Pembrolizumab in Asian patients with microsatellite‐instability‐high/mismatch‐repair‐deficient colorectal cancer

The phase 3 KEYNOTE‐177 study evaluated pembrolizumab versus chemotherapy with or without bevacizumab or cetuximab in patients with newly diagnosed, microsatellite‐instability‐high (MSI‐H)/mismatch‐repair‐deficient (dMMR) metastatic colorectal cancer (mCRC). Primary endpoints were progression‐free survival (PFS) per RECIST v1.1 by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints were overall response rate (ORR) per RECIST v1.1 by BICR and safety. Here, we report results from the post hoc analysis of patients who were enrolled in Asia from the final analysis (FA) of KEYNOTE‐177. A total of 48 patients from Japan, Korea, Singapore, and Taiwan (pembrolizumab, n = 22; chemotherapy, n = 26) were included. At FA, median time from randomization to data cutoff (February 19, 2021) was 45.3 (range 38.1–57.8) months with pembrolizumab and 43.9 (range 36.6–55.1) months with chemotherapy. Median PFS was not reached (NR; 95% confidence interval [CI] 1.9 months–NR) with pembrolizumab versus 10.4 (95% CI 6.3–22.0) months with chemotherapy (hazard ratio [HR] 0.56, 95% CI 0.26–1.20). Median OS was NR (range 13.8 months–NR) versus 30.0 (14.7–NR) months (HR 0.65, 95% CI 0.27–1.55) and ORR was 50% (95% CI 28–72) versus 46% (95% CI 27–67). Grade 3/4 treatment‐related adverse events (TRAEs) were reported by two patients (9%) in the pembrolizumab arm and 20 (80%) in the chemotherapy arm. Immune‐mediated adverse events or infusion reactions were reported by six patients (27%) and 10 patients (40%), respectively. No deaths due to TRAEs occurred. These data support first‐line pembrolizumab as a standard of care for patients from Asia with MSI‐H/dMMR mCRC. ClinicalTrials.gov identifier: {"type":"clinical-trial","attrs":{"text":"NCT02563002","term_id":"NCT02563002"}}NCT02563002.     

Microsatellite instability in colorectal cancer

BACKGROUND: Colorectal cancer (CRC) is the third most common cancer in the world. In 75% CRC develops sporadically, in 25% hereditary or as a consequence of inflammatory bowel disease. CRC carcinogenesis develops over many years. The cause of CRC in 85% is chromosomal instability (CIN) and in 15% microsatellite instability (MSI-H), where hereditary nonpolyposis colorectal cancer (HNPCC) represents 10-20%. Microsatellite sequences (MS) are repeated sequences of short stretches of DNA all over the genome. Microsatellite stability (MSS) means MS are the same in each cell of an individual, whereas microsatellite instability (MSI-H) means MS differ in normal and cancer cells of an individual. The cause of MSI-H is a damaged mismatch repair mechanism (MMR), with the most important MMR proteins being MSH2, MLH1 and MSH6. CONCLUSIONS: MSI-H seems to be an important prognostic factor in CRC and an important predictive factor of CRC chemotherapeutic treatment efficacy. Clinical trials conducted until now have shown contradictory findings in different chemotherapeutic settings, adjuvant and palliative; therefore MSI-H is going to be the object of the future research. The future of cancer treatment is in the individualized therapy based on molecular characteristics of the tumour, such as MSI-H in CRC.     

Pembrolizumab for the treatment of gastric cancer

Introduction: Gastric cancer is one of a few gastrointestinal malignancies in which immunotherapy has shown meaningful activity. Pembrolizumab is the first and only immune checkpoint inhibitor to be FDA-approved in gastric cancer.

Areas Covered: This review summarizes the current and emerging clinical evidence for immune checkpoint inhibitors in advanced and metastatic gastric cancer, with a focus on pembrolizumab.

