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Objectives We assessed the interobserver and interantibody reproducibility of HER2 immunohistochemical scoring in an enriched HER2-low–expressing breast cancer cohort. Methods A total of 114 breast cancer specimens were stained by HercepTest (Agilent Dako) and PATHWAY anti-HER2 (4B5) (Ventana) antibody assays and scored by 6 breast pathologists independently using current HER2 guidelines. Level of agreement was evaluated by Cohen κ analysis. Results Although the interobserver agreement rate for both antibodies achieved substantial agreement, the average rate of agreement for HercepTest was significantly higher than that for the 4B5 clone (74.3% vs 65.1%; P = .002). The overall interantibody agreement rate between the 2 antibodies was 57.8%. Complete interobserver concordance was achieved in 44.7% of cases by HercepTest and 45.6% of cases by 4B5. Absolute agreement rates increased from HER2 0-1+ cases (78.1% by HercepTest and 72.2% by 4B5; moderate agreement) to 2-3+ cases (91.9% by HercepTest and 86.3% by 4B5; almost perfect agreement). Conclusions Our results demonstrated notable interobserver and interantibody variation on evaluating HER2 immunohistochemistry, especially in cases with scores of 0-1+, although the performance was much more improved among breast-specialized pathologists with the awareness of HER2-low concept. More accurate and reproducible methods are needed for selecting patients who may benefit from the newly approved HER2-targeting agent on HER2-low breast cancers.

In light of the significant clinical benefits of novel HER2-targeting antibody-drug conjugates in advanced HER2-low expressing breast cancers in recent phases I and III clinical trials, particularly trastuzumab-deruxtecan (T-Dxd), the new "HER2-low" category in breast cancers (breast cancer with a HER2 IHC score of 1+, or 2+ without gene amplification) has gained increasing attention. In the past year, "HER2-low" breast cancers have been under active investigation by both oncologists and pathologists. In this current review, we update the recent cutting-edge research on HER2-low breast cancers, with a focus on the biology of HER2-low breast cancers, the issues on the identification of HER2-low breast cancers by immunohistochemistry in current practice of pathology, and the future directions in this emerging category in breast cancers.

Recently, clinical trials have demonstrated promising efficacy for novel HER2-targeted therapies in HER2-low breast cancers, raising the prospect of including a HER2-low category (immunohistochemical [IHC] score of 1+, or 2+ with non-amplified in-situ hybridization [ISH]) in the HER2 evaluation of breast cancers. In order to better understand this newly-proposed HER2 category, we investigated the incidence, HER2 staining patterns, clinicopathologic features, and genomic profile of HER2-low breast cancers. HER2-stained slides of 281 consecutive breast cancers were re-reviewed and the clinicopathologic information, MammaPrint, and BluePrint results of these cases were retrospectively analyzed. HER2-low breast cancers were identified in 31% of cases and were more common in estrogen receptor (ER)-positive than ER-negative breast cancers (33.6% vs 15%, p = 0.017). HER2-low cancers were generally clinical stages I-II (79%), ER-positive (93.1%), had homogenous HER2 staining (59.2%), HER2 IHC score of 1+ (87.4%), ductal phenotype (81.6%), histologic grades of 1 or 2 (94.2%) and luminal molecular subtypes (94.3%). Three HER2-low patients received neoadjuvant chemotherapy and none of them achieved pathologic complete response. When compared to HER2-negative (IHC of 0+) and HER2-positive (IHC of 3+ or IHC of 2+ with amplified ISH) cancers, HER2-low breast cancers had significantly lower Ki-67 (p = 0.03 and p 0.01, respectively) and higher ER positivity (p = 0.01 and p = 0.03, respectively). HER2-low breast cancers were less likely to be basal molecular subtype when compared to HER2-negative cancers (p 0.01) and were less likely to have a HER2 molecular subtype when compared to HER2-positive cancers (p 0.01). When adjusted for ER status, there was no significant difference on all the examined variables between HER2-low and HER2-negative groups. Our study provides valuable baseline characteristics of HER2-low breast cancers deriving from consecutive, real-world cases with a consensus confirmation of HER2 status, and would help to increase our understanding of this newly-proposed HER2 category in breast cancers.

Context.— Human epidermal growth factor receptor 2 (HER2) status in breast cancer is currently classified as negative or positive for selecting patients for anti-HER2 targeted therapy. The evolution of the HER2 status has included a new HER2-low category defined as an HER2 immunohistochemistry score of 1+ or 2+ without gene amplification. This new category opens the door to a targetable HER2-low breast cancer population for which new treatments may be effective. Objective.— To review the current literature on the emerging category of breast cancers with low HER2 protein expression, including the clinical, histopathologic, and molecular features, and outline the clinical trials and best practice recommendations for identifying HER2-low–expressing breast cancers by immunohistochemistry. Data Sources.— We conducted a literature review based on peer-reviewed original articles, review articles, regulatory communications, ongoing and past clinical trials identified through ClinicalTrials.gov, and the authors' practice experience. Conclusions.— The availability of new targeted therapy potentially effective for patients with breast cancers with low HER2 protein expression requires multidisciplinary recognition. In particular, pathologists need to recognize and identify this category to allow the optimal selection of patients for targeted therapy.

Supplementary Figure 1 from Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression

Supplementary Figure 2 from Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression

Supplementary Figure Legends 1-2 from Heat Shock Protein 27 Differentiates Tolerogenic Macrophages That May Support Human Breast Cancer Progression

Introduction: Multigene genomic profiling has become the standard of care in the clinical risk-assessment and risk-stratification of ER+, HER2− breast cancer (BC) patients, with Oncotype DX® (ODX) emerging as the genomic profile test with the most support from the international community. The current state of the health care economy demands that cost-efficiency and access to testing must be considered when evaluating the clinical utility of multigene profile tests such as ODX. Several studies have suggested that certain lower risk patients can be identified more cost-efficiently than simply reflexing all ER+, HER2− BC patients to ODX testing. The Magee equationsTM use standard histopathologic data in a set of multivariable models to estimate the ODX recurrence score. Our group published the first outcome data in 2019 on the Magee equationsTM, using a modification of the Magee equationsTM combined with an algorithmic approach—the Rochester Modified Magee algorithm (RoMMa). There has since been limited published outcome data on the Magee equationsTM. We present additional outcome data, with considerations of the TAILORx risk-stratification recommendations. Methods: 355 patients with an ODX recurrence score, and at least five years of follow-up or a BC recurrence were included in the study. All patients received either Tamoxifen or an aromatase inhibitor. None of the patients received adjuvant systemic chemotherapy. Results: There was no significant difference in the risk of recurrence in similar risk categories (very low risk, low risk, and high risk) between the average Modified Magee score and ODX recurrence score with the chi-square test of independence (p > 0.05) or log-rank test (p > 0.05). Using the RoMMa, we estimate that at least 17% of individuals can safely avoid ODX testing. Conclusion: Our study further reinforces that BC patients can be confidently stratified into lower and higher-risk recurrence groups using the Magee equationsTM. The RoMMa can be helpful in the initial clinical risk-assessment and risk-stratification of BC patients, providing increased opportunities for cost savings in the health care system, and for clinical risk-assessment and risk-stratification in less-developed geographies where multigene testing might not be available.

