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

BACKGROUND & AIMS: Tumor genetic testing is indispensable in the management of primary and metastatic colorectal cancer (CRC), yet the indications for genomics-guided precision medicine and immunotherapy must be better understood and defined. METHODS: We prospectively sequenced tumors from 869 Chinese patients with CRC by a large panel and evaluated the clinical significance of single-gene somatic mutations and co-occurring events in metastatic CRC, 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. RESULTS: Single-gene somatic mutations in BRAF or RBM10 were associated with shorter progression-free survival in patients with metastatic CRC. 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 progression-free survival 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 insertion or deletion burden with high microsatellite instability suggested immunogenicity with numerous activated tumor-infiltrating lymphocytes, whereas polymerase epsilon exonuclease mutation with ultrahigh tumor mutation burden indicated a relatively quiescent immunophenotype. The heterogeneous genomic-immunologic interactions were reflected in the divergent neoantigen presentation and depletion, immune checkpoint expression, PD-1/PD-L1 interaction, and T-cell responsiveness to pembrolizumab. CONCLUSIONS: Our integrated analysis provides insights into CRC prognostic stratification, drug response, and personalized genomics-guided targeted and immunotherapies.

Thermal ablation versus hepatic resection for colorectal cancer with synchronous liver metastases: a propensity score matching study.

OBJECTIVES: Several studies have compared the efficacy of hepatic resection (HR) and thermal ablation (TA) for unresectable tumors; however, results remain inconsistent. Most cohorts in previous studies were heterogeneous groups of synchronous colorectal liver metastases (CRLM) and extrahepatic metastases. This retrospective study aimed to compare the therapeutic efficacy between TA and HR in synchronous CRLM without extrahepatic metastases. METHODS: Cases with initially synchronous CRLM without extrahepatic metastases between January 2007 and December 2018 were enrolled. Of the 448 cases, 346 received HR and 102 TA. Propensity score matching with a 1:1 ratio was used to improve the comparability between the HR and TA groups. Technical success, complications, disease-free survival (DFS), and overall survival (OS) were compared before and after matching. RESULTS: All patients achieved technical success. Major complication rates in the HR and TA groups were, respectively, 36.7% and 8.8% (p < 0.001). Before matching, the 5-year OS and DFS (p = 0.004 and p = 0.020, respectively) were significantly higher in the HR group than in the TA group. After matching, no significant difference in the 5-year OS and DFS was found between the groups (p = 0.770 and p = 0.939, respectively). Local tumor progression rate was significantly higher in the TA group both before (p = 0.027) and after (p = 0.029) matching. CONCLUSIONS: For patients with CRC with synchronous CRLM, TA and HR provide comparable OS and DFS. TA is preferable if complete ablation is predicted. KEY POINTS: • Thermal ablation and hepatic resection provide comparable overall survival and disease-free survival. • Thermal ablation is a safe and effective treatment for patients with colorectal cancer with synchronous liver metastases and has a lower major complication rate and higher repeatability than hepatic resection. • Thermal ablation is preferable if complete ablation is predicted.

Plasma Extracellular Vesicle Long RNAs Have Potential as Biomarkers in Early Detection of Colorectal Cancer.

Background: Early detection of colorectal cancer (CRC) is crucial to the treatment and prognosis of patients. Traditional screening methods have disadvantages. Methods: 231 blood samples were collected from 86 CRC, 56 colorectal adenoma (CRA), and 89 healthy individuals, from which extracellular vesicle long RNAs (exLRs) were isolated and sequenced. An CRC diagnostic signature (d-signature) was established, and prognosis-associated cell components were evaluated. Results: The exLR d-signature for CRC was established based on 17 of the differentially expressed exLRs. The d-signature showed high diagnostic efficiency of CRC and control (CRA and healthy) samples with an area under the curve (AUC) of 0.938 in the training cohort, 0.943 in the validation cohort, and 0.947 in an independent cohort. The d-signature could effectively differentiate early-stage (stage I-II) CRC from healthy individuals (AUC 0.990), as well as differentiating CEA-negative CRC from healthy individuals (AUC 0.988). A CRA d-signature was also generated and could differentiate CRA from healthy individuals both in the training (AUC 0.993) and validation (AUC 0.978) cohorts. The enrichment of class-switched memory B-cells, B-cells, naive B-cells, and mast cells showed increasing trends between CRC, CRA, and healthy cohorts. Class-switched memory B-cells, mast cells, and basophils were positively associated with CRC prognosis while natural killer T-cells, naive B-cells, immature dendritic cells, and lymphatic endothelial cells were negatively associated with prognosis. Conclusions: Our study identified that the exLR d-signature could differentiate CRC from CRA and healthy individuals with high efficiency and exLR profiling also has potential in CRA screening and CRC prognosis prediction.

