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Background: Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer., Methods: The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics., Results: A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99)., Conclusions: Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.

Hormone receptor status is an integral component of decision-making in breast cancer management. IHC4 score is an algorithm that combines hormone receptor, HER2, and Ki-67 status to provide a semiquantitative prognostic score for breast cancer. High accuracy and low interobserver variance are important to ensure the score is accurately calculated; however, few previous efforts have been made to measure or decrease interobserver variance. We developed a Web-based training tool, called "Score the Core" (STC) using tissue microarrays to train pathologists to visually score estrogen receptor (using the 300-point H score), progesterone receptor (percent positive), and Ki-67 (percent positive). STC used a reference score calculated from a reproducible manual counting method. Pathologists in the Athena Breast Health Network and pathology residents at associated institutions completed the exercise. By using STC, pathologists improved their estrogen receptor H score and progesterone receptor and Ki-67 proportion assessment and demonstrated a good correlation between pathologist and reference scores. In addition, we collected information about pathologist performance that allowed us to compare individual pathologists and measures of agreement. Pathologists' assessment of the proportion of positive cells was closer to the reference than their assessment of the relative intensity of positive cells. Careful training and assessment should be used to ensure the accuracy of breast biomarkers. This is particularly important as breast cancer diagnostics become increasingly quantitative and reproducible. Our training tool is a novel approach for pathologist training that can serve as an important component of ongoing quality assessment and can improve the accuracy of breast cancer prognostic biomarkers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: To establish the feasibility of a machine scoring method for her2/neu immunohistochemistry in samples of breast carcinoma., Study Design: A total of 65 consecutive cases of breast carcinoma with immunohistochemical stainingfor her2/neu by the Herceptest (Dako Corp., Carpinteria, California, U.S.A.) method (DAB chromogen with hematoxylin counterstain) were analyzed using an Extended Slide Wizard (Tripath Imaging, Inc., Burlington, North Carolina, U.S.A.) workstation running prototype software. Representative fields of view from the positive control, negative control and up to 10 fields from the stained tumor sample were captured interactively with a phased alternating line 3 CCD color camera. To determine the amount of specific membrane staining, chromogen separation of nuclear counterstain and membrane-positive stain was performed based on their respective absorption coefficients in the three color channels. The amount of specific membrane staining was scored based on a training set covering the rangefrom 0 to 3 + staining scores according to Dako. Manual scores of 2 + were tested for amplification by fluorescence in situ hybridization., Results: The automated scoring results correlated highly with the manual scores obtained per the Herceptest (Dako) instructions (R2>.92). The results were obtained in real time in the interactive mode., Conclusion: Machine scoring of immunohistochemical stains is practical, rapid and inherently reproducible, especially for samples with 1+ and 2+ manual scores.