Publications by authors named "Rachel E Factor"

43 Publications

Spatially-resolved quantification of proteins in triple negative breast cancers reveals differences in the immune microenvironment associated with prognosis.

Sci Rep 2020 04 20;10(1):6598. Epub 2020 Apr 20.

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.

Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype. Recent studies have shown that MHC class II (MHCII) expression and tumor infiltrating lymphocytes are important prognostic factors in patients with TNBC, although the relative importance of lymphocyte subsets and associated protein expression is incompletely understood. NanoString Digital Spatial Profiling (DSP) allows for spatially resolved, highly multiplexed quantification of proteins in clinical samples. In this study, we sought to determine if DSP could be used to characterize expression of MHCII and other immune related proteins in tumor epithelial versus stromal compartments of patient-derived TNBCs (N = 10) using a panel of 39 markers. We confirmed that a subset of TNBCs have elevated expression of HLA-DR in tumor epithelial cells; HLA-DR expression was also significantly higher in the tumors of patients with long-term disease-free survival when compared to patients that relapsed. HLA-DR expression in the epithelial compartment was correlated with high expression of CD4 and ICOS in the stromal compartment of the same tumors. We also identified candidate protein biomarkers with significant differential expression between patients that relapsed versus those that did not. In conclusion, DSP is a powerful method that allows for quantification of proteins in the immune microenvironment of TNBCs.
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http://dx.doi.org/10.1038/s41598-020-63539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7170957PMC
April 2020

A Multigene Assay Determines Risk of Recurrence in Patients with Triple-Negative Breast Cancer.

Cancer Res 2019 07 2;79(13):3466-3478. Epub 2019 May 2.

Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Approximately 40% of patients with stage I-III triple-negative breast cancer (TNBC) recur after standard treatment, whereas the remaining 60% experience long-term disease-free survival (DFS). There are currently no clinical tests to assess the risk of recurrence in TNBC patients. We previously determined that TNBC patients with MHC class II (MHCII) pathway expression in their tumors experienced significantly longer DFS. To translate this discovery into a clinical test, we developed an MHCII Immune Activation assay, which measures expression of 36 genes using NanoString technology. Preanalytical testing confirmed that the assay is accurate and reproducible in formalin-fixed paraffin-embedded (FFPE) tumor specimens. The assay measurements were concordant with RNA-seq, MHCII protein expression, and tumor-infiltrating lymphocyte counts. In a training set of 44 primary TNBC tumors, the MHCII Immune Activation Score was significantly associated with longer DFS (HR = 0.17; = 0.015). In an independent validation cohort of 56 primary FFPE TNBC tumors, the Immune Activation Score was significantly associated with longer DFS (HR = 0.19; = 0.011) independent of clinical stage. An Immune Activation Score threshold for identifying patients with very low risk of relapse in the training set provided 100% specificity in the validation cohort. The assay format enables adoption as a standardized clinical prognostic test for identifying TNBC patients with a low risk of recurrence. Correlative data support future studies to determine if the assay can identify patients in whom chemotherapy can be safely deescalated and patients likely to respond to immunotherapy. SIGNIFICANCE: The MHCII Immune Activation assay identifies TNBC patients with a low risk of recurrence, addressing a critical need for prognostic biomarker tests that enable precision medicine for TNBC patients.
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http://dx.doi.org/10.1158/0008-5472.CAN-18-3014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6629024PMC
July 2019

The FDA-Approved Breast Cancer HER2 Evaluation Kit (HercepTest; Dako) May Miss Some HER2-Positive Breast Cancers.

Am J Clin Pathol 2019 04;151(5):504-510

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA.

Objectives: Accurate evaluation of human epidermal growth factor receptor 2 (HER2) in breast cancer is critical.

Methods: HER2 fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) tests were performed on 52 cases using a US Food and Drug Administration (FDA)-approved kit (HercepTest, FDA kit) and a laboratory-developed test (LDT) with the HercepTest antibody and a Leica Bond automated stainer.

Results: By FISH, 22 were HER2 positive, 29 were negative, and one was equivocal. Of the 22 HER2 FISH-positive cases, five were negative by the FDA kit and none by LDT. The five discrepant cases were retested using the same FDA kit in another Clinical Laboratory Improvement Amendments-certified laboratory, and all five cases were still negative. None of the 29 HER2 FISH-negative cases were positive by the FDA kit or LDT. The overall IHC-FISH concordance rate was 90.4% for the FDA kit and 100% for the LDT.

Conclusions: The FDA kit may miss some HER2-positive cases. The LDT has a higher sensitivity and a higher concordance rate with FISH results.
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http://dx.doi.org/10.1093/ajcp/aqy171DOI Listing
April 2019

What Does it Mean for a Recommendation to be Evidence-Based?

Lab Med 2019 01;50(1):5-7

Department of Pathology and ARUP Laboratories, University of Utah Health Sciences Center, Salt Lake City.

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http://dx.doi.org/10.1093/labmed/lmy071DOI Listing
January 2019

Differences in molecular features of triple-negative breast cancers based on the age at diagnosis.

Cancer 2018 12 12;124(24):4676-4684. Epub 2018 Oct 12.

Division of Epidemiology, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.

Background: Although the proportion of triple-negative breast cancers (TNBCs) diagnosed among older women is low, the number of TNBC cases is substantial because of the high incidence of breast cancer after the age of 65 years. The molecular features of TNBC in this age group have not been well described.

Methods: This study examined a population-based cohort of women with stage I to III TNBC diagnosed between the ages of 25 and 91 years with the PAM50 gene expression subtyping assay. The concordance between the TNBC classification by immunohistochemistry and the gene expression classification by PAM50, the expression of individual genes, and 5-year recurrence and breast cancer mortality in older women (≥65 years old) and younger women (<50 years old) was assessed.

