Emerging Landscape of Targeted Therapy of Breast Cancers With Low Human Epidermal Growth Factor Receptor 2 Protein Expression.

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.

Analytical and clinical validation of PATHWAY Anti-HER-2/neu (4B5) antibody to assess HER2-low status for trastuzumab deruxtecan treatment in breast cancer.

In DESTINY-Breast04 (DB-04), safety and efficacy of HER2-targeted antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) in previously treated HER2-low unresectable/metastatic breast cancer were established. This manuscript describes the analytical validation of PATHWAY Anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (PATHWAY HER2 (4B5)) to assess HER2-low status and its clinical performance in DB-04. Preanalytical processing and tissue staining parameters were evaluated to determine their impact on HER2 scoring. The recommended antibody staining procedure provided the optimal tumor staining, and deviations in cell conditioning and/or antibody incubation times resulted in unacceptable negative control staining and/or HER2-low status changes. Comparisons between antibody lots, kit lots, instruments, and day-to-day runs showed overall percent agreements (OPAs) exceeding 97.9%. Inter-laboratory reproducibility showed OPAs of ≥97.4% for all study endpoints. PATHWAY HER2 (4B5) was utilized in DB-04 for patient selection using 1340 tumor samples (59.0% metastatic, 40.7% primary, (0.3% missing data); 74.3% biopsy, 25.7% resection/excisions). Overall, 77.6% (823/1060) of samples were HER2-low by both central and local testing, with the level of concordance differing by sample region of origin and collection date. In DB-04, the efficacy of T-DXd over chemotherapy of physician's choice was consistent, regardless of the characteristics of the sample used (primary or metastatic, archival, or newly collected, biopsy or excision/resection). These results demonstrate that PATHWAY HER2 (4B5) is precise and reproducible for scoring HER2-low status and can be used with multiple breast cancer sample types for reliably identifying patients whose tumors have HER2-low expression and are likely to derive clinical benefit from T-DXd.

Survival outcomes seen with neoadjuvant chemotherapy in the management of locally advanced inflammatory breast cancer (IBC) versus matched controls.

Inflammatory breast cancer (IBC) poses an ongoing challenge as rates of disease recurrence and mortality remain high compared to stage-matched controls. However, frontline therapy has evolved through the years, including the widespread use of neoadjuvant chemotherapy (NAC) given the prognostic importance of pathologic complete response (pCR). Due to these sweeping changes, we need new data to assess current recurrence and survival outcomes for locally advanced IBC in the context of matched non-inflammatory controls. We conducted a retrospective analysis of institutional IBC data from 2010 to 2016 with the primary objective of comparing overall survival (OS), relapse-free survival (RFS), and distant relapse-free survival (DRFS). We matched IBC patients to non-inflammatory controls based on age, receptor status, tumor grade, clinical stage, and receipt of prior NAC. Secondary objectives included assessing pCR rates and identifying prognostic factors. Among NAC recipients, we observed similar pCR rates (47.6 % vs. 49.4 %, p = 0.88) between IBC (n = 84) and matched non-IBC (n = 81) cohorts. However, we noted a significant worsening of OS (p = 0.0001), RFS (p = 0.0001), and DRFS (p = 0.001) in the IBC group. Specifically, 5-year OS in the IBC cohort was 58.9 % vs. 86.7 % for matched controls (p = 0.0003). Older age was a weak negative predictor for OS (HR 1.03, p = 0.001) and RFS (HR 1.02, p = 0.01). For DRFS, older age was also a weak negative predictor (HR 1.02, p = 0.02), whereas the use of NAC was a positive predictor (HR 0.47, p = 0.02). Despite no clear difference in pCR, survival outcomes remain poor for IBC compared to matched non-inflammatory controls.

The Significance of Recognition of Human Epidermal Growth Factor 2 Low in Breast Cancer Therapy.