Critique sessions are an essential educational activity at the center of many design disciplines, especially those involving the creation of physical mockups. Conventional approaches often require the students and the instructor to be in the same space to jointly view and discuss physical artifacts. However, in remote learning contexts, available tools (such as videoconferencing) are insufficient due to ineffective, inefficient spatial referencing. This paper presents ARCritique, a mobile Augmented Reality application that allows users to 1) scan physical artifacts, generate corresponding 3D models, and share them with distant instructors; 2) view the model simultaneously in a synchronized virtual environment with remote collaborators; and 3) point to and draw on the model synchronously to aid communication. We evaluated ARCritique with seven Industrial Design students and three faculty to use the app in a remote critique setting. The results suggest that direct support for spatial communication improves collaborative experiences. Published version

Objectives Recent clinical trials have demonstrated significant clinical benefits from novel therapeutic compounds in breast cancer patient with human epidermal growth factor receptor 2 (HER2) immunohistochemical (IHC) score of 1+ or 2+ and negative in situ hybridization (ISH) result. A new concept of “HER2-low” breast cancer has been proposed and applied in the recent and ongoing clinical trials. In this article, we review the literature on the topic of HER2-low breast cancer. Methods A literature search in PubMed was performed using key words related to HER2-low breast cancer. Major relevant studies that were presented in international breast cancer conferences were also included. Results HER2-low breast cancer is currently defined as breast cancer with HER2 IHC score of 1+ or 2+ and negative ISH result. It likely represents a group of tumors with significant biological heterogeneity. Reports of clinical activity using the next generation of HER2-targeting antibody-drug conjugates in HER2-low breast cancers suggest that some strategies of targeting HER2 might be effective in this patient population while raising considerable concerns over limitations in our current testing methodologies and our ability to accurately identify such patients. Conclusions The promising efficacy of novel HER2-targeted therapy in advanced HER2-low breast cancers has raised the possibility for changing the clinical interpretation of HER2 status in breast cancer to include a HER2-low category; however, the definition of HER2-low breast cancer, the corresponding reliable and accurate quantitative HER2 testing methodology, and the biology of HER2-low breast cancer remain poorly defined.

Construction sites experience low productivity due to particular characteristics such as unique designs in each project, sporadic arrival of projects, and complexity of the process. Another contributing factor to low productivity is poor communication among workers, supervisors, and a site’s centralized knowledge hub. Research shows that introducing advanced artificial intelligence (AI) technology in construction can tackle these problems. In this paper, we analyzed human factors considerations–user, task, environment, and technology and identified their characteristics and challenges to design an interactive AI system to facilitate communication between workers and other stakeholders. Based on the analysis, we propose a voice-based intelligent virtual agent (VIVA) as a multi-purpose AI system on construction sites with a further research agenda. We hope that this effort can guide the design of construction-specific AI systems and that this worker-AI teaming can improve overall work processes, enhance productivity, and promote safety in construction.

INTRODUCTION: There is dearth information on the long-term outcome and role of HER2 targeted therapy in breast cancer patients in the HER2 FISH group 3 category, which is defined as breast cancer with a HER2/CEP17 ratio < 2 and HER2 copy number ≥ 6 signals/cell. In this study, we report the clinicopathologic features and outcomes of breast cancer patients in the HER2 FISH group 3 category at our institution. METHODS: We identified 52/2,874 (1.8%) breast cancer patients with HER2 FISH group 3 results between 1/2007 and 3/2020. 28 of these 52 patients had available detailed clinicopathologic and follow-up data, with an average follow-up of 38.5 months. RESULTS: Most of the cases with group 3 FISH results were high grade ductal carcinomas with positive hormonal receptor expressions and equivocal HER2 expression by immunohistochemistry. Among all the clinicopathologic variables, only tumor size (p=0.048) significantly contributed to the poor clinical outcomes. HER2 copy number failed to show any significant association with histologic grade, tumor size, clinical stage, hormonal receptor status or disease outcomes. There was no statistically significant difference in disease outcome between patients who were treated with HER2 targeted therapy and patients who did not receive HER2 targeted therapy, regardless of the HER2 copy number or clinical stage (Table 1). CONCLUSION: Our preliminary findings suggest that certain patients with HER2 FISH group 3 category breast cancer may not need HER-2 targeted therapy. Larger-scale studies are needed to further evaluate which HER2 FISH group 3 results are more likely to benefit from the HER-2 targeted therapy. Table 1. Response to HER2 targeted therapy in HER2 FISH group 3 breast cancer patients based on HER2 copy numbers and clinical stageHER 2 targeted therapyp-valueGivenNot givenTotal populationGood outcome (n=21)1380.371Bad outcome (n=7)61HER2 copy number < 10Good outcome (n=16)1060.366Bad outcome (n=7)61HER2 copy number ≥ 10Good outcome (n=5)321.000Bad outcome (n=0)00Stage I-IIGood outcome (n=16)970.737Bad outcome (n=3)21Stage III-IVGood outcome (n=5)410.343Bad outcome (n=4)40*Good outcome = No evidence of disease**Bad outcome = Local recurrence, distant metastasis, and/or died of disease Citation Format: Huina Zhang, Rana Ajabnoor, David Hicks, Bradley Turner. Clinicopathologic features and follow-up outcomes of breast cancers with HER2 FISH group 3 Results: A single institution experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-48.

IntroductionWomen who carry a germline mutation in BRCA1 (breast cancer type 1 susceptibility protein) have an increased risk of developing breast cancer in their lifetimes. Carriers tend to develop breast cancer at a younger age and their tumors are generally aggressive. Although BRCA1 breast cancers have been researched, many questions remain. The purpose of this study was to analyze the mutational landscape of tumors from BRCA1 carriers and compare them to tumors of sporadic breast cancer. MethodsPathology reports were reviewed to identify cases of breast cancer (BC) and the ER/PR/HER2 status was noted as well as the Ki67 proliferation index and patient age. Next generation sequencing (NGS) was performed on 72 BC tumors; 26 from BRCA1 carriers and 46 sporadic BC tumors. Two targeted panels were used for sequencing, the Oncomine Comprehensive Assay by Thermo Fisher Scientific on an Ion Torrent S5 XL sequencer and the AmpliSeq for Illumina Cancer HotSpot Panel. Mutations in a total of 44 cancer associated genes common to both panels were analyzed including TP53, RB1, PTEN, NRAS, ERBB2, PIK3CA, and BRAF. Missense and nonsense single nucleotide variants with a variant allele frequency >3% and coverage >150 reads were considered as well as insertions/deletions. Pathogenicity was determined using ClinVar and Varsome. Mutations were classified as benign, likely benign, variants of uncertain significance, likely pathogenic, and pathogenic.ResultsPathogenic/likely pathogenic variants were identified in 15 genes. TP53 was the most commonly mutated gene with pathogenic/likely pathogenic variants in 13 (50%) BRCA1 carriers’ tumors and 18 (39%) sporadic tumors. Having a TP53 mutation did not increase the likelihood of having other pathogenic mutations in either BRCA1 carriers or sporadic tumors; 74% of all tumors with p53 mutations had no additional pathogenic mutations overall. PIK3CA pathogenic/likely pathogenic mutations were significantly more common in sporadic tumors (26%) than BRCA1 carrier tumors (8%). PIK3CA mutation did not increase the likelihood of other gene mutations and did not correlate with TP53 mutations. BRCA1 pathogenic mutations were identified in four cases with no germline testing and likely represent somatic mutations. No pathogenic mutations were found in 12 (46%) of the BRCA1 carriers’ tumors and 10 (22%) sporadic tumors. There were four BRCA1 carriers with bilateral BCs; two pairs had the same mutations, one pair had different TP53 pathogenic mutations and another pair had different PIK3CA pathogenic mutations. A total of twenty-four cases were triple negative, 13 sporadic and 11 BRCA1 carriers (see table below). As expected, BRCA1 carriers were diagnosed with BC at a younger age with 21 (81%) cases diagnosed at age < 60 years while 22 (48%) of sporadic cases were in this age group. Conclusion TP53 is the most commonly mutated gene in BCs, even though more common in BRCA1 carriers’ tumors; however, they are not required for tumor development as seen in the 57% of cases in our study with normal TP53 (50% of BRCA1 carriers). No specific additional pathogenic mutation was commonly seen in BRCA1 tumors with TP53 mutations. PIK3CA was frequently mutated in sporadic cases and not in BRCA1 carriers. BRCA1 tumors were less likely to have other pathogenic mutations than sporadic tumors in this study of 44 genes. Additional studies will help further elucidate the molecular basis of BRCA1 tumor carcinogenesis. Citation Format: Cynthia Reyes Barron, David Hicks, Xi Wang. Comparison of the genetic mutations in sporadic and BRCA1 carrier breast cancer through targeted next generation sequencing [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS16-25.