The impact of COVID-19 pandemic on colorectal cancer patients: a single-center retrospective study.

BACKGROUND: Since December 2019, China has experienced a public health emergency from the coronavirus disease, which has become a pandemic and is impacting the care of cancer patients worldwide. This study evaluated the impact of the pandemic on colorectal cancer (CRC) patients at our center and aimed to share the lessons we learned with clinics currently experiencing this impact. METHODS: We retrospectively collected data on CRC patients admitted between January 1, 2020 and May 3, 2020; the control group comprised patients admitted between January 1, 2019 and May 3, 2019. RESULTS: During the pandemic, outpatient volumes decreased significantly, especially those of nonlocal and elderly patients, whereas the number of patients who received chemotherapy and surgery remained the same. During the pandemic, 710 CRC patients underwent curative resection. The proportion of patients who received laparoscopic surgeries was 49.4%, significantly higher than the 39.5% during the same period in 2019. The proportion of major complication during the pandemic was not significantly different from that of the control group. The mean hospital stay was significantly longer than that of the control group. CONCLUSIONS: CRC patients confirmed to be infection-free can receive routine treatment. Using online medical counseling and appropriate identification, treatment and follow-up can be effectively maintained. Adjuvant and palliative chemotherapy should not be discontinued. Endoscopic polypectomy, elective, palliative, and multidisciplinary surgeries can be postponed, while curative surgery should proceed as usual. For elderly CRC patients, endoscopic surgery and neoadjuvant radiotherapy are recommended.

Comparison of long-term outcomes between Lynch sydrome and sporadic colorectal cancer: a propensity score matching analysis.

BACKGROUND: Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome. Comparison of prognosis between LS and sporadic CRC (SCRC) were rare, with conflicting results. This study aimed to compare the long-term outcomes between patients with LS and SCRC. METHODS: Between June 2008 and September 2018, a total of 47 patients were diagnosed with LS by genetic testing at Fudan University Shanghai Cancer Center. A 1:2 propensity score matching was performed to obtain homogeneous cohorts from SCRC group. Thereafter, 94 SCRC patients were enrolled as control group. All of enrolled patients received curative surgeries and standardized postoperative monitoring. The long-term survival rates between the two groups were compared, and the prognostic factors were also analyzed. RESULTS: The 5-year overall survival rate of LS group was 97.6%, which was significantly higher than of 82.6% for SCRC group (χ2 = 4.745, p = 0.029). The 5-year recurrence free survival rate showed no significant differences between the two groups (78.0% for LS group vs. 70.6% for SCRC patients; χ2 = 1.260, p = 0.262). The 5-year tumor free survival rates in LS group was 62.1% for LS patients, which were significantly lower than of 70.6% for SCRC group (χ2 = 4.258, p = 0.039). Subgroup analysis of recurrent patients show that the LS group had longer overall survival than the SCRC group after combined chemotherapy. By multivariate analysis, we found that tumor recurrence of primary CRC [Risk ratio (95% (confidence interval): 48.917(9.866-242.539); p < 0.001] and late TNM staging [Risk ratio (95% (confidence interval): 2.968(1.478-5.964); p = 0.002] were independent risk factors for OS. CONCLUSION: LS patients have better long-term survival prognosis than SCRC patients, even though the two groups have statistically comparable recurrence free survival. Combined chemotherapy is an effective treatment for LS patients who developed primary CRC recurrence. Standardized postoperative monitoring for LS patients may enable detection of metachronous tumors at earlier stages, which was a guarantee of a favorable prognosis despite lower tumor free survival.

Comparison Between Familial Colorectal Cancer Type X and Lynch Syndrome: Molecular, Clinical, and Pathological Characteristics and Pedigrees.