In response to recent clinical trials that demonstrate the clinical benefit of antibody-drug conjugate drug therapy in breast cancer (BC) with human epidermal growth factor 2 (HER2) immunohistochemical scores of 1+ or 2+ and negative in situ hybridization results, a new concept of "HER2-low BC" has emerged to describe this newly relevant therapeutic category of BC. Clinical recognition of HER2-low BC has caused a paradigm shift in the therapeutic landscape and management of patients with BC and resulted in rapid changes in clinical practice guidelines. In addition the American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) recently updated their HER2 Guidelines Recommendations to specifically address HER2-low BC. A literature search in PubMed of peer-reviewed articles, regulatory communications, and relevant practice guidelines pertaining to HER2-low BC was conducted. In this review, we have summarized current published knowledge regarding the clinicopathologic and molecular features, diagnostic criteria, and most current guideline recommendations regarding HER2-low BC, and also highlight ongoing practical and diagnostic challenges when identifying HER2-low BC in routine clinical practice.

NRK-ABMIL: Subtle Metastatic Deposits Detection for Predicting Lymph Node Metastasis in Breast Cancer Whole-Slide Images.

The early diagnosis of lymph node metastasis in breast cancer is essential for enhancing treatment outcomes and overall prognosis. Unfortunately, pathologists often fail to identify small or subtle metastatic deposits, leading them to rely on cytokeratin stains for improved detection, although this approach is not without its flaws. To address the need for early detection, multiple-instance learning (MIL) has emerged as the preferred deep learning method for automatic tumor detection on whole slide images (WSIs). However, existing methods often fail to identify some small lesions due to insufficient attention to small regions. Attention-based multiple-instance learning (ABMIL)-based methods can be particularly problematic because they may focus too much on normal regions, leaving insufficient attention for small-tumor lesions. In this paper, we propose a new ABMIL-based model called normal representative keyset ABMIL (NRK-ABMIL), which addresseses this issue by adjusting the attention mechanism to give more attention to lesions. To accomplish this, the NRK-ABMIL creates an optimal keyset of normal patch embeddings called the normal representative keyset (NRK). The NRK roughly represents the underlying distribution of all normal patch embeddings and is used to modify the attention mechanism of the ABMIL. We evaluated NRK-ABMIL on the publicly available Camelyon16 and Camelyon17 datasets and found that it outperformed existing state-of-the-art methods in accurately identifying small tumor lesions that may spread over a few patches. Additionally, the NRK-ABMIL also performed exceptionally well in identifying medium/large tumor lesions.

The Immunomodulatory Effects of Dexamethasone on Neoadjuvant Chemotherapy for Triple-Negative Breast Cancer.

INTRODUCTION: The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. METHODS: We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. RESULTS: In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used. CONCLUSION: Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status.

BCR-Net: A deep learning framework to predict breast cancer recurrence from histopathology images.

Breast cancer is the most common malignancy in women, with over 40,000 deaths annually in the United States alone. Clinicians often rely on the breast cancer recurrence score, Oncotype DX (ODX), for risk stratification of breast cancer patients, by using ODX as a guide for personalized therapy. However, ODX and similar gene assays are expensive, time-consuming, and tissue destructive. Therefore, developing an AI-based ODX prediction model that identifies patients who will benefit from chemotherapy in the same way that ODX does would give a low-cost alternative to the genomic test. To overcome this problem, we developed a deep learning framework, Breast Cancer Recurrence Network (BCR-Net), which automatically predicts ODX recurrence risk from histopathology slides. Our proposed framework has two steps. First, it intelligently samples discriminative features from whole-slide histopathology images of breast cancer patients. Then, it automatically weights all features through a multiple instance learning model to predict the recurrence score at the slide level. On a dataset of H&E and Ki67 breast cancer resection whole slides images (WSIs) from 99 anonymized patients, the proposed framework achieved an overall AUC of 0.775 (68.9% and 71.1% accuracies for low and high risk) on H&E WSIs and overall AUC of 0.811 (80.8% and 79.2% accuracies for low and high risk) on Ki67 WSIs of breast cancer patients. Our findings provide strong evidence for automatically risk-stratify patients with a high degree of confidence. Our experiments reveal that the BCR-Net outperforms the state-of-the-art WSI classification models. Moreover, BCR-Net is highly efficient with low computational needs, making it practical to deploy in limited computational settings.

Masson's tumor of the reconstructed breast.

