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Ground breaking advances in medicine, driven in part by major technologic developments in molecular biology have led us to a new model for cancer care that has been termed personalized, or precision medicine. Precision medicine is a model for making medical decisions that employs an innovative clinical approach and advanced tumor testing methods that are tailored to understanding an individual patient's tumor biology and the molecular drivers of their disease. This medical model includes a combination of diagnostic testing and specific treatment options that can be offered to patients at presentation and in theory throughout the course of their disease as new mutations arise with the development of disease recurrence. Although the precision medicine model offers incredible potential to transform cancer care, these advances are only meaningful when they reach the correct patients. The evolving paradigm of precision medicine is changing the practice of pathology, and the pathology community needs to be mindful of these changes because every tissue specimen represents a patient's life, and those patients are depending on the pathology community to handle their tissue correctly. The diagnostic tests performed in the pathology laboratory for precision medicine are increasingly complex, and pathologists along with the entire laboratory and clinical communities need to take steps to ensure that the right diagnosis is given to the right patient to inform the right treatment options, at the right time, along every step of the continuum of care for cancer patients. While hormone receptors and human epidermal growth factor receptor 2 (HER2) overexpression and/or amplification have been the mainstay for risk-stratification, and treatment decision making in breast cancer since the early 2000's, the seminal work on gene expression by Perou and colleagues in the early 2000's opened the door for molecular testing in the prognostic and predictive assessment of breast cancer. Molecular testing is now part of the standard of care in the precision medicine model for breast cancer care. In this article, the reader will gain a better understanding of how the lack of standardization of pre-analytic factors has the potential to negatively impact the quality of the tissue specimen for downstream biomarker and molecular testing, which ultimately can negatively affect patient care. The reader will also gain insight into the current climate surrounding molecular testing in breast cancer.

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Breast cancer (BC) with average human epidermal growth factor receptor 2 (HER2) signals/cell ≥6 and HER2/chromosome enumeration probe 17 (CEP17) ratio <2 (in situ hybridization [ISH] group 3) is very rare, accounting for 0.4% to 3.0% of cases sent for the dual-probe ISH assay. Although such patients are currently eligible for treatment with HER2-targeted therapy, their characteristics and outcomes remain poorly understood. Sixty-two BCs with equivocal HER2 immunohistochemical score (2+) and reflex ISH group 3 results were identified across 4 institutions. Available clinicopathologic characteristics, MammaPrint and BluePrint molecular results, and follow-up information were retrospectively analyzed. Most BCs with HER2 equivocal immunohistochemical and ISH group 3 results were histologic grade 2 or 3 (100%), estrogen receptor (ER) positive (90.3%), with an average HER2 signals/cell of 7.3. Molecular profiles revealed that 80% (16/20) of tumors were luminal subtypes, and HER2 molecular subtype was identified in 10% of tumors (2/20). Twelve (19.4%) out of 62 patients developed local recurrence and/or distant metastasis with a median follow-up of 50 months. One (10%) of 10 patients achieved pathologic complete response after neoadjuvant chemotherapy. Forty-nine (79%) out of 62 patients completed anti-HER2 agents, and exploratory analysis showed no statistically significant difference in disease outcomes between patients who completed anti-HER2 treatment and those who did not. Univariate analysis revealed advanced clinical stage, and ER/progesterone receptor negativity was associated with unfavorable disease outcomes, and exploratory multivariate analysis demonstrated that clinical stage was the most significant factor associated with disease outcomes in the studied population. These findings increase our understanding of this rare, but clinically important HER2 category. Large-scale prospective randomized studies are needed to further evaluate the role of perioperative HER2-targeted therapy in this patient population.

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We compared the performance of two commonly-used HER2 immunohistochemistry (IHC) assays in uterine serous carcinomas (USC), correlating with HER2 gene amplification by fluorescence in-situ hybridization (FISH). Sixty-five USCs were stained by both HercepTest™ and PATHWAY 4B5 assays. FISH was performed by HER2 IQFISH pharmDx. Consensus HER2 IHC scoring was performed, and HER2 testing results were evaluated using USC-specific criteria. Complete concordance between HercepTest and 4B5 assays was achieved in 44/65 tumors (68%). The overall HER2 IHC/FISH concordance was 94% (45/48) by HercepTest and 91% (42/46) by 4B5. All HER2 IHC 3+ cases with HercepTest (n = 6) and 4B5 (n = 4) were gene-amplified, corresponding to specificities of 100%. For cases with IHC 2+, 41% (7/17) by HercepTest and 42% (8/19) by 4B5 had HER2 gene amplification. The sensitivity for HercepTest and 4B5 were 38% and 25%, respectively, at a cut-off of IHC 3+ (P = 0.50), and were 81% and 75%, respectively, at a cut-off of IHC 2+ (P > 0.99). Among HER2 IHC 0-1+ cases, 3/42 cases by HercepTest and 4/42 cases by 4B5 showed amplified FISH results, corresponding to overall false negative rates of 19% for HercepTest and 25% for 4B5. By using USC-specific IHC scoring criteria, both HercepTest and 4B5 assays showed high specificities (100%) for HER2 gene amplification in IHC 3+ cases, high IHC/FISH concordance, and comparable sensitivity for detecting HER2 gene amplification. The notable false negative rates using IHC 2+ as a cut-off for reflexing FISH analysis may warrant consideration for performing FISH in IHC 1+ cases until more data become available.

