Progression from ductal carcinoma in situ to invasive breast cancer: molecular features and clinical significance.

Ductal carcinoma in situ (DCIS) represents pre-invasive breast carcinoma. In untreated cases, 25-60% DCIS progress to invasive ductal carcinoma (IDC). The challenge lies in distinguishing between non-progressive and progressive DCIS, often resulting in over- or under-treatment in many cases. With increasing screen-detected DCIS in these years, the nature of DCIS has aroused worldwide attention. A deeper understanding of the biological nature of DCIS and the molecular journey of the DCIS-IDC transition is crucial for more effective clinical management. Here, we reviewed the key signaling pathways in breast cancer that may contribute to DCIS initiation and progression. We also explored the molecular features of DCIS and IDC, shedding light on the progression of DCIS through both inherent changes within tumor cells and alterations in the tumor microenvironment. In addition, valuable research tools utilized in studying DCIS including preclinical models and newer advanced technologies such as single-cell sequencing, spatial transcriptomics and artificial intelligence, have been systematically summarized. Further, we thoroughly discussed the clinical advancements in DCIS and IDC, including prognostic biomarkers and clinical managements, with the aim of facilitating more personalized treatment strategies in the future. Research on DCIS has already yielded significant insights into breast carcinogenesis and will continue to pave the way for practical clinical applications.

Expression profiles and gene set enrichment analysis of the transcriptomes from the cancer tissue, white adipose tissue and paracancer tissue with colorectal cancer.

Background: Colorectal cancer (CRC) is one of the most common cancers worldwide and is related to diet and obesity. Currently, crosstalk between lipid metabolism and CRC has been reported; however, the specific mechanism is not yet understood. In this study, we screened differentially expressed long non-coding RNAs (lncRNAs) and mRNAs from primary cancer, paracancer, and white adipose tissue of CRC patients. We screened and analyzed the genes differentially expressed between primary and paracancer tissue and between paracancer and white adipose tissue but not between primary and white adipose tissue. According to the results of the biological analysis, we speculated a lncRNA (MIR503HG) that may be involved in the crosstalk between CRC and lipid metabolism through exosome delivery. Methods: We screened differentially expressed long non-coding RNAs (lncRNAs) and mRNAs from primary cancer, paracancer, and white adipose tissue of CRC patients. We screened and analyzed the genes differentially expressed between primary and paracancer tissue and between paracancer and white adipose tissue but not between primary and white adipose tissue. Results: We speculated a lncRNA (MIR503HG) that may be involved in the crosstalk between CRC and lipid metabolism through exosome delivery. Conclusions: In this study, the findings raise the possibility of crosstalk between lipid metabolism and CRC through the exosomal delivery of lncRNAs.

Sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line therapy in RAS-mutant, microsatellite stable, unresectable metastatic colorectal cancer: an open-label, single-arm, phase II trial.

