Chinese Cancer Research Articles

Associations between physical activity and risk of liver cancer: results from a population-based cohort study in Chinese women

Aims : Epidemiological evidence has revealed varying degrees of relationship between physical activity and risk of most cancers, but the association between physical activity and risk for primary liver cancer in Chinese has seldom been reported. This study aims to characterize the associations between different physical activity types and liver cancer risk in Chinese women. Methods: We collected physical activity information through the physical activity questionnaire (PAQ) and assigned a corresponding metabolic equivalent value according to the physical activity compendium. Multivariable-adjusted Cox regression models were utilized to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the relationships between physical activity and liver cancer. Results : A total of 72,674 females were enrolled in the cohort, with a median follow-up time of 18.12 years. By the end of 2016, 255 females were identified as incident cases of liver cancer. In Multivariable-adjusted Cox regression analysis, total physical activity (TPA), daily living physical activity (DPA) and leisure-time physical activity (LTPA) were not associated with the liver cancer risk in women. The highest tertile vs . none of HRs (95%CIs) were 0.82 (0.58, 1.17) for TPA, 0.80 (0.56, 1.15) for DPA, and 1.15 (0.82, 1.61) for adult LTPA in terms of measures as the METs-hour/week. For each activity, we found that the HRs (95%CIs) were 0.77 (0.55, 1.08) for stair climbing and 0.78 (0.53, 1.15) for participation in housework after further adjusting for body mass index and type 2 diabetes. Conclusion : Null significant results were found in the association between physical activity and female liver cancer risk in China.

Pathogenic germline variants in BRCA1 and TP53 increase lung cancer risk in Chinese.

Multiple studies have identified pathogenic germline variants in cancer susceptibility genes (CSGs) in Chinese lung cancer patients; however, accurate assessment of these variants' contributions to cancer predisposition is always hampered by the absence of data on the prevalence of these variants in the general population. It is necessary to conduct a large-scale case-control study to identify CSGs that significantly increase the risk of lung cancer. We performed targeted sequencing of a CSGs panel in 1117 lung cancer patients and 16,327 controls from the general Chinese population. In comparison to controls, lung cancer patients had a considerably higher prevalence of pathogenic and likely pathogenic (P/LP) variations. Among lung cancer patients, 72% of P/LP variants carriers did not have a family cancer history, who would be ignored if germline testing was only provided for patients meeting family history-based criteria. Furthermore, compared to individuals with late-onset lung cancer, patients with early-onset lung cancer had a considerably higher prevalence of P/LP variations. With odds ratios (ORs) ranging from 4-fold (BRCA1: OR, 4.193; 95%CI, 1.382-10.768) to 29-fold (TP53: OR, 29.281; 95%CI, 1.523-1705.506), P/LP variants in the BRCA1 and TP53 genes were discovered to be strongly related to increased lung cancer risk. Additionally, with ORs ranging from 7.322-fold to infinity, we discovered 23 variations previously categorized as non-P/LP variants were highly enriched in lung cancer patients. Our findings indicated that P/LP variants in BRCA1 and TP53 conferred increased risk of lung cancer in Chinese.

Association between rs735482 polymorphism and risk of cancer: A meta-analysis of 10 case-control studies.

Several studies have inspected the relationship between rs735482 polymorphism and the risk of some human cancers, but the findings remain controversial. We designed this meta-analysis to validate the association between rs735482 polymorphism and cancer risk. All articles were published before September 1, 2018 and searched in Pubmed, Embase, Web of Science, China National Knowledge Infrastructure, WangFang, and Chinese BioMedical databases, STATA 12.0 software was used for statistical analysis, which provides reasonable data and technical support for this article. A total of 10 studies were included in the meta-analysis, including 2652 cancer cases and 3536 rs735482 polymorphic controls. Data were directly extracted from these studies and odds ratios with 95% confidence intervals were computed to estimate the strength of the association. By pooling all eligible studies, the rs735482 polymorphism showed no significant association with susceptibility of several cancers in all the five genetic models (the allelic model: OR = 1.019, 95% CI: 0.916–1.134, P = .731). In addition, another adjusted OR data showed a significant increased risk between the rs735482 and susceptibility of several cancers (the codominant model BB vs AA: OR = 1.353, 95% CI: 1.033–1.774, P = .028) and the stratification analysis by ethnicity indicated the rs735482 is associated with an increased risk of cancer in Chinese group (BB vs AA, OR = 1.391, 95% CI = 1.054–1.837, P = .020; AB+BB vs AA OR = 1.253, 95% CI = 1.011–1.551, P = .039). However, the ERCC1 rs735482 is associated with a decreased risk of cancer in Italian group (AB vs AA, OR = 0.600, 95% CI = 0.402–0.859, P = .012; AB + BB vs AA, OR = 0.620, 95% CI = 0.424–0.908, P = .014). The results of this meta-analysis do not support the association between rs735482 polymorphism and cancer risk. But stratified analysis showed that rs735482 significantly increased the risk of cancer in Chinese while decreased the risk of cancer in Italian. Because of the limited number of samples, larger and well-designed researches are needed to estimate this association in detail.

