain probiotics. Prescriptions from the tertiary hospital (1.43,1.36-1.50), clinics (1.30, 1.28-1.33), and senior patients (1.018 per year, 1.017-1.019) were more likely to contain probiotics. Most probiotic prescriptions (95.0%) contained one probiotic product but multiple strains (69.3%). Enterococcus faecalis (49.7%), Lactobacillus acidophilus (39.4%), and Clostridium butyricum (27.9%) were the most prescribed strains. The probiotics co-prescribed with antitumor agents increased rapidly from 6.6% to 13.8% in seven years (Z = 15.31, p < 0.001). Oral fluorouracil agents (2.35, 2.14-2.59), regorafenib (1.70,1.27-2.26), and irinotecan (1.27,1.15-1.41) had a higher probability to co-prescribed with probiotics. There was no correlation between probiotic strain selection and specific antitumor drug use. The increasing prescription of probiotics in colorectal cancer patients in China may be related to treating the gastrointestinal toxicity of anti-cancer drugs. With unapproved indications and a lack of strain selectivity, evidence-based guidelines are urgently needed to improve probiotic use in this population.

A genetic variant in the immune-related gene ERAP1 affects colorectal cancer prognosis.

Findings on the association of genetic factors and colorectal cancer (CRC) survival are limited and inconsistent, and revealing the mechanism underlying their prognostic roles is of great importance. This study aimed to explore the relationship between functional genetic variations and the prognosis of CRC and further reveal the possible mechanism. We first systematically performed expression quantitative trait locus (eQTL) analysis using The Cancer Genome Atlas (TCGA) dataset. Then, the Kaplan-Meier analysis was used to filter out the survival-related eQTL target genes of CRC patients in two public datasets (TCGA and GSE39582 dataset from the Gene Expression Omnibus database). The seven most potentially functional eQTL single nucleotide polymorphisms (SNPs) associated with six survival-related eQTL target genes were genotyped in 907 Chinese CRC patients with clinical prognosis data. The regulatory mechanism of the survival-related SNP was further confirmed by functional experiments. The rs71630754 regulating the expression of endoplasmic reticulum aminopeptidase 1 ( ERAP1 ) was significantly associated with the prognosis of CRC (additive model, hazard ratio [HR]: 1.43, 95% confidence interval [CI]: 1.08-1.88, P = 0.012). The results of dual-luciferase reporter assay and electrophoretic mobility shift assay showed that the A allele of the rs71630754 could increase the binding of transcription factor 3 (TCF3) and subsequently reduce the expression of ERAP1 . The results of bioinformatic analysis showed that lower expression of ERAP1 could affect the tumor immune microenvironment and was significantly associated with severe survival outcomes. The rs71630754 could influence the prognosis of CRC patients by regulating the expression of the immune-related gene ERAP1 . No. NCT00454519 ( https://clinicaltrials.gov/ ).

Molecular Profiling Provides Clinical Insights Into Targeted and Immunotherapies as Well as Colorectal Cancer Prognosis

Tumor genetic testing is indispensable in the management of primary and metastatic colorectal cancer (mCRC), yet the indications for genomics-guided precision medicine and immunotherapy need to be better understood and defined. We prospectively sequenced tumors from 869 Chinese colorectal cancer patients by a large panel and evaluated the clinical significance of single gene somatic mutations and co-occurring events in mCRC, as well as their functional effects and tumorigenic mechanisms. We systematically assessed the heterogeneity of the tumor immune microenvironment in different genomic contexts through the combined analysis of Immunoscore, multiplex immunostaining, whole-exome sequencing, transcriptome, and single-cell sequencing. Single-gene somatic mutations in BRAF or RBM10 were associated with shorter progression-free survival (PFS) in mCRC patients. Functional studies suggested RBM10 acts as a tumor suppressor in CRC development. Co-mutations of KRAS/AMER1 or KRAS/APC were enriched in the metastatic cohort, which had poor PFS and did not benefit from bevacizumab due to accelerated drug metabolism. Forty patients (4.6%) carried pathogenic or likely pathogenic germline alterations in the DNA damage repair pathway, and 37.5% of these tumors had secondary-hit events with loss of heterozygosity or biallelic alterations. A high tumor indel burden with MSI-high suggested immunogenicity with numerous activated tumor-infiltrating lymphocytes, whereas POLE-mutation with TMB-ultrahigh indicated a relatively quiescent immunophenotype. The heterogeneous genomic-immunological interactions were reflected in the divergent neoantigen presentation and depletion, immune checkpoint expression, PD-1/PD-L1 interaction, and T-cell responsiveness to pembrolizumab. Our integrated analysis provides insights into CRC prognostic stratification, drug response, and personalized genomics-guided targeted and immunotherapies.