Background: Microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) patients are characterized by an immunosuppressive microenvironment and a low response rate to immunotherapy. Chemotherapy and anti-angiogenesis therapy have been reported to potentially promote immunotherapy response. This study aims to assess the preliminary anti-tumor activity and safety of sintilimab plus bevacizumab, oxaliplatin and capecitabine as a treatment option for patients with RAS-mutant MSS mCRC. Methods: This study was an open-label, single-arm, phase II trial in China. Patients with unresectable, RAS-mutant and MSS metastatic colorectal adenocarcinoma received treatment by intravenous sintilimab (200 mg, day 1) plus bevacizumab (7.5 mg/kg, day 1), oxaliplatin (135 mg/m2, day 1) and oral capecitabine (1 g/m2, day 1-14) in each 21-day cycle. The primary endpoints included objective response rate (ORR) and adverse events. Biomarker analysis was performed to identify potential predictors of good response to treatment. This study is registered with ClinicalTrials.gov, number NCT04194359. Findings: Between April 2021 and December 2021, 25 patients were enrolled. Two (8%) patients showed complete response (CR), 19 (76%) had partial response (PR) and 4 (16%) presented with stable disease. ORR reached 84% (95% CI, 63.9-95.5) and the disease control rate was 100% (95% CI, 86.3-100). The median progression-free survival (PFS) was 18.2 months for the full analysis set. The most common treatment-related adverse events (TRAEs) in all grades were anemia (21/25, 84%), neutropenia (20/25, 80%), and hand-foot syndrome (14/25, 56%). The most frequent grade 3 or 4 TRAEs were neutropenia (3/25, 12%) and increased alanine transaminase (2/25, 8%). No grade 5 adverse events occurred. In the exploration of biomarkers, 5 patients could be characterized as TTN/OBSCN "double-hit" after treatment, and the copy number variants burden was significantly decreased in tumor tissues after treatment compared with the baseline. Nanostring panel RNA sequencing analysis indicated a better tumor immune microenvironment cell infiltration in CR/PR patients compared with non-CR/PR patients as well as the PFS-long (≥12.5 months) group compared with the PFS-short group. Interpretation: Combination treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine as first-line treatment demonstrated a promising antitumor activity and a manageable safety profile in RAS-mutant, MSS and unresectable mCRC. Exploratory biomarker assessment analysis showed that some RAS-mutant and MSS patients changed into "immune-hot" subtype after the treatment. Funding: This study was supported by the Key R&D Program of Zhejiang Province (2021C03125 to Ying Yuan), the National Natural Science Foundation of China (81872481 to Ying Yuan, 82072624 to Kefeng Ding), the Fundamental Research Funds for the Central Universities (No. 226-2022-00009 to Kefeng Ding), and the Zhejiang Provincial Natural Science Foundation of China (No. LY22H160024 to Hanguang Hu).

Martynoside rescues 5-fluorouracil-impaired ribosome biogenesis by stabilizing RPL27A.

Martynoside (MAR), a bioactive component in several well-known tonic traditional Chinese herbs, exhibits pro-hematopoietic activity during 5-fluorouracil (5-FU) treatment. However, the molecular target and the mechanism of MAR are poorly understood. Here, by adopting the mRNA display with a library of even-distribution (md-LED) method, we systematically examined MAR-protein interactions in vitro and identified the ribosomal protein L27a (RPL27A) as a key cellular target of MAR. Structural and mutational analysis confirmed the specific interaction between MAR and the exon 4,5-encoded region of RPL27A. MAR attenuated 5-FU-induced cytotoxicity in bone marrow nucleated cells, increased RPL27A protein stability, and reduced the ubiquitination of RPL27A at lys92 (K92) and lys94 (K94). Disruption of MAR binding at key residues of RPL27A completely abolished the MAR-induced stabilization. Furthermore, by integrating label-free quantitative ubiquitination proteomics, transcriptomics, and ribosome function assays, we revealed that MAR restored RPL27A protein levels and thus rescued ribosome biogenesis impaired by 5-FU. Specifically, MAR increased mature ribosomal RNA (rRNA) abundance, prevented ribosomal protein degradation, facilitated ribosome assembly, and maintained nucleolar integrity. Collectively, our findings characterize the target of a component of Chinese medicine, reveal the importance of ribosome biogenesis in hematopoiesis, and open up a new direction for improving hematopoiesis by targeting RPL27A.

Sintilimab plus bevacizumab and CapeOx (BBCAPX) on first-line treatment in patients with RAS mutant, microsatellite stable, metastatic colorectal cancer: study protocol of a randomized, open-label, multicentric study.