Results: The molecular subtype distribution in TNBC was significantly different according to the age at diagnosis. TNBC was more likely to be classified as basal-like in women younger than 50 years (sensitivity, 0.91; 95% confidence interval, 0.77-0.97) than women 65 years old or older (sensitivity, 0.72; 95% confidence interval, 0.48-0.87); 35% of clinical TNBC cases in the latter group were the human epidermal growth factor receptor 2 (HER2)-enriched subtype by molecular classification. Older women with TNBC also had significantly higher expression of ERBB2 and lower expression of all 10 proliferation-associated genes tested (P < .01). The risk of breast cancer death within 5 years was significantly higher in women with TNBC in comparison with women with hormone receptor-positive cancers in all age groups.

Conclusions: This study revealed differences in molecular subtypes among clinical TNBC cases based on patient age. A potentially targetable HER2-enriched group raises the possible need for intrinsic subtyping in older women with TNBC.
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http://dx.doi.org/10.1002/cncr.31776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294689PMC
December 2018

Rapid On-Site Evaluation of Fine-Needle Aspiration by Non-Cytopathologists: A Systematic Review and Meta-Analysis of Diagnostic Accuracy Studies for Adequacy Assessment.

Acta Cytol 2018 6;62(4):244-252. Epub 2018 Jun 6.

Department of Pathology and ARUP Laboratories, University of Utah, Salt Lake City, Utah, USA.

Objective: Rapid on-site evaluation (ROSE) has been shown to improve adequacy rates and reduce needle passes. ROSE is often performed by cytopathologists who have limited availability and may be costlier than alternatives. Several recent studies examined the use of alternative evaluators (AEs) for ROSE. A summary of this information could help inform guidelines regarding the use of AEs. The objective was to assess the accuracy of AEs compared to cytopathologists in assessing the adequacy of specimens during ROSE.

Study Design: This was a systematic review and meta-analysis. Reporting and study quality were assessed using the STARD guidelines and QUADAS-2. All steps were performed independently by two evaluators. Summary estimates were obtained using the hierarchal method in Stata v14. Heterogeneity was evaluated using Higgins' I2 statistic.

Results: The systematic review identified 13 studies that were included in the meta-analysis. Summary estimates of sensitivity and specificity for AEs were 97% (95% CI: 92-99%) and 83% (95% CI: 68-92%). There was wide variation in accuracy statistics between studies (I2 = 0.99).

Conclusions: AEs sometimes have accuracy that is close to cytopathologists. However, there is wide variability between studies, so it is not possible to provide a broad guideline regarding the use of AEs.
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http://dx.doi.org/10.1159/000489550DOI Listing
August 2018

Evaluation of the SharkCore needle for EUS-guided core biopsy of pancreatic neuroendocrine tumors.

Endosc Ultrasound 2018 Sep-Oct;7(5):323-328

Division of Gastroenterology, School of Medicine, University of Utah, Salt Lake City, UT, USA.

Background And Objectives: EUS guided core biopsy was once rarely performed but is now entering mainstream practice. Neuroendocrine tumors often warrant core biopsy as sufficient tissue must be obtained to allow for special staining to ensure a correct diagnosis. Traditionally these lesions were sampled with FNA needles. We performed a retrospective pilot study to evaluate the clinical value and efficacy of the a new EUS core needle biopsy needle as compared to a standard EUS FNA needle in the evaluation of patients with known or suspected neuroendocrine tumors.

Methods: A retrospective analysis of the first 10 patients (between January 2015 and April 2016) to undergo EUS-FNA with the SharkCore needle at the University of Utah School of Medicine/Huntsman Cancer Center with neuroendocrine tumors. Each case was retrospectively reviewed by a board certified cytopathologist (BLW) for the following cytologic parameters on the aspirate smears or touch/squash preparations: overall cellularity [1 (low) to 3 (high)], percentage of obtained cells that were lesional/representative (<25%, 26%-50%, and >50%), relative ease of interpretation [1 (difficult) to 3 (easy)]. Pathologic material and reporting records were also reviewed for each case to confirm the number of needle passes to achieve diagnostic adequacy, the presence or absence diagnostic material on H&E slide (from cell block, if prepared), whether a definitive diagnosis was able to be rendered, and the presence or absence of a true core/core fragments (within the cell block, if prepared).

Results: A total of 20 patients underwent EUS-FNA for suspected neuroendocrine lesions. Ten patients underwent either transgastric or transduodenal EUS-FNA with the 22 gauge SharkCore needle. The comparison cohort of 10 patients underwent either transgastric or transduodenal EUS-FNA with the standard 22 gauge Echotip needle. The SharkCore needle required a fewer mean number of needle passes to obtain diagnostic adequacy than the Echotip (P=0.0074). For cases with cell blocks, the SharkCore needle produced diagnostic material in 100% of cases, whereas Echotip produced diagnostic material in 60% of cases. There was no significant difference between specimen cellularity, percentage of lesional material, or ease of interpretation between the two needle types.

Conclusion: Our pilot investigation targeting patients with known or suspected pancreatic NETs indicates that the SharkCore needle shows promise in obtaining suitable tissue for ancillary testing that can allow for more definitive pathologic interpretations on EUS FNA specimens. Fewer passes were needed with the core needle when compared to a standard needle.
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http://dx.doi.org/10.4103/eus.eus_51_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199904PMC
April 2018

Publisher Correction: Combating subclonal evolution of resistant cancer phenotypes.

Nat Commun 2018 02 5;9(1):572. Epub 2018 Feb 5.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, UT, 84112, USA.