A comparison of Chinese multicenter breast cancer database and SEER database

There are different characteristics of BC in developing countries and developed countries. We intended to study the factors which influence the survival and prognosis of BC between southern China and the United States. (a) To study the two groups BC patients in southern China from 2001 to 2016 and SEER database from 1975 to 2016. (b) To register, collect and analyze the clinicopathological features and treatment information. Our study found that there are significant differences in tumor size, positive lymph node status and KI-67 between southern China and SEER cohort (P < 0.000). The positive lymph node status may be one of the causes of difference of morbidity and mortality of BC patients in China. Furthermore, the differences in treatment methods may also account for the differences between China and seer databases.

Nutrition Risk Screening and Related Factors Analysis of Non-hospitalized Cancer Survivors: A Nationwide Online Survey in China

PurposesThis study investigated the nutritional problems and risks of Chinese non-hospitalized cancer survivors through an online survey.MethodsThe survey included nutritional and clinical questions distributed to non-hospitalized cancer survivors. All data were screened and analyzed with strict quality control. Nutrition Risk Screening-2002 (NRS-2002) was adopted and the related factors were analyzed.ResultsSix thousand six hundred eighty-five questionnaires were included. The prevalence of nutritional risk was 33.9%, which varied according to age, sex, cancer type, TNM staging, oncologic treatment, time interval since last treatment, etc. In the regression analysis, nutritional risk was associated with age, TNM staging, and nutrition support. Patients with leukemia and digestive cancer had the highest NRS-2002 score (3.33 ± 1.45 and 3.25 ± 1.61); the prevalence of nutritional risk (NRS-2002 ≥ 3) was 66.7 and 55.1%, respectively. Patients with a higher TNM stage had higher NRS-2002 scores in non-digestive cancer, which was not seen in digestive cancer. Among digestive, bone, nervous, and respiratory cancer patients, the NRS-2002 score mainly consisted of “impaired nutritional status,” which coincided with the “disease severity score” in leukemia patients. Nutrition intervention was achieved in 79.7 and 15.2% of patients with nutritional risk and no risk. Of the patients, 60.3% exhibited confusion about nutritional problems, but only 25.1% had professional counseling.ConclusionsRegular nutritional risk screening, assessment, and monitoring are needed to cover non-hospitalized cancer survivors to provide nutrition intervention for better clinical outcome and quality of life. By online survey, the nutritional risk of non-hospitalized cancer survivors was found high in China, but the nutrition support or professional consultation were not desirable. The composition of nutritional risk should also be aware of.

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 5774: Investigating the characteristics of BRAF Mutations and its potential relationship with therapy in a large Chinese Lung Cancer cohort

Abstract Background: In lung cancer, the proportion of BRAF mutations is low. Rare specific studies have evaluated the BRAF mutation characteristics in lung cancer. Currently, there are some studies suggesting that patients with BRAF mutations may be benefit from immunotherapy, while patients with BRAF V600E may benefit from targeted therapy. Here, the characteristics of BRAF mutation, including BRAF V600E, in a lung cancer cohort of Chinese were analyzed. The characteristics of BRAF mutation with PD-L1 expression were also analyzed. Method: BRAF mutant samples were extracted from 12,051 our cohort samples of lung cancer that from Onco Panscan࣪ (Genetron Health) based sequencing of tissue. The characteristics of them were then investigated. Co-mutations of PD-L1 expressed BRAF samples were also analyzed. Results: 684 samples (5.68%) in our cohort had BRAF mutations. Only 134 (19.59%) of them were V600E mutation, maybe good response to BRAF inhibitors. 550 (80.41%) of samples were BRAF non-V600E mutation, maybe benefit from immunotherapy. BRAF mutations were more happened in male (58.3%), while female patients were increased in V600E mutation group when compared with non-V600E group (49.25% vs. 39.82%, P=0.0509). BRAF mutations were more likely to occur in LUAD than in LUSC (6.37% vs. 3.89%, P=0.0022), especially BRAF V600E mutation. The mean age of BRAF mutant patients was 61.56 ± 10.32 years. BRAF V600E patients was significantly older than BRAF non-V600E patients on average (63.01 ± 9.76 years vs. 61.20 ±10.43, P=0.0129). BRAF mutations were distributed across all exons but concentrated on exon 15 (269/684, 39.33%). Moreover, BRAF V600E mutation accounted for 49.81% (134/269) of exon 15. In our data, there were 108 samples with BRAF mutation and PD-L1 positive (TPS≥1%). Among them, 95 samples (87.96%), including samples with BRAF V600E or non-V600E mutation, had no co-mutations or without other medication targets, may be benefit from BRAF inhibitors, or may be good response to immunotherapy, especially the 20 samples with TMB-high. Interestingly, 13 samples had EGFR sensitive co-mutation or EML4-ALK fusion. These 13 patients may be benefit from TKI firstly, then immunotherapy can be considered. Conclusions: Most of BRAF mutations in Chinese lung cancer samples were non-V600E mutations (80.26%). BRAF mutations were more occurred in male and LUAD patients whose age around 61.56 ± 10.32 years. BRAF V600E patients were much older. Among PD-L1 positive and BRAF mutant samples, most BRAF mutations (87.96%), including V600E, were mutually exclusive with driver mutations of other genes. These patients will most likely benefit from BRAF inhibitors or immunotherapy. For the samples with co-mutation of BRAF and EGFR or ALK, may be treated EGFR or ALK TKI firstly. Citation Format: Jianqing Zhang, Jiagang Feng, Ling Liu, Man Jia, Tong Liu, Jiaqiang Zhang, Zehua Liao, Jianmei Zhao, Yu Fang, Jing Chen, Xiaoyan Zhang, Tonghui Ma. Investigating the characteristics of BRAF Mutations and its potential relationship with therapy in a large Chinese Lung Cancer cohort [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 5774.