Short-term outcomes following purse-string versus conventional closure of ileostomy wounds in Chinese colorectal cancer patients — a single center retrospective study

BackgroundNearly 15% colorectal cancer (CRC) patients received ileostomy, while surgical site infection (SSI) is a common complication after ileostomy wound closure. Purse-string closure was reported to reduce SSI rate in ileostomy wound closure compared with conventional linear closure, but had never been systematically reported in CRC patients. The present study aimed to compare the short-term outcomes between purse-string and conventional closure in Chinese CRC patients.Patients and methodsA total of 57 CRC patients underwent ileostomy wounds closure in the Second Affiliated Hospital of Zhejiang University during November, 2015 and October, 2017 were retrospectively reviewed. Twenty-nine received purse-string closure while the others received conventional closure. The short-term outcomes including SSI rate, scar length, pain score and hospital stay were reviewed and analyzed.ResultsThere were no significant differences in the characteristics of the patients between two groups. The SSI rate was similar within two groups (10.3% vs 10.7%, p = 1.000). The purse-string closure group had a significantly short scar length (1.66 cm vs 5.30 cm, p < 0.0001), but had no difference in operation time, hospital stay and postoperative pain.ConclusionThe present study did not find superiority of Purse-string closure in SSI rate control. It seemed only had a cosmetic effect according to its shorter scar length.

Relationship between self-efficacy and physical activity among colorectal cancer patients: A cross-sectional study.

To investigate the current status of self-efficacy and physical activity among Chinese colorectal cancer (CRC) patients and explore the relationship between them. A cross-sectional study. This study was conducted on 282 CRC patients in China. Structured questionnaires were used to collect data on demographic and clinical information, self-efficacy (Exercise Self-Efficacy Scale [ESES]) and physical activity (International Physical Activity Questionnaire-Short Form [IPAQ-SF]). The median (interquartile range) total self-efficacy score for patients with CRC was 52.78 (42.08-61.11), and the median (interquartile range) total physical activity score was 1776.00 (1142.25-2812.05). Only 28.37% of CRC patients met the guideline recommendations for physical activity. The total self-efficacy score was significantly positively correlated with the total physical activity score (r=0.123, p=0.040). CRC patients contributed to the data of this study. Hospital administrators facilitated the implementation of the study.

Mid-Arm Muscle Circumference or Body Weight-Standardized Hand Grip Strength in the GLIM Superiorly Predicts Survival in Chinese Colorectal Cancer Patients.

Our objective was to identify the optimal method to assess reduced muscle mass (RMM) using the Global Leadership Initiative on Malnutrition (GLIM) approach and investigate the roles of the GLIM approach in nutrition assessment and survival prediction in colorectal cancer (CRC) patients. During a median follow-up period of 4.2 (4.0, 4.4) years, a development cohort of 3612 CRC patients with a mean age of 64.09 ± 12.45 years was observed, as well as an external validation cohort of 875 CRC patients. Kaplan−Meier curves and multivariate Cox regression were adopted to analyze the association between GLIM-diagnosed malnutrition and the overall survival (OS) of CRC patients. A nomogram predicting individualized survival was constructed based on independent prognostic predictors. The concordance index, calibration curve, and decision curve were applied to appraise the discrimination, accuracy, and clinical efficacy of the nomogram, respectively. Patients diagnosed with severe malnutrition based on either the mid-arm muscle circumference (MAMC) or body weight-standardized hand grip strength (HGS/W) method had the highest mortality hazard ratio (HR, 1.51; 95% CI, 1.34−1.70; p < 0.001). GLIM-defined malnutrition was diagnosed in 47.6% of patients. Severe malnutrition was an independent mortality risk factor for OS (HR, 1.25; 95% CI, 1.10−1.42; p < 0.001). The GLIM nomogram showed good performance in predicting the survival of CRC patients and was clinically beneficial. Our findings support the effectiveness of GLIM in diagnosing malnutrition and predicting OS in CRC patients.