The originally published version of this Article contained an error in Figure 4. In panel a, grey boxes surrounding the subclones associated with patients #2 and #4 obscured adjacent portions of the heatmap. This error has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41467-017-02383-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5799176PMC
February 2018

BRCA1 through Its E3 Ligase Activity Regulates the Transcription Factor Oct1 and Carbohydrate Metabolism.

Mol Cancer Res 2018 03 12;16(3):439-452. Epub 2018 Jan 12.

Department of Pathology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.

The tumor suppressor BRCA1 regulates the DNA damage response (DDR) and other processes that remain incompletely defined. Among these, BRCA1 heterodimerizes with BARD1 to ubiquitylate targets via its N-terminal E3 ligase activity. Here, it is demonstrated that BRCA1 promotes oxidative metabolism by degrading Oct1 (POU2F1), a transcription factor with proglycolytic and tumorigenic effects. BRCA1 E3 ubiquitin ligase mutation skews cells toward a glycolytic metabolic profile while elevating Oct1 protein. CRISPR-mediated Oct1 deletion reverts the glycolytic phenotype. RNA sequencing (RNAseq) confirms deregulation of metabolic genes downstream of Oct1. BRCA1 mediates Oct1 ubiquitylation and degradation, and mutation of two ubiquitylated Oct1 lysines insulates the protein against BRCA1-mediated destabilization. Oct1 deletion in MCF-7 breast cancer cells does not perturb growth in standard culture, but inhibits growth in soft agar and xenograft assays. In primary breast cancer clinical specimens, Oct1 protein levels correlate positively with tumor aggressiveness and inversely with BRCA1. These results identify BRCA1 as an Oct1 ubiquitin ligase that catalyzes Oct1 degradation to promote oxidative metabolism and restrict tumorigenicity. .
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http://dx.doi.org/10.1158/1541-7786.MCR-17-0364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835178PMC
March 2018

Combating subclonal evolution of resistant cancer phenotypes.

Nat Commun 2017 11 1;8(1):1231. Epub 2017 Nov 1.

Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, UT, 84112, USA.

Metastatic breast cancer remains challenging to treat, and most patients ultimately progress on therapy. This acquired drug resistance is largely due to drug-refractory sub-populations (subclones) within heterogeneous tumors. Here, we track the genetic and phenotypic subclonal evolution of four breast cancers through years of treatment to better understand how breast cancers become drug-resistant. Recurrently appearing post-chemotherapy mutations are rare. However, bulk and single-cell RNA sequencing reveal acquisition of malignant phenotypes after treatment, including enhanced mesenchymal and growth factor signaling, which may promote drug resistance, and decreased antigen presentation and TNF-α signaling, which may enable immune system avoidance. Some of these phenotypes pre-exist in pre-treatment subclones that become dominant after chemotherapy, indicating selection for resistance phenotypes. Post-chemotherapy cancer cells are effectively treated with drugs targeting acquired phenotypes. These findings highlight cancer's ability to evolve phenotypically and suggest a phenotype-targeted treatment strategy that adapts to cancer as it evolves.
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http://dx.doi.org/10.1038/s41467-017-01174-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5666005PMC
November 2017

HER2 immunohistochemical and fluorescence in situ hybridization discordances in invasive breast carcinoma with micropapillary features.

Mod Pathol 2017 11 28;30(11):1561-1566. Epub 2017 Jul 28.

Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA.

The 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) recommendations for HER2 testing contain a recommendation for pathologists with respect to invasive micropapillary carcinoma. The guidelines suggest that HER2 immunohistochemical staining that is intense but incomplete and would be considered 1+ may actually be HER2-amplified by fluorescence in situ hybridization. Thus, pathologists should consider reporting the immunohistochemistry as equivocal (2+) and employ an alternative testing methodology. This recommendation is based largely on one paper wherein the authors tested a series of 22 micropapillary carcinomas that were considered 1+ by immunohistochemistry and identified HER2 amplification in one case (5%). In order to assess for a possible discordance between HER2 immunohistochemistry and fluorescence in situ hybridization, we evaluated a series of invasive carcinomas with micropapillary features using both methodologies. As described by the WHO, invasive carcinomas with micropapillary features have small, hollow, or morula-like clusters of cells surrounded by clear stromal spaces. All cases had HER2 immunohistochemistry and fluorescence in situ hybridization performed, and for cases with equivocal fluorescence in situ hybridization results, an alternative Chromosome 17 probe (RAI1) was employed. All assays were scored according to the 2013 ASCO/CAP guidelines. Specifically for this study, immunohistochemistry was scored irrespective of the presence of micropapillary features. Overall, we identified HER2 amplification in 21 (47%) of the cases assayed, with the corresponding immunohistochemistry being 1+ (n=9), 2+ (n=11), and 3+ (n=1). The ASCO/CAP recommendation that this morphology may deviate from the typical staining pattern is highlighted, as we found that 43% of cases with micropapillary features and HER2 staining that would otherwise be scored as 1+ were HER2-amplified by fluorescence in situ hybridization. This study supports the ASCO/CAP recommendation that pathologists should consider reporting immunohistochemistry in this morphology as equivocal and perform reflex testing using in situ hybridization.
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http://dx.doi.org/10.1038/modpathol.2017.65DOI Listing
November 2017

Window-of-Opportunity Study of Valproic Acid in Breast Cancer Testing a Gene Expression Biomarker.

JCO Precis Oncol 2017 7;1. Epub 2017 Apr 7.

, , , , , , , , and , University of Utah; , , , , and , Huntsman Cancer Institute, Salt Lake City; , Brigham Young University, Provo, UT; , University of Arizona, Tucson, AZ; and , Advanced Imaging Research Center, Portland, OR.