BACKGROUND: Rat sarcoma viral oncogene homolog (RAS) gene mutation is a common molecular event in colorectal cancer (CRC). The prognosis of mCRC (metastatic colorectal cancer) patients with RAS mutation is poor and capecitabine and oxaliplatin (CapeOx) plus bevacizumab has shown to be one of the standard therapeutic regimens as first line for these patients with objective response rate (ORR) of ~ 50% and median progression-free survival (mPFS) of 8-9 months. Immunotherapy, especially anti-programmed death 1 (PD-1) monoclonal antibody has demonstrated ground-breaking results in deficient mismatch repair (dMMR) / microsatellite instability-high (MSI-H) mCRC patients. However, the response rate of in microsatellite stable (MSS) patients is extremely low. In addition, preclinical studies have demonstrated that anti-Vascular endothelial growth factor (VEGF) agents, such as bevacizumab, can induce tumor vascular normalization and enhance antitumor immunity. Previous study indicated the combination of chemotherapy, anti-VEGF agents (bevacizumab) with immune checkpoint inhibitors may have promising clinical activity in RAS mutant, MSS refractory mCRC patients. Based on these evidences, we will explore the combination of CapeOx with bevacizumab and sintilimab (anti-PD-1 monoclonal antibody) in RAS mutant, MSS mCRC patients as first-line therapy. METHODS: This is a randomized, open-label, multicentric clinical trial. In the sintilimab arm, patients will receive sintilimab in combination with CapeOx and bevacizumab. In the control arm, patients will receive CapeOx and bevacizumab. This trial will recruit 494 patients from 20 centers and randomly (1:1) disseminated into two groups. The primary endpoint is the PFS. The secondary endpoints include overall survival, safety, ORR, and disease control rate. DISCUSSION: This study may provide new ideas for optimizing oncology treatment planning for RAS mutant, MSS mCRC patients in the first-line set. TRIAL REGISTRATION: This study is short for BBCAPX and has been registered at clinicaltrials.gov registry with identifier NCT05171660.

A prognostic signature associated with cell senescence predicts survival outcomes and strongly associates with immunotherapy and chemotherapy response in breast cancer.

The objective of this study is to assess the predictive potency of cell senescence-related genes (CSRGs) in breast cancer (BC) and establish a risk signature. Trascriptome data of CSRGs were obtained from the TCGA and GEO databases. Consensus clustering was used to generate CSRGs-based molecular clusters for BC patients. A CSRGs-derived risk signature was built using multiple Cox regression analyses of differentially expressed genes (DEGs) between clusters. The prognosis, immune infiltration, chemotherapy and immunotherapy response between different risk groups were analyzed and compared. Two molecular clusters of BC patients were generated on the basis of 79 differentially expressed CSRGs, which showed distinct prognosis and immune infiltration. A total of 1403 DEGs between the CSRGs-derived clusters were found, and 10 of them were independent prognostic genes that used to construct a risk signature. The results demonstrated that patients with older age and advanced stage presented with a higher risk scores. In addition, the risk signature was found to be associated with outcomes, immune infiltration, chemotherapy and immunotherapy response. Patients in the low-risk group showed a favorable prognosis and higher immunotherapy response than those in the high-risk group. Finally, we developed a highly stable nomogram that incorporates risk signature, chemotherapy, radiotherapy, and stage variables, enabling accurate prediction of the overall survival (OS) of individual patients. To conclude, the signature derived from CSRGs holds great promise as a biomarker for prognostic assessment of BC and may serve as a valuable tool in guiding immunotherapy.

Dual targeted therapy with pyrotinib and trastuzumab for HER2-positive advanced colorectal cancer: A phase 2 trial.

