| Purpose: To compare the impact of Ki-67 expression levels on the survival of breast cancer(BC)patients with and without postoperative radiotherapy(RT).Methods:All 779 women who had the first ever primary surgery of breast cancer from Jan.2009 to Dec.2009 at the Fourth Hospital of Hebei Medical University were identified for retrospective analyses.A few patients who were male,double-sided BC,ductal carcinoma in-situ or Paget’s disease(13 patients)were excluded.Each patient was assigned into Ki-67 high(≥15%)group and Ki-67 low group according to Ki-67 expression levels determined through immunohistochemical test of primary tumor.All patients were followed up to all events of tumor recurrence,metastasis,death and loss of contacts or alive on July 1,2015.Both Ki-67 expression levels and RT status were treated as main independent variables in analysis.The covariates included age at surgery date,menopausal status,surgical approach,tumor size,histological type,grade,number of lymph nodes involved tumor,vascular invasion status,chemotherapy(neoadjuvant or postoperative),and endocrine therapy.Outcome were overall survival(OS)and disease-free survival(DFS).Cox proportional hazard(PH)models were used for survival analyses along with the generation of Kaplan-Meier curves and log rank test.Hazard ratios(HR)and its 95% confidence interval(CI)from models were calculated with p values(P<0.05 as significant level unless stated otherwise).The statistical tool was SPSS 22.0.Results:1 Description of overall study populationThe study population had mean age 50.5 years old with range of 20-82,50.3%(392 cases)pre menopause,5%(44)breast conserving surgery,96.9%(683)axillary lymph node dissection,74.3%(579)ductal carcinoma,10.8%(84)lobular carcinoma,33.4%(260)postoperative radiotherapy,60.4%(470)endocrine therapy,98.6%(706)postoperative chemotherapy.The distributions of Ki-67 groups were 41.3%(322)Ki-67 low group(Ki-67<15%),54.4%(424)Ki-67 high group(Ki-67≥15%).The overall mortality was 13.0%(92)and treatment failure(defined as either death or relapse or metastasis)was 19.7%(141).The median follow-up was 73.3 months.2 Comparative analyses between RT and non-RT subgroup patientsThere were statistically significant distribution differences of age,menopausal status,mastectomy,pathologic tumor size,vascular invasion,tumor grade,number of lymph node involved between RT(260 cases)and non-radiotherapy subgroup(519 cases).In general,RT patients had more advanced stage than non-RT subgroup patients which reflected the practice pattern of patient selection.No statistical difference was detected for Ki-67 low or high groups(p = 0.092).3 Association of Ki-67 expression levels with patient character overalland stratified by radiotherapy statusFor all patients,mastectomy rates had marginal statistical significance between Ki-67 high/low patients(P=0.059).There were statistically significant distribution differences of ALND,use of endocrine therapy,pathological tumor type,tumor grade,pathologic tumor size,vascular invasion status(P<0.05).No differences were noticed for age,menopausal status,number of positive lymph nodes(P>0.10).Among the non-RT subgroup patients,there were statistically significant differences of age,use of endocrine therapy,pathological tumor type,pathological grade,pathologic tumor size,vascular invasion status.Among the RT subgroup patients,there were statistically significant differences of use of endocrine therapy,pathological grade,pathologic tumor size.