Purpose: The anticancer activity of valproic acid (VPA) is attributed to the inhibition of histone deacetylase. We previously published the genomically derived sensitivity signature for VPA (GDSS-VPA), a gene expression biomarker that predicts breast cancer sensitivity to VPA in vitro and in vivo. We conducted a window-of-opportunity study that examined the tolerability of VPA and the ability of the GDSS-VPA to predict biologic changes in breast tumors after treatment with VPA.

Patients And Methods: Eligible women had untreated breast cancer with breast tumors larger than 1.5 cm. After a biopsy, women were given VPA for 7 to 12 days, increasing from 30 mg/kg/d orally divided into two doses per day to a maximum of 50 mg/kg/d. After VPA treatment, serum VPA level was measured and then breast surgery or biopsy was performed. Tumor proliferation was assessed by using Ki-67 immunohistochemistry. Histone acetylation of peripheral blood mononuclear cells was assessed by Western blot. Dynamic contrast-enhanced magnetic resonance imaging scans were performed before and after VPA treatment.

Results: Thirty women were evaluable. The median age was 54 years (range, 31-73 years). Fifty-two percent of women tolerated VPA at 50 mg/kg/d, but 10% missed more than two doses as a result of adverse events. Grade 3 adverse events included vomiting and diarrhea (one patient) and fatigue (one patient). The end serum VPA level correlated with a change in histone acetylation of peripheral blood mononuclear cells (ρ = 0.451; = .024). Fifty percent of women (three of six) with triple-negative breast cancer had a Ki-67 reduction of at least 10% compared with 17% of other women. Women whose tumors had higher GDSS-VPA were more likely to have a Ki-67 decrease of at least 10% (area under the curve, 0.66).

Conclusion: VPA was well tolerated and there was a significant correlation between serum VPA levels and histone acetylation. VPA treatment caused a decrease in proliferation of breast tumors. The genomic biomarker correlated with decreased proliferation. Inhibition of histone deacetylase is a valid strategy for drug development in triple-negative breast cancer using gene expression biomarkers.
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http://dx.doi.org/10.1200/PO.16.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446454PMC
April 2017

X-Ray of Excised Cancerous Breast Tissue Does Not Affect Clinical Biomarker Expression.

Appl Immunohistochem Mol Morphol 2018 08;26(7):501-508

Departments of Pathology.

Context: College of American Pathologists (CAP) and the American Society of Clinical Oncology have emphasized the need to reduce preanalytic variables for evaluating predictive biomarker expression in breast cancer. Postoperative x-ray of excised breast tissue is commonplace, yet is a variable that has not been investigated previously. We asked whether such radiation affects expression of relevant biomarkers.

Design: A previous study found that human breast cancers grown in mice demonstrate the same immunohistochemical and molecular profiles as the original tumors. Thirteen patient-derived xenografts were harvested fresh and divided for specimen radiography and a matched nonirradiated control, while following CAP/ASCO guidelines for cold ischemia time and fixation. Samples were processed in a tissue microarray for immunohistochemistry. Estrogen receptor (ER), progesterone receptor (PR), p53, and Ki67 staining was evaluated using an optimized scoring algorithm performed on digitally scanned slides. Samples were also scored manually by a blinded pathologist using the H-score method, and HER2 by the CAP/ASCO 2013 protocol. Histologic scores were compared by analysis of variance.

Results: There was no significant difference in quantity or intensity of staining between irradiated and nonirradiated samples for estrogen receptor (P=0.28), p53 (P=0.96), and Ki67 (P=0.94). A small but statistically significant difference was observed for PR (P=0.0058). HER2 staining was similarly unchanged in the 1 tumor exhibiting 3+ staining.

Conclusions: Our study demonstrates that x-ray of breast carcinomas does not significantly affect the expression of predictive biomarkers, with the exception of PR for unclear reasons. It also highlights the utility of the patient-derived xenograft model for biomarker studies.
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http://dx.doi.org/10.1097/PAI.0000000000000454DOI Listing
August 2018

An unexpected diagnosis of ectopic liver diagnosed by fine needle aspiration.

Cytojournal 2016 20;13:29. Epub 2016 Dec 20.

Address: Department of Pathology, University of Utah, Salt Lake City, Utah, USA.

The differential diagnosis of perigastric masses is broad, ranging from benign to malignant entities. Among the benign entities, accessory liver lobes and ectopic liver are unusual and often incidentally discovered. Here, we report a patient with malignant melanoma who was clinically suspected to have a perigastric metastasis or a gastrointestinal stromal tumor but was ultimately diagnosed by fine needle aspiration (FNA) to have benign ectopic liver. A 47-year-old male was diagnosed with malignant melanoma of the scalp in May 2015 at a tertiary care hospital. He was found to have a 2.6 cm enhancing mass adjacent to the fundus of the stomach and below the diaphragm by computed tomography imaging. To exclude metastasis, the patient was referred to endoscopy, and an endoscopic ultrasound-guided FNA was performed with rapid on-site evaluation (ROSE) by a cytopathologist. A relatively new FNA needle (Shark Core) was used, which produced useful core biopsy material. Cytopathology demonstrated flat sheets, single cells, and small clusters of polygonal cells. There was abundant granular cytoplasm, often containing pigment. Cells lacked pleomorphism. The smear findings appeared consistent with hepatocytes. The cell block demonstrated small core fragments of hepatic parenchyma with portal tracts. Immunohistochemistry for arginase-1 confirmed that this was hepatic tissue. ROSE was useful for communicating with the endoscopist that the mass was both far from, and not connected to, the liver. This is the first documented account of perigastric ectopic liver diagnosed by FNA. This entity should be considered in the differential of perigastric masses.
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http://dx.doi.org/10.4103/1742-6413.196239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5200975PMC
December 2016

Statistical Literacy Among Academic Pathologists: A Survey Study to Gauge Knowledge of Frequently Used Statistical Tests Among Trainees and Faculty.

