Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients

BACKGROUND RAS,BRAF,and mismatch repair(MMR)/microsatellite instability(MSI)are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer(CRC).However,their characteristics and influencing factors in Chinese patients have not been thoroughly described.AIM To analyze the clinicopathological features of KRAS,NRAS,BRAF,and PIK3CA mutations and the DNA MMR status in CRC.METHODS We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital.MMR proteins were tested using immunohistochemical analysis,and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction.Microsatellite status was determined using an MSI detection kit.Statistical analyses were conducted using SPSS software and logistic regression.RESULTS The KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 44.6%,3.4%,3.7%,and 3.9% of CRC patients,respectively.KRAS mutations were more likely to occur in patients with moderate-to-high differentiation.BRAF mutations were more likely to occur in patients with right-sided CRC,poorly differentiated,or no perineural invasion.Deficient MMR(dMMR)was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas.KRAS,NRAS,BRAF,and PIK3CA mutations were detected in 29.6%,1.1%,8.1%,and 22.3% of patients with dMMR,respectively.The dMMR was more likely to occur in patients with a family history of CRC,aged<50 years,right-sided CRC,poorly differentiated histology,no perineural invasion,and with carcinoma in situ,stage I,or stage II tumors.CONCLUSION This study analyzed the molecular profiles of KRAS,NRAS,BRAF,PIK3CA,and MMR/MSI in CRC,identifying key influencing factors,with implications for clinical management of CRC.

Low prevalence of mismatch repair deficiency in Chinese colorectal cancers:a multicenter study

Background:Although universal testing for mismatch repair deficiency(dMMR)has been recommended to all colorectal cancer(CRC)patients,related evidence for the Chinese population is lacking.Here,we investigated the prevalence and clinicopathological features of dMMR patients in a large Chinese CRC cohort.Methods:We included 7,373 CRC patients treated at four Chinese medical centers between August 2010 and September 2016.Patients’baseline characteristics and pathological features were recorded.The clinicopathological features were compared between patients with MLH1/PMS2 deficiency(dMLH1/PMS2)and MSH2/MSH6 deficiency(dMSH2/MSH6).Results:Among the investigated patients,654(8.9%)were identified with dMMR CRCs and,of them,401(61.3%)were males,with a median age of 55 years(range,22-87 years);355(54.3%)had stage II CRC based on American Joint Committee on Cancer 8th edition.The prevalence of the dMLH1/PMS2 group and the dMSH2/MSH6 group were 51.5%(337/654)and 25.1%(164/654),respectively.Compared with dMSH2/MSH6 patients,those with dMLH1/PMS2 were older(57 vs 52 years,P<0.001),more likely to be female(45.7%vs 31.5%,P=0.004),prone to having tumors located in the right-hand side of the colon(59.0%vs 47.6%,P=0.015),and less likely to have a family history of tumors(29.7%vs 43.3%,P=0.003).Conclusions:The prevalence of dMMR in Chinese CRC patients was low,especially in the dMLH1/PMS2 group.The clinicopathological features were different between dMMR subgroups.

Evaluation of 30 DNA damage response and 6 mismatch repair gene mutations as biomarkers for immunotherapy outcomes across multiple solid tumor types