Expert Commentary: Pembrolizumab has shown impressive activity in the third-line treatment of locally advanced and metastatic gastric cancer. It is currently being studied as upfront therapy in combination with chemotherapy. The emerging understanding of the molecular alterations and tumor immune microenvironment as predictors of immunotherapy response in gastric cancer are discussed. The impact of gastric mucosal dysbiosis on gastric carcinogenesis and the modulation of immunotherapy response by the gut microbiome are also reviewed.     

微卫星不稳定结直肠癌临床病理特征及生存预后

目的 国内外已有学者提出微卫星不稳定(microsatellite instability,MSI)状态可能是影响结直肠癌(colorectal cancer,CRC)患者预后的因素,同时提出微卫星不稳定结直肠癌患者存在较为特殊的临床病理特征,本研究旨在探讨微卫星不稳定CRC的临床病理特征及生存预后.方法 应用免疫组织化学方法检测2010-03-24-2015-12-24济南市第四人民医院60例CRC组织中人MutL蛋白同系物1(human mutl homologue 1,hMLH1)、人MutS蛋白同系物2(human muts homologue 2,hMSH2)及人MutS蛋白同系物6(human muts homologue 6,hMSH6)3种DNA错配修复蛋白表达缺失情况,判断肿瘤微卫星不稳定状态,并分析高度微卫星不稳定(microsatellite instability-high,MSI-H)和低度微卫星不稳定(microsatellite instability-low,MSI-L)/微卫星稳定(microsatellite stable,MSS)不同组别间的临床病理特征及生存预后情况;应用Cox风险比例模型对可能影响CRC患者预后的因素进行多因素分析.结果 60例CRC患者的肿瘤组织中MSI-H为40.0%(24/60),MSI-L为31.7%(19/60),MSS为28.3%(17/60).MSI-H的CRC患者,与MSS和MSI-L患者相比,好发于右半结肠(χ2=6.279,P=0.043),黏液腺癌多见(χ2=6.025,P=0.049);3组在性别、年龄、分期、肿瘤浸润深度、淋巴结转移和分化程度差异无统计学意义.MSI-H患者的中位无病生存期(disease-free survival,DFS)为21个月,明显长于MSS的11个月及MSI-L的13个月,χ2=7.994,P=0.018.多因素Cox分析结果显示,淋巴结转移(P=0.013)和MSI(P=0.018)为CRC患者DFS的独立预后因素.结论 MSI-H的CRC患者与MSI-L及MSS相比,具有独特的临床病理特征且预后相对较好.检测MSI状态对提高CRC治疗水平,及改善预后有重要的临床意义.     

Candidate driver genes in microsatellite-unstable colorectal cancer

Defects in the mismatch repair system lead to microsatellite instability (MSI), a feature observed in ～ 15% of all colorectal cancers (CRCs). Microsatellite mutations that drive tumourigenesis, typically inactivation of tumour suppressors, are selected for and are frequently detected in MSI cancers. Here, we evaluated somatic mutations in microsatellite repeats of 790 genes chosen based on reduced expression in MSI CRC and existence of a coding mononucleotide repeat of 6-10 bp in length. All the repeats were initially sequenced in 30 primary MSI CRC samples and whenever frameshift mutations were identified in >20%, additional 70 samples were sequenced. To distinguish driver mutations from passengers, we similarly analyzed the occurrence of frameshift mutations in 121 intronic control repeats and utilized a statistical regression model to determine cut-off mutation frequencies for repeats of all types (A/T and C/G, 6-10 bp). Along with several know target genes, including TGFBR2, ACVR2, and MSH3, six novel candidate driver genes emerged that harbored significantly more mutations than identical control repeats. The mutation frequencies in 100 MSI CRC samples were 51% in G8 of GLYR1, 47% in T9 of ABCC5, 43% in G8 of WDTC1, 33% in A8 of ROCK1, 30% in T8 of OR51E2, and 28% in A8 of TCEB3. Immunohistochemical staining of GLYR1 revealed defective protein expression in tumors carrying biallelic mutations, supporting a loss of function hypothesis. This is a large scale, unbiased effort to identify genes that when mutated are likely to contribute to MSI CRC development.     