INTRODUCTION: Oncotype DX® (ODX) is a multigene assay estimating risk of distant recurrence and chemotherapy benefit in estrogen receptor (ER) positive breast cancer patients. Cost ($4,620.00) impedes its adoption in poorer countries, and the cost is unnecessary in certain patients. TAILORx results suggest that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-positive, HER2-negative, node-negative invasive breast carcinomas with an ODX recurrence score < 26. Bhargava et al. and Turner et al. have suggested that a Magee scoreTM or a modified Magee score, respectively, of < 18 will identify patients who are highly likely to have an ODX recurrence score of < 26, and we previously presented data at SABCS 2019 (Abstract P3-07-06) that there is no significant difference in recurrence rate between patients with a modified Magee score of ≤ 18 and patients with an ODX recurrence score < 26 (in preparation for publication). We now present additional recurrence data on patients with a modified Magee score of > 18. METHODS: A total of 301 consecutive patients with ER+ invasive breast cancer from the University of Rochester and the University of Louisville were included in this study, with a mean of 6.6 years of follow-up. All patients had at least 5 years of follow-up (range 5-11 years) except for seven patients , who had a breast cancer recurrence prior to five years. Information on ER, PR, HER-2, Ki-67, Nottingham score , and tumor size were extracted from the pathology report in order to calculate the modified Magee score. Information, on hormone therapy, chemotherapy, radiation therapy, recurrence status, and mortality were extracted from the medical record. For all results, a p-value of < 0.05 was considered significant. RESULTS: 117/301 (39%) patients had a modified Magee score of > 18. The recuurence rate for patients with a modified Magee score > 18 was 11.1%. There was no significant difference in recurrence rate between patients with both a modified Magee score > 18 and ODX recurrence score < 26 compared to patients with both a modified Magee score >18 and ODX recurrence score ≥ 26 (p = 0.547, Table 1). CONCLUSIONS: Patients with a modified Magee score > 18 may be at increased risk for breast cancer recurrence, even if the ODX recurrence score is < 26. Additional studies are necessary to further evaluate these findings. Table 1: Modified Magee score > 18, Oncotype DX recurrence score (ODXRS), and outcomeRecurrenceNo recurrenceModified Magee score > 18 and ODXRS < 26870Modified Magee score > 18 and ODXRS ≥ 26633 Citation Format: Bradley M Turner, Mary Ann Gimenez-Sanders, Ioana Moisini, Huina Zhang, Xi Wang, Linda Schiffhauer, Hani Katerji, Kristin Skinner, Jessica Gooch, Michelle Shayne, Marilyn Ling, Carla Falkson, David Hicks. Are we missing something? Increased recurrence rates in patients with an oncotype DX score < 26 and a modified magee score > 18: A multi-institutional study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-24.

INTRODUCTION: The literature suggests that there is no difference in the Oncotype DX® (ODX) recurrence score between African American (AA) women and Caucasian (CA) women; however, an analysis of clinical outcomes in participants enrolled in the TAILORx trial found that AA women had worse clinical outcomes than CA women, despite similar ODX recurrence scores. The TAILORx trial suggested that chemoendocrine therapy may not be necessary in women with hormone-positive, HER2-negative, node-negative invasive breast carcinomas with an ODX recurrence score < 26. We examine Ki-67 (a marker of tumor proliferation) in relation to an ODX recurrence score of 26 in AA and CA women from two seperate institutions. METHODS: A total of 851 consecutive cases of AA (n = 78) and CA women (n = 773) with ER+ invasive breast cancer and available ODX recurrence scores from the University of Rochester and the University of Louisville were included in this study. For all results, a p-value of < 0.05 was considered significant. RESULTS: Consistent with the previous literatuere, there was no significant difference between the average ODX recurrence score of AA and CA women (p = 0.44, Table 1), and we found no significant difference in average ER, PR, Nottingham score, or tumor size between AA and CA patients; however, the Ki-67 was significantly higher in AA patients with an ODX recurrence score < 26 compared to CA patients with and ODX recurrence score < 26 (p = 0.002, Table 2). This significant difference in Ki-67 was not evident with an ODX recurrence score ≥ 26 (p = 0.98, Table 2). CONCLUSIONS: Our preliminary results suggest that compared to CA women, AA patients are more likely to have a higher Ki-67 if the ODX recurrence score is < 26. AA breast cancer patients with an ODX < 26 are at increased risk for recurrence compared to CA women with an ODX < 26. Ki-67 evaluation is not routinely done as part of the breast cancer workup in many institutions. Ki-67 evaluation may be helpful to help guide treatments decisions in AA patients with and ODX < 26. Additional investigation is warranted. Table 1: Oncotype DX and histopathologic variables for African American and Caucasian womenODXRS* (mean)ER** (mean)PR** (mean)NS***(mean)Ki-67 (mean)****Tumor size (mean)ODXRS < 26 (n) ODXRS ≥ 26 (n)ALL17.6255.3168.96.016.42.2713138AA18.3250.7175.96.321.42.26315CA17.5255.8168.26.015.92.2650123*Oncotype DX recurrence score** modified H-score*** Nottingham score****n = KI-67 available for 777 total patients (650 with ODXRS < 26 and 127 with ODXRS ≥ 26); KI-67 available for 71 AA patients (51 with ODXRS < 26 and 14 with ODXRS ≥ 26); KI-67 available for 706 CA patients (593 with ODXRS < 26 and 113 with ODXRS ≥ 26) Table 2: Oncotype DX < 26 and ≥ 26 and associated histopathologic variables for African American and Caucasian womenODXRS* (mean)ER** (mean)PR** (mean)NS*** (mean)Ki-67 (mean)****Tumor size (mean)ODXRS < 2614.5260.5189.15.813.72.2AA15.4262.8200.76.019.22.3CA14.4260.3188.05.813.12.2ODX ≥ 2633.8228.464.47.330.52.1AA30.3199.871.97.730.41.6CA34.2231.963.57.330.52.2*Oncotype DX recurrence score** modified H-score*** Nottingham score****n = KI-67 available for 777 total patients (650 with ODXRS < 26 and 127 with ODXRS ≥ 26); KI-67 available for 71 AA patients (51 with ODXRS < 26 and 14 with ODXRS ≥ 26); KI-67 available for 706 CA patients (593 with ODXRS < 26 and 113 with ODXRS ≥ 26) Citation Format: Bradley M Turner, Mary Ann Gimenez-Sanders, Huina Zhang, Ioana Moisini, Xi Wang, Linda Schiffhauer, Hani Katerji, Kristin Skinner, Jessica Gooch, Michelle Shayne, Marilyn Ling, Carla Falkson, David Hicks. Are we missing something? Ki-67 evaluation is important in African American women with an oncotype DX score< 26: A multi-institutional study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-18.