Arch Pathol Lab Med 2017 Feb 13;141(2):279-287. Epub 2016 Dec 13.

Context: -Statistical literacy can be defined as understanding the statistical tests and terminology needed for the design, analysis, and conclusions of original research or laboratory testing. Little is known about the statistical literacy of clinical or anatomic pathologists.

Objective: -To determine the statistical methods most commonly used in pathology studies from the literature and to assess familiarity and knowledge level of these statistical tests by pathology residents and practicing pathologists.

Design: -The most frequently used statistical methods were determined by a review of 1100 research articles published in 11 pathology journals during 2015. Familiarity with statistical methods was determined by a survey of pathology trainees and practicing pathologists at 9 academic institutions in which pathologists were asked to rate their knowledge of the methods identified by the focused review of the literature.

Results: -We identified 18 statistical tests that appear frequently in published pathology studies. On average, pathologists reported a knowledge level between "no knowledge" and "basic knowledge" of most statistical tests. Knowledge of tests was higher for more frequently used tests. Greater statistical knowledge was associated with a focus on clinical pathology versus anatomic pathology, having had a statistics course, having an advanced degree other than an MD degree, and publishing research. Statistical knowledge was not associated with length of pathology practice.

Conclusions: -An audit of pathology literature reveals that knowledge of about 12 statistical tests would be sufficient to provide statistical literacy for pathologists. On average, most pathologists report they can interpret commonly used tests but are unable to perform them. Most pathologists indicated that they would benefit from additional statistical training.
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http://dx.doi.org/10.5858/arpa.2016-0200-OADOI Listing
February 2017

POWERPIINC (PreOperative Window of Endocrine TheRapy Provides Information to Increase Compliance) trial: Changes in tumor proliferation index and quality of life with 7 days of preoperative tamoxifen.

Breast 2017 Feb 6;31:219-223. Epub 2016 Dec 6.

Department of Surgery, College of Medicine, University of Utah, 30 North 1900 East, Salt Lake City, UT 84124, USA.

Objectives: A decrease in Ki67 during neoadjuvant therapy predicts response to tamoxifen. Previous trials have shown a decreased Ki67 in breast tumors with as little as two or more weeks of preoperative tamoxifen. Shortening the preoperative treatment time in window of opportunity clinical trials makes these trials more attractive to women. POWERPIINC examined the effect of 7 days of preoperative tamoxifen on breast tumor proliferation and patient symptoms.

Methods: Women with untreated stage I/II, ER-positive, invasive breast cancer with no contraindications to tamoxifen were enrolled. Women received 20 mg of tamoxifen for 7 days up to the day of surgery. Proliferation was assessed by Ki67 immunohistochemistry before and after 7 days of tamoxifen. Symptoms and QOL were assessed by the FACT-ES and MENQOL. Adherence was measured by pill counts.

Results: 52 women were enrolled, and 44 were evaluable for Ki67. The median age was 58.5 years, and the median tumor diameter was 1.2 cm. Most women (73%) were post-menopausal. Most tumors were PR positive (88%) and HER2-negative (92%). The Ki67 decreased by a geometric mean of 40% (95% CI 29%-63%), and 73% (95% CI 57%-85%) of women had tumors with decreased proliferation (p = 0.0001 by paired t-test). Adherence to taking tamoxifen during the preoperative period was 100%. Women reported minimal bother from psychosocial or physical symptoms at baseline or on the day of surgery.

Conclusion: Seven days of tamoxifen showed a similar relative decrease in Ki67 as that reported for longer courses, was acceptable to women, and could be considered for window of opportunity studies.
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http://dx.doi.org/10.1016/j.breast.2016.11.016DOI Listing
February 2017

The molecular basis of breast cancer pathological phenotypes.

J Pathol 2017 Feb 29;241(3):375-391. Epub 2016 Dec 29.

Cancer Research Institute, Beth Israel Deaconess Cancer Center, Boston, MA, USA.

The histopathological evaluation of morphological features in breast tumours provides prognostic information to guide therapy. Adjunct molecular analyses provide further diagnostic, prognostic and predictive information. However, there is limited knowledge of the molecular basis of morphological phenotypes in invasive breast cancer. This study integrated genomic, transcriptomic and protein data to provide a comprehensive molecular profiling of morphological features in breast cancer. Fifteen pathologists assessed 850 invasive breast cancer cases from The Cancer Genome Atlas (TCGA). Morphological features were significantly associated with genomic alteration, DNA methylation subtype, PAM50 and microRNA subtypes, proliferation scores, gene expression and/or reverse-phase protein assay subtype. Marked nuclear pleomorphism, necrosis, inflammation and a high mitotic count were associated with the basal-like subtype, and had a similar molecular basis. Omics-based signatures were constructed to predict morphological features. The association of morphology transcriptome signatures with overall survival in oestrogen receptor (ER)-positive and ER-negative breast cancer was first assessed by use of the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset; signatures that remained prognostic in the METABRIC multivariate analysis were further evaluated in five additional datasets. The transcriptomic signature of poorly differentiated epithelial tubules was prognostic in ER-positive breast cancer. No signature was prognostic in ER-negative breast cancer. This study provided new insights into the molecular basis of breast cancer morphological phenotypes. The integration of morphological with molecular data has the potential to refine breast cancer classification, predict response to therapy, enhance our understanding of breast cancer biology, and improve clinical management. This work is publicly accessible at www.dx.ai/tcga_breast. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499709PMC
February 2017

Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus.

Cancer Res 2016 04 21;76(7):1916-25. Epub 2016 Jan 21.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.