Clinicopathological significance of microsatellite instability and mutated RIZ in colorectal cancer.

BACKGROUND: Several studies have shown that microsatellite instability (MSI) is related to favourable survival in colorectal cancer patients but there are controversial results. Tumour suppressor gene RIZ is a susceptible mutational target of MSI. However, its clinicopathological significance has not been investigated. We investigated the prognostic significance of MSI in Swedish colorectal cancer patients and the clinicopathological significance of RIZ mutations. PATIENTS AND METHODS: We analysed 438 colorectal adenocarcinomas for MSI by microsatellite analysis. Among them, 29 MSI and 28 microsatellite stable (MSS) tumours were examined for RIZ mutations by DNA sequencing. RESULTS: MSI (13% of 438 cases) was not associated with survival (rate ratio = 0.97, 95% confidence interval = 0.57-1.64, P = 0.90), although it was related to proximal tumour (P <0.001), poor differentiation and mucinous carcinomas (P <0.001), multiple tumours (P = 0.01) and negative/weak expression of hMLH1 (P = 0.03). RIZ mutations were detected in 31% of 29 MSI tumours but in none of the 28 MSS tumours. The mutations were related to female (P = 0.01), proximal tumour (P = 0.01), stage B (P = 0.01) and poor differentiation (P = 0.047). CONCLUSIONS: MSI was not a prognostic factor in the Swedish patients included in this study. Clinicopathological variables associated with RIZ mutations might be a consequence of the MSI characteristics.     

错配修复基因与大肠癌相关性研究进展

目的 MMR系统是一组高度保守基因及其产物蛋白构成,其主要功能是纠正DNA复制、重组及基因损伤时出现的碱基配对错误.本研究总结国内外错配修复基因与大肠癌相关性的研究进展.方法 检索Pubmed和万方数据库,以“错配修复基因、微卫星不稳定、大肠癌”等为关键词,检索1997-01-2016-06的相关文献共102篇.纳入标准:(1)错配修复基因与微卫星不稳定的关系.(2)错配修复基因大肠癌的发生及预后的关系.根据纳入标准,最终选取49篇文献纳入分析.结果 错配修复系统是一种广泛存在于机体细胞内的自我修复机制,对防止基因突变和维持基因组稳定性方面起着重要作用.错配修复基因突变与微卫星不稳定关系密切,错配修复基因发生突变时,使机体肿瘤易感性明显增加.结论 错配修复系统是大肠癌的发生、发展的重要预后指标.     

检测微卫星不稳在中国遗传性非息肉病性结直肠癌患者诊断中的应用

背景与目的：遗传性非息肉病性结直肠癌（hereditary nonpolyposis colorectal cancer，HNPCC）是常染色体显性遗传综合征，国外报道90％的HNPCC肿瘤表现为微卫星不稳（microsatellite instability，MSI），可作为筛查HNPCC的金标准。本研究旨在了解中国HNPCC肿瘤MSI发生率以及可疑HNPCC患者大肠癌肿瘤中的MSI发生率，由此探讨大肠癌患者家族中的胃癌等HNPCC相关肿瘤对发现HNPCC患者的意义。方法：选择符合Amsterdam标准的HNPCC组大肠癌标本18例，和不符合Amsterdam标准、但高度怀疑为HNPCC的可疑HNPCC组大肠癌标本16例，检测BAT26、D2S123、BAX、IGFIIR、hMSH3和hMSH66个做卫星位点的微卫星不稳在两组中的发生率，比较两组微卫星不稳频率的差异。结果：上述各傲卫星位点在HNPCC组和可疑HNPCC组标本中均显示较高的突变率。高度微p星不稳肿瘤在两组标本中的检出率分别为94．4％和93．7％．差异无显著性。BAT26对高度微卫星不稳肿瘤敏感度高。结论：MSI在中国HNPCC患者中的发生频率与国外类同。仅用BAT26可发现大部分高度微卫星不稳肿瘤。将胃癌等HNPCC相关肿瘤纳入临床诊断标准，可能有助于避免在中国大肠癌人群中漏诊HNPCC患者。     