Objectives Tumor biomarker analyses accompanying immuno-oncology therapies are coupled with a tumor tissue journey aiming to guide tissue procurement and allow for accurate diagnosis and delivery of test results. The engagement of pathologists in the tumor tissue journey is essential because they are able to link the preanalytic requirements of this process with pathologic evaluation and clinical information, ultimately influencing treatment decisions for patients with cancer. The aim of this review is to provide suggestions on how cancer diagnosis and the delivery of molecular test results may be optimized, based on the needs and available resources of institutions, by placing the tumor tissue journey under the leadership of pathologists. Methods Literature searches on PubMed and personal experience provided the necessary material to satisfy the objectives of this review. Results Pathologists are usually involved across many steps of the tumor tissue journey and have the requisite knowledge to ensure its efficiency. Conclusions The expansion of oncology diagnostic testing emphasizes the need for pathologists to acquire a leadership role in the multidisciplinary effort to optimize the accuracy, completeness, and delivery of diagnoses guiding personalized treatments.

Visualizing History: Tunnels of Vauquois is an educational immersive virtual reality (VR) exhibit that makes the invisible history of World War I soldiers' experiences in the tunnels of Vauquois, France, visible to contemporary audiences. The exhibit presents the visitor with both discrete knowledge and the opportunity for emotional awareness. The virtual environment is recreated from scanned data of the original site. Visitors traverse the tunnel through the use of a head-mounted display, redirected walking, passive haptics, aligned physical and virtual environments, interactive tracked props, and narration. In this article, we describe the motivation and rationale for creating an immersive exhibit for informal learning environments, such as museums, libraries, and school VR laboratories. We also describe how the current exhibit functions and our iterative design process informed by observational feedback from pilot testing.

Background Progranulin (GP88) is a critical player in breast tumorigenesis. GP88 tumor expression is associated with increased recurrence and mortality, whereas GP88 circulating levels are elevated in patients with breast cancer compared with healthy individuals. We examined here the correlation between serum GP88 levels in patients with metastatic breast cancer (MBC) with overall survival and disease status determined as response to therapy or progression of disease. Patients and Methods An institutional review board (IRB)-approved study prospectively enrolled 101 patients with MBC at the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. GP88 serum levels were correlated with patients’ disease status determined by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 criteria and survival outcomes by Kaplan-Meier analysis and log rank statistics. Results Patients’ survival was stratified by serum GP88 level. Patients with serum GP88 55 ng/mL. Examination of GP88 serum levels in association with disease status showed a statistically significant association between serum GP88 levels and disease progression or response to therapy while CA15-3 level was only associated to progression. Conclusion The association of serum GP88 level with survival and disease status suggests the potential of using the serum GP88 test for monitoring disease status in patients with MBC. Measurement of serum GP88 levels in patients with MBC may have clinical value as a cost-effective adjunct to the management of patients with MBC with imaging.

The 1983 discovery of a mouse monoclonal antibody—the Ki-67 antibody—that recognized a nuclear antigen present only in proliferating cells represented a seminal discovery for the pathologic assessment of cellular proliferation in breast cancer and other solid tumors. Cellular proliferation is a central determinant of prognosis and response to cytotoxic chemotherapy in patients with breast cancer, and since the discovery of the Ki-67 antibody, Ki-67 has evolved as an important biomarker with both prognostic and predictive potential in breast cancer. Although there is universal recognition among the international guideline recommendations of the value of Ki-67 in breast cancer, recommendations for the actual use of Ki-67 assays in the prognostic and predictive evaluation of breast cancer remain mixed, primarily due to the lack of assay standardization and inconsistent inter-observer and inter-laboratory reproducibility. The treatment of high-risk ER-positive/human epidermal growth factor receptor-2 (HER2) negative breast cancer with the recently FDA-approved drug abemaciclib relies on a quantitative assessment of Ki-67 expression in the treatment decision algorithm. This further reinforces the urgent need for standardization of Ki-67 antibody selection and staining interpretation, which will hopefully lead to multidisciplinary consensus on the use of Ki-67 as a prognostic and predictive marker in breast cancer. The goals of this review are to highlight the historical evolution of Ki-67 in breast cancer, summarize the present literature on Ki-67 in breast cancer, and discuss the evolving literature on the use of Ki-67 as a companion diagnostic biomarker in breast cancer, with consideration for the necessary changes required across pathology practices to help increase the reliability and widespread adoption of Ki-67 as a prognostic and predictive marker for breast cancer in clinical practice.

Cultural heritage sites, such as historic buildings, ruins, or archaeological digs can provide a glimpse into the past via physical and/or geographic context. Augmented Reality (AR) can be used to enhance real artifacts and places to allow for deeper understanding. However, to date, AR experiences for history education have been primarily handheld experiences on smartphones or tablets. The design and use of head-worn AR for on-site history education needs further investigation. In this work, we aimed to explore best practices for creating such experiences. We describe the design and evaluation of Solitude AR, a head-worn AR experience exploring the history of Solitude, a historic site on the campus of our university. We present findings from a user-experience study of Solitude AR and lessons learned for the design of future head-worn AR experiences for on-site history education.

INTRODUCTION: The recent TAILORx results suggest that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-positive, HER2-negative, node-negative invasive breast carcinomas with an Oncotype Dx® recurrence score < 26. Oncotype Dx® is an expensive test (current list price of $4,620.00). Although the Oncotype Dx® test has gained widespread acceptance, cost may be an impediment to its adoption in certain areas of the world, and it may not be the most cost-effective or cost-efficient option in certain subsets of breast cancer patients. Based on a modification of the new Magee equations, we published an algorithmic approach in 283 ER+ cases using an average modified Magee equation (Turner BM, et al. Mod Pathol. 2015;28(7):921-31), and subsequently published a validation of this algorithmic approach in an additional 620 ER+ cases (Cancer Med. 2019 Jun 14. doi: 10.1002/cam4.2323. [Epub ahead of print]), supporting only reflex Oncotype Dx® testing for certain subsets of breast cancer patients. We now have recurrence data and at least five years of outcome data on 310 cases. METHODS: A total of 310 cases with ER+ invasive breast cancer, all with Oncotype Dx® recurrence scores, were included in this study from the University of Rochester and the University of Louisville. The outcome analysis included all patients who had at least five years of follow-up data, and all patients who had a breast cancer recurrence. In order to calculate the average modified Magee score, information on the Nottingham score, ER, PR, Ki-67, HER-2, and tumor size was extracted from the pathology report. RESULTS: 255/310 cases had an Oncotype Dx® < 26, and 4% (10/255) of these cases were associated with a breast cancer recurrence. 187/310 cases had an average modified Magee score ≤ 18, and 184 of these 187 cases (98%) had an Oncotype Dx® recurrence score < 26. Only 2% (n = 4) of these 184 cases were associated with a breast cancer recurrence. On average, the Nottingham score and Ki-67 were lower for cases with an average modified Magee score ≤ 18 compared to cases with an Oncotype Dx® recurrence score < 26 (Table 1). On average, the modified ER and PR H-scores were higher for cases with an average modified Magee score ≤ 18 compared to cases with an Oncotype Dx® recurrence score < 26 (Table 1). CONCLUSION: If the average modified Magee score is ≤ 18, the patient has a low likelihood of recurrence, and the Oncotype Dx® recurrence score will likely be < 26. Given the recent TAILORx findings, we suggest that patients with an average modified Magee score ≤ 18 not be sent out for Oncotype Dx® testing if an Oncotype Dx® recurrence score < 26 is the basis on which the clinician will use to decide whether or not to give chemotherapy. The information needed to use the average modified Magee equation is already generated by many pathology laboratories during the initial assessment of breast cancer, and the Magee equations are free of charge (https://path.upmc.edu/onlineTools/mageeequations.html). Based on the Genomic Health 2017 Annual Report, our data suggests that not sending out cases with an average modified Magee score ≤ 18 would have resulted in a potential cost savings to the health-care system in 2018 of almost 300 million dollars. Table 1: Average Nottingham score, modified ER H-score, modified PR H-score, and Ki-67, with number and percent recurrence for cases with an average modified Magee score ≤ 18 and cases with an Oncotype Dx® recurrence score < 26AVERAGERecurrence Sore typeNNS**ER***PR***Ki-67Recurrence N (%)Average modified Magee score ≤ 18*1875.2262.3235.410.34 (2)Oncotype Dx® recurrence score < 262555.5253.2192.613.610 (4)*98% (184/187) of patients with an average modified Magee score ≤ 18 had an Oncotype Dx® recurrence score < 26**Nottingham score***modified H-score (Turner BM, et al. Mod Pathol. 2015;28(7):921-31) Citation Format: Hasan Khatib, Mary Ann G Sanders, Andrea Breaux, Armen Soukiazian, Nyrie Soukiazian, David Hicks, Bradley M Turner. ER+ patients with an average modified Magee score ≤ 18 have a low likelihood of breast cancer recurrence and a high likelihood of an Oncotype Dx® recurrence score < 26 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-07-06.