Effect of hospital-based case management on psychosocial wellbeing and treatment outcomes in colorectal cancer patients: A quasi-experimental study.

Case management has been regarded as the front line of necessary change for fragmented healthcare system. This study proposed a case management intervention that is suitable for Chinese colorectal cancer patients and explored its effectiveness over a 12-month follow-up. A quasi-experimental study was conducted in an oncology hospital in China. A total of 188 patients were recruited from May 2015 to February 2017; 85 patients in the control group and 80 patients in the intervention group were included in data analysis. The intervention group was managed for 1 year by a case manager who organized the multidisciplinary team, provided regular assessment, a consulting service and referrals. Quality of life, anxiety and depression, symptom distress, treatment adherence and unplanned readmission rates were measured. Repeated measurement ANOVA showed significant intervention and time effects in global quality of life, anxiety and depression, symptom distress and oral chemotherapy adherence. The intervention group showed statistically significantly better overall treatment adherence and lower unplanned readmission rate. Nurse-led case management was effective in improving psychosocial outcomes, treatment adherence and unplanned readmission rate of colorectal cancer patients. A case management model is feasible and effective in colorectal cancer patients and in hospital-dominated healthcare systems where primary care is underutilized.

Prognostic Role of Pretreatment Geriatric Nutritional Risk Index in Colorectal Cancer Patients: A Meta-Analysis

To identify the prognostic value of the pretreatment geriatric nutritional risk index (GNRI) in colorectal cancer. Several electronic databases were searched up to March 15, 2022, for relevant studies. The primary and secondary outcomes were overall survival (OS) and disease-free survival (DFS), respectively. The hazard ratios (HRs) with 95% confidence intervals (CIs) were combined. Bess’s funnel plot and Egger’s test were conducted to detect publication bias, and the trim-and-fill method was performed to identify potentially unpublished papers and their impacts on the overall results. Nine studies from Japan and China involving 3440 participants were enrolled in the current meta-analysis. The pooled results indicated that a low pretreatment GNRI was significantly associated with poorer OS (HR = 2.28, 95% CI: 1.69–3.07, P < 0.001; I 2=63.5%, P heterogeneity=0.005) and DFS (HR = 1.62, 95% CI: 1.35–1.96, P < 0.001; I 2=46.4%, P heterogeneity=0.114). Subgroup analysis stratified by country and treatment showed similar results. Significant publication bias was manifested by the asymmetric Begg’s funnel plot and P = 0.012 of Egger’s test, but three potentially unpublished studies did not have a significant impact on the overall results. A lower pretreatment GNRI was a novel prognostic risk factor for Japanese and Chinese colorectal cancer patients.

Identification of APC Mutation as a Potential Predictor for Immunotherapy in Colorectal Cancer.

