COX Analysis Between Microsatellite Instability(MSI) And Clinicalpathologic Features In Colorectal Cancer Patients

Objective: Adjuvant chemotherapy is a very important therapeuticmethod, patients with the same stage sometimes have different prognosis,patients with later stage even have better prognosis. So we conclude that inaddition to the stage, still exist other factors influencing patients' prognosis.Some scholars at home and abroad suggest that microsatellite states maybecome an influence factors for the prognosis of patients, and guess thatmicrosatellite status affect patients' prognosis by affecting the sensitivity offluorouracil drugs, and they also suggest that patients with microsatelliteinstability have special clinicalpathologic features. Six mismatch repairgenes (hMSH2,hMSH3,MSH6,hMLH1,hPMS1,hPMS2) related tocolorectal cancers, but hMLH1,hMSH2are the main genes. In our country,over90%microsatellite instability due to the hMLH1or hMSH2. This studyaims to use immunohistochemistry testing protein expression condition ofhMLH1, hMSH2to discuss the connection between microsatelliteinstability(MSI) and incidence,prognostic,sensibility of the5-fluorouracil incolorectal cancer patients.Methods:1This study selected cases in the Fourth Hospital of Hebei Medical Universityfrom the March2001to April2009. We obtained one hundred and sixty-twocases at last. All the patients were given radical surgery, none of them weregiven neoadjuvant radiotheraphy and neoadjuvant chemotheraphy. Onehundred and fifty-seven patients were given fluorouracil-based chemotheraphy.Five patients were not given chemotheraphy after surgery. Took out the tumorspecimens from pathology department of all these patients, preparation topathological section, and detected hMLH1,hMSH2and TS protein expressionby SP immunohistochemistry (IHC). If any of the two protein didn't express, we call it microsatellite stable(MSS), that is also proficient mismatch repair(pMMR); if hMLH1,hMSH2protein express at the same time, we call itmicrosatellite stable(MSS), that is also proficient mismatch repair (pMMR).MSI are devided into MSI-L and MSI-H. One of the hMLH1,hMSH2didn'texpress, it is MSI-L; none of hMLH1,hMSH2express, it is MSI-H. Werecorded clinicalpathologic information of all these patients, and followed upall these patients (telephone and out-patient follow-up review), the follow-upperiod ended september31,2011, or recurrence and metastasis, death, lost todate. DFS (disease-free survival) means from the beginning to the diagnosis tothe end of recurrence and metastasis of any part of the time. Cancer drugsadvisory committee (ODAC) agreed that longer DFS represent the clinicalbenefit. We see it complete data if patients appeared recurrence and metastasis;and we see it censored value if patients did not appear relapse and metastasisor die of other disease. All the follow-up data will be proofread and correctinput SPSS13.0statistical software of statistical analysis.Consulting the literature from at home and abroad and combining theclinical condition, we chosed clinicalpathologic features (gender, age, diseaseplace, pathological type, tumor infiltration depth, lymph node metastasissituation, stages, preoperative tumor markers) to analyse of these one hundredand sixty-two patients. We try to find out clinicalpathologic features related tomicrosatellite status by using chi-square test,.We eliminated the five patientswho weren't given adjuvant chemotheraphy, and made univariate andmultivariate analysis performed by Cox proportional hazard model in otherpatients to find out independent prognostic determinants. And usingKaplan-Meier method (Kaplan-Meier) drawed survival plots, appliedLog-rank test between the two groups. All tests were performed at the0.05level of significances.2We selected patients received operation (radical mastectomy and palliativesurgery) in the department of surgery in the Fourth Hospital of Hebei MedicalUniversity from the January2007to April2009, and their tumor specimenswere taken to the scientific research centre for drug sensitivity. We obtained one hundred and four patients, recorded the tumor cell inhibition ratio of5-fluorouracil in their medical record. Took out the tumor specimens frompathology department of all these patients, preparation to pathologicalsection, and detected hMLH1, hMSH2expression by SP immunohistochemistry (IHC). We also put patients into MSS (pMMR) and MSI(dMMR)group. Use cell toxic index representing the tumor cell inhibition ratio. Referto "anti-tumor drugs general index" set by the National Cancer Drugs Meeting,CI≥70%is highly sensitive,50%~69%is moderate sensitive,30to49%islow sensitive,<30%is not sensitive. Using chi-square test to analysis whetherexists the difference of5-fluorouracil sensitivity between two groups.Result:There are162patients were included in follow-up examples,157of them were given adjuvant chemotheraphy,5of them were not given. All ofthese patients, the youngest25years old, the oldest79years old, with theaverage age56.27, showed a normal distribution. All of these patients,78women and84men.157cases given adjuvant chemotheraphy were followedup, of which2cases were lost (1.27%), cut off to follow-up to the end of,71cases of recurrence and metastasis,84cases of no recurrence and nometastasis. All these patients' data are analyzed as follows:1Clinicalpathologic feature1.1hMLH1,hMSH2expression rate: All of the162patients,26cases(16.05%) with MSI-H for expressing none of hMLH1,hMSH2,37cases(22.84%) with MSI-L for only expressing hMLH1,9cases (5.56%) withMSI-L for only expressing hMSH2. No expression rate of hMLH1was38.89%, No expression rate of hMSH2was21.60%.1.2Patients with MSI-L and MSI-H have difference in gender (P=0.05), buthave no obvious difference in age, pathological types, tumor location,preoperative tumor markers level, tumor infiltration depth, lymph nodemetastasis number, TS express.1.3Patients with MSI and MSS have difference in tumor location (P=0.018),lymph node metastasis number (P=0.002),TS express (P=0.004) and familyhistory(P=0.013), but have no obvious difference in gender, age, pathological types, preoperative tumor markers level and tumor infiltration depth.2survival analysis2.12year recurrence and metastasis ratePatients with MSI (47.78%) have much higher recurrence and metastasisrate than patients with MSS(29.85%)(P=0.023).2.2COX univariate analysisThe DFS affecting factors includes lymph node metastasis number(P=0.002),clinical stage(P=0.010)and microsatellite status(P=0.010).2.3COX multivariate analysisWe put the factors into COX multivariate analysis which get P<0.1inunivariate analysis, independent DFS determinants include lymph nodemetastasis number(P=0.016)and microsatellite status(P=0.010).2.3.1lymph node metastasis status: The recurrence/metastasis risk of N1,N2group is2.042times,2.343times of N0group separately. Lymph nodemetastasis status is DFS independent determinants (P=0.016).2.3.2microsatellite status:The recurrence/metastasis risk of MSS group is2.007times of MSI group. Microsatellite status is DFS independentdeterminants (P=0.010).3sensitivity of5-fluorouracilThere is no difference in the sensitivity of5-fluorouracil between thepatients with MSI and MSS (P=1.000).Conclusion:1Patients with MSI and MSS have difference in tumor location, lymph nodemetastasis number,TS express and family history. Concrete as follows:Patients with microsatellite instability frequently occurring on the right side,having fewer lymph node metastasis numbers, more family history and higherTS expression.2Patients with microsatellite instability have better prognosis, appear lessrecurrence/metastasis in2years and longer DFS than with microsatellitestable.3Lymph node metastasis number and microsatellite status are independent determinants for prognosis.4This study didn't show difference between the sensitivity of5-fluorouraciland microsatellite status.