Validating the prognostic value of proliferation measured by Phosphohistone H3 (PPH3) in invasive lymph node-negative breast cancer patients less than 71 years of age

We validated and compared the prognostic value of the proliferation marker phosphohistone H3 (PPH3) with classical variables in 241 T1–2N0M0 breast cancer patients less than 71 years old with long-term follow-up (median 117 months) and without adjuvant treatment. PPH3 was measured by automated digital image analysis. Thirty-seven patients (15%) developed distant metastases and 29 (12%) died. The previously established PPH3 prognostic threshold H3 <13 (n = 157; 65% of all cases) vs. ≥13 (n = 84; 35% of all cases) was the strongest prognostic threshold exceeding all other characteristics, with 10-year recurrence-free survival of distant metastases of 96 and 64%, respectively (P =  < 0.0001, hazard ratio = 7.8, 95% confidence interval = 3.4–17.9). PPH3 is robust as it showed high inter-observer reproducibility and was prognostic over wide range of thresholds around 13 and is the strongest prognostic variable in invasive node-negative breast cancer patients less than 71 years old.

[1]  J A Beliën,et al.  Counting mitoses by image processing in Feulgen stained breast cancer sections: the influence of resolution. , 1997, Cytometry.

[2]  A. Jarry,et al.  Phosphohistone H3 labelling for histoprognostic grading of breast adenocarcinomas and computer-assisted determination of mitotic index , 2006, Journal of Clinical Pathology.

[3]  Peter Devilee,et al.  Pathology and Genetics of Tumours of the Breast and Female Genital Organs , 2003 .

[4]  J. Baak,et al.  Prognostic value of proliferation in invasive breast cancer: a review , 2004, Journal of Clinical Pathology.

[5]  A. Smeulders,et al.  Image processing for mitoses in sections of breast cancer: a feasibility study. , 1984, Cytometry.

[6]  Urs Eppenberger,et al.  Low E2F1 transcript levels are a strong determinant of favorable breast cancer outcome , 2007, Breast Cancer Research.

[7]  P. V. van Diest,et al.  Prognostic differences of World Health Organization-assessed mitotic activity index and mitotic impression by quick scanning in invasive ductal breast cancer patients younger than 55 years. , 2008, Human pathology.

[8]  J. Baak,et al.  Phosphohistone H3 expression has much stronger prognostic value than classical prognosticators in invasive lymph node-negative breast cancer patients less than 55 years of age , 2007, Modern Pathology.

[9]  M. J. van de Vijver,et al.  Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. , 2006, Journal of the National Cancer Institute.

[10]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[11]  P. V. van Diest,et al.  The prognostic value of proliferation in lymph-node-negative breast cancer patients is age dependent. , 2007, European journal of cancer.

[12]  F. Shammas,et al.  Bone marrow cytokeratin 19 mRNA level is an independent predictor of relapse-free survival in operable breast cancer patients , 2008, Breast Cancer Research and Treatment.

[13]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. , 2002, Histopathology.

[14]  J. Baak,et al.  Proliferation accurately identifies the high-risk patients among small, low-grade, lymph node-negative invasive breast cancers. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[15]  Catherine Legrand 1687Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials : Early Breast Cancer Trialists' Collaborative Group (EBCTCG) , 2005 .

[16]  L. V. van't Veer,et al.  Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer. , 2006, Journal of the National Cancer Institute.

[17]  I. Ellis,et al.  Pathological prognostic factors in breast cancer. , 1999, Critical reviews in oncology/hematology.

[18]  Yudong D. He,et al.  A cell proliferation signature is a marker of extremely poor outcome in a subpopulation of breast cancer patients. , 2005, Cancer research.

[19]  Thomas J. Smith,et al.  Review: chemotherapy and hormonal therapy reduce recurrence and mortality at 15 years in early breast cancer , 2005, ACP journal club.

[20]  P. V. van Diest,et al.  Prospective multicenter validation of the independent prognostic value of the mitotic activity index in lymph node-negative breast cancer patients younger than 55 years. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  De Jong,et al.  Hot spot microvessel density and the mitotic activity index are strong additional prognostic indicators in invasive breast cancer , 2000, Histopathology.

[22]  J. Xie,et al.  Signal transducer and activator of transcription-5 activation and breast cancer prognosis. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.