This trial was initiated to evaluate the efficacy and safety of pyrotinib in combination with trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive recurrent/metastatic colorectal cancer (CRC). In this single-arm, open-label, multicenter, phase 2 trial patients with HER2-positive recurrent/metastatic CRC were enrolled and received oral pyrotinib 400 mg once a day plus intravenous trastuzumab 8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks. The primary endpoint was the objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), duration of response, and safety were assessed as secondary endpoints. From December 2019 to October 2021, a total of 20 patients were enrolled and 18 of them were evaluable for response. All patients were B-rapidly accelerated fibrosarcoma (BRAF) wild type. Four patients achieved partial response, with an ORR of 22.2% (4/18, 95% confidence interval [CI] 6.4-47.6) and DCR of 61.1% (11/18, 95% CI 35.8-82.7), while the ORR and DCR were 33.3% (4/12, 95% CI 13.8-60.9) and 83.3% (10/12, 95% CI 51.6-97.9), respectively, in RAS wild-type patients. At the time of cut-off day, median follow-up was 10.7 months (range 3.8-13.8). The median PFS was 3.4 months (95% CI 1.8-4.3) in the overall population and 4.3 months (95% CI 3.2-8.5) in the RAS wild-type group. The most common adverse event of grade ≥3 was diarrhea (13/20, 65.0%). Pyrotinib combined with trastuzumab showed promising antitumor activity and a manageable safety profile in patients with RAS/BRAF wild-type HER2-positive advanced CRC.

Neoadjuvant Endocrine Therapy: A Potential Way to Make Cold Hormone Receptor-Rich Breast Cancer Hot.

BACKGROUND: Turning the "cold" tumor immune microenvironment into "hot" is a critical issue in cancer treatment today. Hormone receptor-rich breast cancer (HR+ BC) was previously considered immunologically quiescent. OBJECTIVE: This study aims to explore the immunomodulatory effects of endocrine therapy on HR+ BCs. METHODS: The infiltrations and alterations of the tumor immune microenvironment in HR+ BCs before, after 10-14 days, and after three months of neoadjuvant endocrine therapy were computationally analyzed according to MCP-counter, CIBERSORT, xCell algorithms, and gene-set enrichment analysis (GSEA). The primary microarray data were obtained from three HR+ BC gene expression datasets (GSE20181, GSE55374, and GSE59515). Single-sample GSEA of hallmark and immune response gene sets was performed to evaluate the correlation between suspected treatment response and activated immune pathways in tumors. RESULTS: Both immune and stromal cells were specifically recruited into the HR+ BCs who responded to the neoadjuvant endocrine therapy by letrozole. Besides the enhanced infiltrations of immunosurveillance-related cells such as CD8+ T cells, dendritic cells, and the activation of immune response-related signals, the immunosuppressive M2-like macrophages, as well as the expression of immune checkpoint genes like PDCD1, SIRPA, and some HLA genes, were also stimulated in responders. We identified four pretreatment indicators (the intrinsic luminal subtype, the estrogen response early/late pathway, and the epithelial-mesenchymal transition pathway) as potential predictors of both clinical response and the activation of the tumor immune microenvironment post letrozole. CONCLUSION: Neoadjuvant endocrine therapy showed a promising way to convert the immunologically "cold" HR+ BCs into "hot" tumors. This study provides new insights into the application of immunotherapy for HR+ BCs, especially those who respond to endocrine therapy.

Comparison of changes in lipid profiles of premenopausal women with early-stage breast cancer treated with different endocrine therapies.

Adjuvant endocrine therapy improves the prognosis of early breast cancer with hormone receptor positivity. However, there is no systematic report on the effect of endocrine therapy (particularly ovarian function suppression, OFS) on serum lipids in premenopausal women. This retrospective cohort study aimed to determine whether various endocrine treatments had different effects on blood lipids. This study enrolled 160 premenopausal patients with stage I-III breast cancer in eastern China. The initial diagnostic information was retrieved from patient's medical records, including age at the time of diagnosis, tumor characteristics, anticancer treatment and past medical history. The changes in blood lipids in patients receiving different types of endocrine therapy were compared at the 3rd, 6th, 12th, and 24th months after initiating endocrine therapy. Generalized linear mixed model was used in our analyses. Our data revealed that low-density lipoprotein cholesterol (LDL-C) levels in patients with tamoxifen (TAM) were significantly lower in the 6th, 12th, and 24th months than that in the 3rd month, while high-density lipoprotein cholesterol (HDL-C) levels in the 6th, 12th, and 24th months were significantly higher than that in the 3rd month, indicating that blood lipid levels generally improved with time. While in TAM plus OFS group, HDL-C levels were significantly higher in the 24th month than in the 3rd month, total cholesterol (TC) levels were significantly higher in the 24th month than in the 6th month. The lipid profiles of OFS plus aromatase inhibitor (AI) group did not show significant differences at any time point but were significantly higher than those of the other two groups especially in LDL and TC. TAM group tended to have lower serum lipid levels. With longer follow-up, no statistically significant difference in values was observed between TAM and TAM plus OFS groups at various time points. Compared with the other two groups, OFS plus AI group presented an increasing trend toward LDL-C and TC. The risk of dyslipidemia requires further investigation using a large sample size.

