Neural Analyses Validate and Emphasize the Role of Progesterone Receptor in Breast Cancer Progression and Prognosis.

Oestrogen receptor (ER) expression is routinely measured in breast cancer management, but the clinical merits of measuring progesterone receptor (PR) expression have remained controversial. Hence the major objective of this study was to assess the potential of PR as a predictor of response to endocrine therapy. We report on analyses of the relative importance of ER and PR for predicting prognosis using robust multilayer perceptron artificial neural networks. Receptor determinations use immunohistochemical (IHC) methods or radioactive ligand binding assays (LBA). In view of the heterogeneity of intratumoral receptor distribution, we examined the relative merits of the IHC and LBA methods. Our analyses reveal a more significant correlation of IHC-determined PR than ER with both nodal status and 5-year disease-free survival (DFS). In LBA, PR displayed higher correlation with survival and ER with nodal status. There was concordance of correlation of PR with DFS by both IHC and LBA. This study suggests a clear distinction between PR and ER, with PR displaying greater correlation than ER with disease progression and prognosis, and emphasizes the marked superiority of the IHC method over LBA. These findings may be valuable in the management of patients with breast cancer.

[1]  M. Mukaka,et al.  Statistics corner: A guide to appropriate use of correlation coefficient in medical research. , 2012, Malawi medical journal : the journal of Medical Association of Malawi.

[2]  D. Rueckert,et al.  Prediction of stroke thrombolysis outcome using CT brain machine learning , 2014, NeuroImage: Clinical.

[3]  J. Bergh,et al.  Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen , 2011, Breast Cancer Research and Treatment.

[4]  G. Chenevix-Trench,et al.  Germ‐line mutations in BRCA1 or BRCA2 in the normal breast are associated with altered expression of estrogen‐responsive proteins and the predominance of progesterone receptor A , 2004, Genes, chromosomes & cancer.

[5]  G. V. Sherbet,et al.  Growth Factors and Their Receptors in Cell Differentiation, Cancer and Cancer Therapy , 2011 .

[6]  Predicting response to endocrine therapy in human breast cancer: a hypothesis. , 1976, Science.

[7]  S S Dlay,et al.  Oestrogen and progesterone receptor expression influences DNA ploidy and the proliferation potential of breast cancer cells. , 2003, Anticancer research.

[8]  Prabhat Panday,et al.  Decision Support System for Cardiovascular Heart Disease Diagnosis using Improved Multilayer Perceptron , 2012 .

[9]  Mårten Fernö,et al.  Comparison of Immunohistochemical and Biochemical Assay of Steroid Receptors in Primary Breast Cancer Clinical Associations and Reasons for Discrepancies , 2003, Acta oncologica.

[10]  Z. Hall.  Cancer , 1906, The Hospital.

[11]  C. Perou,et al.  Prognostic significance of progesterone receptor-positive tumor cells within immunohistochemically defined luminal A breast cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Mark D. Aupperlee,et al.  Progesterone receptor isoform functions in normal breast development and breast cancer. , 2008, Critical reviews in eukaryotic gene expression.

[13]  F. Monti,et al.  Prediction of nodal metastasis and prognosis of breast cancer by ANN-based assessment of tumour size and p53, Ki-67 and steroid receptor expression. , 2013, Anticancer research.

[14]  A. Nassar,et al.  Intratumoral Heterogeneity of Immunohistochemical Marker Expression in Breast Carcinoma: A Tissue Microarray-based Study , 2010, Applied immunohistochemistry & molecular morphology : AIMM.

[15]  E. Cho,et al.  Relationship between p53‐associated proteins and estrogen receptor status in ovarian serous neoplasms , 2006, International journal of gynecological cancer : official journal of the International Gynecological Cancer Society.

[16]  Andrea Rocca,et al.  Efficacy of endocrine therapy in relation to progesterone receptor and Ki67 expression in advanced breast cancer , 2015, Breast Cancer Research and Treatment.

[17]  K. Jirström,et al.  High Progesterone Receptor Expression Correlates to the Effect of Adjuvant Tamoxifen in Premenopausal Breast Cancer Patients , 2006, Clinical Cancer Research.

[18]  A. Thompson,et al.  Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study , 2013, British Journal of Cancer.

[19]  S. Hyakin,et al.  Neural Networks: A Comprehensive Foundation , 1994 .

[20]  J. Pollard,et al.  Progesterone inhibits the estrogen-induced phosphoinositide 3-kinase-->AKT-->GSK-3beta-->cyclin D1-->pRB pathway to block uterine epithelial cell proliferation. , 2005, Molecular endocrinology.

[21]  C K Osborne,et al.  Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  Keda Yu,et al.  Molecular essence and endocrine responsiveness of estrogen receptor-negative, progesterone receptor-positive, and HER2-negative breast cancer , 2015, BMC Medicine.

[23]  R. Schiff,et al.  Endocrine responsiveness: understanding how progesterone receptor can be used to select endocrine therapy. , 2005, Breast.

[24]  Ian H. Witten,et al.  The WEKA data mining software: an update , 2009, SKDD.

[25]  C. Osborne,et al.  Steroid hormone receptors in breast cancer management , 2004, Breast Cancer Research and Treatment.

[26]  S. Hilsenbeck,et al.  Progesterone Receptor Isoform-Specific Promoter Methylation: Association of PRA Promoter Methylation with Worse Outcome in Breast Cancer Patients , 2011, Clinical Cancer Research.

[27]  Susan G. Hilsenbeck,et al.  Breast Cancer Patients with Progesterone Receptor PR-A-Rich Tumors Have Poorer Disease-Free Survival Rates , 2004, Clinical Cancer Research.

[28]  Yingtao Jiang,et al.  A multilayer perceptron-based medical decision support system for heart disease diagnosis , 2006, Expert Syst. Appl..

[29]  Bohn Stafleu van Loghum,et al.  Online … , 2002, LOG IN.

[30]  D. Hinkle,et al.  Applied statistics for the behavioral sciences , 1979 .

[31]  Rachel Schiff,et al.  Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer. , 2003, Breast.

[32]  Y. Çelik,et al.  Prediction of mortality in stroke patients using multilayer perceptron neural networks , 2012, Turkish Journal of Medical Sciences.

[33]  S. Luoh,et al.  Quantitative Progesterone Receptor Expression and Efficacy of Anti‐estrogen Therapy in Breast Cancer , 2014, The breast journal.

[34]  M. Beato,et al.  Two Domains of the Progesterone Receptor Interact with the Estrogen Receptor and Are Required for Progesterone Activation of the c-Src/Erk Pathway in Mammalian Cells , 2003, Molecular and Cellular Biology.

[35]  Jack Cuzick,et al.  Relationship between quantitative estrogen and progesterone receptor expression and human epidermal growth factor receptor 2 (HER-2) status with recurrence in the Arimidex, Tamoxifen, Alone or in Combination trial. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[36]  S. Nass,et al.  The Loss of Estrogen and Progesterone Receptor Gene Expression in Human Breast Cancer , 2004, Journal of Mammary Gland Biology and Neoplasia.

[37]  D. Allred,et al.  Progesterone receptor by immunohistochemistry and clinical outcome in breast cancer: a validation study , 2004, Modern Pathology.