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.

Abstract 5765: Genomic characterization of Chinese biliary tract cancers identifies differences between subtypes and therapeutic biomarkers

Abstract Background: Biliary tract carcinoma (BTC) is a relatively rare cancer worldwide and accounts for 3% gastrointestinal cancers in China. BTCs are mainly classified as gallbladder cancer (GBC) and cholangiocarcinomas (CCA) with dismal prognosis. Genetic landscape of BTC can offer a comprehensive understanding of its carcinogenesis and clinical associations. The present study aims to compare the molecular features between BTC subtypes and explore clues for treatment therapies. Methods: We analyzed 258 BTC tissue samples including 70 GBCs and 188 CCAs with targeted sequencing (NGS) using a 425 caner-relevant genes panel. We identified the somatic alterations and MSI status of all samples. TMB was counted by summing all base substitutions and indels in the coding region of targeted genes. TMB-high (TMB-H) was defined as mutation number ≥ 10mut/Mb. Results: The most frequently mutated genes in 258 BTCs were TP53 (56.6%), KRAS (27.9%), CDKN2A (21.3%), TERT (17.8%) and MCL1 (14.3%). Four gene mutations and 2 gene amplifications were significantly enriched in GBC compared to CCA (mutations P&amp;lt;0.05, amplifications P&amp;lt;0.01): TP53 (78.8% vs 47.9%), ARID2 (15.7% vs 3.7%), STK11 (12.9% vs 4.3%), TERT (24.3% vs 11.2%), CCNE1 and SOX2 amplifications (21.4% vs 2.7%, 4.3% vs 0%). However, ARID1A mutation (15.4% vs 5.7%), PBRM1 mutation (10.1% vs 0%), and MCL1 amplification (17.0% vs 5.7%) were more frequently existed in CAA (all P&amp;lt;0.05). Seven actionable alterations, including IDH1/2 (5.4%), FGFR1-4 (4.7%), ERBB2 (6.2%), PIK3CA (5.4%), MET (3.5%), and BRCA1/2 (5.0%), were detected with different occurrence frequencies in two subtypes. ERBB2 was predominant in GBC (15.7% vs 7.4%, p&amp;lt;0.001), while IDH1/2 and KRAS alteration rates were much higher in CCA (8% vs 0%, 31.4% vs 18.6%, both P&amp;lt;0.05). FGFR3 alterations were also tended to be enriched in CCA (7.1% vs 2.7%), although no significant difference was found. In general, there were 25.7% of GBC patients harboring actionable alterations versus 29.3% of CCA patients. In addition, 40 (15.5%, 13 GBCs and 27 CCAs) and 11 (4.3%, 10 GBCs and 1 CCA) patients were TMB-H and MSI-H, respectively, suggesting the possibility of benefit from immunotherapy. Conclusions: There were distinct molecular features in somatic variations and actionable alterations between GBSs and CCAs. In general, 44.3% of GBC and 46.3% CCA may benefit from targeted therapy and immunotherapy. This study could be helpful to establish treatment therapies for BTCs according to genetic information. Citation Format: Xiaofeng Chen, Jiaohui Pang, Cuicui Liu, Sha Wang, Yang Shao. Genomic characterization of Chinese biliary tract cancers identifies differences between subtypes and therapeutic biomarkers [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 5765.