Glycosyltransferase-related long non-coding RNA signature predicts the prognosis of colon adenocarcinoma.

Purpose: Colon adenocarcinoma (COAD) is the most common type of colorectal cancer (CRC) and is associated with poor prognosis. Emerging evidence has demonstrated that glycosylation by long noncoding RNAs (lncRNAs) was associated with COAD progression. To date, however, the prognostic values of glycosyltransferase (GT)-related lncRNAs in COAD are still largely unknown. Methods: We obtained the expression matrix of mRNAs and lncRNAs in COAD from The Cancer Genome Atlas (TCGA) database. Then, the univariate Cox regression analysis was conducted to identify 33 prognostic GT-related lncRNAs. Subsequently, LASSO and multivariate Cox regression analysis were performed, and 7 of 33 GT-related lncRNAs were selected to conduct a risk model. Gene set enrichment analysis (GSEA) was used to analyze gene signaling pathway enrichment of the risk model. ImmuCellAI, an online tool for estimating the abundance of immune cells, and correlation analysis were used to explore the tumor-infiltrating immune cells in COAD. Finally, the expression levels of seven lncRNAs were detected in colorectal cancer cell lines by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: A total of 1,140 GT-related lncRNAs were identified, and 7 COAD-specific GT-related lncRNAs (LINC02381, MIR210HG, AC009237.14, AC105219.1, ZEB1-AS1, AC002310.1, and AC020558.2) were selected to conduct a risk model. Patients were divided into high- and low-risk groups based on the median of risk score. The prognosis of the high-risk group was worse than that of the low-risk group, indicating the good reliability and specificity of our risk model. Additionally, a nomogram based on the risk score and clinical traits was built to help clinical decisions. GSEA showed that the risk model was significantly enriched in metabolism-related pathways. Immune infiltration analysis revealed that five types of immune cells were significantly different between groups, and two types of immune cells were negatively correlated with the risk score. Besides, we found that the expression levels of these seven lncRNAs in tumor cells were significantly higher than those in normal cells, which verified the feasibility of the risk model. Conclusion: The efficient risk model based on seven GT-related lncRNAs has prognostic potential for COAD, which may be novel biomarkers and therapeutic targets for COAD patients.

Prominin 1 Significantly Correlated with Bone Metastasis of Breast Cancer and Influenced the Patient's Prognosis.

Background: This study is aimed at identifying the important biomarkers associated with bone metastasis (BM) in breast cancer (BRCA). Methods: The GSE175692 dataset was used to detect significant differential expressed genes (DEGs) between BRCA samples with or without BM, and DEG-related pathways were then explored. Further, we constructed the protein-protein interaction (PPI) network on GEGs and filtered 5 vital nodes. We then performed the Cox regression, Kaplan-Meier analysis, nomogram, and ROC curve to filter the most significant prognosis genes. The GSE14020 and GSE124647 datasets were used to verify the expression and prognostic value of hub genes, respectively. Finally, the gene set enrichment analysis (GSEA) was performed to reveal the potential mechanism. Results: Totally, 74 DEGs were detected, which mainly correlated with infectious disease, signaling molecules, and interaction. The 5 important DEGs were then filtered, and the Cox regression further showed that 2 genes, including prominin 1 (PROM1) and C-C motif chemokine ligand 2 (CCL2), were related to the prognosis of BRCA metastasis patients. Especially, PROM1 presented a better prognostic performance on the survival probability of patients than CCL2. Verification analysis further confirmed the abnormal expression and significant prognostic influence of PROM1. Finally, GSEA revealed that PROM1 was negatively related to IGF1 and mTOR pathways in BRCA metastasis. Conclusion: PROM1 was an important biomarker associated with BRCA bone metastasis and affected the prognosis of metastatic BRCA patients. It may play a vital role in metastatic BRCA by negatively regulating IGF1 and mTOR pathways.

