The Correlation Between Ki67, Traditional Biomarkers, Clinicopathological Characteristics And Response To Adjuvant Therapy In Breast Cancer

Objective:Breast cancer is one of the leading causes of cancer death in women. For thepast few years, significant improvements in disease-free survival and overallsurvival have been obtained with the progression of surgery, adjuvantchemotherapy, radiotherapy and the extensive use of comprehensive therapy,especially the utilization of neochemotherapy and monoclonal antibodyTrastuzumab. But now there is controversy about the nonstandard, insufficientand excessive treatment for patients with breast cancer. With the developmentof molecular biology, many biomarkers are discovered in breast cancer andki67is one of these biomarkers. Several studies have suggested that higherki67espression level in breast cancer is associated with a higher sensitivity toneoadjuvant chemotherapy. Meanwhile, some studied indicated thatER-negative breast cancer maybe more sensitive to chemotherapy. The resultof the study on ki67as a predictive factor of the response to adjuvantchemotherapy and endocrine therapy is rarely reported. To choose favourableadjuvant therapyaccording to ki67level, this study investigated the predictivevalue of ki67in patients with breast cancer receiving adjuvant chemotherapyandendocrine therapy for breast cancer.Methods:1This study included739patients diagnosed with intermediate-/high-riskbreast cancer using postoperative pathological examination and treated inthe Breast Cancer Center of Fourth Hospital of Hebei Medical Universi-ty between January012008and December312009. The status of ER,PR, HER-2and ki67were documented and All patients received at leastone cycle of adjuvant chemotherapy after surgery. 2The ki67-positive cells refer to the cells that the brown-yellow granu-les have appeared in the nuclei. Then randomly selecting10fields,100tumor cells per field were observed under the high magnification(×400).The percentage of positive cells to the total number of tumor cells is ki67-labling index (ki67LI). The ki67LI less than10%was defined as"-", between10%-30%as "+", between30%-50%as "++", higher th-an50%as "+++". Furthermore, ki67LI<10%was determined to be ki67-positive tumor,ki67≥10%was determined to be ki67-negative tumor.3Disease Free Survival (DFS) was defined as the length of time fromthe date of surgery to events such as local relapse, distant metastasis,de-ath from any cause, or last follow-up. Overall survival(OS) was calcula-ted from the date of surgery to the date of death or last follow-up.4The follow-up was carried out by out-patient rechecking, rehospitalizi-ngor telephone interviewing. Every patient was followed-up at least one.The starting time of following-up was the date of surgery, and the ter-mination of following-up was the date of death, loss to follow-up or la-st follow-up. The deadline of the following-up was on December312011.5The correlation between ki67and traditional biomarkers and clinicopathological characteristics. This study estimated the correlation between ki-67and ER, PR, HER-2and tumor size, number of positive lymph nod-es, stage, grade and lymphovascular invasion.6The correlation between ki67and response to postoperative adjuvantchemotherapy in breast cancer.A total of702patiens received chemothe-rapy after surgery. The statistical analysis was performed for patients w-ho received adjuvant anthracycline-based regimen or taxane-based regim-en. Stratification was by ki67expression and ki67/ER status to comparethe effectiveness of two regimens in breast cancer. Usage of anthracycli-ne-based regimen: FAC/FEC: fluorouracil,500mg/m~2, intravenous infusi-on, day1,8; doxorubicin,50mg/m~2(100for erirubicin), intravenous i-nfusion, day1and cyclophosphamide,500mg/m~2, intravenous infusion, day1; cycled every21days. Usage of the sequential regimen of anthra-cycline followed by taxane: FAC/FEC followed by docetaxel: the usageof FAC/FEC is similar as described above; docetaxel,100mg/m~2, intrave-nous infusion, day1; cycled every21days. AC followed by paclitaxel:doxorubicin,50mg/m~2(100for erirubicin), intravenous infusion, day1,and cyclophosphamide,500mg/m~2, intravenous infusion, day1; cycledevery21days for4cycles; paclitaxel,135mg/m~2, intravenous infusion,day1; cycled every21days.7The correlation between ki67and response to postoperative adjuvantendocrine therapy in breast cancer.531hormonal receptor-positive