Promoter methylation of Wnt5a is associated with microsatellite instability and BRAF V600E mutation in two large populations of colorectal cancer patients

Background:

In colorectal cancer (CRC), tumour microsatellite instability (MSI) status and CpG island methylator phenotype (CIMP) status are indicators of patient outcome, but the molecular events that give rise to these outcomes remain largely unknown. Wnt5a is a critical regulator of non-canonical Wnt activity and promoter hypermethylation of this gene has emerging prognostic roles in CRC; however the frequency and prognostic significance of this epigenetic event have not been explored in the context of colorectal tumour subtype. Consequently, we investigated the frequency and prognostic significance of Wnt5a methylation in a large cohort of MSI-stratified CRCs.

Methods:

Methylation was quantified in a large cohort of 1232 colorectal carcinomas from two clinically distinct populations from Canada. Associations were examined between methylation status and clinicopathlogical features, including tumour MSI status, BRAF V600E mutation, and patient survival.

Results:

In Ontario, Wnt5a methylation was strongly associated with MSI tumours after adjustment for age, sex, and tumour location (odds ratio (OR)=4.2, 95% confidence interval (CI)=2.4–7.4, P<10⁻⁶) and with BRAF V600E mutation, a marker of CIMP (OR=12.3, 95% CI=6.9–21.7, P<10⁻¹⁷), but was not associated with patient survival. Concordant results were obtained in Newfoundland.

Conclusion:

Methylation of Wnt5a is associated with distinct tumour subtypes, strengthening the evidence of an epigenetic-mediated Wnt bias in CRC.     

Three molecular pathways model colorectal carcinogenesis in Lynch syndrome

Lynch syndrome is caused by germline mutations of DNA mismatch repair (MMR) genes. MMR deficiency has long been regarded as a secondary event in the pathogenesis of Lynch syndrome colorectal cancers. Recently, this concept has been challenged by the discovery of MMR‐deficient crypt foci in the normal mucosa. We aimed to reconstruct colorectal carcinogenesis in Lynch syndrome by collecting molecular and histology evidence from Lynch syndrome adenomas and carcinomas. We determined the frequency of MMR deficiency in adenomas from Lynch syndrome mutation carriers by immunohistochemistry and by systematic literature analysis. To trace back the pathways of pathogenesis, histological growth patterns and mutational signatures were analyzed in Lynch syndrome colorectal cancers. Literature and immunohistochemistry analysis demonstrated MMR deficiency in 491 (76.7%) out of 640 adenomas (95% CI: 73.3% to 79.8%) from Lynch syndrome mutation carriers. Histologically normal MMR‐deficient crypts were found directly adjacent to dysplastic adenoma tissue, proving their role as tumor precursors in Lynch syndrome. Accordingly, mutation signature analysis in Lynch colorectal cancers revealed that KRAS and APC mutations commonly occur after the onset of MMR deficiency. Tumors lacking evidence of polypous growth frequently presented with CTNNB1 and TP53 mutations. Our findings demonstrate that Lynch syndrome colorectal cancers can develop through three pathways, with MMR deficiency commonly representing an early and possibly initiating event. This underlines that targeting MMR‐deficient cells by chemoprevention or vaccines against MMR deficiency‐induced frameshift peptide neoantigens holds promise for tumor prevention in Lynch syndrome.     