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 5844: A comprehensive pan-cancer analysis of MDM2/MDM4 gene amplification in Chinese solid cancer patients

Abstract Background: Many patients with cancer have benefited from immunotherapy represented by the blockade of immune checkpoint PD-1/PD-L1. However, about 4-29% of cancer patients treated with immunotherapy developed hyper-progressive diseases(HPD) with accelerated tumor growth. MDM2/MDM4 amplification was suggested as genomic correlates for elevated risk hyperprogression. The objective of this study was to evaluate the frequency of amplification of MDM2/MDM4 in the Chinese solid tumor patients and to provide advice on the selecting of optimal treatment decisions. Methods: Tumor or blood samples were collected from 2,937 patients with solid cancer, genetic mutations and amplification was detected using the next-generation sequencing(NGS). Results: A total 112 patients with MDM2/MDM4 amplification were identified, including lung cancer 50.9% (57/112), colorectal cancer 14.3% (16/112), gastric cancer 8.0% (9/112), liver cancer 5.4% (6/112), Biliary tract cancers 4.5% (5/112), breast cancer 2.7% (3/112), and pancreatic ductal adenocarcinoma 2.7% (3/112). TMB value was identified, The median TMB for lung cancer was 9.13 mutations/Mb, median TMB for colorectal cancer was 13.8 mutations/Mb, a high TMB value in gastric cancer (median TMB=20.22 mutations/Mb), and median TMB for liver cancer was 17.9 mutations/Mb. Meanwhile, MSI was detected in 8% of patients with MDM2/MDM4 amplification, of which 3 in lung cancer, 5 in colorectal cancer, and 1in gastric cancer. Conclusions: Although amplification of MDM2/MDM4 was observed only in a small proportion of patients, it demonstrated an association with high TMB in several common cancer types. In addition, our data indicate that amplification of MDM2/MDM4 in different types of cancer is heterogeneous and that an appropriate immunotherapy strategy for patients with solid cancer should be noted. Citation Format: xiangyu sun, Zhichao Fu. A comprehensive pan-cancer analysis of MDM2/MDM4 gene amplification in Chinese solid 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 5844.

Abstract 5771: The refined stratification of receptor tyrosine kinase fusions in lung cancer

Abstract Background: The overall survival of patients with the actionable receptor tyrosine kinase (TRK) fusions can be significantly prolonged after taking targeted kinase inhibitors. However, the outcomes are variable due to the different fusion types of the same driver gene. Method: Formalin fixed paraffin embedded tissues from patients with lung cancer between March 2018 and September 2021 were performed by using next generation sequencing (NGS) at Genetronhealth, a laboratory accredited by College of American Pathologists and Clinical Laboratory Improvement Amendments. Results: In a large cohort of 3768 patients with lung cancer, 348 cases harboring the actionable TKR fusions, including ALK, ROS1, RET, EGFR, MET, BRAF, NTRK1/2/3. TRK fusions can be divided into three types based on the breakpoints, partners and fusion models: single 3’ fusions, nonreciprocal fusions with the intact tyrosine kinase domain (TKD); single 5’ fusions, reciprocal fusions with the incomplete TKD; complex fusions, nonreciprocal/reciprocal fusions or nonreciprocal fusions with different partners. At the gene level, 58% (203 of 348) of TRK fusions were ALK, among which 71% of single 3’ ALK (144 of 203), 3% of single 5’ ALK (6 of 203) and 26% of complex fusions (53 of 203) were included. ROS1 fusions accounted for 14% (50 of 348) of all TRK fusions, and the proportions of single 3’ fusions, single 5’ fusions and complex fusions were 60% (30 of 50), 6% (3 of 50) and 34% (17 of 50), respectively. RET captured 19% (66 of 348) TRK fusions with 70% of single 3’ RET (46 of 66), 5% of single 5’ RET (3 of 66) and 26% of the complex fusions (17 of 66). EGFR owned 3% (9 of 348) with 33% of single 3’ EGFR (3 of 9), 33% of single 5’ EGFR (3 of 9) and 33% of the complex (3 of 9). MET, BRAF and NTRK1/2/3 shared the rest 5% of total fusions without complex type. Conclusion: Our research shows different types of TRK fusions in Chinese lung cancer patients, which can help guide the precise treatment in clinical. Citation Format: Chaoyang Liang, Lin Li, Xiaofang Liu, Qiuhua Liu, Baoming Wang, Chunyang Wang, Tonghui Ma, Fanlu Meng. The refined stratification of receptor tyrosine kinase fusions in lung 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 5771.

