“Score the Core” Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring

Engelberg, Jesse A.; Retallack, Hanna; Balassanian, Ronald; Dowsett, Mitchell; Zabaglo, Lila; Ram, Arishneel A.; Apple, Sophia K.; Bishop, John W.; Borowsky, Alexander D.; Carpenter, Philip M.; Chen, Yunn-Yi; Datnow, Brian; Elson, Sarah L.; Hasteh, Farnaz; Lin, Fritz; Moatamed, Neda A.; Zhang, Yanhong; Cardiff, Robert D.

doi:10.1016/j.humpath.2015.07.008

Cited by 15 publications

(15 citation statements)

References 26 publications

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“…There have been various harmonization efforts within laboratory medicine, including harmonization of cancer biomarkers by pathologists [31]. The University of California Athena Breast Health Network demonstrated variation between expert observers and concluded that technical and interpretive harmonization between expert observers is possible [32]. Another notable example is clinical sequence variant interpretation from the vast amounts of genome-scale sequencing.…”

Section: Discussionmentioning

confidence: 99%

Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement

Quinones¹,

Ritchie²,

Carpenter³

et al. 2019

Biology of Blood and Marrow Transplantation

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order, were area under the curve (AUC) in mM £ min, AUC in mg £ h/L, concentration at steady state (Css) in ng/ mL, AUC in mM £ h, and AUC in mg £ h/L. All respondents conceptually agreed on the ideal properties of a BPEU and to adopt a harmonized BPEU. Respondents were equally divided between selecting AUC in mM £ min versus mg £ h/L for harmonization. AUC in mg £ h/L was finally selected as the harmonized BPEU, because it satisfied most of the survey-determined ideal properties for the harmonized BPEU and is read easily understood in the clinical practice environment. Furthermore, 10 major professional societies have endorsed AUC in mg £ h/L as the harmonized unit for reporting to HCT registry databases and for use in future protocols and publications.

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Section: Discussionmentioning

confidence: 99%

Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement

Quinones¹,

Ritchie²,

Carpenter³

et al. 2019

Biology of Blood and Marrow Transplantation

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“…Ten pathologists (RB, JB, PC, YC, BD, FH, GK, FL, YZ, and AB) at the University of California with expertise in breast diagnostics, as a part of the ATHENA Breast Health network, scored (on whole-tumor sections with microscopes) the percentage of positive breast cancer cells for each ER intensity level (0, +1, +2, or + 3) compared with established standards, after completing an online training module developed to standardize the distinctions between intensity levels ( Supplementary Material , available online) ( 19 ). In addition, the pathologists scored the percentage of cancer cells positive for PR, HER2, and Ki-67, where a threshold of 10% or greater was used to define ER and PR receptor positivity, HER2 positivity was defined as intensity 3+ by immunohistochemistry, and the Ki-67 threshold for positivity was 15% or greater.…”

Section: Methodsmentioning

confidence: 99%

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer

Lindström

Yau

Czene

et al. 2018

JNCI: Journal of the National Cancer Institute

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BackgroundBreast 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.MethodsThe 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.ResultsA 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).ConclusionsPatients 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.

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“…Further, when dealing with IHC assays, there is often some degree of subjective inaccuracy. However, the clinical IHC markers in STO-3 were recently re-assessed at a single medical laboratory by dedicated breast cancer pathologists harmonized with regard to their IHC scoring of these breast cancer markers (27). Despite our relatively small study size with only 98 ER-positive patients classi ed with ultralow risk tumors, we were able to identify signi cant and informative differences between the analyzed groups.…”

Section: Discussionmentioning

confidence: 96%

Clinical and Molecular Characteristics of ER-Positive Breast Cancer Tumors Identified as Ultralow Risk by the 70-Gene Signature in a Randomized Clinical Trial

Johansson¹,

Yu²,

Iftimi³

et al. 2020

Preprint

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BackgroundBreast cancer tumors are heterogenous, including their metastatic potential and time to distant metastasis. Patients with estrogen receptor (ER)-positive tumors have a continuous long-term risk of fatal disease decades after diagnosis. Recently, ER-positive breast cancer patients classified as having ultralow risk tumors by the 70-gene expression signature (MammaPrint) were associated with a minimal risk of fatal disease. However, the underlying tumor characteristics of ultralow risk tumors are unknown.MethodsSecondary analysis of the Stockholm tamoxifen randomized trial (STO-3, 1976-1990) enrolling postmenopausal lymph node-negative breast cancer patients. Immunohistochemistry of the clinically used breast cancer markers (n=727 patients) and gene expression profiling by Agilent microarrays (n=652 patients) were performed in 2014. Ultralow risk tumors, identified by the 70-gene signature, were compared to other ER-positive tumors (of low/high risk) and Luminal A and B PAM50 subtype tumors (ER-positive, low/high risk) by the clinical markers and multi-gene modules, representative of specific biological processes and pathways, using Fisher’s exact test. Furthermore, differential gene expression analysis was performed contrasting ultralow risk tumors to other ER-positive tumors (of low/high risk) using t-statistics and false discovery rate (FDR).ResultsUltralow risk tumors were significantly (P<0.05) more likely to be of smaller tumor size, lower tumor grade, progesterone receptor (PR)-positive, human epidermal growth factor receptor 2 (HER2)-negative and Ki-67-low. Moreover, several multi-gene modules were significantly differentially expressed in ultralow risk tumors, including AKT/mTOR, proliferation-marker AURKA, HER2/ERBB2, IGF1, PTEN-loss, PI3KCA-mutations, and immune response-modules IMMUNE1 and STAT1. Furthermore, ultralow risk tumors showed significantly (FDR<0.001) lower expression of genes involved in the immune response, histone modulation, PI3K/Akt/mTOR pathway, and higher expression of homeobox genes and genes involved in epithelial-to-mesenchymal transition, among others.ConclusionsUltralow risk tumors have significantly different tumor characteristics compared to other ER-positive tumors. Identifying clinical and biological characteristics of low-risk tumors is important to improve our understanding of non-fatal versus fatal breast cancer.Trial registrationThe trial center for the STO-3 trial was the Regional Cancer Center Stockholm-Gotland in Sweden. However, the start of the trial in 1976 was well before trial registration started in Sweden, therefore information on trial number is not available.

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“Score the Core” Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring

Cited by 15 publications

References 26 publications

Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement

Harmonization of Busulfan Plasma Exposure Unit (BPEU): A Community-Initiated Consensus Statement

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer

Clinical and Molecular Characteristics of ER-Positive Breast Cancer Tumors Identified as Ultralow Risk by the 70-Gene Signature in a Randomized Clinical Trial

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