Intravascular papillary endothelial hyperplasia (Masson's Tumor) is a rare benign endothelial vascular lesion that can mimic angiosarcoma if not properly recognized. It represents less than 2% of all vascular tumors, but has been seen in the postradiation setting, which also makes differentiating it from angiosarcoma crucial. It is classically characterized as a circumscribed, intravascular mass that is hypoechoic on ultrasound, and T1 isointense and T2 heterogenous on MRI with variable enhancement. Histologically, it demonstrates papillary architecture without significant atypia, and associated vascular thrombus. Although it typically occurs in the soft tissues of the trunk and neck, a very small percentage of cases have been found in the breast. The following case will involve a 64-year-old female with a Masson's tumor involving the capsule of her left breast implant, in the setting of previously treated ductal carcinoma in situ, which was surgically excised and irradiated over 20 years prior.

Incidence, Clinicopathologic Features, HER2 Fluorescence In Situ Hybridization Profile, and Oncotype DX Results of Human Epidermal Growth Factor Receptor 2-Low Breast Cancers: Experience From a Single Academic Center.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer, defined by an immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization, is emerging as a predictive marker for the use of the antibody-drug conjugate. To understand how this category differs from HER2-zero cases, we investigated clinicopathological characteristics and HER2 fluorescence in situ hybridization results in a large cohort of 1309 continuous HER2-negative invasive breast carcinomas from 2018 to 2021 evaluated by the Food and Drug Administration-approved HER2 IHC test. Additionally, we compared Oncotype DX recurrence scores and HER2 mRNA expression between HER-low and HER2-zero cases in a separate cohort of 438 estrogen receptor-positive (ER+) early-stage breast carcinoma cases from 2014 to 2016. Based on the cohort from 2018 to 2021, the incidence of HER2-low breast cancers was approximately 54%. HER2-low cases had less frequent grade 3 morphology, less frequent triple-negative results, ER and progesterone receptor negativity, and a higher mean HER2 copy number and HER2/CEP17 ratio than HER2-zero cases (P < .0001). Among ER+ cases, HER2-low cases showed significantly less frequent Nottingham grade 3 tumors. In the cohort from 2014 to 2016, HER2-low cases showed significantly higher ER+ percentages, fewer progesterone receptor-negative cases, lower Oncotype DX recurrence scores, and higher HER2 mRNA expression scores than HER2-zero cases. In summary, this is the first study, to our knowledge, using a large cohort of continuous cases evaluated by the Food and Drug Administration-approved HER2 IHC companion diagnostic test for HER2-low expression and HER2 fluorescence in situ hybridization profile in a real-world setting. Although HER2-low cases showed a higher HER2 copy number, ratio, and mRNA level than HER2-zero cases statistically, such small differences are unlikely to be biologically or clinically meaningful. However, our study suggests that HER2-low/ER+ early-stage breast carcinoma may represent a less aggressive group of breast carcinoma, given its association with a lower Nottingham grade and Oncotype DX recurrence score.

Anastomosing hemangioma: A case report of a benign tumor often misdiagnosed as a malignant epithelioid angiosarcoma.

Anastomosing hemangioma (AH), a rare benign genitourinary tract hemangioma is subject to frequent misdiagnosis due to its rarity and clinical, histological, and immunohistochemical similarities it shares with several diagnoses, including well-differentiated angiosarcoma (AS). This is particularly true of angiosarcoma, nearly identical to AH when presented in tissue samples of limited size. Lack of specific clinical and radiologic manifestations on initial preoperative assessment, coupled with limited diagnostic experience or awareness, can lead to misinterpretation of this entity, potentially leading to unnecessary clinical management. We present an initial misdiagnosis of AS which, upon review of the entire lesion, was identified as AH.

What's new in breast pathology 2022: WHO 5th edition and biomarker updates.

The 5th edition WHO Classification of Breast Tumours (2019) has introduced changes to our practices. Highlights are presented below, with a focus on modifications to morphological subtype categorization. In addition, we summarize important updates to ER and PR testing made in the 2020 ASCO/CAP guidelines, and briefly discuss PD-L1 and Ki-67 testing in breast cancer.

Evaluating Mismatch Repair Status to Screen Clinical Advanced Breast Carcinomas for Immunotherapy: Experience From a Large Academic Institution.