Abstract 5250: Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric cancer

Abstract Objective: Uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) is a key enzyme in irinotecan metabolism. However, the relationship between UGT1A1 genotype and the safety and efficacy of irinotecan monotherapy in the treatment of Chinese advanced gastric cancer remains unclear. Methods: A total of 110 patients were enrolled. Intravenous irinotecan was administered every 3 weeks. Irinotecan dose was selected according to the polymorphism of UGT1A1 gene, which was divided into 3 groups: UGT1A1*6 wild-type (GG type): 125mg/m2, d1, d8; UGT1A1*6 mutant heterozygosity (GA type) 100mg/m2, d1, d8; UGT1A1*6 homozygosity mutation (AA type) 75mg/m2, d1, d8 or paclitaxel 125mg/m2, d1, d8. UGT1A1 genotypes were determined by direct sequencing or next-generation sequencing of genomic DNA extracted from peripheral blood. Results: Among 110 patients of the subjects, the genotypes of UGT1A1*28 were wild-type in 78 patients (70.91%), mutant heterozygosity in 28 (25.45%) and mutant homozygosity in 4 (3.64%). UGT1A1*6 were GG in 67 cases (60.91%), GA in 35 cases (31.82%), and AA in 8 cases (7.27%). There were two heterozygous mutations in 3 patients, and no homozygous mutation was detected. A total of 10 cycles of irinotecan were administered, with a median of five cycles per patient. There was no significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*28 genotypes (P&amp;gt;0.05), while there was significant difference in the risk of delayed diarrhea and granulocytopenia in patients with different UGT1A1*6 genotypes (P&amp;lt;0.05). The dose intensity of irinotecan was different in patients with different subtypes of UGT1A1*6 gene, and the dose intensity of heterozygous mutant patients was lower than that of wild-type patients. However, there were no significant differences in PFS and OS among patients with different subtypes after dose adjustment and program adjustment (P&amp;gt;0.05). Conclusion: UGT1A1*6 gene polymorphism was significantly associated with diarrhea and neutropenia induced by irinotecan. The safety and effectiveness of antitumor therapy might be significantly improved by individualized drug administration according to the results of UGT1A1*6 gene polymorphism. Citation Format: Huifang Lv, Yunduan He, Caiyun Nie, Beibei Chen, Jianzheng Wang, Weifeng Xu, Jing Zhao, Xiaobing Chen, Junling Zhang. Association between UGT1A1 gene polymorphism and safety and efficacy of irinotecan monotherapy as the second-line treatment for advanced gastric 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 5250.

Verification of the association of the cycle threshold (Ct) values from HPV testing on Cobas4800 with the histologic grades of cervical lesions using data from two population-based cervical cancer screening trials

ObjectiveTo verify the association of high-risk human papillomavirus (hrHPV) viral load reflected by cycle threshold (Ct) values from HPV testing on Cobas4800 assay with the histologic grades of cervical lesions via analysis on the combined data from two cervical cancer screening trials and to explore the referability of Ct values in management of the abnormalities from cervical cancer primary screening.MethodsWe analyzed the data from Chinese Multi-Center Screening Trial (CHMUST) and BUJI Cervical Cancer Screening Study Project (BUJI Study). All data to be analyzed in this paper were related to provider-collected samples. One-way ANOVA was performed to compare the Ct values among different histological groups, and Kendall’s tau-b correlation was applied to examine the association between Ct values and cervical lesion grades. The stepwise incidence of CIN2+ and CIN3+ in every 100 HPV positive individuals were calculated according to the descending of the genotype specific Ct values. The highest Ct values related to CIN3+ incidence rate 4% (or 25%) were used as the cutoffs to distinguish low-Ct value cases from the high-Ct value ones.ResultsA total of 1376 women in CHUMUST and BUJI Study who were aged 30–59 and positive of hrHPV for provider-collected samples on Cobas4800 with complete data in terms of the relevant Ct values (CtV) and the histological diagnosis were included for analysis. Our data showed significant difference among different histological grades of cervical lesions in the CtV of hrHPV, HPV16-plus (positive of HPV16 only or HPV16 plus 18 and/or pooled 12-HPV), and pooled 12-HPV (P < 0.05). No significant difference was found among different grades of lesions in term of correlated CtV of HPV18-plus (positive of HPV18 only or HPV18 plus pooled 12-HPV) (P > 0.05). The CIN2+ or CIN3+ incidence per 100 positives significantly increased corresponding to the descending of the CtV of hrHPV, HPV16-plus and pooled 12-HPV. Compared with high-CtV groups (CtV > 33.2 for hrHPV, CtV > 29.6 for pooled 12-HPV), the relevant risks (RRs) of CIN2+ for hrHPV and pooled 12-HPV positive groups with low-CtV (CtV ≤ 33.2 and ≤ 29.6, respectively) were 3.2 (95%CI 2.18–4.80) and 2.3 (95%CI 1.50–3.45). Similarly, the RRs of CIN3+ for hrHPV and pooled 12-HPV positive groups with low-CtV were 6.5 (95%CI 2.83–14.80) and 2.7 (95%CI 1.15–6.39), respectively. The RRs of CIN2+ for medium- (30.3 < CtV ≤ 37.4) and low- (≤ 30.3) CtV HPV16-plus positives were 5.1 (95%CI 0.68–38.38) and 20.6 (95%CI 2.96–143.92) related to high-CtV (> 37.4) groups, and the CIN3+ incidence in low-CtV value group was nine-fold higher of that in medium-CtV ones [RRs, 9.0 (95%CI 2.89–28.10)]. In comparing with the algorithms of “HPV16-plus/18-plus + cytology ≥ ASCUS for pooled 12-HPV”, triage algorithm “HPV16-plus/18-plus + Ct value ≤ 33.2 for pooled 12-HPV” could achieve a comparable sensitivity of 93.2%.ConclusionHPV viral loads reflected by Ct values for hrHPV, HPV16-plus and pooled 12-HPV from Cobas4800 HPV testing were directly associated with the severity of cervical lesions. A lower HPV genotype-specific Ct value prompted a significantly high CIN3+ risk of 4% or higher in women positive of hrHPV, HPV16-plus or pooled 12-HPV, indicating that HPV viral load reflected by Ct values on Cobas4800 may be a promising risk indicator in management of abnormalities from primary cervical cancer screening.