N4BP3 promotes breast cancer metastasis via NEDD4-mediated E-cadherin ubiquitination and degradation.

The molecular mechanisms driving metastatic progression in breast cancer patients remain poorly understood. Here, we identified N4BP3 as a new regulator in promoting breast cancer metastasis. N4BP3 is enriched in breast tumor tissue and negatively correlates with clinical outcomes in breast cancer patients. The results show that N4BP3 plays a crucial role in regulating breast cancer cell invasion in vitro, and N4BP3 depletion suppresses metastases formation in vivo. N4BP3 alters the expression of epithelial-mesenchymal transition markers and specifically targets E-cadherin in breast cancer cells. Intriguingly, we identified a novel E3 ligase NEDD4 for E-cadherin, and further revealed that N4BP3 promotes breast cancer metastasis via NEDD4-mediated E-cadherin ubiquitination and degradation. Together, this study uncovers an unprecedented role for N4BP3 in breast cancer metastasis and elucidates the underlying molecular mechanisms.

Postmastectomy Radiotherapy After Neoadjuvant Chemotherapy in cT1-2N+ Breast Cancer Patients: A Single Center Experience and Review of Current Literature.

Purpose: Postmastectomy radiotherapy (PMRT) after neoadjuvant chemotherapy (NAC) in breast cancer patients with initial clinical stage cT1-2N+, especially for those who achieved ypT1-2N0, is still controversial. This study was to evaluate the survival prognosis of cT1-2N+ patients after NAC with or without PMRT, and to discuss the selection of patients who may omit PMRT. Patients and Methods: From January 2005 to December 2017, 3055 female breast cancer patients underwent mastectomy in our medical center, among whom 215 patients of cT1-2N+ stage, receiving NAC with or without PMRT were finally analyzed. The median follow-up duration was 72.6 months. The primary endpoint was disease-free survival (DFS), and secondary endpoint was overall survival (OS). Comparison was conducted between PMRT and non-PMRT subgroups. Results: Of the 215 eligible patients, 35.8% (77/215) cT1-2N+ patients achieved ypT0-2N0 after NAC while 64.2% (138/215) of the patients remained nodal positive (ypT0-2N+). The 5-year DFS of ypT0-2N0 non-PMRT was 79.5% (95% confidence interval [CI] 63.4-95.6%). No statistically significant difference was observed between the ypT0-2N0 PMRT and non-PMRT subgroups for the 5-year DFS (78.5% vs 79.5%, p = 0.673) and OS (88.8% vs 90.8%, p = 0.721). The 5-years DFS didn't obviously differ between the ypT0-2N0 non-PMRT subgroup and cT1-2N0 subgroup (79.5% vs 93.3%, p = 0.070). By using Cox regression model in multivariate analyses of prognosis in ypT0-2N+ PMRT subgroup, HER2 overexpression and triple-negative breast cancer were significantly poor predictors of DFS and OS, while ypN stage was significant independent predictors of OS. Conclusion: An effective response to NAC (ypT0-2N0) indicates a sufficiently favorable prognosis, and PMRT might be omitted for cT1-2N+ breast cancer patients with ypT0-2N0 after NAC.