BACKGROUND: Very few studies have investigated mismatch repair (MMR) deficiency in breast carcinoma (BC) in clinical setting. Given the recent approval of Pembrolizumab for solid tumors with MMR deficiency, we screened clinically advanced breast carcinoma patients for immunotherapy by examining their MMR status. PATIENTS AND METHODS: The cohort consisted of 163 clinical advanced BCs, including 5 primary, 14 locally recurrent, and 144 metastatic BCs. Immunohistochemistry (IHC) with anti-MMR proteins or next generation sequencing (NGS) to detect microsatellite instability was performed to evaluate MMR status. The relationship between MMR status and clinicopathologic characteristics was evaluated. RESULTS: Among 163 advanced BCs, 19 were hormone receptor (HR)-positive (≥ 10%)/HER2-negative, 17 were HER2+, and 127 were TNBCs/low HR-positive (< 10%). MMR status was evaluated by IHC in 131 cases and by NGS in 32 cases. Among all cases, only 1 case (0.6%) showed MMR deficiency. The case with MMR deficiency showed loss of MLH1 and PMS2 proteins, but no hypermethylation of MLH1 promoter. Sequencing analysis revealed MLH1 genetic alteration with a splice site mutation (208-1G > A), which results in disruption of the N-terminal ATPase-containing domain (amino acids 25-336). All 127 TNBCs/low HR-positive BCs showed preserved MMR. PD-L1 (SP142) testing was performed in 66 cases with 18 (27%) as positive and 48 (73%) as negative, and its expression showed no correlation with MMR status. CONCLUSION: MMR deficiency exists in an extremely low percentage of breast carcinomas, including TNBCs, suggesting a routine MMR testing to screen BC patients for immunotherapy may not be cost effective.

Ductal carcinoma in situ (DCIS) presenting as a cystic retroareolar lesion in an African American man.

Ductal carcinoma in situ (DCIS) in males is rare, and there are limited data aimed at understanding the adequate workup, imaging, and follow-up for men who present with breast masses. Attention should be given to black men who have a higher cancer risk and worse prognosis than white male counterparts.

Comprehensive Review of Molecular Mechanisms and Clinical Features of Invasive Lobular Cancer.

Invasive lobular carcinoma (ILC) accounts for 10% to 15% of breast cancers in the United States, 80% of which are estrogen receptor (ER)-positive, with an unusual metastatic pattern of spread to sites such as the serosa, meninges, and ovaries, among others. Lobular cancer presents significant challenges in detection and clinical management given its multifocality and multicentricity at presentation. Despite the unique features of ILC, it is often lumped with hormone receptor-positive invasive ductal cancers (IDC); consequently, ILC screening, treatment, and follow-up strategies are largely based on data from IDC. Despite both being treated as ER-positive breast cancer, querying the Cancer Genome Atlas database shows distinctive molecular aberrations in ILC compared with IDC, such as E-cadherin loss (66% vs. 3%), FOXA1 mutations (7% vs. 2%), and GATA3 mutations (5% vs. 20%). Moreover, compared with patients with IDC, patients with ILC are less likely to undergo breast-conserving surgery, with lower rates of complete response following therapy as these tumors are less chemosensitive. Taken together, this suggests that ILC is biologically distinct, which may influence tumorigenesis and therapeutic strategies. Long-term survival and clinical outcomes in patients with ILC are worse than in stage- and grade-matched patients with IDC; therefore, nuanced criteria are needed to better define treatment goals and protocols tailored to ILC's unique biology. This comprehensive review highlights the histologic and clinicopathologic features that distinguish ILC from IDC, with an in-depth discussion of ILC's molecular alterations and biomarkers, clinical trials and treatment strategies, and future targets for therapy. IMPLICATIONS FOR PRACTICE: The majority of invasive lobular breast cancers (ILCs) are hormone receptor (HR)-positive and low grade. Clinically, ILC is treated similar to HR-positive invasive ductal cancer (IDC). However, ILC differs distinctly from IDC in its clinicopathologic characteristics and molecular alterations. ILC also differs in response to systemic therapy, with studies showing ILC as less sensitive to chemotherapy. Patients with ILC have worse clinical outcomes with late recurrences. Despite these differences, clinical trials treat HR-positive breast cancers as a single disease, and there is an unmet need for studies addressing the unique challenges faced by patients diagnosed with ILC.