Identified potential pathogenic variants of BARD1 in 1449 Chinese high-risk breast cancer patients.

e22525 Background: BARD1 (BRCA1-associated ring domain 1), nuclear partner of BRCA1, has been recognized as a breast cancer predisposition gene. Recently, two large-scale population-based case–control studies confirmed that germline loss-of-function mutations in BARD1 were associated with a risk of breast cancer. Since the germline mutation frequency of BARD1 is much less than that of BRCA1/2, the distinct mutation spectrum of BARD1 is still obscure, especially in Chinese breast cancer patients. To verify the utility of BARD1 genetic testing in Chinese population, we assessed the mutational frequency and spectrum of BARD1 in a sequential series of Chinese high-risk breast cancer patients. Methods: A cohort of high-risk breast cancer patients (n = 1449) were collected in Zhejiang Cancer Hospital from 2008 through 2020, including 608 familial breast cancer (BC) cases, 173 bilateral BC cases, 222 triple negative BC cases, 436 early-onset BC cases (≤40 years) and 10 male BC cases. The complete coding sequence and intron–exon boundaries of BARD1 were screened by a 98-gene panel sequencing assay. The SIFT, Polyphen2 and MutationTaster prediction programs were used for analyzing the effect of the variants of unknown significance (VUS) on the BARD1 protein function. Results: A total of three BARD1 pathogenic mutations (c.1348_1349delinsCAT, c.70_71insGT and c.373G &gt; T) were identified, which had been all reported, and accounting for 0.2% (3/1449) in Chinese high-risk breast cancer patients. The frequencies were 0.33% (2/608) and 0.12% (1/841) in familial and non-familial breast cancer patients, respectively. In total, 19 VUSs including 17 missenses, one inframe deletion and one inframe insertion of BARD1 were identified in this study. Based on in silico analysis, nine BARD1 missense variants (c.76A &gt; G, c.1912G &gt; A, c.1693C &gt; T, c.2191C &gt; T, c.127C &gt; A, c.1601C &gt; T, c.443G &gt; A, c.233G &gt; A and c.1972C &gt; T) were classified as potentially damaging. However, the two newly variants c.420_422del and c.68_69insTCCGGGAACGAGCCTCGTTCC still remain VUS, and the other eight variants were classified as benign. Conclusions: Our data presented the germline mutations of BARD1 in a large-scale Chinese high-risk breast cancer population, which accounted for 0.2% in our cohort. Moreover nine potential pathogenic variants were found based on in silico analysis. Clinically, these data may be helpful in genetic counseling of breast cancer patients with BARD1 germline mutation. While the further research on the VUS are needed.

Characterization of mutational signatures of homologous recombination deficiency (HRD) in Chinese breast cancer.

e15129 Background: Homologous recombination deficiency (HRD) is a common molecular characteristic of genomic instability and has been proved to be an important biomarker for personalized therapy decisions and stratified management in breast cancer. In this study, we explored the mutational features of HRD tumors identified by HRD score in Chinese breast cancer. Methods: Tumor tissue DNA from 68 breast cancer patients was isolated and sequenced by next-generation sequencing (NGS) technologies with AcornMed 808-genes panel. HRD score was calculated as an unweighted sum of loss of heterozygosity (LOH) score, telomeric allelic imbalance (TAI) score and large-scale state transition (LST) score by AcornHRD algorithm, and mutations in 39 homologous recombination (HR) related genes including BRCA1/2 were identified for each case. Results: Based on the mutation alternation profiles from our cohort, somatic BRCA1/2 mutations were present in 15 patients (22.1%) while 29 patients (42.6%) harbored one or more mutations in HR-related genes excluding BRCA1/2. Germline mutations of BRCA1/2 and other HR-related genes occurred in 11.8% and 4.4% of cases detected, respectively.In our cohort, the median HRD score was 40 (range from 3 to 92). Sixty-eight cases were divided into HRD-high or HRD-low group based on a cut-off value of ≥ 42 or &lt; 42, with HRD-high group accounting for approximately 47% of our cohort, indicating the combination with HRD score yielded an increment of 26.5% in coverage of HRD within BRCA1/2 wildtype cases. The HRD-high group covered 82.4% of the BRCA-mutated cases and also showed higher mutation level of BRCA1/2-excluded HR genes than HRD-low group (p = 0.001). Prevalence of mutations in a total of 12 genes, including BRCA1(31.3% vs 5.6%, p = 0.009) and NBN (25% vs 5.6%, p = 0.038), were significant difference between HRD-high and HRD-low group. Besides, Cosmic Signature 1 (spontaneous deamination of 5-methylcytosine) and 5 (unknown) were existed in both groups, whereas Signature 6 (defective DNA mismatch repair) was only discovered in HRD-high group. Compared with HRD-low ones, copy number variations ratio was higher in HRD-high group (p = 0.031). Meanwhile, the patients with ERBB2 amplification (HER2+) showed a lower level of HRD score than HER2- ones. Conclusions: This study comprehensively delineated the genetic characteristics of HRD tumors, which suggests that HRD status marked by HRD score is strongly associated with BRCA1/2 and HR-related genes mutation as well as other genomic instability signatures, thus indicating its predictive value as a promising biomarker for DNA repair deficiency related drugs or therapies in Chinese breast cancer.

