Prognosis and immunotherapy efficacy in dMMR&MSS colorectal cancer patients and an MSI status predicting model.

The inconsistency between mismatch repair (MMR) protein immunohistochemistry (IHC) and microsatellite instability PCR (MSI-PCR) methods has been widely reported. We aim to investigate the prognosis and the effect of immunotherapy in dMMR by IHC but MSS by MSI-PCR (dMMR&MSS) colorectal cancer (CRC) patients. A microsatellite instability (MSI) predicting model was established to help find dMMR&MSS patients. MMR and MSI states were detected by the IHC and MSI-PCR in 1622 CRC patients (ZS6Y-1 cohort). Logistic regression analysis was used to screen clinical features to construct an MSI-predicting nomogram. We propose a new nomogram-based assay to find patients with dMMR&MSS, in which the MSI-PCR assay only detects dMMR patients with MSS predictive results. We applied the new strategy to a random cohort of 248 CRC patients (ZS6Y-2 cohort). The consistency of MMR IHC and MSI-PCR in the ZS6Y-1 cohort was 95.7% (1553/1622). Both pMMR&MSS and dMMR&MSS groups experienced significantly shorter overall survival (OS) than those in dMMR by IHC and MSI-H by MSI-PCR (dMMR&MSI-H) group (hazard ratio [HR] = 2.429, 95% confidence interval [CI]: 1.89-3.116, p < .01; HR = 21.96, 95% CI: 7.24-66.61, p < .01). The dMMR&MSS group experienced shorter OS than the pMMR&MSS group, but the difference did not reach significance (log rank test, p = .0686). In the immunotherapy group, the progression-free survival of dMMR&MSS patients was significantly shorter than that of dMMR&MSI-H patients (HR = 13.83, 95% CI: 1.508-126.8, p < .05). The ZS6Y-MSI-Pre nomogram (C-index = 0.816, 95% CI: 0.792-0.841, already online) found 66% (2/3) dMMR&MSS patients in the ZS6Y-2 cohort. There are significant differences in OS and immunotherapy effect between dMMR&MSI-H and dMMR&MSS patients. Our prediction model provides an economical way to screen dMMR&MSS patients.

Testing region selection and prognostic analysis of MLH1 promoter methylation in colorectal cancer in China.

Background: MLH1 promoter methylation analysis is recommended in screening for Lynch syndrome (LS) in patients with MLH1-deficient colorectal cancer (CRC). The study aims to identify specific methylation regions in the MLH1 promoter and to evaluate the clinicopathologic characteristics of and prognosis for patients with MLH1 methylation. Methods: A total of 580 CRC cases were included. The DNA mismatch repair (MMR) protein expression was assessed by using immunohistochemistry (IHC). The methylation status of the Regions A, B, C, D, and E in the MLH1 promoter was tested by using bisulfite sequencing PCR. The specificities of the five regions were calculated. Associations between MLH1 methylation and clinicopathologic characteristics were evaluated. Kaplan-Meier analyses for overall survival (OS) were carried out. Results: In 580 CRC cases, the specificities of the methylation test in Regions D and E were both 97.8%. In the MLH1-deficient CRCs, the frequencies of MLH1 methylation and BRAFV600E mutation were 52.6% and 14.6%, respectively; BRAFV600E mutation occurred in 27.7% of patients with MLH1-methylated CRC. In the MMR-deficient patients, compared with MLH1 unmethylation, MLH1 methylation was more common in patients who were aged ≥50 years, female, had no family history of LS-related tumors, and had tumors located at the right colon. In the MMR-deficient patients, the MLH1-methylated cases had lower OS rates than the unmethylated cases with a family history of LS-related tumors (P = 0.047). Conclusions: Regions D and E in the MLH1 promoter are recommended for determining the MLH1 methylation status in screening for LS in MLH1-deficient CRC. In MMR-deficient patients, the MLH1-methylated cases had a worse OS than the unmethylated cases with a family history of LS-related cancer.

Head-to-head comparative study: evaluating three panels for MSI-PCR testing in patients with colorectal and gastric cancer.