Objective:DNA damage response(DDR)genes have low mutation rates,which may restrict their clinical applications in predicting the outcomes of immune checkpoint inhibitor(ICI)treatment.Thus,a systemic analysis of multiple DDR genes is needed to identify potential biomarkers of ICI efficacy.Methods:A total of 39,631 patients with mutation data were selected from the cBioPortal database.A total of 155 patients with mutation data were obtained from the Fudan University Shanghai Cancer Center(FUSCC).A total of 1,660 patients from the MSK-IMPACT cohort who underwent ICI treatment were selected for survival analysis.A total of 249 patients who underwent ICI treatment from the Dana-Farber Cancer Institute(DFCI)cohort were obtained from a published dataset.The Cancer Genome Atlas(TCGA)level 3 RNA-Seq version 2 RSEM data for gastric cancer were downloaded from cBioPortal.Results:Six MMR and 30 DDR genes were included in this study.Six MMR and 20 DDR gene mutations were found to predict the therapeutic efficacy of ICI,and most of them predicted the therapeutic efficacy of ICI,in a manner dependent on TMB,except for 4 combined DDR gene mutations,which were associated with the therapeutic efficacy of ICI independently of the TMB.Single MMR/DDR genes showed low mutation rates;however,the mutation rate of all the MMR/DDR genes associated with the therapeutic efficacy of ICI was relatively high,reaching 10%–30%in several cancer types.Conclusions:Coanalysis of multiple MMR/DDR mutations aids in selecting patients who are potential candidates for immunotherapy.

Precision medicine becomes reality- tumor type--agnostic therapy

Precision medicine just witnessed two breakthroughs in oncology in 2017.Pembrolizumab(Keytruda),Merck’s anti-programmed cell death-1(PD-1)monoclonal antibody(mAb),received accelerated approval in May 2017 by the US Food and Drug Administration for the treatment of adult and pediatric patients with unresectable or metastatic solid tumors that have been identified as having microsatellite instability-high(MSI-H)or deficient DNA mismatch repair(dMMR).Shortly after,nivolumab(Opdivo),Bristol-Myers Squibb’s anti-PD-1 mAb,gained an accelerated approval in August 2017 for adult and pediatric patients with MSI-H or dMMR metastatic colorectal cancer that has progressed after standard chemotherapy.These regulatory approvals marked an important milestone that a cancer treatment may be approved based on a common biomarker rather than the anatomic location in the body where the tumor originated,and therefore established a precedent for tumor type-agnostic therapy.In the 2017 American Society for Clinical Oncology annual meeting,larotrectinib(LOXO-101),Loxooncology’s oral,potent,and selective inhibitor of tropomyosin receptor kinases(TRK),demonstrated unprecedented efficacy on unresectable or metastatic solid tumors with neurotrophic tropomyosin receptor kinase(NTRK)-fusion proteins in adult and pediatric patients.Both the anti-PD-1 mAbs and the TRK-targeting therapies share some basic features:(a)biomarker-based,well-defined rare patient population;(b)exceptionally high clinical efficacy,e.g.,near 40%overall response rate(ORR)for pem-brolizumab across 15 tumor types with MSI-H/dMMR and 75%ORR for larotrectinib across more than 12 tumor types with NTRK-fusion proteins;(c)durable responses lasting at least 6 months with complete responses observed;and(d)parallel development in adult and pediatric populations.With increasing accessibility to genetic analysis tools such as next-generation sequencing,tumor type-agnostic therapy has become a reality,both during clinical development and in clinical practice.Adjustments in our approaches to developing new anti-cancer drugs and to adopting these new cancer treatments in clinical practice need to occur in order to prepare ourselves for the new era of precision medicine.

The tumor microenvironment of pancreatic adenocarcinoma and immune checkpoint inhibitor resistance: a perplex relationship

Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease.Although recent studies with novel therapeutic approaches have led to modest improvement in survival outcomes,limited progress is achieved for the use of immunotherapeutics in this challenging cancer.Immune checkpoint inhibitors,thus far,single-agent or in combination,have not yielded significant improvement in survival outcomes except in mismatch repair-deficient pancreatic cancer.The tumor microenvironment of pancreatic cancer has been considered as an attractive target for over a decade based on preclinical studies that suggested it may adversely affect drug delivery and antitumor immunity.In this review article,we elaborate on the biology of pancreatic cancer microenvironment,its highly complicated interaction with cancer cells,and the immune system.We also discuss plausible explanations that led to the failure of immune checkpoint inhibitors as therapeutic agents and the potential impacts of pancreatic cancer stroma on these negative studies.