Molecular classification for predicting the efficacy of neoadjuvant tislelizumab combining nab-paclitaxel in Chinese bladder cancer.

e14563 Background: Bladder cancer is a molecularly diverse disease with heterogeneous clinical outcomes. Transcriptome-based molecular subtypes of muscle invasive bladder cancer (MIBC) and non-muscle invasive bladder cancer (NMIBC) have been shown to be both prognostic and predictive. However, its predictive role in Chinese bladder cancer remains unclear. The aim of this study was to identify the predictive role of molecular subtypes in China bladder cancer with neoadjuvant therapy. Methods: The study was conducted from May 2020 to August 2021. Patients who were age 18 years or older, were diagnosed with NMIBC or MIBC, and neoadjuvant tislelizumab combining nab-paclitaxel followed by surgery were included. Multigenomic sequencing was performed. Molecular subtypes were identified by published consensus. Results: We prospectively recruited 30 patients for neoadjuvant tislelizumab combining nab-paclitaxel, including 14 patients with NMIBC and 16 patients with MIBC. For bladder cancer, 73.3% (22/33) patients responded to neoadjuvant tislelizumab combining nab-paclitaxel. In NMIBC groups, 64.3% (9/14) patients were pCR. The objective remission rate ( ORR) was 71.4%. 4 molecular classes were identified in Chinese NMIBC, including class 1 (7.1%), class 2a (35.7%), class 2b (50%), class 3 (7.1%). Interesting, ORR was significantly higher for patients with class 2b (5/7, 71.4%) as compared to class 2a (3/5,60%) before neoadjuvant. Molecular classes changed in 35.7% (5/14) of patients before and after neoadjuvant. After neoadjuvant, 80% of class 2b patients responded to neoadjuvant, and all class 2a patients did not respond to neoadjuvant. In MIBC groups, a pPR was achieved by 37.5% patients (6/16). The ORR was 75%. We found 4 molecular classes in Chinese MIBC: basal/squamous (43.8%), luminal unstable (25%), luminal papillary (25%), and stroma-rich (6.2%). Patients with basal/squamous (85.7%) and luminal unstable (75%) had significantly higher ORR than luminal papillary (50%) before neoadjuvant. Molecular classes changed in 44.4% (4/9) of patients before and after neoadjuvant. After neoadjuvant, all patients with stroma-rich responded to neoadjuvant. Conclusions: Molecular classification could predict the efficacy of neoadjuvant tislelizumab combining nab-paclitaxel in Chinese bladder cancer, which may be preferable when studying biomarkers of bladder cancer in the future.

The distribution of genetic mutations correlated with resistance to KRASG12C inhibitors in Chinese patients with lung cancer.

3141 Background: In lung cancer, p.G12C is the most frequent variant in Kirsten rat sarcoma viral oncogene homologue (KRAS) gene. KRASG12C inhibitors have shown promising efficacy in lung cancer in recent clinical trials, acquired resistance, however, eventually occurred in most patients. Preliminary studies revealed that a number of genetic mutations were correlated with resistance to this type of drugs, including KRAS secondary mutations, KRAS activating mutations, mutations in RTK-RAS-MAPK signaling pathways members, oncogene rearrangements and copy number gain. To clarify the potential clinical application of KRASG12C inhibitors, herein we analyzed the distribution of reported resistance gene alterations in a large and natural group of Chinese lung cancer, as well as the gene mutation landscape of the subset of patients with suspected resistant mutations. Methods: A total of 32878 Chinese lung cancer including early-stage, late-stage without treatment or late-stage with previously treated were analyzed in this study. Wide NGS panel testing was used to detected single nucleotide variants (SNV), copy number variants (CNV) and oncogenic gene rearrangements. Results: KRAS mutations were detected in 2767 (8.4%) cases, of which KRAS G12C was the most common variant (30.86%). Among 854 patients (2.6%) harbored KRAS G12C, 75 (10%) carried the above resistance mutations, such as G12D/R/V (n = 7). Fusions (20%) which previously observed only in coloretal cancer were unexpectedly detected in this corhort, including EML4-ALK (n = 1), FGFR1-MECOM (n = 1), EWSR1-CHEK2 (n = 2), SPEN-KAZN (n = 2), MET-KCNB2 (n = 1), NOTCH2-NOTCH2NLA (n = 5), SMARCA4-DNAH8 (n = 1), and LIPM-FAS (n = 1). Furthermore, KRAS (46.7%), MYC (25.3%) and MET (10.7%) were amplified. Among this subset of patients with resistant mutations, TP53 (66%), LRP1B (25%), and STK11 (22%) were the most frequently mutated genes. It is noteworthy that STK11/KEAP1 /NFE2L2 gene mutation was detected in nearly 30% in this group of patients. Conclusions: The results of our analysis suggested that about 10% KRAS G12C-mutated Chinese lung cancer patients would be resistant to KRAS G12C inhibitors. Moreover, a small number patients have co-mutated genes which were negatively related to immunotherapy in NSCLC, indicating they were also inappropriate for immunotherapy.