patie-nts received adjuvant endocrine therapy after surgery.The data of261p-ostmenopausal patients divided into two groups based on ki67status w-as analyzed to compare the effectiveness of selective estrogen receptormodulator(SERM) with aromatase inhibitor(AI) in breast cancer.8All statistical analyses were carried out in SPSS version13.0. The e-xamination of the balance test was using chi-squared test, the ranked d-ata using nonparametric test and Spearman rank correlation.DFS and OSwere calculated using Kaplan-Meier and Log Rank test. A P-value of <0.05was considered significant.Results:1ki67expression level was found to be negative correlation with ERand PR, wheras positive correlation with HER-2(P<0.05).2ki67expression level was positively correlated with tumor size, numb-er of positive lymph nodes, stage and grade(P<0.05), and there was a s-ignificant difference for ki67expression level between lymphovascular invasion-positive group and lymphovascular invasion-negative group (P<0.05). This meant that Higher ki67expression level, larger tumor size, mo-re positive lymph nodes, later stage and higher grade.3the correlation between ki67and response to adjuvant chemotherapyin breast cancer 3.1comparison of response to anthracycline-based regimen with the seq-uential taxane regimen in ki67-negative breast cancerThe median DFS and OS of167patients with ki67-negative breast c-ancer was49.4months and51.5months, respectively. The median DFSof122patients receiving anthracycline monotherapy and the median OSwas51.3months. Among these pati-ents,17patients suffered a relapse or metastasis(DFS Ratio:86.1)and13patiens died(OS Ratio:89.3%). However,the median DFS of45patients was41.1months in the sequential t-axane group and the median OS was46.2months.4patients with recu-rrence or metastasis(DFS ratio:91.1%) were observed and3patients died(OS ratio:93.3%) in this group. The Kaplan-Meier survival analysis sho-wed that there was no significant difference in the DFS or OS of twogroups(P=0.56).3.2comparison of response to anthracycline-based regimen with the seq-uential taxane regimen in ki67-positive breast cancerOf527patients with ki67-positive breast cancer, the median DFS was37.0months and the median OS was38.0months. The median DFS of389patients administered the anthracycline-based regimen was36.5mo-nths and116patients suffered a relapse or metastasis(DFS Ratio:70.2%);the median OS was38.0months and67patients died(OS Ratio:82.8%).In the sequential taxane group, the median DFS and OS of138patientswas38.0months and39.0months, respectively. Among these patients,28patients occurred a relapse or metastasis(DFS Ratio:79.7) and13pat-ients died(OS Ratio:90.6%). The Kaplan-Meier survival analysis showedthat the DFS as well as the OS was significantly different between twogroups(P<0.05), that is, the DFS of patients receiving the sequential tax-ane-based regimen was longer than those who receiving only anthracycl-ine-based regimen as well as the OS.4the correlation between ki67/ER status and response to adjuvantchemotherapy in breast cancer 4.1The median DFS of379patients with ki67-positive and ER-positiv-e breast cancer was42.7months and the median OS was45.8months.Inanthracycline monotherapy group, the median DFS of285patients was41.9months and55patients suffered a relapse or metastasis(DFS Ratio:80.7%); the median OS of these patients was45.0months and31pati-ents died(OS Ratio:89.1%).Of94patients in sequential taxane group, themedian DFS was43.8months and relapse or metastasis was observed i-n14patients(DFS Ratio:85.1%); the median OS was46.7months and5patients died(OS Ratio:94.7%).The Kaplan-Meier survival analysis was f-ailed to show significant difference in DFS or OS between two group.4.2The median DFS of148patients with ki67-positive and ER-negativebreast cancer was32.2months and the median OS was40.3months. T-he median DFS and OS of104patients was30.5months and39.2mo-nths in anthracycline group, respectively. Among these patients,61pati-ents suffered a relapse or metastasis(DFS Ratio:41.3%) and36patientsdied(OS Ratio:65.4%). The median DFS and OS of44patients in sequ-ential taxane group was35.9months and42.1months, respectively.14patients had a relapse or metastasis(DFS Ratio:68.2%) and8patients di-ed(OS Ratio:81.8%). The Kaplan-Meier survival analysis showed that th-ere was a significant difference in DFS between two groups, although t-he difference in OS was not