INTRODUCTION: Breast cancer is the most prevalent non-skin cancer in women worldwide. Women with metastatic breast cancer to the liver have poor outcomes compared to metastases to other sites, frequently develop resistance to available hormonal and chemotherapeutic agents, and have poor overall survival. Conflicting evidence exists regarding the association of body mass index (BMI) with progression free and overall survival in patients with metastatic breast cancer. METHODS: A single institution retrospective study of women with breast cancer metastasis to the liver was conducted. The pathology reports and medical records from 2011 to 2017 were searched to identify cases with biopsy proven liver metastases. Several factors were considered including breast cancer histologic type and stage at diagnosis; estrogen receptor, progesterone receptor, and HER2-neu amplification status of the initially diagnosed breast cancer as well as the metastatic disease; patient age and ethnicity; BMI (kg/m2) at time of metastasis and at initial diagnosis; and, outcome to include survival after liver metastasis diagnosis. RESULTS: In our population, the BMI ranged from 21.2 kg/m2 to 56.3 kg/m2 (mean 28.4 kg/m2). Eighteen patients (62%) were either overweight or obese. Twenty-one patients (72.4%) were deceased at the time of the study with an average survival of 659 days after liver metastasis diagnosis (Table 1). Patients with a BMI > 30 (obese) had a significantly lower (p Table 1: Mean overall survival in patients with liver metastasisTotalER+ Liver MetastasisHER2+ Liver MetastasisBMI kg/m2N (%)Mean Survival (days)*N (%)Mean Survival (days)*N (%)Mean Survival (days)*Underweight ( 30)7 (33.3)3237 (43.7)3233 (60)315NA: not applicable*p-values Citation Format: Cynthia Reyes Barron, Maricarmen Planas-Silva, David G Hicks, Bradley M Turner. Body mass index and liver metastasis in women with invasive breast carcinoma [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-25.

In this paper, we conduct a secondary analysis of The Institute of Educational Sciences’ (IES) 2011-2012 Schools and Staffing Survey (SASS) data, a self-reported, nationally representative database to examine: (a) the average caseload of students with disabilities and emergent bilingual learners within and across social studies content areas, as well how social studies teachers’ caseloads compare with other content area disciplines and (b) the extent and perceived utility of professional development opportunities social studies teachers receive to support both students with disabilities and emergent bilingual learners.

Historians spend significant time looking for relevant, high-quality primary sources in digitized archives and through web searches. One reason this task is time-consuming is that historians’ research interests are often highly abstract and specialized. These topics are unlikely to be manually indexed and are difficult to identify with automated text analysis techniques. In this article, we investigate the potential of a new crowdsourcing model in which the historian delegates to a novice crowd the task of labeling the relevance of primary sources with respect to her unique research interests. The model employs a novel crowd workflow, Read-Agree-Predict (RAP), that allows novice crowd workers to label relevance as well as expert historians. As a useful byproduct, RAP also reveals and prioritizes crowd confusions as targeted learning opportunities. We demonstrate the value of our model with two experiments with paid crowd workers (n=170), with the future goal of extending our work to classroom students and public history interventions. We also discuss broader implications for historical research and education. This research was supported by U.S. National Historical Publications and Records Commission Grant DH50013-15. Published version

Biospecimens acquired during routine medical practice are the primary sources of molecular information about patients and their diseases that underlies precision medicine and translational research. In cancer care, molecular analysis of biospecimens is especially common because it often determines treatment choices and may be used to monitor therapy in real time. However, patient specimens are collected, handled, and processed according to routine clinical procedures during which they are subjected to factors that may alter their molecular quality and composition. Such artefactual alteration may skew data from molecular analyses, render analysis data uninterpretable, or even preclude analysis altogether if the integrity of a specimen is severely compromised. As a result, patient care and safety may be affected, and medical research dependent on patient samples may be compromised. Despite these issues, there is currently no requirement to control or record preanalytical variables in clinical practice with the single exception of breast cancer tissue handled according to the guideline jointly developed by the American Society of Clinical Oncology and College of American Pathologists (CAP) and enforced through the CAP Laboratory Accreditation Program. Recognizing the importance of molecular data derived from patient specimens, the CAP Personalized Healthcare Committee established the Preanalytics for Precision Medicine Project Team to develop a basic set of evidence-based recommendations for key preanalytics for tissue and blood specimens. If used for biospecimens from patients, these preanalytical recommendations would ensure the fitness of those specimens for molecular analysis and help to assure the quality and reliability of the analysis data.

This case study explored how a teacher, Mr. Smith, and his students experienced a mandated performance assessment while simultaneously preparing for an end of the year high-stakes, multiple-choice assessment. We employed qualitative research methods to examine how the teacher enacted a mandated performance assessment during a unit on Byzantium and how students described their learning and classroom experiences from the unit. Drawing on Grant's idea of ambitious teaching and learning of history and Ball's work on policy realization, analysis of these data indicated that Mr. Smith interpreted and enacted a performance assessment in ways that differed from how district and state policy makers intended. Despite an assessment that the district designed to promote historical thinking skills, students learned primarily factual knowledge.

Distinguishing between a breast intraductal papilloma and a papillary lesion with atypia or malignancy can be very challenging on core biopsy. There has been a long ongoing debate over whether or not it is necessary for breast papillary lesions diagnosed on core biopsies to be surgically excised, and the upgrading rate after excision varies.This study was carried out in a subspecialized academic pathology department, with well-formed criteria established among the faculty for the categorization of breast papillary lesions, with emphasis on the morphology evaluation of cellular features. A total of 320 breast core biopsies with follow-up excisions were identified. Of these, 286 cases had concordant results between the biopsy and excision, giving a concordance rate of 89.4%, with 98% concordance (143/146) in benign papilloma, 100% (111/111) in papillary carcinoma, and 51% (32/63) in papilloma with atypia. Of the upgraded cases, two were upgraded from benign to atypical, 11 from atypia to malignancy, and only one from benign to malignant. The overall average upgrading rate was 4.4% (14/320), with the critical upgrading (from benign to atypia or malignancy) rate of 0.94% (3/320). Downgrading was only identified in the group of papilloma with atypia, with 20 of 63 cases downgraded to benign papilloma on excision.Our study indicates that surgical excision may not be necessary for all papillary lesions after detailed evaluation of the morphology on core biopsies. Assessing the morphological features of the epithelial cells is critical for the accurate classification and clinical management of papillary lesions.

