Intra-tumoral distribution of Ki-67 and Cyclin D1 in ER+ mammary carcinoma: quantitative evaluation

Abstract

Background: In spite of the strong evidence demonstrating the role of overexpression of Ki-67 and Cyclin D1 markers in breast carcinomas, clinical and pathological data remain to be discussed. This can be explained partly by intratumor het- erogeneity. Objectives: To define the prevalence and clinical significance of Ki-67 and Cyclin D1 overexpression in primary breast tumors ER positive, while highlighting the existence of intratumor heterogeneity in this type of cancer. Materials and methods: 51 ER positive breast cancer tumors were used to evaluate the intratumoral distribution of Ki-67 and Cyclin D1 expression. Image acquisition and visualization of the markers were performed by optical microscopy and stereology sampling method. Results: The mean Ki-67 labeling index was distributed heterogeneously in the same tumor, from 20.67±6.87 to 45.10±10.65. The coefficient of variation (COV) revealed dispersion values between 13.4% and 42.9%. Associated with positive ER status, all the tumors presented a Cyclin D1 expression with a COV varying between 19% and 28.5% and a mean labeling index fluctuating between 19.40±4.42 and 41.64±10.08 within the same patient showing important intratumor heterogeneous distribution. Conclusion: In this study, we have adopted a strictly quantitative approach to evaluate and demonstrate intratumor hetero- geneity. This establishes one of the main factors for poor response to cancer therapy. To achieve this, intratumor heteroge- neity should be usually definable and quantifiable but this domain awaits future progress and methods need to move towards a better understanding of molecular and cellular mechanisms that initiate and maintain this tumor heterogeneity. Keywords: Breast cancer; Cyclin D1; ER+; Intra-tumoral heterogeneity; Ki-67.