OBJECTIVE: This study aimed to compare the molecular, clinical, and pathological characteristics and pedigrees of familial colorectal cancer type X (FCCTX) with those of Lynch syndrome (LS) to provide a theoretical basis for the management of FCCTX. METHODS: Overall, 46 cases of FCCTX and 47 LS probands and affected families were enrolled between June 2008 and September 2018 for this study. Multigene cancer panel tests that included 139 genes were performed for all patients, and variants in each group were described. The clinical, pathological, and pedigree characteristics were also compared between the two groups. RESULTS: In total, 42 variants were detected in 27 (58.7%) cases in the FCCTX group, with BRCA1, BRCA2, POLE, POLD1, ATR, and ATM being the most frequently mutated genes. The mean onset age of colorectal cancer (CRC) was significantly older in the FCCTX group than in the LS group (53.57 ± 12.88 years vs. 44.36 ± 11.26 years, t = -9.204, p < 0.001). The proportion of patients with rectal cancer was also higher in the FCCTX group than in the LS group [43.5% (20/46) vs. 10.6% (5/47), χ2 = 12.823, p = 0.005]. Within a median follow-up time of 53.9 ± 37.0 months, the proportion of patients who developed metachronous CRC was significantly higher in the LS group than in the FCCTX group [34.0% (16/47) vs. 13.0% (6/46), χ2 = 5.676, p = 0.017]. When comparing pedigrees, older age at cancer onset and rectal cancer clustering were observed in the FCCTX families. A higher prevalence in male patients was also observed in the FCCTX families. CONCLUSION: FCCTX is an entity distinct from LS, but its genetic etiology remains unknown. A larger multigene panel would be recommended for determining the underlying pathogenic variants. Considering the pathology and moderate penetrance of the CRC link to FCCTX, less stringent surgical treatments and colonoscopy surveillance would be preferable. Rectum preference is a typical feature of FCCTX. Colonoscopy surveillance in FCCTX families could be less intensive, and more attention should be given to male members.

Comparison of Molecular, Clinicopathological, and Pedigree Differences Between Lynch-Like and Lynch Syndromes.

In this study, we compared the molecular, clinical, and pathological characteristics, as well as pedigrees, between patients with Lynch-like syndrome (LLS) and confirmed Lynch syndrome (LS) to develop appropriate management strategies for patients with LLS and their affected family members. Between June 2008 and September 2018, 81 patients with LLS and 47 patients with LS who developed colorectal cancer (CRC) were enrolled in this study. Multigene panel testing included 139 genes and was performed for all patients. The variants identified in each group were described, and clinicopathological characteristics and pedigrees were compared between the two groups. In the LLS group, a total of 52 variants were detected in 44 (54.3%) patients. Among the 52 variants, 17 were variants of unknown significance in mismatch repair genes, and the other most frequently mutated genes were MUYTH, POLE, BRCA2, and GJB2. The proportion of early-onset patients was significantly higher among the LS probands than among the LLS probands (74.5 and 53.1%, respectively; χ2 = 5.712, P = 0.017). On the other hand, the proportion of primary CRC developed in the rectum was higher in the LLS group than in the LS group (25.9 and 10.6%, respectively; χ2 = 2.358, P = 0.046). There were no significant differences in the occurrence of metachronous CRC (P = 0.632) and extra-colorectal cancer (extra-CRC) (P = 0.145) between the two groups. However, analysis of pedigrees showed that more patients developed CRC in the LS families (P = 0.013), whereas more patients with extra-CRC were observed in the LLS families (P = 0.045). A higher prevalence of male patients was observed in the LLS families (P = 0.036). In conclusion, LLS should be classified as a mixed entity, containing cases of LS, other hereditary cancer syndromes, and sporadic CRC. The high risks of CRC and extra-CRCs, which were found in this study, suggest tailored management policy and surveillance should be formulated based on individual and family risk. The surveillance regimen can be based on the presence of confirmed pathogenic/likely pathogenic germline variant(s) and family history.

Clinicopathologic features and prognostic value of KRAS, NRAS and BRAF mutations and DNA mismatch repair status: A single-center retrospective study of 1,834 Chinese patients with Stage I-IV colorectal cancer.