Residual breast tissue after robot-assisted nipple sparing mastectomy.

INTRODUCTION: While the long-term oncologic safety of robot-assisted nipple sparing mastectomy (RNSM) remains to be elucidated, histologically detected residual breast tissue (RBT) can be a surrogate for oncologically sound mastectomy. The objective of this study is to determine the presence of RBT after RNSM. METHODS: Between August 2019-January 2020, we completed 5 cadaveric RNSMs. Full thickness biopsies from the mastectomy skin flap were obtained from predefined locations radially around the mastectomy skin envelop and nipple areolar complex to histologically evaluate for RBT. RESULTS: The first case was not technically feasible due to inability to obtain adequate insufflation. Five mastectomy flaps were analyzable. The average mastectomy flap thickness was 2.3 mm (range 2-3 mm) and the average specimen weight was 382.72 g (range 146.9-558.3 g). Of 70 total biopsies, RBT was detected in 11 (15.7%) biopsies. Most common location for RBT was in the nipple-areolar complex, with no RBT detected from the peripheral skin flaps. CONCLUSIONS: In this cadaveric study, RNSM is feasible leaving minimal RBT on the mastectomy flap. The most common location for RBT is in the periareolar location consistent with previous published findings after open NSM. Clinical studies are underway to evaluate the safety of RNSM.

Features, Outcomes, and Management Strategies of Male Breast Cancer: A Single Institution Comparison to Well-Matched Female Controls.

OBJECTIVE: The primary objective of this study was to delineate differences in management, overall and distant disease-free survival in males diagnosed with breast cancer and treated at The Ohio State University Comprehensive Cancer Center as compared to comprehensively matched female subjects. Secondary objectives included assessment of clinical and histopathologic features and recurrence score, as measured by Oncotype DX and the modified Magee equation #2. MATERIALS AND METHODS: This single institution retrospective study compared male and comprehensively matched female patients (1:2) with stage I-III breast cancer between 1994 and 2014. Recurrence risk was estimated using a modified Magee equation. Overall survival and distant disease-free survival were estimated and compared using Kaplan-Meier and Log-rank methods. RESULTS: Forty-five male breast cancer patients were included (stage I: 26.7%; stage II: 53.3%; stage III: 20.0%; hormone receptor positive: 97.8%; human epidermal growth factor receptor 2 negative: 84.4%) with a median age of 63.8 (43.0-79.4) years at diagnosis. Intermediate and low recurrence scores were most common in male and female patients respectively; mean score was similar between groups (20.3 vs. 19.8). The proportion of male breast cancer patients treated with adjuvant chemotherapy and post-mastectomy radiation was lower compared to female patients (42.2% vs. 65.3%, p=0.013; 22.7% vs. 44.4%, p=0.030, respectively). Overall survival and distant disease-free survival between male and female patients were similar. CONCLUSION: Male breast cancer patient outcomes were similar compared to well-matched female patients suggesting that breast cancer specific factors are more prognostic than gender.

TTF-1 Positive Primary Small Cell Carcinoma of the Breast: A Case Report and Review of the Literature.

Primary small cell carcinoma of the breast (SCCB) is a rare tumor subtype comprising <0.1% of all breast carcinomas. Here we present a case of thyroid transcription factor-1 (TTF-1) positive SCCB that recurred within 3 years of diagnosis in the lung and lymph nodes. Given the small number of cases, no clear guidelines exist on the appropriate management of patients with these aggressive tumors. We present a case study and review the current literature to highlight the knowledge gaps and needs of patients with these rare tumors. A 50-year-old premenopausal woman with no family history, presented with a palpable right breast mass. Biopsy was consistent with primary SCCB that was poorly differentiated, positive for synaptophysin and chromogranin and TTF-1 and presence of ductal carcinoma in situ component showing neuroendocrine differentiation. Imaging with PET, CT, and MRI brain excluded any other sites of primary disease. She underwent a right lumpectomy with axillary lymph node dissection and was treated with adjuvant cisplatin-based chemotherapy and concurrent radiation therapy. Thirty-four months later, routine scans showed a new right lower-lobe lung nodule and an enlarged sub-carinal node that was proven to be poorly differentiated neuroendocrine cancer. This case report sheds light on a rarely described disease and provides a comprehensive approach to diagnosis and management. Primary SCCB is an extremely rare, aggressive form of breast cancer that is molecularly and histologically similar to SCLC. However, a review of the literature highlights recent mutational analyses that show important differences between these two cancer types, including an increase in PIK3CA mutations in primary SCCB. Further studies, including genomic analyses are needed to better define this malignancy and to develop a standard treatment.