The findings from genome-wide association studies hold enormous potential for novel insight into disease mechanisms. A major challenge in the field is to map these low-risk association signals to their underlying functional sequence variants (FSV). Simple sequence study designs are insufficient, as the vast numbers of statistically comparable variants and a limited knowledge of noncoding regulatory elements complicate prioritization. Furthermore, large sample sizes are typically required for adequate power to identify the initial association signals. One important question is whether similar sample sizes need to be sequenced to identify the FSVs. Here, we present a proof-of-principle example of an extreme discordant design to map FSVs within the 2q33 low-risk breast cancer locus. Our approach employed DNA sequencing of a small number of discordant haplotypes to efficiently identify candidate FSVs. Our results were consistent with those from a 2,000-fold larger, traditional imputation-based fine-mapping study. To prioritize further, we used expression-quantitative trait locus analysis of RNA sequencing from breast tissues, gene regulation annotations from the ENCODE consortium, and functional assays for differential enhancer activities. Notably, we implicate three regulatory variants at 2q33 that target CASP8 (rs3769823, rs3769821 in CASP8, and rs10197246 in ALS2CR12) as functionally relevant. We conclude that nested discordant haplotype sequencing is a promising approach to aid mapping of low-risk association loci. The ability to include more efficient sequencing designs into mapping efforts presents an opportunity for the field to capitalize on the potential of association loci and accelerate translation of association signals to their underlying FSVs. Cancer Res; 76(7); 1916-25. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-1629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873429PMC
April 2016

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Cell 2015 Oct;163(2):506-19

Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.
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http://dx.doi.org/10.1016/j.cell.2015.09.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603750PMC
October 2015

Breastfeeding, PAM50 tumor subtype, and breast cancer prognosis and survival.

J Natl Cancer Inst 2015 Jul 28;107(7). Epub 2015 Apr 28.

Division of Research, Kaiser Permanente Northern California, Oakland, CA (MLK, CHK, LAH, EKW, AC, EPG, CPQJr, LHK, BJC); Huntsman Cancer Institute, University of Utah, Salt Lake City, UT (PSB, REF, IJS, CS); Associated Regional and University Pathologist Institute for Clinical and Experimental Pathology, Salt Lake City, UT (PSB, REF); Division of Epidemiology, Department of Internal Medicine, School of Medicine, University of Utah, Salt Lake City, UT (KSM, CS); Department of Preventive Medicine, University of Southern California, Los Angeles, CA (BML).

Background: Breastfeeding is associated with decreased breast cancer risk, yet associations with prognosis and survival by tumor subtype are largely unknown.

Methods: We conducted a cohort study of 1636 women from two prospective breast cancer cohorts. Intrinsic tumor subtype (luminal A, luminal B, human epidermal growth factor receptor 2 [HER2]-enriched, basal-like) was determined by the PAM50 gene expression assay. Breastfeeding history was obtained from participant questionnaires. Questionnaires and medical record reviews documented 383 recurrences and 290 breast cancer deaths during a median follow-up of nine years. Multinomial logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) between breastfeeding and tumor subtype. Cox regression was used to estimate hazard ratios (HRs) for breast cancer recurrence or death. Statistical significance tests were two-sided.

Results: Breast cancer patients with basal-like tumors were less likely to have previously breastfed than those with luminal A tumors (OR = 0.56, 95% CI = 0.39 to 0.80). Among all patients, ever breastfeeding was associated with decreased risk of recurrence (HR = 0.70, 95% CI = 0.53 to 0.93), especially breastfeeding for six months or more (HR = 0.63, 95% CI = 0.46 to 0.87, P trend = .01). Similar associations were observed for breast cancer death. Among women with luminal A subtype, ever breastfeeding was associated with decreased risks of recurrence (HR = 0.52, 95% CI = 0.31 to 0.89) and breast cancer death (HR = 0.52, 95% CI = 0.29 to 0.93), yet no statistically significant associations were observed among the other subtypes. Effects appeared to be limited to tumors with lower expression of proliferation genes.

Conclusions: History of breastfeeding might affect prognosis and survival by establishing a luminal tumor environment with lower proliferative activity.
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http://dx.doi.org/10.1093/jnci/djv087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4554253PMC
July 2015

Association of high obesity with PAM50 breast cancer intrinsic subtypes and gene expression.

BMC Cancer 2015 Apr 14;15:278. Epub 2015 Apr 14.

Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA, 94612, USA.

Background: Invasive breast cancers are now commonly classified using gene expression into biologically and clinically distinct tumor subtypes. However, the role of obesity in breast tumor gene expression and intrinsic subtype is unknown.

Methods: Early-stage breast cancer (BC) patients (n = 1,676) were sampled from two prospective cohorts. The PAM50 qRT-PCR assay was used to: a) assess tumor gene expression levels for ESR1, PGR, ERBB2, and 10 proliferation genes and b) classify tumors into intrinsic subtype (Luminal A, Luminal B, Basal-like, HER2-enriched, Normal-like). Body mass index (BMI) around BC diagnosis (kg/m(2)) was categorized as: underweight (<18.5), normal (18.5-24), overweight (25-29), mildly obese (30-34), and highly obese (≥35). In a cross-sectional analysis, we evaluated associations of BMI with gene expression using linear regression models, and associations of BMI with non-Luminal A intrinsic subtypes, compared with Luminal A subtype, using multinomial logistic regression. Statistical significance tests were two-sided.