Population‐based detection of Lynch syndrome in young colorectal cancer patients using microsatellite instability as the initial test

Approximately 1–2% of colorectal cancers (CRC) arise because of germline mutations in DNA mismatch repair genes, referred to as Lynch syndrome. These tumours show microsatellite instability (MSI) and loss of expression of mismatch repair proteins. Pre‐symptomatic identification of mutation carriers has been demonstrated to improve survival; however, there is concern that many are not being identified using current practices. We evaluated population‐based MSI screening of CRC in young patients as a means of ascertaining mutation carriers. CRC diagnosed in patients aged <60 years were identified from pathology records. No prior information was available on family history of cancer. PCR techniques were used to determine MSI in the BAT‐26 mononucleotide repeat and mutation in the BRAF oncogene. Loss of MLH1, MSH2, MSH6 and PMS2 protein expression was evaluated in MSI+ tumours by immunohistochemistry. MSI+ tumours were found in 105/1,344 (7.8%) patients, of which 7 were excluded as possible Lynch syndrome because of BRAF mutation. Of the 98 “red flag” cases that were followed up, 25 were already known as mutation carriers or members of mutation carrier families. Germline test results were obtained for 35 patients and revealed that 22 showed no apparent mutation, 11 showed likely pathogenic mutations and 2 had unclassified variants. The proportion of MSI+ cases in different age groups that were estimated to be mutation carriers was 89% (<30 years), 83% (30–39), 68% (40–49) and 17% (50–59). We recommend MSI as the initial test for population‐based screening of Lynch syndrome in younger CRC patients, regardless of family history. © 2008 Wiley‐Liss, Inc.     

Smooth-muscle myosin mutations in hereditary non-polyposis colorectal cancer syndrome

We examined adenomas and cancers from hereditary non-polyposis colorectal cancer (HNPCC) syndrome patients for the presence of frameshift mutations in the smooth-muscle myosin gene, MYH11. Our results show that mutations in MYH11 occur more frequently in cancers than adenomas (P=0.008) and are dependent on microsatellite instability (MSI+).     

APC gene methylation is inversely correlated with features of the CpG island methylator phenotype in colorectal cancer

The notion of a CpG island methylator phenotype (CIMP) was proposed to describe a subset of colorectal cancers (CRC) displaying frequent and concordant methylation of CpG islands located within gene promoter regions. Some workers have failed to observe associations between CIMP and specific clinicopathological features of CRC, possibly because of the choice of genes used to define this phenotype. The aim of the current study was to determine whether the aberrant methylation of 6 genes implicated in CRC development was associated with the same phenotypic features of this tumour type. The MethyLight assay was used to provide quantitative estimates of MLH1, P16, TIMP3, P14, DAPK and APC methylation levels in 199 unselected colorectal tumours. The methylation of MLH1, P16, TIMP3 and P14 was highly concordant (p < 0.0001 for each pair) but that of DAPK and APC was not. An inverse association was observed between the methylation of APC and TIMP3 (p = 0.004). Methylation of the MLH1, P16, TIMP3 and P14 genes was associated with tumour infiltrating lymphocytes (p < 0.05), microsatellite instability (p < 0.001), BRAF mutation (p < 0.0001) and elevated concentrations of the methyl group carriers tetrahydrofolate (THF) and 5,10-methylene THF (p < 0.05). In contrast, APC methylation was associated with wildtype BRAF (p = 0.003) and with lower concentrations of methyl group carriers (p < 0.05). These findings highlight the importance of gene selection in studies that aim to characterize the biological features and clinical behaviour of CIMP+ tumours.     