To date, anticancer immunotherapy has presented some clinical benefits to most of advanced mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC) patients. In addition to MSI status, we aimed to reveal the potential predictive value of adenomatous polyposis coli (APC) gene mutations in CRC patients. A total of 238 Chinese CRC patients was retrospectively identified and analyzed for clinical features and gene alternations in APC-mutant type (MT) and APC-wild-type (WT) groups. Clinical responses were then evaluated from the public TCGA database and MSKCC immunotherapy database. Although programmed cell death ligand 1 (PD-L1) level, MSI status, loss of heterogeneity at the human leukocyte antigen (HLA LOH), and tumor neoantigen burden (TNB) level were not statistically different between the APC-MT group and APC-WT group, tumor mutation burden (TMB) level was significantly higher in APC-MT patients (P < 0.05). Furthermore, comutation analysis for APC mutations revealed co-occurring genomic alterations of PCDHB7 and exclusive mutations of CTNNB1, BRAF, AFF3, and SNX25 (P < 0.05). Besides, overall survival from MSKCC-CRC cohort was longer in the APC-WT group than in the APC-MT group (HR 2.26 (95% CI 1.05–4.88), P < 0.05). Furthermore, most of patients in the APC-WT group were detected as high-grade immune subtypes (C2–C4) comparing with those in the APC-MT group. In addition, the percentages of NK T cells, Treg cells, and fibroblasts cells were higher in APC-WT patients than in APC-MT patients (P < 0.05). In summary, APC mutations might be associated with poor outcomes for immunotherapy in CRC patients regardless of MSI status. This study suggested APC gene mutations might be a potential predictor for immunotherapy in CRC.

Abstract 5133: Genetic characteristics &amp; clonal evolution of Chinese resectable colorectal cancer patients with lung metastases

Abstract Background Colorectal cancer (CRC) has a high incidence and mortality. In CRC, the lung is the most common extra-abdominal site of metastasis. Understanding the genetic characteristics and clonal evolution of primary tumor and lung metastases (LM) will help oncologists better outline treatments. To date, few studies for CRC with LM exist. As such, revealing the genetic characteristics and clonal evolution of resectable CRC with LM was the goal of this study. Methods From January 2012 to July 2019, clinical data and formalin-fixed, paraffin-embedded samples were collected from 33 Chinese CRC patients. Nineteen (19) primary tumors and 10 matched LM samples were examined using a 450 cancer gene next-generation sequencing assay. Genomic alterations, including single base substitutions, indels, copy number variations (CNVs), and gene fusion and rearrangement, were assessed. A phylogenetic reconstruction of sequencing data using LICHeE was also performed for each patient. Results Median patient age was 60 years old (48-67 years), with most having right lung metastasis. A significant difference existed between single (21/33, 63.6%) and multiple LM (12/33, 36.4%) (P &amp;lt; 0.01). Median disease-free survival was 20 months (95% CI, 0-84), from primary CRC to LM. The most frequently mutated genes were TP53 (90%), APC (90%), KRAS (53%), MUC16 (26%), ARID1A (21%). A comparison of mutational profiles for primary and matched LM samples revealed that 65.70% of alterations were consistent and that the most frequently mutated genes, including APC, TP53, and KRAS, of the primary tumor were completely consistent with LM. However, some differences between metastatic and primary samples were determined. More CNVs were found in primary samples (11.4% vs. 4.6%), indicating that CNVs are early molecular events for tumorigenesis and disease progression. SMAD4 was only present in two primary samples, while LRP1B was only present in two LM samples. Clonal evolution for eight patients indicated that phylogenetic structure was similar across patients. All patients had at least seven mutations on trunks. In trunks, TP53 (87.5%), APC (87.5%), KRAS (50%), and LRP2 (37.5%) were frequently identified. A new actionable gene (BRCA2) emerged in LM sample was identified in one patient. The mean value of TMB for the primary was almost the same as that for the LM site (5.3 vs. 5 muts/Mb, P &amp;gt; 0.05). Conclusions Our data indicated that the genetic characteristics and clonal evolution of LM are highly consistent with those of the primary tumor, suggesting that suitable treatments can be selected based on the genetic characteristics of primary tumor in CRC patients with LM that cannot be surgically treated. Citation Format: Yong Cheng, Ming-Jian Ge, Peng Dong, Yan-Yu Qiu, Xin-Peng Shu, Jin-Dou Li, Jun-Wei Wang, Xiao-Fang Qi. Genetic characteristics &amp; clonal evolution of Chinese resectable colorectal cancer patients with lung metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5133.