Diagnostic terminology used to describe atypia on breast core needle biopsy: correlation with excision and upgrade rates.

BACKGROUND: Subjective qualitative descriptors are sometimes used to describe atypical breast lesions diagnosed on core needle biopsy (CNB) which are limited in extent. In clinical practice, this terminology is used to imply a lower expected risk of upgrade on surgical excision (EXC). It is uncertain how subjective terminology impacts clinical management. METHODS: We conducted a retrospective review of CNB with atypia and compared the EXC and upgrade rates of atypical ductal hyperplasia (ADH) and flat epithelial atypia (FEA) to lesions described as "focal" atypical ductal hyperplasia (FADH), to determine the impact of this diagnostic phrasing on surgical management and risk of malignancy. RESULTS: FADH and ADH were excised at similar rates (82% vs. 78%). FADH lesions showed a similar upgrade rate (13%) compared to non-focal ADH (10%), and both showed a trend towards higher upgrade and EXC rates compared to FEA. ADH, FADH and FEA all had an upgrade risk that warranted EXC. In non-upgraded EXC, for each diagnostic category we observed similar rates of residual atypia in the EXC. CONCLUSIONS: Pathologists should avoid the use of qualitative descriptors when describing ADH on CNB because of the potential of this terminology to influence clinical decision making which is unwarranted.

Impact of the 2018 ASCO/CAP HER2 Guideline Focused Update.

OBJECTIVES: The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) human epidermal growth factor receptor 2 (HER2) guideline focused update revises the HER2 scoring criteria. We evaluated the impact on HER2 rates in breast carcinoma diagnosed at our center. METHODS: In a retrospective series of breast core biopsies with invasive carcinoma diagnosed between 2014 and 2017 (n = 1,350), HER2 status was classified according to 2013 and 2018 ASCO/CAP guidelines and changes in HER2 status identified. RESULTS: The 2018 guidelines reclassified the HER2 status of 6% of patients. Most changed from HER2 equivocal status (equivocal by immunohistochemistry and fluorescence in situ hybridization under the 2013 guidelines) to HER2-negative status (2018 guidelines). The HER2-positive rate decreased by 0.4%. CONCLUSIONS: The 2018 guidelines decrease the rate of HER2 equivocal and positive breast cancer and reduce repeat HER2 testing on excision specimens. Approximately 0.4% of patients will become newly ineligible for anti-HER2 therapy.

Identification of HER2 Immunohistochemistry-Negative, FISH-Amplified Breast Cancers and Their Response to Anti-HER2 Neoadjuvant Chemotherapy.

Objectives: Either immunohistochemistry (IHC) or in situ hybridization (ISH) can be used to determine human epidermal growth factor receptor 2 (HER2) status. Breast cancers (BCs) with HER2 IHC-negative (IHC-) and ISH-amplified (ISH+) results have been rarely reported but not well studied. We investigated the frequency of HER2 IHC-/ISH+ BCs and their response to anti-HER2 neoadjuvant chemotherapy (NAC). Methods: Seventeen BCs with HER2 IHC-/ISH+ results were identified from 1,107 consecutive invasive BCs (1.5%, 17/1,107). Results: Gene protein assay confirmed the original HER2 IHC and ISH results. Increased HER2 RNA level was detected in HER2 IHC-/ISH+ cases compared with HER2 IHC-/ISH- cases. Eight patients had anti-HER2 NAC; three had pathologic complete response, and five had residual tumors. Conclusions: A small percentage of patients (1.5%) showed discordant HER2 IHC and ISH results (IHC-/ISH+) and would have lost the opportunity for potentially beneficial anti-HER2-targeted therapy if only HER2 IHC testing had been used.