Efficacy and safety of chemotherapy combined with bevacizumab in Chinese patients with metastatic colorectal cancer: A prospective, multicenter, observational, non-interventional phase IV trial.

OBJECTIVE: Bevacizumab has an important and evolving role in improving outcomes in patients with metastatic colorectal cancer (mCRC) worldwide and was approved in China in 2010. However, there are limited real-world data on the efficacy and safety of chemotherapy regimens combined with bevacizumab in Chinese patients with mCRC. This observational, phase IV trial study aimed to obtain more experience on the efficacy and safety of bevacizumab combined with chemotherapy in Chinese mCRC patients. METHODS: Between September 2013 and November 2016, patients with histologically confirmed mCRC were enrolled in a prospective, multicenter, observational, non-interventional phase IV trial at 26 centers across China. Eligible patients received different chemotherapeutic regimens combined with bevacizumab. The efficacy and safety data in the intention-to-treat study population were analyzed. RESULTS: A total of 611 patients were included in the efficacy analysis. The median overall survival and median progression-free survival was 18.00 and 10.05 months, respectively. The objective response rate was 21.00% and disease control rate was 89.40%. In subgroup analyses, the survival differences were observed according to metastatic status, duration of treatment and elevation in blood pressure. A total of 613 patients were evaluable for safety assessments. And 569 (92.82%) patients reported at least one adverse event (AE), and 151 (24.63%) experienced grade 3 or higher AEs. The incidence of bevacizumab-associated AEs of special interest was reported in 31 (5.06%) patients with hypertension (n=12), abscesses and fistulae (n=7), bleeding (n=6), proteinuria (n=3), gastrointestinal perforation (n=2) and venous thrombotic events (n=1). CONCLUSIONS: This observational phase IV trial broadens our experience and knowledge of bevacizumab in the Chinese population and provides a good indication of its overall efficacy and safety. Bevacizumab in combination with chemotherapy offers clinical benefits to Chinese patients with mCRC and has an acceptable and manageable safety profile.

Development and external validation of a novel nomogram for screening Chinese Lynch syndrome: based on a multicenter, population study.

BACKGROUND: This multicenter study aimed to reveal the genetic spectrum of colorectal cancer (CRC) with deficient mismatch repair (dMMR) and build a screening model for Lynch syndrome (LS). METHODS: Through the immunohistochemical (IHC) screening of mismatch repair protein results in postoperative CRC patients, 311 dMMR cases, whose germline and somatic variants were detected using the ColonCore panel, were collected. Univariate and multivariate logistic regression analysis was performed on the clinical characteristics of these dMMR individuals, and a clinical nomogram, incorporating statistically significant factors identified using multivariate logistic regression analysis, was constructed to predict the probability of LS. The model was validated externally by an independent cohort. RESULTS: In total, 311 CRC patients with IHC dMMR included 95 identified MMR germline variant (LS) cases and 216 cases without pathogenic or likely pathogenic variants in MMR genes (non-Lynch-associated dMMR). Of the 95 individuals, approximately 51.6%, 28.4%, 14.7%, and 5.3% cases carried germline MLH1, MSH2, MSH6, and PMS2 pathogenic or likely pathogenic variants, respectively. A novel nomogram was then built to predict the probability of LS for CRC patients with dMMR intuitively. The receiver operating characteristic (ROC) curve informed that this nomogram-based screening model could identify LS with a higher specificity and sensitivity with an area under curve (AUC) of 0.87 than current screening criteria based on family history. In the external validation cohort, the AUC of the ROC curve reached 0.804, inferring the screening model's universal applicability. We recommend that dMMR-CRC patients with a probability of LS greater than 0.435 should receive a further germline sequencing. CONCLUSION: This novel screening model based on the clinical characteristic differences between LS and non-Lynch-associated dMMR may assist clinicians to preliminarily screen LS and refer susceptible patients to experienced specialists.

Six years of colorectal cancer mortality surveillance in the screening population for a risk stratified screening program.