Clinical implications of next-generation sequencing on pediatric solid tumors.

e22012 Background: To assess the impact of next-generation sequencing (NGS) on Chinese pediatric cancer, we reported the first study of largest cohort in Chinese children with genomic landscape and highlighted the potential application with respect to molecular diagnosis and predictive biomarkers etc. Methods: A retrospective analysis was conducted on patients aged &lt; 19 years diagnosed with solid tumors sequenced by targeted NGS panel. Somatic variants were analyzed following CAP/CLIA-certificated workflows, including Single Nucleotide Variant (SNV), Copy Number Variation (CNV), large insertion and deletions (Lindel) and gene rearrangements. Results: A total of 356 patients enrolled with three major cancer types including osteosarcoma (OS) (n = 78), rhabdomyosarcoma (RMS) (n = 51), Ewing sarcoma (EWS) (n = 13). Hepatocellular carcinoma (n = 9), medulloblastomas (n = 7) and colorectal adenocarcinoma (n = 5) were also included. 3487 somatic alterations were identified, TP53 (16%), EWSR1 (8.7%), CDKN2A (7.8%), BCOR (7%) and RB1 (5.6%) rank the top five reported. TP53 (21% % vs 7.9%), RB1 (10% vs 5.3%) mutations showed higher frequency in OS and BCOR (14% vs 17.6%) showed lower frequency in RMS compared to published paper (Gröbner et al 2018). We found PIK3CA mutations presented in RMS with 11.7% frequency, twice than reported (5.8%), mostly occurring at the known oncogenic codon E545. The obscure boundary of soft tissue tumor and bone tumor perplexed the pathologic diagnosis, NGS provide an important auxiliary examination. In 140 soft tissue tumor and bone tumor patients, 14.2% patients were further diagnosed with different subtype, 4.2% patients with unknown subtype were diagnosed with a specified subtype by supportive genetic alterations. Moreover, 41.5% (138/356) patients received treatment recommended . Twelve NTRK-fusions were detected and the patients were recommended therapy method upon Larotrectinib, recruitment in matched clinical trial is still on-going. Conclusions: We investigated the different genetic profiling of Chinese pediatric solid cancer and found the clinical value of NGS in pathological diagnosis and biomarker discovery.

Psychological symptoms and quality of life in Chinese early-stage breast cancer patients throughout chemotherapy.

e24145 Background: Breast cancer survivors with psychological problems have lower quality of life (QOL) and higher mortality than those without. It is important to monitor and manage their psychological status. The aim of this study was to examine the incidence and dynamic changes of anxiety/depression during postoperative adjuvant chemotherapy in Chinese breast cancer patients and to clarify the factors associated with anxiety/depression, the importance of family support, and the impact of anxiety/depression on QOL. Methods: In a prospective observational single-centre cohort study with early-stage breast cancer patients (n = 290), d epression and anxiety severity, QOL and social support were measured before chemotherapy, after 2 cycles of chemotherapy, and after the entire course of chemotherapy using the Hospital Anxiety and Depression Scale (HADS), Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) and Chinese version of the Social Support Rating Scale (SSRS), respectively. Canonical correlations were applied to identify correlates between anxiety/depression and demographic and clinical variables. Paired t tests were used to analyse dynamic changes in QOL. Relationships between anxiety/depression and QOL were analysed using two-way repeated measures analysis of covariance (RMANCOVA). Results: Throughout the entire course of chemotherapy, the incidences of anxiety and depression were 35.2% and 44.1%, respectively. 31.4% of the patients had an increased risk for an anxiety disorder before chemotherapy, which decreased to 29.0% after 2 cycles of chemotherapy and slightly increased to 29.3% after completion of chemotherapy. 20.0% of patients had an increased risk of depression before chemotherapy, which shifted to 25.2% and 24.8% after 2 cycles and the entire course of chemotherapy, respectively. Through multivariable analysis, age (p = 0.042), surgical method (p = 0.009), social support (p = 0.001) and breast cancer family history (p = 0.045) were significantly associated with depression. No variables were significantly associated with anxiety. Patients with higher HADS depression/anxiety scores had lower FACT-B scores during chemotherapy (p &lt; 0.001). Conclusions: We observed dynamic changes in depression, anxiety and QOL throughout adjuvant chemotherapy and the associated factors of depression and anxiety. These findings provide guidance for psychological monitoring and support during postoperative chemotherapy of breast cancer patients. Clinical trial information: NCT05055375. [Table: see text]