Abstract 5763: Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer

Abstract Background: Colorectal cancer (CRC) is a malignant tumor that seriously threatens human health. Valuable diagnostic and prognostic biomarkers are urgently needed for colorectal cancer. We aim to analyze the mutational characteristics of Chinese CRC patients with different tumor differentiation degree, in order to improve the diagnosis and prognosis of this population. Methods: We retrospectively analyzed tumor tissue specimens from colorectal cancer patients who were treated at the First Affiliated Hospital of Shanxi Medical University from 2019 to 2021. Targeted NGS for 450 genes was performed in OrigiMed (Shanghai, China), a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory. Results: There were 35 males (55.6%) and 28 females (44.4%) with a median age of 60 (range 23-87) years were involved, including 55 moderately and well differentiated and 8 poorly differentiated colorectal tumors. The mutational frequency of BRAF in the poorly differentiated group was significantly higher than that in moderately and well differentiated group(25% vs. 1.8%, p=0.04). The mutational frequencies of the chromosome folding pathway, notch pathway, and PI3K pathway in poorly differentiated group were significantly lower than that in moderately and well differentiated group(p=0.975X10-15,p=0.97 X 10-26,and p=0.00517, respectively). In this study, the mutations of PDCD1 (programmed cell death 1) and TSC2 Significantly associated with tumor mutation burden (p=0.007 and p=0.047, respectively). In addition, high-frequency co-mutations of chromosome folding-related genes and DNA damage repair-related genes, such as co-mutations between ARID1A-MLH1,KMT2D-MSH6,KMT2D-MSH2, KMT2D-BRCA1, ARID1A-CHEK2, were detected in this study. Conclusions: We compared the genomic alterations between well-differentiated group and poorly-differentiated group in Chinese CRC patients. Our data showed significant differences in mutational frequency of chromosome folding pathways, notch pathways, and PI3K pathways between well-differentiated group and poorly-differentiated group. Meanwhile, we also identified the high-frequency and complex co-mutation characteristics of chromosome folding pathway genes and DNA damage repair genes in Chinese CRC patients. Citation Format: Xiaolong Cui, Aigang Ren, Hao Chen, Yaoliang Huo, Yanwu Zeng, Hao Zhang, Meizhen Hu, He Huang, Yuntong Guo. Comprehensive characteristics between genomic alterations and tumor differentiation in Chinese patients with colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5763.

Abstract 5095: Investigation of NOTCH mutation and correlation with immunotherapy biomarker in Chinese colorectal cancer patients