(P<0.05)4 Impact of Ki-67 expression levels on OSFor all patients,the mortality rates for every group were Ki-67 high 17.0%(64/424)and Ki-67 low 8.4%(25/322).The univariate Cox analyses showed that Ki-67 high group had HR as 2.060(95%CI,1.346-3.15,P=0.001)compared to Ki-67 low group(reference).Multivariable Cox analyses showed that Ki-67 high group had HR as 2.211(95%CI,1.228-3.981,P=0.008).The result to suggested poorer prognosis of OS for Ki-67 high group.For the non-RT patients,univariate Cox analyses showed that Ki-67 high group had HR as 1.585(95%CI,0.937-2.679,P=0.086)compared to Ki-67 low group(reference).Multivariable Cox analyses showed that Ki-67 high group had HR as 2.228(95%CI,0.909-5.463,P=0.080).The result suggested marginal statistical significance between the groups.It indicated that Ki-67 high group had poorer tendency of OS compared to Ki-67 low group.For the RT patients,univariate Cox models showed statistical differences of OS between the groups(Ki-67 high,HR 3.242,95%CI,1.502-6.994,P=0.003).However,multivariate Cox models showed no statistical significant differences of OS between the two groups(P=0.455).5 Impact of Ki-67 expression levels on DFSFor all patients,the failure rates were 24.5%(94/424)for Ki-67 high and 14.6%(44/322)for Ki-67 low.The univariate Cox analyses showed that Ki-67 high group had HR as 1.773(95%CI = 1.261-2.492,P=0.001)compared to Ki-67 low group(reference).Multivariable Cox analyses showed that Ki-67 high group had HR as 2.027(95%CI= 1.299-3.164,P=0.002).That appeared to suggest Ki-67 high group was associated with significant higher risk of failure compared to Ki-67 low group.For the non-RT patients,The univariate Cox analyses showed that Ki-67 high group had HR as 1.439(95%CI=0.937-2.211,P=0.096)compared to Ki-67 low group(reference).There was marginal statistical significance between the groups.Multivariable Cox analyses showed that Ki-67 high group had HR as 1.650(95%CI=0.879-3.097,P=0.119).It showed no statistical differences of DFS between the groups.For the RT patients,univariate Cox models showed statistical differences of DFS between the groups(Ki-67 high,HR 2.410,95%CI,1.349-4.304,P=0.003).However,multivariate Cox models showed no statistical significant differences of DFS between the two groups(P=0.687).6 Overall impact of radiotherapy status on OS and DFSThe mortality rates of non-RT and RT patients were 11.4%(53/519),and 16.1%(39/260)respectively.Univariate Cox analysis showed that radiotherapy was associated with marginal significant higher death risk with HR 1.435(95%CI,0.980-2.102,P=0.063).The multivariable analysis had lead to the reversed HR 0.549(95%CI = 0.309–0.976,P=0.041).It demonstrated the benefit of RT.In term of treatment failure,the rates of non-RT and RT patients were 16.8% and 25.2% respectively.Cox analyses of DFS showed HR of radiotherapy was 1.493(95%CI=1.088–2.049,P=0.013)from univariate one and 0.755(95%CI =0.485–1.177,P=0.215)from multivariate one.The reversed HR seemed to indicate the benefit of RT on improvement of DFS.7 Two-dimensional(2D)analysis of RT*Ki-67 on OS and DFSWhile Ki-67 low patients with RT were cited as referent subgroup,the 2D univariate analysis of OS did not show any statistically difference(P> 0.05)except the Ki-67 high*non-RT group(HR 4.585,P=0.003).Nonetheless,the multivariate analysis demonstrated the HR were 4.585(Ki-67 high*non-RT,P=0.003),3.104(Ki-67 high*RT P=0.024)and 2.784(Ki-67 low*non-RT P=0.005),respectively.It seemed to suggest that Ki-67 low with RT patients had better prognosis while Ki-67 high with non-RT patients was associated with highest mortality.In terms of DFS,the univariate analysis showed the statistically significant difference of Ki-67 high*RT(HR=2.408,P=0.003)compared to Ki-67 low*RT.No differences were noticed among other groups(P>0.10).The multivariable analyses showed that Ki-67 high*non-RT(HR 3.044,P=0.002)and Ki-67 high*RT(HR 2.672,P=0.006)were associated with higher failure rates at statistical level.Last but not least,multivariate analyses with the interaction term RT*Ki-67 at Cox modeling of both variables on OS and DFS had not indicated its significant roles of associating with OS(P=0.793)or DFS(P=0.217).This result indicated the parallel survival profiles of Ki-67 expression levels between RT and non-RT patients.Conclusion:1 High Ki-67 expression levels without postoperative radiotherapy associates with low OS and DFS.2 Ki-67 expression levels present similar profiles of OS and DFS between RT and non-RT patients.No interaction effect observed. |
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