Egeland Nina Gran, Jonsdottir Kristin, Lauridsen Kristina Lystlund, Skaland Ivar, Hjorth Cathrine F, Gudlaugsson Einar G, Hamilton-Dutoit Stephen, Lash Timothy L, Cronin-Fenton Deirdre, Janssen Emiel A M
Department of Pathology, Stavanger University Hospital, Stavanger, Norway.
Department of Chemistry, Bioscience and Environmental Engineering, University of Stavanger, Stavanger, Norway.
Clin Epidemiol. 2020 Jul 20;12:771-781. doi: 10.2147/CLEP.S248167. eCollection 2020.
The proliferation marker Ki-67 has been used as a prognostic marker to separate low- and high-risk breast cancer subtypes and guide treatment decisions for adjuvant chemotherapy. The association of Ki-67 with response to tamoxifen therapy is unclear. High-throughput automated scoring of Ki-67 might enable standardization of quantification and definition of clinical cut-off values. We hypothesized that digital image analysis (DIA) of Ki-67 can be used to evaluate proliferation in breast cancer tumors, and that Ki-67 may be associated with tamoxifen resistance in early-stage breast cancer.
Here, we apply DIA technology from Visiopharm using a custom designed algorithm for quantifying the expression of Ki-67, in a case-control study nested in the Danish Breast Cancer Group clinical database, consisting of stages I, II, or III breast cancer patients of 35-69 years of age, diagnosed during 1985-2001, in the Jutland peninsula, Denmark. We assessed DIA-Ki-67 score on tissue microarrays (TMAs) from breast cancer patients in a case-control study including 541 ER-positive and 300 ER-negative recurrent cases and their non-recurrent controls, matched on ER-status, cancer stage, menopausal status, year of diagnosis, and county of residence. We used logistic regression to estimate odds ratios and associated 95% confidence intervals to determine the association of Ki-67 expression with recurrence risk, adjusting for matching factors, chemotherapy, type of surgery, receipt of radiation therapy, age category, and comorbidity.
Ki-67 was not associated with increased risk of recurrence in tamoxifen-treated patients (ORadj =0.72, 95% CI 0.54, 0.96) or ER-negative patients (ORadj =0.85, 95% CI 0.54, 1.34).
Our findings suggest that Ki-67 digital image analysis in TMAs is not associated with increased risk of recurrence among tamoxifen-treated ER-positive breast cancer or ER-negative breast cancer patients. Overall, our findings do not support an increased risk of recurrence associated with Ki-67 expression.
增殖标志物Ki-67已被用作一种预后标志物，以区分低风险和高风险乳腺癌亚型，并指导辅助化疗的治疗决策。Ki-67与他莫昔芬治疗反应之间的关联尚不清楚。Ki-67的高通量自动评分可能会使临床临界值的量化和定义标准化。我们假设，Ki-67的数字图像分析（DIA）可用于评估乳腺癌肿瘤中的增殖情况，并且Ki-67可能与早期乳腺癌的他莫昔芬耐药性相关。
在此，我们在丹麦乳腺癌组临床数据库中进行的一项病例对照研究中，应用了来自Visiopharm的DIA技术，该技术使用一种定制设计的算法来量化Ki-67的表达，该研究纳入了1985年至2001年期间在丹麦日德兰半岛诊断的35至69岁的I、II或III期乳腺癌患者。在一项病例对照研究中，我们对乳腺癌患者组织微阵列（TMA）上的DIA-Ki-67评分进行了评估，该研究包括541例雌激素受体（ER）阳性和300例ER阴性复发病例及其非复发对照，根据ER状态、癌症分期、绝经状态、诊断年份和居住县进行匹配。我们使用逻辑回归来估计比值比及相关的95%置信区间，以确定Ki-67表达与复发风险之间的关联，并对匹配因素、化疗、手术类型、放疗接受情况、年龄类别和合并症进行了调整。
Ki-67与他莫昔芬治疗患者（校正比值比=0.72，95%置信区间0.54，0.96）或ER阴性患者（校正比值比=0.85，95%置信区间0.54，1.34）的复发风险增加无关。
我们的研究结果表明，TMA中Ki-67的数字图像分析与他莫昔芬治疗的ER阳性乳腺癌或ER阴性乳腺癌患者的复发风险增加无关。总体而言，我们的研究结果不支持Ki-67表达与复发风险增加相关。
