Comparison of Proliferation Markers Ki67 and Phosphohistone-H3 (pHH3) in Breast Ductal Carcinoma In Situ

Proliferative index is a prognostic feature of invasive ductal carcinoma of the breast, and has more recently emerged as a predictor of ductal carcinoma in situ (DCIS) local recurrence and progression when used in combination with other predictive markers. Ki67 is the most commonly used immunohistochemical marker of proliferative index. However, high interobserver and interlaboratory variability has been reported, in part due to differences in staining methodologies, positivity thresholds, and approaches to quantification. Phosphohistone-H3 (pHH3) is a marker of mitotic activity that has emerged as a more reliable indicator of proliferation in other neoplasms. Quantification of proliferative index was compared in 48 cases of DCIS using Ki67 and pHH3 immunohistochemistry. A strong linear relationship between Ki67 and pHH3 quantification was observed (P<0.0001, R2=0.75). Interobserver concordance was modestly higher for pHH3 than Ki67 proliferative indices. However, positive pHH3 staining was more dichotomous (either negative or uniformly positive) and specific for mitotic activity, and interpretation of pHH3 proliferative indices was significantly faster than that of Ki67. The strong correlation between pHH3 and Ki67 supports the use of this marker as a measure of proliferative activity in DCIS.

[1]  D. Garfield,et al.  Surgery time interval and molecular subtype may influence Ki67 change after core needle biopsy in breast cancer patients , 2015, BMC Cancer.

[2]  Parvez M Lokhandwala,et al.  Mitotic Count by Phosphohistone H3 Immunohistochemical Staining Predicts Survival and Improves Interobserver Reproducibility in Well-differentiated Neuroendocrine Tumors of the Pancreas , 2015, The American journal of surgical pathology.

[3]  John M S Bartlett,et al.  An international Ki67 reproducibility study. , 2013, Journal of the National Cancer Institute.

[4]  R. Shui,et al.  An Interobserver Reproducibility Analysis of Ki67 Visual Assessment in Breast Cancer , 2015, PloS one.

[5]  E. Rakovitch,et al.  HER2/neu and Ki-67 expression predict non-invasive recurrence following breast-conserving therapy for ductal carcinoma in situ , 2012, British Journal of Cancer.

[6]  H. Tsuda,et al.  Interobserver concordance of Ki67 labeling index in breast cancer: Japan Breast Cancer Research Group Ki67 Ring Study , 2013, Cancer science.

[7]  A. Shimo,et al.  Comparison between Ki67 labeling index determined using image analysis software with virtual slide system and that determined visually in breast cancer , 2016, Breast Cancer.

[8]  Xiaomin Lu,et al.  Interobserver variability of mitotic index and utility of PHH3 for risk stratification in gastrointestinal stromal tumors. , 2015, American journal of clinical pathology.

[9]  I. Ellis,et al.  Impact of tissue sampling on accuracy of Ki67 immunohistochemistry evaluation in breast cancer , 2016, Diagnostic Pathology.

[10]  D. Shen,et al.  The Utility of Phosphohistone H3 in Breast Cancer Grading , 2015, Applied immunohistochemistry & molecular morphology : AIMM.

[11]  John M S Bartlett,et al.  An international study to increase concordance in Ki67 scoring , 2015, Modern Pathology.

[12]  Š. Polák,et al.  Ki67, PCNA, and MCM proteins: Markers of proliferation in the diagnosis of breast cancer. , 2016, Acta histochemica.

[13]  M. Fernö,et al.  Immunohistochemical assessment of Ki67 with antibodies SP6 and MIB1 in primary breast cancer: a comparison of prognostic value and reproducibility , 2014, Histopathology.

[14]  Lik Hang Lee,et al.  Association Between Phosphorylated Histone H3 and Oncotype DX Recurrence Scores in Breast Cancer , 2016, Applied immunohistochemistry & molecular morphology : AIMM.

[15]  G. Shieh.  Choosing the best index for the average score intraclass correlation coefficient , 2016, Behavior research methods.

[16]  Rikke Riber-Hansen,et al.  Proliferation assessment in breast carcinomas using digital image analysis based on virtual Ki67/cytokeratin double staining , 2016, Breast Cancer Research and Treatment.

[17]  Jack Cuzick,et al.  Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. , 2011, Journal of the National Cancer Institute.

[18]  Distribution pattern of Ki67 immunoreactivity in ductal intraepithelial neoplasia: Correlation with lesion grade and potential utility. , 2016, Pathology, research and practice.

[19]  B. Nemesure,et al.  Her2 and Ki67 Biomarkers Predict Recurrence of Ductal Carcinoma in Situ , 2016, Applied immunohistochemistry & molecular morphology : AIMM.

[20]  Anais Malpica,et al.  Comparison of the effect of different techniques for measurement of Ki67 proliferation on reproducibility and prognosis prediction accuracy in breast cancer , 2012, Histopathology.

[21]  I. Ellis,et al.  Ki67/SATB1 ratio is an independent prognostic factor of overall survival in patients with early hormone receptor-positive invasive ductal breast carcinoma , 2015, Oncotarget.

[22]  Soldano Ferrone,et al.  Phosphorylated Histone H3 (PHH3) Is a Superior Proliferation Marker for Prognosis of Pancreatic Neuroendocrine Tumors , 2016, Annals of Surgical Oncology.

[23]  Naoki Kagawa,et al.  Prognostic value of Ki67 and p53 in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer: Validation of the cut-off value of the Ki67 labeling index as a predictive factor. , 2016, Molecular and clinical oncology.

[24]  M. Kurosumi,et al.  ER, PgR, Ki67, p27Kip1, and histological grade as predictors of pathological complete response in patients with HER2-positive breast cancer receiving neoadjuvant chemotherapy using taxanes followed by fluorouracil, epirubicin, and cyclophosphamide concomitant with trastuzumab , 2015, BMC Cancer.

[25]  A. Vincent-Salomon,et al.  High Ki67 expression is a risk marker of invasive relapse for classical lobular carcinoma in situ patients. , 2012, Breast.

[26]  A. Luini,et al.  Proposed new clinicopathological surrogate definitions of luminal A and luminal B (HER2-negative) intrinsic breast cancer subtypes , 2014, Breast Cancer Research.

[27]  Charles M. Perou,et al.  Ki67 Index, HER2 Status, and Prognosis of Patients With Luminal B Breast Cancer , 2009, Journal of the National Cancer Institute.

[28]  T. D’alfonso,et al.  Phosphohistone H3 expression correlates with manual mitotic counts and aids in identification of "hot spots" in fibroepithelial tumors of the breast. , 2016, Human pathology.