The Ki-67 antigen is used to evaluate the proliferative activity of breast cancer (BC); however, Ki-67's role as a prognostic marker in BC is still undefined. In order to better define the prognostic value of Ki-67/MIB-1, we performed a meta-analysis of studies that evaluated the impact of Ki-67/MIB-1 on disease-free survival (DFS) and/or on overall survival (OS) in early BC. Sixty-eight studies were identified and 46 studies including 12 155 patients were evaluable for our meta-analysis; 38 studies were evaluable for the aggregation of results for DFS, and 35 studies for OS. Patients were considered to present positive tumours for the expression of Ki-67/MIB-1 according to the cut-off points defined by the authors. Ki-67/MIB-1 positivity is associated with higher probability of relapse in all patients (HR=1.93 (95% confidence interval (CI): 1.74-2.14); P<0.001), in node-negative patients (HR=2.31 (95% CI: 1.83-2.92); P<0.001) and in node-positive patients (HR=1.59 (95% CI: 1.35-1.87); P<0.001). Furthermore, Ki-67/MIB-1 positivity is associated with worse survival in all patients (HR=1.95 (95% CI: 1.70-2.24; P<0.001)), node-negative patients (HR=2.54 (95% CI: 1.65-3.91); P<0.001) and node-positive patients (HR=2.33 (95% CI: 1.83-2.95); P<0.001). Our meta-analysis suggests that Ki-67/MIB-1 positivity confers a higher risk of relapse and a worse survival in patients with early BC.

/pdf/ki-67-as-prognostic-marker-in-early-breast-cancer-a-meta-3k1r2ewqr8.pdf

Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12,155 patients.

Molecular markers have been extensively investigated with a view to providing early and accurate information on long-term outcome and prediction of response to treatment of early breast cancer Proliferation is a key feature of the progression of tumors and is now widely estimated by the immunohistochemical assessment of the nuclear antigen Ki-67 The expression of Ki-67 correlates with other measurements of proliferation, including S-phase and bromodeoxyuridine uptake High Ki-67 is a sign of poor prognosis associated with a good chance of clinical response to chemotherapy, but its independent significance is modest and does not merit measurements in most routine clinical scenarios However, its application as a pharmacodynamic intermediate marker of the effectiveness of medical therapy holds great promise for rapid evaluation of new drugs

Proliferation Marker Ki-67 in Early Breast Cancer

The antigen defined by mAb Ki-67 is a human nuclear protein the expression of which is strictly associated with cell proliferation and which is widely used in routine pathology as a "proliferation marker" to measure the growth fraction of cells in human tumors. Ki-67 detects a double band with apparent molecular weights of 395 and 345 kD in immunoblots of proteins from proliferating cells. We cloned and sequenced the full length cDNA, identified two differentially spliced isoforms of mRNA with open reading frames of 9,768 and 8,688 bp encoding for this cell proliferation-associated protein with calculated molecular weights of 358,761 D and 319,508 D, respectively. New mAbs against a bacterially expressed part and a synthetic polypeptide deduced from the isolated cDNA react with the native Ki-67 antigen, thus providing a circle of evidence that we have cloned the authentic Ki-67 antigen cDNA. The central part of the Ki-67 antigen cDNA contains a large 6,845-bp exon with 16 tandemly repeated 366-bp elements, the "Ki-67 repeats", each including a highly conserved new motif of 66 bp, the "Ki-67 motif", which encodes for the epitope detected by Ki-67. Computer analysis of the nucleic acid and the deduced amino acid sequence of the Ki-67 antigen confirmed that the cDNA encodes for a nuclear and short-lived protein without any significant homology to known sequences. Ki-67 antigen-specific antisense oligonucleotides inhibit the proliferation of IM-9 cell line cells, indicating that the Ki-67 antigen may be an absolute requirement for maintaining cell proliferation. We conclude that the Ki-67 antigen defines a new category of cell cycle-associated nuclear nonhistone proteins.