OBJECTIVE: To evaluate the impact of a colorectal cancer (CRC) risk predicting system on CRC mortality rates. METHOD: An organized population screening program targeted at all the subjects (n = 102,076) at age 40-74 in nine towns of Jiashan county, China was conducted from 2007 to 2012. All of the screening participants were first triaged into high-risk & low-risk groups by a questionnaire and two fecal immunuochemical tests, only the high-risk subjects were subject to colonocopy. The screening participants were surveyed death caused by CRC for a total of six years after the enrollment. The CRC mortality in subgroups of the screening population was analyzed. RESULTS: A total of 82,184 (80.51 % of the targeted population) screening participants were identified. CRC death were recorded for 142 subjects (28.819 per 105 person-years). The age-adjusted relative risk(RR) of CRC death in the high-risk subjects (n = 12862, 84.48 per 105 person-years) was 3.92 (95 % CI = 2.81-5.49) compared with the low-risk subjects (n = 69322, 18.52 per 105 person-years). In the high-risk group, the age-adjusted RR of CRC death for those accepted colonoscopies (51.44 per 105 person-years) compared with those refused colonoscopies (187.94 per 105 person-years, P < 0.0001) was 0.34 (95 % CI = 0.21-0.56). The first three years after screening has seen the largest difference of CRC death hazard in both comparing groups. CONCLUSION: The high-risk subjects triaged by the risk predicting system have a higher CRC mortality rate than the low-risk subjects, especially in the first three years after screening. Refusal of colonoscopy is risky behavior for the high-risk subject.

Emerging roles of N6-methyladenosine (m6A) modification in breast cancer.

N6-Methyladenosine (m6A) is the most abundant, dynamic, and reversible epigenetic RNA modification that is found in coding and non-coding RNAs. Emerging studies have shown that m6A and its regulators affect multiple steps in RNA metabolism and play broad roles in various cancers. Worldwide, breast cancer is the most prevalent cancer in female. It is a very heterogeneous disease characterized by genetic and epigenetic variations in tumor cells. Increasing evidence has shown that the dysregulation of m6A-related effectors, as methyltransferases, demethylases, and m6A binding proteins, is pivotal in breast cancer pathogenesis. In this review, we have summarized the most up-to-date research on the biological functions of m6A modification in breast cancer and have discussed the potential clinical applications and future directions of m6A modification as a biomarker as well as a therapeutic target of breast cancer.

Factors Prognostic for Peritoneal Metastases from Colorectal Cancer Treated with Surgery.

PURPOSE: To analysis factors prognostic for peritoneal metastases (PM) from colorectal cancer (CRC) treated with surgery using data from two sources and investigate the origin and effective treatment of ovarian metastases (OM). PATIENTS AND METHODS: Data from CRC patients with PM who had undergone surgery were collected from the Surveillance, Epidemiology, and End Results (SEER) database (n = 639) and a single Chinese institution (n = 60). Cumulative survival was evaluated by Kaplan-Meier analysis. Factors associated with overall survival (OS) and progression-free survival (PFS) prognosis were assessed using Cox's proportional hazard regression models. RESULTS: Median OS values for patients who underwent surgery were 19 and 32 months in the SEER database and Chinese center, respectively. Age was an independent predictor of OS in both datasets. Signet-ring cell cancer and perineural invasion were independent predictors of inferior OS only in the SEER dataset, while completeness of cytoreduction (CC) and peritoneal carcinomatosis index were independent predictors for OS and PFS only in the Chinese center. Median OS was 24 months in CRC patients with PM alone and 36 months in those with both PM and OM (p = 0.181). Further, median PSF in patients with PM alone was 10 months, while that in individuals with both PM and OM was 20 months (p = 0.181). CONCLUSION: Surgical treatment of the primary and metastatic sites is effective and safe for CRC patients with PM. CC-0 is recommended for improved prognosis. Moreover, OM should be recognized as a feature of PM, and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is beneficial for CRC patients with OM.