Results: Highly obese women had tumors with higher expression of proliferation genes compared with normal weight women (adjusted mean difference = 0.44; 95% CI: 0.18, 0.71), yet mildly obese (adjusted mean difference = 0.16; 95% CI: -0.06, 0.38) and overweight (adjusted mean difference = 0.18; 95% CI: -0.01, 0.36) women did not. This association was stronger in postmenopausal women (p for interaction = 0.06). Being highly obese, however, was inversely associated with ESR1 expression (adjusted mean difference = -0.95; 95% CI: -1.47, -0.42) compared with being normal weight, whereas being mildly obese and overweight were not. In addition, women with Basal-like and Luminal B subtypes, relative to those with Luminal A subtype, were more likely to be highly obese, compared with normal-weight.

Conclusions: ER expression may not increase correspondingly with increasing degree of obesity. Highly obese patients are more likely to have tumor subtypes associated with high proliferation and poorer prognosis.
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http://dx.doi.org/10.1186/s12885-015-1263-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403771PMC
April 2015

Researchers should be aware of partial verification bias in diagnostic accuracy studies.

Oral Surg Oral Med Oral Pathol Oral Radiol 2015 May 14;119(5):593. Epub 2015 Feb 14.

Department of Pathology, University of Utah School of Medicine and ARUP Laboratories, Salt Lake City, Utah, USA.

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http://dx.doi.org/10.1016/j.oooo.2014.11.027DOI Listing
May 2015

Quantitative Assessment of Multiorgan Sequestration of Parasites in Fatal Pediatric Cerebral Malaria.

J Infect Dis 2015 Oct 7;212(8):1317-21. Epub 2015 Apr 7.

College of Osteopathic Medicine, Michigan State University, East Lansing Blantyre Malaria Project, University of Malawi College of Medicine.

Children in sub-Saharan Africa continue to acquire and die from cerebral malaria, despite efforts to control or eliminate the causative agent, Plasmodium falciparum. We present a quantitative histopathological assessment of the sequestration of parasitized erythrocytes in multiple organs obtained during a prospective series of 103 autopsies performed between 1996 and 2010 in Blantyre, Malawi, on pediatric patients who died from cerebral malaria and controls. After the brain, sequestration of parasites was most intense in the gastrointestinal tract, both in patients with cerebral malaria and those with parasitemia in other organs. Within cases of histologically defined cerebral malaria, which includes phenotypes termed "sequestration only" (CM1) and "sequestration with extravascular pathology" (CM2), CM1 was associated with large parasite numbers in the spleen and CM2 with intense parasite sequestration in the skin. A striking histological finding overall was the marked sequestration of parasitized erythrocytes across most organs in patients with fatal cerebral malaria, supporting the hypothesis that the disease is, in part, a result of a high level of total-body parasite sequestration.
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http://dx.doi.org/10.1093/infdis/jiv205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4577044PMC
October 2015

Race and breast cancer survival by intrinsic subtype based on PAM50 gene expression.

Breast Cancer Res Treat 2014 Apr 7;144(3):689-99. Epub 2014 Mar 7.

Division of Research, Kaiser Permanente Northern California, 2000 Broadway, 5th Floor, Oakland, CA, 94612, USA,

To evaluate whether differences in PAM50 breast cancer (BC) intrinsic (Luminal A, Luminal B, Basal-like, and HER2-enriched) subtypes help explain the Black-White BC survival disparity. Utilizing a stratified case-cohort design, this study included 1,635 women from the Pathways and Life After Cancer Epidemiology cohorts, selecting women with tumors based upon IHC classification, recurrences, and deaths.One millimeter punches were obtained from tumor tissue, and expression of the PAM50 genes for molecular subtype was determined by RT-qPCR of extracted RNA. Cox proportional hazards models were used to analyze associations between race and BC outcomes, adjusted for PAM50 BC subtype. All tests of statistical significance were two-sided. Black women had a higher prevalence of the Basal-like BC subtype. Adjusted for potential confounding variables and disease characteristics at diagnosis, Black women had higher risks of recurrence (HR 1.65, 95 % CI 1.06-2.57) and breast cancer-specific mortality (HR 1.71, 95 % CI 1.02-2.86) than White women, but adjusting further for subtype did not attenuate survival disparities. By contrast, Hispanic women had a lower risk of recurrence (HR 0.54, 95 % CI 0.30-0.96) than Whites. Among those with the Basal-like subtype, Black women had a similar recurrence risk as women in other race groups but a higher recurrence risk for all other subtypes. Hispanic women had a lower recurrence risk within each subtype, though associations were not significant, given limited power. Although Black women had a higher risk of the Basal-like subtype, which has poor prognosis, this did not explain the Black-White BC survival disparity.
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http://dx.doi.org/10.1007/s10549-014-2899-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4035036PMC
April 2014

Intrinsic subtypes from the PAM50 gene expression assay in a population-based breast cancer survivor cohort: prognostication of short- and long-term outcomes.

Cancer Epidemiol Biomarkers Prev 2014 May 12;23(5):725-34. Epub 2014 Feb 12.

Authors' Affiliations: Division of Research, Kaiser Permanente Northern California, Oakland, California; Department of Internal Medicine, Division of Epidemiology; Huntsman Cancer Institute, University of Utah; and The Associated Regional and University Pathologist Institute for Clinical and Experimental Pathology, Salt Lake City, Utah.

Background: The PAM50, a gene expression assay to categorize breast tumors into intrinsic subtypes, has not been previously used to examine short- and long-term prognostication in a population-based cohort where treatment patterns and time of initial follow-up vary.

Methods: In a stratified case-cohort design of 1,691 women from the LACE and Pathways breast cancer survivor cohorts, we used PAM50 to categorize tumors into Luminal A (LumA), Luminal B (LumB), HER2-enriched (HER2-E), Basal-like and Normal-like, and to examine risk of early and late recurrence and mortality by Cox proportional hazards regression.