Mutations of KRAS, NRAS, BRAF and DNA mismatch repair (MMR) status have become an important part of the assessment of patients with colorectal cancer (CRC), while respective clinicopathologic features and prognostic significance in specific stages and related detection strategies remain unclear. We retrospectively analyzed clinicopathologic features and prognosis of 1,834 patients with Stage I-IV colorectal adenocarcinoma. Mutations in KRAS, NRAS and BRAF and DNA MMR status were determined. The mutation rates of KRAS, NRAS and BRAF were 46.4, 3.2 and 3.5%, respectively, and the mismatch repair gene deletion (dMMR) rate was 5.6%. In a multivariate analysis, female, advanced age, tumor type histology, mucinous carcinoma and positive tumor deposits were associated with a high KRAS mutation rate. A high BRAF mutation rate was associated with female, poor differentiation, lymphovascular invasion and positive tumor deposits. Factors associated with high dMMR rates included low age, large tumor size, poor differentiation, Stages I-III. Tumor site was independently associated with KRAS mutation, BRAF mutation and dMMR. KRAS and BRAF mutations were independent risk factors for shorter overall survival (OS) in Stage IV tumors but not in Stage I-III tumors. NRAS mutation was an independent risk factor for shorter OS in Stage I-II tumors. dMMR was independently associated with longer OS in Stage III tumors.

A negative-doughnut distal resection margin less than 5 mm does not affect prognosis in rectal cancer.

AIM: Many issues relating to the distal margin of anterior resection of the rectum still exist. We aimed to investigate whether negative distal resection margin (DRM) and positive DRM in the main specimen with negative doughnut has equivalent prognosis in patients with rectal cancer. METHODS: We included 287 patients with rectal cancer, including 69 cases with positive margins and 218 cases with negative margins, all of whom underwent regular follow-up. Survival rate was calculated using Kaplan-Meier survival analysis, while the log-rank test was used to determine statistical difference. Prognostic factors were found using the Cox regression model. RESULTS: There was no significant difference in clinicopathological features between the two groups with the exception of tumor location. Positive findings in the DRM with negative findings in the doughnut resection do not affect the overall survival, local recurrence, or distant metastasis. Factors relating to resection margin, such as the length of resection, negative, or positive findings, were not found to be prognostic. CONCLUSION: Given postoperative pathology results with positive DRM but negative findings in the doughnut resection, a second surgery was not necessary. Instead, adjuvant radiochemotherapy and close follow-up will suffice.

[Trend analysis of morbidity and mortality of colorectal cancer in China from 1988 to 2009].

OBJECTIVE: To explore the trend change of the morbidity and mortality of colorectal cancer in China in order to provide reference to the prevention and control of colorectal cancer. METHODS: According to the 1-3 volumes of "Pathogenesis and death of malignancies in pilot program city and county of China", "Pathogenesis and death of cancer in China"(2003-2007) and "Registration annual report of tumor in China" published in 2011 and 2012, data of pathogenesis and death of colorectal cancer from 10 tumor registration spots, including Beijing urban, Shanghai urban, Wuhan urban, Harbin urban (defined as city urban), and Hebei Ci County, Jiangsu Qidong District, Zhejiang Jiashan District, Guangxi Fusui County, Fujian Changle District, Henan Lin County (defined as rural district), between 1988 and 2009 were collected. The morbidity and mortality were elucidated with world population standardized rate. Ratio of pathogenesis to death was calculated with crude rate of morbidity and mortality. Data of 22 years were enrolled into the linear regression analysis to calculate the annual change rate of morbidity and mortality statistically. RESULTS: (1) Colon cancer: morbidity presented increasing trend; male morbidity in city urban increased faster; mortality presented increasing trend as well; no significant difference of increasing velocity was observed between city urban and rural district; morbidity and mortality in city urban were higher compared to rural district; morbidity and mortality of males were higher compared to females; except stable Fujian Changle District, ratio of pathogenesis to death presented decreased trend in Shanghai urban and Hebei Ci County, and increased trend in other 7 spots (all P<0.05). (2) Rectal cancer: morbidity presented increasing trend, and its increasing velocity of city urban was faster compared to rural district; mortality presented decreased trend, especially in females, and this trend in rural district was worse compared to city urban; morbidity and mortality of males were higher compared to females, while no significant difference was observed between city urban and rural district; morbidity and mortality of males and females in Zhejiang Jiashan District were all decreased (all P<0.05); except stable Harbin city, ratio of pathogenesis to death presented increased trend in other 9 spots (all P<0.05). (3) Ratio analysis of morbidity and mortality showed that percentage of colon cancer increased gradually in all 10 spots between 1988-2009. CONCLUSIONS: In the past 2 decades, the overall morbidity and mortality of colorectal cancer are higher in city urban and in male as compared with rural district and female. Colon cancer has higher morbidity than rectal cancer and its morbidity and mortality present increased trend, while morbidity of rectal cancer presents increased trend but its mortality presents decreased trend.