Abstract Background: NOTCH pathway, a highly conserved signaling system, is regulated by short-range cell-cell interaction between NOTCH receptor (NOTCH1-4) and “canonical” ligand, or non-canonically through activation of other pathways. Previous research on the NOTCH gene revealed that NOTCH signaling is associated with tumorigenesis, mutagenesis, and immune tolerance in several tumors, indicating its association with the clinical benefit of immune checkpoint inhibitors (ICIs). However, the NOTCH characteristics, its correlation with immunogenic marker, and the predictive value of immunotherapy in colorectal cancer (CRC) was unknown. Methods: An independent cohort (the MSKCC study cohort) with next-generation sequencing (NGS) data from 109 patients with CRC of pan-cancer, were used to analyze the prognostic effect of NOTCH1-4 on immunotherapy. Tumor tissue samples from Chinese head and neck cancer were analyzed using NGS (panel on 381/733-gene). TMB was defined as the total number of somatic non-synonymous mutations in coding region. MSI was evaluated by NGS of 500 known MSI loci. PD-L1 expression was evaluated using immunohistochemistry (Dako 22C3). Result: In the MSKCC cohort, there were 49 (45.0%) patients harbored NOTCH mutation(NOTCHmut), including 16 (14.7%) patients of NOTCH1, 7 (6.4%) patients of NOTCH2, 16 (14.7%) patients of NOTCH3, and 10 (10.9%) patients of NOTCH4. NOTCH1 mutation (median, 65.4 Muts/Mb) was associated with higher TMB (P&amp;lt;0.001) than NOTCH1 wild-type (NOTCHwt) (median, 6.8 Muts/Mb), same as NOTCH2 (median, 61.4 Muts/Mb vs 7.8 Muts/Mb; P&amp;lt;0.001), NOTCH3 (median, 64.9 Muts/Mb vs 6.8 Muts/Mb; P&amp;lt;0.001), and NOTCH4 (median, 76.7 Muts/Mb vs 7.8 Muts/Mb; P&amp;lt;0.001). In terms of prognostic effect, there was significant difference on overall survival (OS) (HR = 0.17, P=0.008) between NOTCH3mut (median, 11.5 months) and NOTCH3wt (median, 8 months), but there was no difference in others of NOTCH. In Chinese patients, genetic mutation of 1166 CRC patients were analyzed using NGS, of which 157 (13.5%) harbored NOTCH mutation, including NOTCH1 (123, 10.5%), NOTCH2 (221, 18.9%), NOTCH3 (135, 11.6%), and NOTCH4 (55, 4.7%). NOTCH3mut (median, 47,5 Muts/Mb) was associated with higher TMB (P&amp;lt;0.001) than NOTCH3wt (median, 7.3 Muts/Mb), which was significant difference, same as the other three. For the TMB, there was also significant difference in MSI between NOTCH1-4mut and NOTCH1-4wt (all of the four P&amp;lt;0.001). There was significant difference in PD-L1 expression between NOTCHwt with NOTCH1mut (P =0.005) and NOTCH2mut (P&amp;lt;0.001), but not with NOTCH3mut and NOTCH4mut. Conclusions: The results showed that the NOTCH genes had a high correlation with TMB and MSI in CRC, and the NOTCH3 might a potential biomarker for immune checkpoint therapy. Citation Format: Xiyu Yuan, Xue Hu, Yating Zheng, Mengli Huang. Investigation of NOTCH mutation and correlation with immunotherapy biomarker in Chinese colorectal cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5095.

Abstract 5757: Germline and somatic mutational landscape of Chinese early-onset colorectal cancers

Abstract Background: The incidence of colorectal cancer (CRC) in young people, described as early-onset colorectal cancer (EOCRC) has been rising up in decades. Apart from definite familial genetic disease, a considerable proportion of EOCRC remained unknown of the mechanism. Characterizing the difference in genomic features of EOCRC and late-onset CRC (LOCRC) would help us to understand it. Methods: A total of 1777 Chinese CRC patients diagnosed in 2019-2020 were included. 489 patients under 50 years were defined as EOCRC. A 733-gene panel next-generation sequencing (NGS) testing and measurement of tumor mutational burden (TMB) levels based on the panel were conducted in all patients’ tumor specimen. Lynch syndrome (LS) was defined as patients harboring at least one non-benign germline mutation in four LS MMR genes (MLH1, MSH2, MSH6, PMS2). Results: 43 of 489(8.8%) cases and 54 of 1288 (4.2%) cases were MSI-H in EOCRC and LOCRC, separately. Excluded 97 LS patients (84.3% in MSI-H EOCRC and 72.0% in MSI-H LOCRC), the proportion of non-LS MSI-H in EOCRC and in LOCRC were 1.8% and 1.7%, separately. Compared to non-LS MSI-H LOCRC, EOCRC has higher germline mutational frequencies in APC, CD74, ATM, BCL2L11, CHEK2, and RECQL4 genes and somatic mutational frequencies in APC, ERCC4, CHD2, ARHGAP5, CASP8, and ATM genes. In non-LS MSS patients, germline mutations in CHEK2, NBN and POLE genes, somatic SNV/indels in RNF43, ATR, AFF3, JAK2, POLG, CHD2 genes and somatic copy number gain in genes on chromosome 8 (ZNF703, FGFR1, MYC, PTK2) occurred more frequently in EOCRC. KEGG enrichment analysis in somatic mutations indicated significant overexpressed MAPK signaling pathway. The TMB level was significantly lower in non-LS MSS EOCRC than in LOCRC. Conclusions: The proportion of non-LS MSI-H in Chinese EOCRC and LOCRC were approximate. Non-LS MSS EOCRC had marked chromosome 8 somatic copy number gain and MAPK signaling pathway, indicating the potential mechanism. The comparative lower TMB level in EOCRC was concordance with previous studies and the correlations between low TMB level and high CNV burden also corroborate the etiopathogenesis. Citation Format: Xiancheng Zeng, Junhao Liu, Yurong Luo, Hailiang Li, Xinyi Liu, Mengli Huang. Germline and somatic mutational landscape of Chinese early-onset colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5757.