Objectives: Recently-published phase I clinical trials have demonstrated promising efficacy of novel HER2-targeted therapy in advanced breast cancers with a HER2 immunohistochemistry (IHC) score of 1+, or 2+ with a non-amplified in-situ hybridization (ISH). This has raised the possibility for changing the categories for clinical interpretation of HER2 in breast cancers into: 1) HER2-negative (HER2 IHC score of 0+), 2) HER2-low (IHC score of 1+, or 2+ with a non-amplified ISH), and 3) HER2-positive (HER2 IHC score of 3+ and IHC score of 2+ with amplified ISH). Earlier studies on low HER2-expressing breast cancers focused on differences between HER2 2+ with negative ISH and HER2 0/1+. The aims of this study are to investigate the clinical, pathologic and molecular features of HER2-low breast cancers, in comparison to HER2-negative breast cancers. Methods: 281 breast cancers with HER2 IHC were diagnosed between 04/2020 and 12/2020 at our institution, including 164 HER2-negative, 87 HER2-low, and 30 HER2-positve cases. The clinicopathologic information and molecular subtyping (Agendia BluePrint) results of HER2-low breast cancers were retrospectively collected, and compared to those of HER2-negative cases. A p-value of < 0.05 was considered statistically significant. Results: HER2-low breast cancers accounted for 31% (87/281) of breast cancers in our study population. The majority of these HER2-low cases were clinical stage I-II, with 6 cases (6.9%) being stage IV. Most of the HER2-low cancers had a HER2 IHC score of 1+ (87%, 76/87), a ductal phenotype (82%, 71/87), histologic grades of 1 or 2 (94%, 82/87), were ER positive (94%, 81/86), PR positive (86%, 74/86), and had luminal molecular subtypes (96%, 83/87). Four patients received neoadjuvant chemotherapy and none of them achieved pathologic complete response. Compared to HER2-negative cancers, HER2-low breast cancers showed a lower Ki-67 (p Table 1. Comparison of clinicopathologic parameters and molecular subtypes between HER2-low and HER2-negative breast cancersHER2-Low (n=87)HER2-Negative (n=164)P valueAge (year)66.6264.380.22Tumor size (mm)21.4919.290.49Histologic typeDuctal711390.57Lobular1524Mixed11Histologic grade143640.156239813519pT Stage142880.0452817362Unknown2735PN stage036760.351613210300Unknown2353ER positivity94.2 % (81/86)82.9% (136/64)0.01PR positivity86% (74/86)76.8% (126/164)0.09Ki-67 (%)12.8118.290.03Molecular subtypeLuminal A571050.003Luminal B2630HER210Basal328 Citation Format: Huina Zhang, Hani Katerji, Bradley M Turner, David G Hicks. Clinicopathologic characteristics and molecular profiling of HER2-low breast cancer: A single academic institution experience [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-05-09.

Objectives We compared the clinicopathologic features, clinical management, and outcomes of human epidermal growth factor receptor 2 (HER2)–expressing and nonexpressing microinvasive breast carcinomas (MiBC) to explore the significance of HER2 in MiBC. Methods Clinicopathologic and follow-up information of cases with final diagnosis of MiBC with known HER2 status between 2007 and 2019 were analyzed. Results Nineteen (41.3%) HER2-positive (HER2+) and 27 (58.7%) HER2-negative (HER2−) MiBCs were identified. HER2 positivity was likely to be associated with high nuclear grade, presence of tumor-infiltrating lymphocytes, hormonal receptor negativity, and increased Ki-67 in both microinvasive and associated in situ carcinomas. Nodal metastases were found in 2 ER+/HER2− cases (5.3%). One HER2+ case was found to have isolated tumor cells in the axillary node. The majority of patients with HER2+ MiBCs (76.5%) did not receive HER2-targeted therapy. All patients with available follow-up were alive without recurrence or distant metastasis, with a median follow-up of 38 months. Conclusions Similar to the larger size of invasive breast carcinomas, HER2 positivity is associated with high-grade morphologic features in MiBCs. However, HER2 overexpression in MiBCs does not appear to be associated with nodal metastasis or worse outcome in our study cohort. The role of HER2-targeted therapy in this clinical setting merits additional study.

Recent advances in molecular biology and molecular techniques have led to a better understanding of biologic diversity of breast and gynecologic tumors, the refinement of molecular taxonomies, the development of novel prognostic and predictive molecular assays, and the identification of new therapeutic targets. Molecular testing has become increasingly important in the diagnosis and management of breast and gynecologic tumors in the era of precision medicine. In the first part of this chapter, by using the format of frequently asked questions (FAQ), we review the roles of molecular testing in breast and gynecologic pathology, the common hereditary syndromes associated with breast and gynecologic tumors, the molecular subclassifications of breast and endometrial cancers, as well as the common biomarkers and the commonly used molecular testing in breast and gynecologic tumors. These FAQs are an attempt to provide evidence-based answers to common questions from clinicians, pathologists and trainees. In the second part of this chapter, we present four cases to further illustrate the application of molecular testing in our daily practices on breast and gynecologic tumors.

OBJECTIVE College of American Pathologists and the American Society of Clinical Oncology guidelines provide straightforward criteria for HER2 interpretation in breast carcinomas; however, a subset of cases present unusual diagnostic dilemmas. MATERIALS AND METHODS Ten challenging HER2 fluorescence in situ hybridization (FISH) cases were selected for analysis. The study included a variety of problematic cases such as those with discordant immunohistochemistry (IHC) and FISH results, cases with high intratumoral variability in HER2 copy number, a case with a highly amplified clone in 5% to 10% of the tumor sample, and a case with tumor cells containing tightly clumped HER2 signals. Six high volume HER2 FISH laboratories performed and interpreted HER2 FISH (adding HER2 IHC if necessary). Interpretation strategies were discussed. RESULTS There was 100% concordance between laboratories in 4/10 cases. Tumors with increased intratumoral variability (tumors with high variability in HER2 copy number per cell but which otherwise do not fulfill College of American Pathologists and the American Society of Clinical Oncology criteria for heterogeneity) exhibited 100% concordance in 3/4 cases, but 1 case had only 50% agreement. Low positive HER2 cases (group 1 cases with

Background: We investigate L1CAM expression in ER positive/HER2 negative breast carcinomas. The finding of a potential correlation between high L1CAM expression and recurrent/metastatic disease in luminal A and B breast carcinomas may be helpful for risk stratification and open opportunities for targeted therapies.Methods: 304 cases comprising 152 cases of ER positive, PR positive/negative and HER2 negative recurrent/metastatic breast carcinomas and 152 non-recurrent controls were included. ER, PR, HER-2, Ki-67 status, Nottingham grade, tumor size, tumor stage, number of foci, lymph node status, lymphovascular invasion, phenotype, laterality, age at diagnosis and first distant or local recurrence were recorded. Results: L1CAM positive cases showed increased specificity for recurrence and these patients were significantly younger than L1CAM negative ones. Compared to L1CAM negative recurrent cases, L1CAM positive ones had a noticeably higher Ki-67, tended to be larger and recurred sooner. All L1CAM positive recurrent/metastatic cases were of the luminal B subtype compared to 67.3% of the L1CAM negative cases. Conclusions: L1CAM is highly specific for recurrence in a subset of breast cancer patients and may be associated with more aggressive behavior, particularly in luminal B breast cancers with higher Ki-67 expression. Further investigation about the prognostic value of L1CAM is warranted.