Results: Compared with LumA, cumulative risk of recurrence and breast cancer death was higher for LumB, HER2-E, and Basal-like tumors at 2, 5, and 10 years. However, HR of breast cancer death varied over time [<5 years (early) vs. > 5 years (late)] for both Basal-like (HR, 6.23 early vs. HR, 0.63 late) and HER2-E tumors (HR, 2.97 early vs. HR, 0.73 late) but not for LumB tumors where risk was elevated consistently (HR, 2.67 early vs. HR, 1.47 late). The contrast between LumB, HER2-E, and Basal-like compared with LumA on early recurrence was stronger when subtype was defined by PAM50 than by immunohistochemistry (IHC) markers.

Conclusions: The PAM50 categorized intrinsic subtypes in a manner that more accurately predicts recurrence and survival, especially for luminal tumors, compared with commonly used methods that rely on traditional IHC clinical markers.

Impact: The PAM50 is robust for use in epidemiologic studies and should be considered when archived tumor tissues are available.
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http://dx.doi.org/10.1158/1055-9965.EPI-13-1017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105204PMC
May 2014

Intrinsic subtypes from PAM50 gene expression assay in a population-based breast cancer cohort: differences by age, race, and tumor characteristics.

Cancer Epidemiol Biomarkers Prev 2014 May 12;23(5):714-24. Epub 2014 Feb 12.

Authors' Affiliations: Division of Epidemiology, Department of Internal Medicine; Huntsman Cancer Institute, University of Utah; The Associated Regional and University Pathologist Institute for Clinical and Experimental Pathology, Salt Lake City, Utah; and Division of Research, Kaiser Permanente Northern California, Oakland, California.

Background: Data are lacking to describe gene expression-based breast cancer intrinsic subtype patterns for population-based patient groups.

Methods: We studied a diverse cohort of women with breast cancer from the Life After Cancer Epidemiology and Pathways studies. RNA was extracted from 1 mm punches from fixed tumor tissue. Quantitative reverse-transcriptase PCR was conducted for the 50 genes that comprise the PAM50 intrinsic subtype classifier.

Results: In a subcohort of 1,319 women, the overall subtype distribution based on PAM50 was 53.1% luminal A, 20.5% luminal B, 13.0% HER2-enriched, 9.8% basal-like, and 3.6% normal-like. Among low-risk endocrine-positive tumors (i.e., estrogen and progesterone receptor positive by immunohistochemistry, HER2 negative, and low histologic grade), only 76.5% were categorized as luminal A by PAM50. Continuous-scale luminal A, luminal B, HER2-enriched, and normal-like scores from PAM50 were mutually positively correlated. Basal-like score was inversely correlated with other subtypes. The proportion with non-luminal A subtype decreased with older age at diagnosis, P Trend < 0.0001. Compared with non-Hispanic Whites, African American women were more likely to have basal-like tumors, age-adjusted OR = 4.4 [95% confidence intervals (CI), 2.3-8.4], whereas Asian and Pacific Islander women had reduced odds of basal-like subtype, OR = 0.5 (95% CI, 0.3-0.9).

Conclusions: Our data indicate that over 50% of breast cancers treated in the community have luminal A subtype. Gene expression-based classification shifted some tumors categorized as low risk by surrogate clinicopathologic criteria to higher-risk subtypes.

Impact: Subtyping in a population-based cohort revealed distinct profiles by age and race.
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http://dx.doi.org/10.1158/1055-9965.EPI-13-1023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4011983PMC
May 2014

Diagnostic accuracy studies of fine-needle aspiration show wide variation in reporting of study population characteristics: implications for external validity.

Arch Pathol Lab Med 2014 Jan;138(1):88-97

From the Department of Pathology, University of Utah School of Medicine and ARUP Laboratories, Salt Lake City, Utah.

Context: Study comparisons rest on the assessment of applicability or external validity. Population characteristics are an important component of external validity and, although there has been a heightened awareness of deficiencies in reporting in diagnostic test accuracy (DTA) studies, the reporting of populations in DTA studies has not been investigated.

Objective: To assess the quality of reporting of population descriptions in DTA studies for fine-needle aspiration cytology (FNAC).

Design: Literature survey of common population parameters and usage patterns in FNAC DTA studies. We randomly selected 20 FNAC DTA studies in 4 categories (salivary glands, lung, thyroid, and pancreas) and determined the frequency of parameter usage.

Results: Studies showed considerable variability in reporting patterns. On average, studies reported 2 to 4 parameters to describe study populations. Age, sex, and lesion size were most frequently reported. Sixteen percent of studies did not provide any population description. Population parameters were used to describe the sample population more frequently than to describe the selection process (P = .001). There were significant differences in the number of parameters specified by anatomic site (P = .001). Only 21% of studies provided a flow diagram. Thirty-three percent of studies mentioned the target population.

Conclusions: Studies show considerable variability in the description of sample populations and the population selection process. Studies often fail to provide flow diagrams or to provide a clear statement of the research problem. There is considerable opportunity for studies to improve both descriptions of sample populations and the process used to select them.
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http://dx.doi.org/10.5858/arpa.2013-0036-OADOI Listing
January 2014

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia.

Breast Cancer Res 2014 Dec 23;16(6):3419. Epub 2014 Dec 23.

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.

Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.

Results: ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).

Conclusions: These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.
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http://dx.doi.org/10.1186/s13058-014-0474-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352262PMC
December 2014

Invasive carcinoma with acinic cell-like features of the breast.

Breast J 2013 May-Jun;19(3):334-5. Epub 2013 Apr 18.

Department of Radiology, University of Utah, Salt Lake City, UT 84132, USA.

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http://dx.doi.org/10.1111/tbj.12119DOI Listing
November 2013