Methylation and microsatellite status and recurrence following adjuvant FOLFOX in colorectal cancer

The prognostic impact of CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) on the treatment outcome of colon cancer patients receiving adjuvant 5‐fluorouracil/leucovorin/oxaliplatin (FOLFOX) is unclear. We investigated CIMP and MSI status in colorectal cancer patients treated with adjuvant FOLFOX. Stages II and III sporadic colorectal cancer patients who underwent curative resection followed by adjuvant FOLFOX were included. Eight CpG island loci (CACNA1G, CRABP1, IGF2, MLH1, NEUROG1, CDKN2A (p16), RUNX3 and SOCS1) and five microsatellite markers were examined. Disease‐free survival (DFS) was analyzed according to CIMP and MSI status. A total of 322 patients were included: male/female 192/130, median age 61 years (range 30–78), proximal/distal location 118/204 and Stages II/III 43/279. CIMP status was high in 25 patients (7.8%) and 21 patients (6.5%) had MSI‐high tumor. CIMP/MSI status was not significantly associated with DFS: 3‐year DFS 100% in CIMP(?)/MSI(+), 84% in CIMP(?)/MSI(?), 82% in CIMP(+)/MSI(?) and 75% in CIMP(+)/MSI(+) (p = 0.33). Results of exploratory analysis showed that concurrent methylation at NEUROG1 and CDKN2A (p16) was associated with shorter DFS: 3‐year DFS 69% in NEUROG1(+)/CDKN2A (p16)(+) versus 87% in NEUROG1(?)/CDKN2A (p16)(?) (p = 0.006). In conclusion, concurrent methylation of NEUROG1 and CDKN2A (p16) is associated with recurrence following adjuvant FOLFOX in Stages II/III colorectal cancer.     

Mitochondrial microsatellite instability of colorectal cancer stroma

Mitochondrial microsatellite instability (mtMSI) and mutations of mitochondrial DNA has been reported in cancer epithelia of carcinomas. However, mtMSI in cancer stroma has not yet been identified in human cancers. In this study, we attempted to determine if mtMSI occurs in the cancer stroma of sporadic colorectal cancers, and if the stromal mtMSI has any correlations with stromal nuclear MSI (nMSI) and cancer epithelial mtMSI. Nine microsatellite sequences within the D-loop and 5 coding genes for mtMSI, and 9 microsatellites for nMSI were analyzed in the microdissected cancer epithelia and adjacent stromas of 48 sporadic colorectal cancers. Overall, 23 somatic mitochondrial DNA alterations were detected in 15 cancer epithelia (31.2%) and 5 stromas (10.4%). The mutations consisted of 19 D-loop mtMSI alterations, and 1 missense and 3 framshift mutations of repeat sequences within the coding genes. All of the 5 stromal genetic alterations showed D-loop mtMSI. In regards to other MSI status, the stromal mtMSI had no association with stromal nMSI or epithelial mtMSI, either. These findings indicate that in addition to the cancer epithelia the cancer stroma harbor mtMSI, and suggest a possible role of stromal mtMSI in the pathogenesis of colorectal cancers. Furthermore, the data suggest that stromal mtMSI may occur independently of stromal nMSI and epithelial mtMSI in sporadic colorectal cancers.     

Contrasting molecular pathology of colorectal carcinoma in Egyptian and Western patients

Colorectal carcinoma is uncommon in Egypt, but a high proportion of cases occurs before age 40 years and in the rectum. We compared the molecular pathology of 59 representative Egyptian patients aged 10-72 to Western patients with sporadic, young-onset, or hereditary non-polyposis colorectal cancer syndrome (HNPCC)-associated carcinoma and found significant differences. Most Egyptian cancers were rectal (51%) and poorly differentiated (58%). High levels of microsatellite instability (MSI-H) were frequent (37%) and attributable in some cases (36%) to methylation of the promoter of the hMLH1 mismatch repair gene, but no MSI-H cancer had loss of hMSH2 mismatch repair gene product of the type seen with germline hMSH2 mutation in HNPCC. K-ras mutation was uncommon (11%). In subset analyses, high frequencies of MSI-H in rectal carcinomas (36%) and p53 gene product overexpression in MSI-H cancers (50%) were found. MSI-H and K-ras mutation in Egyptians under age 40 were unusual (17% and 0%, respectively), and schistosomiasis was associated with MSI and K-ras mutation. Cluster analysis identified 2 groups: predominantly young men with poorly differentiated mucinous and signet-ring cell colorectal carcinoma lacking K-ras mutation; older patients who had well- or moderately differentiated adenocarcinoma often with MSI-H, K-ras mutation and schistosomiasis. Our findings show that the molecular pathology of colorectal cancer in older as well as younger Egyptians has unique differences from Western patients, and schistosomiasis influences the molecular pathogenesis of some tumours.     