AIMS: Due to the lack of large clinical cohorts in the Chinese populations with colorectal cancer (CRC) and gastric cancer (GC), there is no consensus among the preferred panel for microsatellite instability (MSI)-PCR testing. This study aims to evaluate a more appropriate panel. METHODS: We tested the MSI status of 2572 patients with CRC and GC using the NCI panel and 2 mononucleotide panels (5 and 6 mononucleotide panels). Immunohistochemistry (IHC) was employed to perform mismatch repair protein testing in 1976 samples. RESULTS: We collected 2572 patients with CRC and GC. The National Cancer Institute (NCI) panel failed to detect 13 cases. Of the 2559 cases that received results from all three panels, 2544 showed consistent results. In the remaining 15 cases, 9 showed discrepancies between MSI-H and MSI-L, and 6 showed discrepancies between MSI-L and microsatellite stability (MSS). The misdiagnosis rate of MSI-L was significantly lower in two mononucleotide panels than in the NCI panel (12.5% vs 87.5%, p=0.010) in CRC. In patients with GC, only the NCI panel detected three MSI-L cases, while the results of the two mononucleotide panels were one MSI-H and two MSS. Based on their IHC results, the MSI-L misdiagnosis rate of the NCI panel was 33.3%. Furthermore, compared with two mononucleotide panels, the NCI panel had a much lower rate of all loci instability in CRC (90.8% and 90.3% vs 25.2%) and GC (89.5% and 89.5% vs 12.0%). CONCLUSION: In Chinese patients with CRC and GC, the five and six mononucleotide panels have advantages for detecting MSI over the NCI panel.

HBV Infection Status Indicates Different Risks of Synchronous and Metachronous Liver Metastasis in Colorectal Cancer: A Retrospective Study of 3132 Patients with a 5-Year Follow-Up.

Purpose: Previous studies on the effect of hepatitis B virus (HBV) infection on colorectal liver metastasis (CRLM) are contradictory. This study revealed different, more specific impacts of HBV on CRLM. Patients and Methods: A total of 3132 colorectal cancer patients treated from 2013 to 2015 were analyzed retrospectively and followed up for five years. The patients were divided into three groups: group A (chronic HBV infection, CHB); group B, (occult HBV infection, OHB) and group C (no HBV infection, NHB). The risk factors for CRLM, 5-year overall survival (OS), and liver disease-free survival (LDFS) were analyzed. Results: A total of 905 patients (28.9%) had CRLM, with poor survival compared to those without CRLM (P < 0.01). The incidence of CRLM was 33.41% (138/413) in group A, 21.63% (138/638) in group B and 30.23% (629/2081) in group C (P < 0.05). Synchronous colorectal cancer liver metastasis (SYN-CRLM) was found in 425 patients (13.57%). CHB increased the risk of SYN-CRLM (P < 0.01), with a worse prognosis (P < 0.05). Metachronous colorectal cancer liver metastasis (MET-CRLM) was found in 480 patients (15.33%). OHB decreased the risk of MET-CRLM after surgery (P = 0.02), with a better 5-year LDFS (P = 0.01). Even without surgery, patients with OHB showed a lower incidence rate of MET-CRLM (P < 0.01). Conclusion: The incidence of CRLM in this study was approximately 28.9%. Surgery and different HBV infection statuses affected the occurrence of CRLM. Chronic HBV infection increased the risk of SYN-CRLM with poor prognosis. Occult HBV infection reduced the risk of MET-CRLM with better LDFS after surgery.

Local environment in biopsy better predict the pathological response to neoadjuvant chemoradiotherapy in rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) followed by surgery is the standard treatment for locally advanced rectal cancer. Here, we analyzed the impact of local and systemic environments on the tumor response to preoperative chemoradiotherapy in rectal cancer. We recruited 141 patients with rectal cancer treated with nCRT. We evaluated the local tumor environment, including tumor-infiltrating lymphocytes (TILs), intratumor budding (ITB), and the systemic inflammatory environment, including the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) level. Our finding revealed that tumor regression was significantly associated with the density of CD8+ TILs in the intraepithelial, the presence of ITB, the combination of NLR and CRP (NLR-CRP) value, and the combination of CD8+ intraepithelial TIL (iTIL) density and ITB presence. Moreover, multivariate analysis showed that only the combination of CD8+ iTILs and ITB was an independent predictive factor for the pathological response to nCRT in rectal cancer. Our finding demonstrate that the local tumor environment was a better predictor of the tumor response than the systemic environment and thus provided new insight into screening for patients who are more likely to benefit from cancer treatment.