Comparison of 3 PCR-based assays for microsatellite instability detection in formalin-fixed paraffin-embedded tissues of patients with colorectal cancer.

e15042 Background: Routine assessment of microsatellite instability (MSI) status in colorectal cancer (CRC) patients can help with initial screening for Lynch syndrome, prediction of tumor prognosis and selection of patients for immunotherapy. Immunohistochemistry (IHC) and PCR-based approaches represent the current clinical laboratory standard for the evaluation of MSI status. Both Bethesda and Promega marker panels have been used widely in the world and the Bethesda panel and the six mononucleotides panel (NR21/BAT25/NR24/NR27/MONO27/BAT26) have been approved by the National Medical Products Administration (NMPA) in China. The Idylla MSI Test, a fully automated system based on real-time PCR, which incorporates 7 novel MSI loci (ACVR2A/BTBD7/DIDO1/MRE11/RYR3/SEC31A/SULF2) can perform MSI analysis within 150min using 1-3 tissue slides. The aim of this study was to evaluate the performance of the three 3 PCR-based assays for MSI detection including Idylla MSI Test, Bethesda and that six mononucleotides panel. Methods: One hundred and fifty-three formalin-fixed paraffin-embedded (FFPE) tumor tissues from patients with CRC were collected and their MSI status were analyzed using 3 PCR-based assays, respectively, i.e. the Idylla MSI, “2B3D” NCI panel and the six mononucleotides panel. All samples were previously evaluated by IHC method. Results: In the all 153 patients, IHC identified 27 cases to be MMR-deficient (dMMR), and 126 to be MMR-proficient (pMMR). Using IHC as a reference, the Idylla MSI had a higher consistency that showed overall agreement, sensitivity and specificity as 93.46%, 92.89% and 93.65%, respectively, while the corresponding values of the six mononucleotides panel were 84.31%, 92.59% and 82.54% respectively, and the “2B3D” NCI panel showed a sensitivity of 92.16%, a specificity of 88.89% and an overall concordance of 92.86%. The PCR-based approaches identified 11 more MSI-H cases than IHC while 22 dMMR cases identified by IHC were detected by all the 3 assays, 2 dMMR by 2 assays, 1 dMMR by one assay only and 1 dMMR by neither assays above. Moreover, the Idylla MSI showed advantages in ease of use, turnaround time (TAT) and small dose of tissue input. Conclusions: Our findings support that the Idylla MSI assay provides a rapid, reliable, and ease-to-use solution to MSI detection in Chinese CRC patients with high sensitivity and specificity. The inconsistent cases between IHC and PCR-based approaches need a further analysis.

A multiple centers real-world study of regorafenib treatment modalities in Chinese metastatic colorectal cancer patients.

e15543 Background: To evaluate the efficacy and safety of different treatment modalities of regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) in the real-world setting. Methods: Individual patient data were retrieved from three leading oncology centers in China from January 2016 to March 2021. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The characteristics of patients who received treatment are shown in the table. Twenty-one patients received regorafenib combined with capecitabine as the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. The median PFS and median OS were 8 (95% CI 4.36 - 11.00) months and 26.9 (95%CI 20.54 -NR) months. 101 patients received regorafenib and 69 patients received regorafenib plus immune checkpoint inhibitor (ICIs) as third or higher line treatment, the overall response was 4.1%(7/170), including one complete response. Patients combined with ICIs have longer PFS than those with regorafenib monotherapy (median PFS = 3.3 versus 2.1 months; p = 0.01). Starting dose was 80、120 and 160 mg in 64、40 and 39 patients, respectively. Dose reduction was observed in 43.3% (39/79) of patients receiving 120 and 160 mg as the initial dose. Conclusions: Different treatment modalities of regorafenib all showed promising efficacy and safety in the treatment of mCRC. Regorafenib combination is better than regorafenib monotherapy. Regorafenib combined with capecitabine provided a new treatment strategy during the epidemic but requires further investigation. Key words:Colorectal cancer; Regorafenib; Immune check point inhibitors; Real world[Table: see text]