筛查结直肠癌DNA错配修复基因缺失的方法分析

目的:通过对筛查结直肠癌DNA错配修复(mismatch repair,MMR)基因缺失两种最常用的检测方法的分析,寻找更为经济有效的检测策略。方法:分析新疆医科大学第一附属医院2018年9月至2019年9月收治并行手术的结直肠癌患者的肿瘤组织223例,采用免疫组织化学法检测平台检测MLH1、MSH2、PMS2、MSH6的表达缺失情况,PCR-毛细管电泳法检测肿瘤微卫星不稳定(microstatellites instability,MSI)状态。结果:在223例结直肠癌中,27例(12.1%)MMR蛋白表达缺失(MMR deficiency,dMMR),196例(87.9%)MMR蛋白表达完整(MMR proficient,pMMR)。MLH1、MSH2、MSH6和PMS2的缺失率分别为9.0%(20/223)、1.8%(4/223)、2.7%(6/223)和9.4%(21/223)。包含PMS2和MSH6的2种抗体试验筛查dMMR结直肠癌的灵敏度和特异度与4种抗体试验(MLH1、MSH2、PMS2、MSH6)的灵敏度和特异度均相同。微卫星高度不稳定(MSI-high,MSI-H)2...     

Microsatellite instability in sporadic colorectal cancer is not an independent prognostic factor.

Hereditary non-polyposis colorectal cancer (HNPCC) is linked to an inherited defect in the DNA mismatch repair system. DNA from HNPCC tumours shows microsatellite instability (MSI). It has been reported that HNPCC patients have a better prognosis than patients with sporadic colorectal cancer. We examined whether the presence of MSI in a series of unselected colorectal tumours carries prognostic information. In a series of 181 unselected colorectal tumours, 22 tumours (12%) showed MSI. Survival analysis at 5-10 years follow-up showed no statistically significant difference in prognosis between MSI-positive and -negative tumours. Our results suggest that the MSI phenotype as such is not an independent prognostic factor.     

Mismatch repair status in patients with primary operable colorectal cancer: associations with the local and systemic tumour environment

Background:

Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is associated with a conspicuous local immune infiltrate; however, its relationship with systemic inflammatory responses remains to be determined. The present study aims to examine the relationships and prognostic value of assessment of the local and systemic environment in the context of MMR status in patients with CRC.

Methods:

The relationship between MMR status, determined using immunohistochemistry, and the local inflammatory cell infiltrate, differential white cell count, neutrophil : platelet score (NPS), neutrophil : lymphocyte ratio and modified Glasgow Prognostic Score (mGPS), and cancer-specific survival was examined in 228 patients undergoing resection of stage I–III CRC.

Results:

Thirty-five patients (15%) had dMMR CRC. Mismatch repair deficiency was associated with a higher density of CD3⁺, CD8⁺ and CD45R0⁺ T lymphocytes within the cancer cell nests and an elevated mGPS (mGPS2: 23% vs 9%, P=0.007) and NPS (NPS2: 19% vs 3%, P=0.001). CD3⁺ density (P<0.001), mGPS (P=0.01) and NPS (P=0.042) were associated with survival independent of MMR status (P=0.367) and stratified 5-year survival of patients with MMR-competent CRC from 94% to 67%, 83% to 46% and 78% to 60% respectively.

Conclusions:

Mismatch repair deficiency was associated with local and systemic environments, and in comparison with their assessment, dMMR had relatively poor prognostic value in patients with primary operable CRC. In addition to MMR status, local and systemic inflammatory responses should be assessed in these patients.