significant. That is,the DFS of patients wi-th ki67-positive and ER-negative breast cancer administered the sequenti-al taxene regimen was longer than the DFS of whom administered theanthracycline monotherapy.4.3The median DFS and OS of127patients with ki67-negative and E-R-positive breast cancer was50.9months and52.5months, respectively.The median DFS of91patients receiving anthracycline monotherapy w-as51.2months(DFS ratio:92.3%) and44.4months in sequential taxanegroup(DFS ratio:88.9%).7patients suffered a relapse or metastasis in a-nthracycline group and4patients in sequential taxane group. The medi-an OS was52.9months in anthracycline group and45.8months in se- quential taxne group.95.6%of patients in anthracycline group(4patientsdied) and91.7%of those in sequential taxane group(3patients died) w-ere alive. The Kaplan-Meier survival analysis showed that the DFS andOS of patients in anthracycline monotherapy group were similar to those of whom in sequential taxane group(P>0.05).4.4Of40patients with ki67-negative and ER-negative breast cancer, th-e median DFS was39.2months and the median OS was43.1months.The median DFS of31patients in anthracycline monotherapy was36.9months and10patients suffered relapse or metastasis(DFS Ratio:67.7%);the median OS of these patients was42.1months and9patients died(OS Ratio:71.0%).In sequential taxane group, the median DFS and OS of9patients both were41.0months because no patients suffered a relapseor metastasis or died(DFS or OS Ratio:100%).The Kaplan-Meier survivalanalysis showed that the difference in DFS and OS was not significantbetween two group(P>0.05).5the correlation between ki67and response to endocrine therapy in br-east cancer5.1comparison of response to SERM with AI in ki67-negative breastcancerThe median DFS and OS of61patients with ki67-negative breast ca-ncer was52.0months and53.3months, respectively. The median DFSand OS both were45.0months because no patient suffered a relapse ormetastasis, and all patients were alive in SERM group.Of43patients inAI group, the median DFS was51.2months and the median OS was53.0months. Among these patients,4patients occurred a relapse or met-astasis(DFS Ratio:90.7%) and2patients died(OS Ratio:95.3%). The Ka-plan-Meier survival analysis showed that there was no significant differ-ence in DFS or OS between two groups(P>0.05).5.2comparison of response to SERM with AI in ki67-negative breastcancer The median DFS was38.0months and the median OS was39.0mo-nths for200patients with ki67-positive breast cancer. The median DFSwas39.8months for54patients in SERM group and7patients occurr-ed relapse or metastais(DFS ratio:87.0%). The median OS was40.0mo-nths and4patients had died in SERM group(OS ratio:92.6%). The me-dian DFS was38.0months and36patients suffered relapse or metastas-is for146patients in AI group(DFS ratio:75.3%). The median OS was38.5months and20patients had died in AI group(OS ratio:83.3%).TheKaplan-Meier survival analysis showed that there was no significant dif-ference in DFS or OS between two groups(P>0.05).Conclusions:1ki67was associated with ER,PR and HER-2.Ki67was correlated nega-tively with ER and PR,and the correlation between ki67and HER-2waspositive.2Ki67was associated with clinicopathological characteristics. Higher ki-67expression level, larger tumor size, more positive lymph nodes, laterstage and higher grade. The lymphovascular invasion existed frequentlywhen ki67expression level was higher.3.The efficacy of anthracycline-based regimen was similar to that of ta-xanes-based regimen in the adjuvant setting in ki67-negative breast can-cer,and the DFS and OS was not significantly different between two tr-eatment groups. The efficacy of taxanes-based regimen was superior toanthracycline-based regimen in ki67-positive breast cancer.The patients r-eceiving taxanes-based regimen had longer DFS and OS.4Compared with anthracycline-based regimen, the taxanes-based regimenprolonged the DFS in patients with ki67-positive, ER-negative breast ca-ncer, but the difference in OS was not significant. The efficacy of anth-racycline-based regimen was similar to that of taxanes-based regimen forother groups stratified by ki67/ER status. The difference in DFS or OSwas not significant. 5The efficacy of SERM was similar to that of AI in patients with ki-67-positive breast cancer and in patients with ki67-negative breast canc-er. The difference in DFS or OS between two regimens was not signifi-cant.