Our transdisciplinary team performed a comprehensive site survey of the Hill of Vauquois, combining a variety of to create a digital recreation of the above and below ground features of the craters, trenches, tunnels and galleries that allows us to see and explore the destroyed village of Vauquois as it has never been seen before. Vauquois was a small French village before it became critical high ground that was fiercely contested for four years by the French and Germans during World War I, with the Americans finally taking the position during the Meuse-Argonne offensive of 1918. A quiet, agricultural village became a killing ground starting in the streets, moving to trenches, and finally moving underground into a network of miles of tunnels used to set over 500 mine explosions in four horrific years of continuous combat. This immersive virtual reality informal learning exhibit allows visitors to experience and learn about life and conditions in the tunnels of Vauquois as never before. Visitors can walk through the virtual environment but also interact with physical representations of objects that are based on actual artifact and material culture left behind 100 years ago. They can touch a carving within the tunnel, pick up and carry a lantern and other objects as they move through the physical exhibit. They are also provided with learning challenge cards in order to guide their learning and exploration. Finally, handouts will be provided detailing the teams research and development trajectory (process and product) and links to educational online resources to download so visitors can continue to explore the tunnels of Vauquois at home or in classrooms. Our project seeks to make the invisible visible and give visitors a sense of walking in the footsteps of others over time and space. We do so by immersing the visitor in experiences of life underground in the French and German World War I tunnels under the village of Vauquois. It is within these tunnels that soldiers slept, ate, took shelter, mined and fought, for over three years, experiencing first-hand the ravages of a war of attrition. Vauquois spans the spectrum of experience in the First World War, from street fighting, to trench warfare, to tunnel warfare. Unlike other examples of mining on the Western Front, the warring armies at Vauquois built underground cities where the combatants spent the majority of their time and in some cases were actually engaged in combat. The team has laser scanned a large proportion of the site (Figure 1); the primary challenge faced in the design of this exhibit is how to make visible what would otherwise be invisible and inaccessible and begin to convey the feeling of being under the hill of Vauquois as authentically as possible, while utilizing a small fraction of the space that the site covers. Multiple techniques are utilized to overcome these challenges, including typical physical displays found in many museums, as well as the immersive experience affordances of passive haptics (augmenting high fidelity visuals within the tunnel with touch) and redirected walking (exploring the virtual tunnels that are larger and more complex than the physical exhibit space itself), creating an engaging and informative exhibit. Together these experiences are specifically designed to allow visitors to engage with and persist in a historical inquiry of World War I experiences. Not only will visitors be able to walk through the virtual environment (see point of view video), they will be able to interact with physical representations of objects that are based on actual artifacts and material culture left behind 100 years ago. For example, they will be able to reach out and touch a carving within the tunnel and pick up and carry a lantern and other objects as they move through the virtual reality tunnel itself. They will also be provided with learning challenge cards in order to guide their learning and exploration. In addition to the virtual environment itself, the exhibit includes physical props of segments of the tunnels, artifacts from the site, audio and still photos, and documentary video of the history of the destroyed village of Vauquois and the process of creating the exhibit. Our exhibit is fully immersive, making use of sight, sound and touch to make the most of the technologies we have at our disposal to give a sense of life and walking in the footsteps of the common soldier and miner at Vauquios. Figure 2 and the following text describe what a visitor will see and experience at each point during the exhibit.

Background: Over-expression of Human Epidermal Growth Factor receptor-2 (HER2) in breast cancer is associated with an aggressive clinical course and poor prognosis. Targeting HER2 over-expression has been shown to be a remarkably effective therapeutic modality in the metastatic, adjuvant and neoadjuvant setting and the pathologic response to neoadjuvant treatment in HER2-positive breast cancer has been shown to be an excellent surrogate for a good outcome. The stromal tumor microenvironment is implicated in fostering tumor growth, facilitating cell migration and ultimately resulting in metastatic disease. Specifically, the collagenous extracellular matrix, which includes fibrillar collagen, has been suggested to play a role in the migration of malignant breast epithelial cells within the surrounding stroma. We have developed a novel methodology which uses an intrinsic optical signature to quantitatively evaluate fibrillar collagen (Burke et al. BMC Cancer 15 (2015): 929). Here, we evaluate the ability of this quantitative methodology to predict the pathologic response after neoadjuvant HER2-targeted treatment as assessed by the Residual Cancer Burden score/class (RCB). This quantitative evaluation in pre-treatment biopsies is then correlated with the pathologic response to treatment in the post-therapy resection. Material and Methods: Clinical pathologic variables for 29 cases of HER2-positive breast cancer that had undergone neoadjuvant chemotherapy plus HER2-targeted therapy were retrieved from the medical record database at URMC, including the post-treatment RCB score and ER/PR/HER2 status. Second harmonic generation (SHG) is an intrinsic optical signal produced by fibrillar collagen. To quantify collagen microstructure in the pre-treatment core biopsy, we used SHG imaging to determine the average forward to backward-light scattering ratio (F/B). The F/B ratio is sensitive to structural properties of collagen fibers. Results: Logistic regression was used to assess the association between F/B and the binary response variable RCB class (0/1 or 2/3). A likelihood ratio test was used to calculate the p-value to test whether the regression coefficient for F/B was zero (i.e. no effect) in the tumor-stromal interface. The average F/B ratio at the leading edge of the tumor stratified by RCB class is shown in Table 1. When evaluated in the bulk of the tumor tissue, F/B was not correlated with RCB status; however, when evaluated at the leading edge of the tumor stromal interface, F/B was significantly correlated with RCB status (p=0.035). Table 1:RCB class and average F/BRCB class (n)Average F/B ± SEM0/1 (19)16.95 ± 1.062/3 (10)12.32 ± 1.84 Conclusions: We have previously shown that the measurement of F/B in the primary tumor after resection is an independent prognostic indicator of metastasis-free survival in breast cancer. Our results in the current study furthers these observations and suggests that the evaluations of the microstructure of collagen fibers by F/B measurement from the pre-treatment biopsy, specifically at the leading edge of the tumor-stroma interface, may be useful for predicting pathologic response to trastuzumab-based neoadjuvant therapy. Further studies in a larger patient cohort are warranted. Citation Format: Desa DE, Turner BM, Buscaglia B, Hill RL, Strawderman RL, Hicks DG, Brown EB. Using multiphoton laser scanning microscopy to assess neoadjuvant therapy outcome in core needle biopsies: A novel methodology [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-12.