/pdf/the-cell-proliferation-associated-antigen-of-antibody-ki-67-2026v6jgrr.pdf

The cell proliferation-associated antigen of antibody Ki-67: a very large, ubiquitous nuclear protein with numerous repeated elements, representing a new kind of cell cycle-maintaining proteins.

Although histologically benign, one-third of all pituitary tumors will be invasive of surrounding structures. In this study, the relationship between the proliferative activity in pituitary adenomas and their invasiveness was investigated. Invasion was defined as gross, operatively or radiologically apparent infiltration of dura or bone. Using the recently developed MIB-1 monoclonal antibody, which recognizes the Ki-67 cell cycle-specific nuclear antigen, the growth fractions of 37 noninvasive adenomas, 33 invasive adenomas, and 7 primary pituitary carcinomas were determined. All tumors were fully classified by histology, immunohistochemistry, and electron microscopy. The mean Ki-67 -derived growth fractions for noninvasive adenomas, invasive adenomas, and pituitary carcinomas were 1.37 +/- 0.15%, 4.66 +/- 0.57%, and 11.91 +/- 3.41%, respectively (mean +/- standard error of the mean). An analysis of variance and then individual pairwise comparisons confirmed significant differences in the mean Ki-67 labeling index between each of the three tumor groups (P < 0.01). The mean growth fraction of hormonally active pituitary adenomas (3.25 +/- 0.26%) was significantly higher than that for nonfunctioning adenomas (2.06 +/- 0.23%) (P = 0.03). Establishing a threshold labeling index of 3% served to distinguish invasive from noninvasive adenomas with 97% specificity and 73% sensitivity and was associated with positive and negative predictive values of 96 and 80%, respectively. Although invasive pituitary tumors exhibited significantly higher growth fractions than did noninvasive tumors, there were individual exceptions, indicating that in a subpopulation of invasive pituitary tumors, factors other than proliferative activity determine invasive potential.

Proliferative Activity and Invasiveness among Pituitary Adenomas and Carcinomas: An Analysis Using the MIB-1 Antibody

In recent years the discovery of cancer biomarkers has become a major focus of cancer research. The widespread use of prostate-specific antigen in prostate cancer screening has motivated researchers to identify suitable markers for screening different types of cancer. Biomarkers are also useful for diagnosis, monitoring disease progression, predicting disease recurrence and therapeutic treatment efficacy. With the advent of new and improved genomic and proteomic technologies such as DNA and tissue microarray, two-dimensional gel eletrophoresis, mass spectrometry and protein assays coupled with advanced bioinformatic tools, it is possible to develop biomarkers that are able to reliably and accurately predict outcomes during cancer management and treatment. In years to come, a serum or urine test for every phase of cancer may drive clinical decision making, supplementing or replacing currently existing invasive techniques.

Cancer biomarkers: knowing the present and predicting the future.

Ki-67 labeling was quantified in 37 nonmalignant breast tissues and in 63 breast carcinomas by counting ten random high-power fields each in three section planes (RC) or by evaluation of the area with the highest labeling density (HDC). Both procedures proved to be highly correlated (rs = 0.94). Ki-67-positive fractions of the nonmalignant tissues (mean, 2.1% for RC and 4.1% for HDC) were significantly lower as compared with the carcinomas (mean, 14.5% for RC and 17.5% for HDC). In carcinomas the Ki-67 labeling was significantly associated with pT stage, axillary lymph node status, and tumor grading and inversely related to progesterone receptor status. Using the medians of both counting methods (12% for RC and 17% for HDC) as cutoff points, significantly different curves for overall and disease-free survival (median follow-up, 37 months) were obtained. However, Cox multivariate analysis failed to demonstrate an independent effect of Ki-67 labeling. In contrast, Ki-67 reactivity seems to be of independent prognostic value if a higher cutoff level was selected.

Ki-67 immunostaining in human breast tumors and its relationship to prognosis.

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Ki-67 immunostaining in human breast tumors and its relationship to prognosis.