Milk and Egg Are Risk Factors for Adverse Effects of Capecitabine-Based Chemotherapy in Chinese Colorectal Cancer Patients.

Background:Chemotherapy-induced adverse effects (CIAEs) remain a challenging problem due to their high incidences and negative impacts on treatment in Chinese colorectal cancer (CRC) patients. We aimed to identify risk factors and predictive markers for CIAEs using food/nutrition data in CRC patients receiving post-operative capecitabine-based chemotherapy.Methods:Food/nutrition data from 130 Chinese CRC patients were analyzed. Univariate and multivariate analyses were used to identify CIAE-related food/nutrition factors. Prediction models were constructed based on the combination of these factors. The area under the receiver operating characteristic curve (AUROC) was used to evaluate the discrimination ability of models.Results:A total of 20 food/nutrition factors associated with CIAEs were identified in the univariate analysis after adjustments for total energy and potential confounding factors. Based on multivariate analysis, we found that, among these factors, dessert, eggs, poultry, and milk were associated with several CIAEs. Most importantly, poultry was an overall protective factor; milk and egg were risk factors for hand-foot syndrome (HFS) and bone marrow suppression (BMS), respectively. Developed multivariate models in predicting grade 1 to 3 CIAEs and grade 2/3 CIAEs both had good discrimination (AUROC values from 0.671 to 0.778, 0.750 to 0.946 respectively), which had potential clinical application value in the early prediction of CIAEs, especially for more severe CIAEs.Conclusions:Our findings suggest that patients with high milk and egg intakes should be clinically instructed to control their corresponding dietary intake to reduce the likelihood of developing HFS and BMS during capecitabine-based chemotherapy, respectively.Trial registration:ClinicalTrials.gov Identifier: NCT03030508.

Construction of Risk Assessment Model for Venous Thromboembolism After Colorectal Cancer Surgery: A Chinese Single-Center Study.

ObjectiveA retrospective study was carried out to construct a postoperative venous thromboembolism (VTE) risk assessment model (RAM) applicable for Chinese colorectal cancer patients.Methods541 Patients who underwent colorectal cancer surgery from June 2019 to May 2020 at Sir-Run-Run-Shaw Hospital affiliated to Zhejiang University School of Medicine were enrolled in this study. Multi-factor analysis was used to determine the independent risk factors of VTE. A novel RAM of VTE which we called Sir-Run-Run-Shaw VTE RAM were constructed basing on the independent risk factors. Another study cohort consisted of 287 colorectal cancer patients underwent surgery from January 2021 to June 2021was used for model evaluation.ResultsThe incidence of VTE after colorectal cancer surgery was 12.0%(65/541). Among the 65 VTE Patients, DVT accounted for 92.3% (60/65) and DVT + PE accounted for 7.7% (5/65). Multi-factor analysis showed that age ≥ 69 years (P < 0.01), preoperative plasma D-dimer ≥ 0.49 mg/L (P = .004), stage IV of cancer (P = .018) and transfusion (P = .004) are independent risk factors of VTE after surgery. Sir-Run-Run-Shaw VTE RAM includes the above 4 factors, and the total score is 4 points. The score of the low, medium and high risk groups are 0, 1 and ≥2 points. The area under the ROC curve (AUC) of Sir-Run-Run-Shaw VTE RAM is 0.769, while Caprini RAM is 0.656. There is statistical difference between the two risk score tables (Z = 2.337, P = .0195).ConclusionA VTE RAM is constructed basing on a single center retrospective study. This score table may be applicable for Chinese patients with colorectal cancer surgery.