Introduction: The recent TAILORx results suggests that adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone–positive, HER2-negative, axillary node–negative breast cancer who had an Oncotype Dx recurrence score (ODXRS) between 11 and 25. These findings, along with updated results that patients with an ODXRS < 11 have a 9-year recurrence rate of only 3%, suggest that certain populations of patients with an ODXRS ≤ 25 may not benefit from additional systemic chemotherapy. Oncotype Dx is an expensive test (current list price of $4,650.00), and cost has been an impediment to its adoption in many centers throughout the United States, and internationally. The test can be performed only at a commercial specialized laboratory. Based on a modification of the new Magee equations (Klein ME, et al. Mod Pathol. 2013;26(5):658–664) we published an algorithm based on 283 patients with ODXRS's (Turner BM, et al. Mod Pathol. 28(7):921-31) that suggested our algorithm offered a less expensive alternative to Oncotype DX testing. We have validated this algorithm in a multi-institutional study on an additional 619 patients with ODXRS's (in preparation for publication). Our validation data, and our data from the original study, also suggests that the average modified Magee equation can reliably predict patients who will have an ODXRS ≤ 25. Methods: 903 cases with an available ODXRS (2006-2018) were identified from the pathology files at the University of Rochester Medical Center (n = 752) and the University of Louisville (n = 151). Information required to calculate the average modified Magee score, which includes estrogen receptor (ER) and progesterone receptor (PR) status, Her-2 status, Nottingham score, tumor size, and Ki-67 were also extracted from the medical record. 78 patients did not have an available Ki-67, leaving 825 patients for inclusion in this study. Results: 478/488 (98%) patients with an average Modified Magee score ≤ 18 had an ODXRS ≤ 25 (only 2% had an ODXRS > 25 - Table 1). 125/337 (37%) patients with an average Modified Magee score >18 had an ODXRS > 25 (Table 1) . Conclusions: The average Modified Magee Score can be helpful in predicting an ODXRS ≤ 25. Patients with an average Modified Magee score ≤ 18 may not need to be sent out for Oncotype Dx testing. The potential cost savings to the health care system would be enormous. Table 1:Average Modified Magee score and risk of an Oncotype Dx recurrence score (ODXRS) > 25Magee scorenAverage ODXRSMinimum ODXRS valueMaximum ODXRS valueCases with ODXRS > 25 [n (%)]≤ 91811.02190 (0)102110.90261 (4.8)113712.10250 (0)126012.00281 (1.7)136412.00230 (0)147012.90271 (1.4)156513.61313 (4.6)165614.12292 (3.6)175214.50272 (3.8)184514.30250 (0)195418.96379 (16.7)204319.30348 (18.6)215921.193715 (25.4)223819.32496 (15.8)232523.383811 (44)242920.83329 (31)252325.0144011 (47.8)> 25-272729.2174620 (74.1)> 27-301634.9225113 (81.3)> 302345.7317823 (100)≤ 1848812.903110 (2)> 1833723.7078125 (37) Citation Format: Turner BM, Sanders MA, Breaux A, Soukiazian A, Soukiazian N, Hicks DG. The average modified Magee score can be helpful in predicting an Oncotype DX recurrence score ≤ 25 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-24.

Introduction: The recent TAILORx results suggest that additional systemic chemotherapy may not be necessary in certain hormone +, HER2 -, node negative breast cancer patients with an Oncotype Dx recurrence score (ODXRS) ≤ 25. ODX is an expensive test (current list price of $4,650.00), and cost has been an impediment to its adoption in many centers throughout the world. Based on a modification of the new Magee equations (Klein ME, et al. Mod Pathol. 26[5]) we published data based on 283 patients with ODXRS's (Turner BM, et al. Mod Pathol. 28[7]), suggesting that the modified Magee equation (MME) offered a less expensive alternative to ODX testing in certain breast cancer patients. We now have outcome data suggesting that the MME along with progesterone receptor (PR), Ki-67, lymph node (LN) status, and lymphovascular invasion (LVI) status can be helpful in predicting which patients with an ODXRS ≤ 25 are more likely to recur. Methods: 248 patients with information on estrogen receptor (ER), PR, Ki-67, Her-2 status, Nottingham score, tumor size, LN status, LVI status, and an available ODXRS (2008-2018) were identified from the pathology files at the University of Rochester Medical Center. Results: All of the patients that recurred had an average modified Magee score (MMS) ≥ 14 (Table 1). Patients with LN involvement (5/43,12% ) or with LVI (5/27,19%) had a higher percentage of recurrence than patients without LN involvement (8/197, 4%) or without LVI (8/216, 4%). Patients that recurred had a significantly (p < 0.05) lower PR and higher Ki-67 than patients in the same risk class that did not recur (Table 2). Neither grade nor ER status was significantly different between patients that recurred and did not recur (Table 2). All of the patients that recurred had at least a lowered PR, higher Ki-67, LN involvement, or LVI, and most had some combination of these variables (Table 1). 8 of the 13 patients that recurred in our population (61.5%) had an ODXRS of ≤ 25. Conclusions: Risk stratification is still important in patients with an ODX score ≤ 25. The MMS along with PR, Ki-67, LN, and LVI status can be helpful in predicting patients with a higher risk of recurrence. Table 1:Recurrence dataODXRSMMSType of therapy*Nodal and LVI status**Nottingham scoreER-H score***PR-H score***Ki-671119.1NONENONE6240180271319.7HNONE530015201521.6HN51209051514HNONE5270210UNKNOWN1615HLVI527018051727.2HB62701601916.3HNONE428545UNKNOWN2424.5CLVI8240105352723.9BNONE7210100352821HN527021252823.4HB528530353128.7HB82701454432.3HNONE9210607021.4****21.4****--5.9****250.7****93.4****31.4*****H = Hormone only;C = Chemo only;B = Both; ** N = Nodal involvement;L = LVI;B = Both; ***modified (Turner BM, et al. Mod Pathol. 2015;28(7):921-31); **** average Table 2:Recurrence data in specific populationsPopulation typeNGradeER*PR*Ki-67≤ 25 no recurrence2165.4249.7185.712.8**≤ 25 recurrence85.5249.4103.325.3***> 25 no recurrence267.3211.776.834.1****> 25 recurrence56.8249.042.542.0* modified (Turner BM, et al. Mod Pathol. 2015;28(7):921-31); ** n = 181; *** n = 6; **** n = 23 Citation Format: Turner BM, Sanders MAG, Soukiazian A, Soukiazian N, Hicks DG. Reconsidering “at risk” criteria for breast cancer recurrence in hormone positive patients: Risk stratification is still important in patients with an Oncotype Dx recurrence score ≤ 25! [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-40.

OBJECTIVES Human epidermal growth factor receptor 2 (HER2) is expressed in some gastric and gastroesophageal junction adenocarcinomas. There were two goals: assess the impact of specimen type on HER2 status and evaluate HER2 concordance with multiple specimens. METHODS All cases were evaluated by immunohistochemistry (IHC) for HER2 and interpreted using established criteria. Fluorescence in situ hybridization (FISH) was performed on a subset. RESULTS Of 460 specimens, 83.9% were IHC negative, 5.4% were equivocal, and 10.7% were IHC positive. Of those with FISH testing, 78.5% were FISH negative, and 21.5% were FISH positive. IHC-FISH concordance for biopsy specimens, resections, and metastases was 82%, 84%, and 86%, respectively. With one vs two vs three or more specimens, the HER2-positive rate increased from 10.5% to 18.1% to 24.1%, respectively. CONCLUSIONS HER2 testing may be performed on biopsy specimens with a relatively high concordance rate with resection specimens, and if multiple samples are analyzed from a single patient, the HER2-positive rate increases over twofold.

The human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive biomarker in the breast cancer. The American Society of Clinical Oncology/College of American Pathology (ASCO/CAP) has published HER2 testing guidelines in breast cancer. We herein reviewed the HER2 testing guidelines in breast cancer with a focus on the application of the current guidelines. The continual investigation of HER2 testing in breast cancer has resulted in updates in the HER2 testing guidelines. The current guidelines focus on the uncommon clinical scenarios and emphasize the coordination between immunohistochemistry and in situ hybridization results, in an effort to improve clarity and accuracy. The ASCO/CAP guidelines provide valuable recommendations to ensure the accurate evaluation of HER2 status in breast cancer patients through standardization. Additional studies, particularly those with long-term outcome data are still needed to validate the guideline recommendations, especially the uncommon cases.