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The significant clinical benefits of human epidermal growth factor receptor 2 (HER2)-targeted therapeutic agents have revolutionized the clinical treatment landscape in a variety of human solid tumours. Accordingly, accurate evaluation of HER2 status in these different tumour types is critical for clinical decision making to select appropriate patients who may benefit from life-saving HER2-targeted therapies. HER2 biomarker scoring criteria is different in different organ systems, and close adherence to the corresponding HER2 biomarker testing guidelines and their updates, if available, is essential for accurate evaluation. In addition, knowing the unusual patterns of HER2 expression is also important to avoid inaccurate evaluation. In this review, we discuss the key considerations when evaluating HER2 status in solid tumours for clinical decision making, including tissue handling and preparation for HER2 biomarker testing, as well as pathologist's readout of HER2 testing results in breast carcinomas, gastroesophageal adenocarcinomas, colorectal adenocarcinomas, gynaecologic carcinomas, and non-small cell lung carcinomas.

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With the approval of trastuzumab deruxtecan for treating advanced human epidermal growth factor receptor-2 (HER2) low breast cancer (BC), it has become increasingly important to develop more accurate and reliable methods to identify HER2-low BC. In addition, HER2 immunohistochemistry (IHC) has limitations for quantification of HER2. We explored the relationship between HER2 IHC and mRNA levels and evaluated whether HER2 IHC scores and mRNA levels are associated with clinicopathologic features and Oncotype DX Recurrence Score (RS) in estrogen receptor (ER)-positive, HER2-negative BCs. A total of 750 BCs sent for Oncotype DX (ODX) testing were included in this study, and 559 with HER2 mRNA levels were available. There were no statistically significant differences between HER2 0 and HER2-low BC in clinicopathologic variables or ODX RS using HER2 IHC. There was a significant difference in median HER2 mRNA values between HER2 0 and HER2-low (8.7 vs 9.3, P < .001); however, the HER2 mRNA distribution had substantial overlap between these 2 groups with a suboptimal area under the receiver operating characteristic curve (area under the receiver operating characteristic curve = 0.68). A HER2 mRNA value of 9.2 was generated as the optimal cutoff for distinguishing HER2 0 and HER2-low BC. Comparing ER+ BCs with HER2 mRNA high (>9.2) and low (≤9.2) revealed a statistically significant difference in most clinicopathologic variables and ODX RS. From this large cohort of ER-positive, HER2-negative BC, our results demonstrated that HER2 mRNA levels correlated better with clinicopathologic features and recurrence risk as assessed by ODX RS than HER2 IHC scores. Our findings suggest that HER2 mRNA-detecting methods could potentially serve as a quantitative and reliable method for identifying a biologically meaningful group of HER2-low BC. Further study is needed to determine whether HER2 mRNA levels could be more reliable than IHC for identifying which patients will be most likely to benefit from trastuzumab deruxtecan.

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Understanding the changes of HER2 expression after neoadjuvant chemotherapy (NAC) in breast cancer (BC) is more important than ever, since it may allow more patients to access the effective therapeutic drugs targeting HER2-low BC. 192 matched pre- and post-NAC BCs were analyzed. HER2 immunohistochemistry (IHC) was re-evaluated with consensus according to the current ASCO/CAP guidelines. Tumors were categorized into HER2-0 (IHC0+), HER2-low (IHC1+ or IHC2+/ISH-) and HER2-positive (IHC3+ or IHC2+/ISH+) subgroups. 55 (28.6 %) patients achieved pathologic complete response (pCR). HER2-low BC accounted for 75/192 (39.1 %) baseline tumors, and 48/133 (36.1 %) residual tumors. In the non-pCR cohort, 53 (39.9 %) patients had HER2 categorical change after NAC, most commonly converting from HER2-low to HER2-0 (20.3 %, n = 27). Among patients with residual tumor, 25.6 % (11/43) of patients with baseline HER2-0 expression experienced a categorical change to HER2-low after NAC, significantly higher (p < 0.05) in the hormone receptor (HR) positive (9/23, 39.1 %) compared to the HR negative tumors (10 %, 2/20). Exploratory analysis failed to reveal a statistically significant difference in disease free survival and overall survival in non-pCR patients with or without HER2 change. Our results suggest that a substantial number of patients may experience HER2 categorical change after NAC, supporting re-testing of HER2 status in post-NAC residual tumors. Retesting HER2 status may be particularly important for evaluating post-NAC HER2-low status, in order to better assess which patients will more likely benefit from therapeutic drugs targeting HER2-low BC.

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Uterine involution has 2 major components-(1) involution of vessels; and (2) involution of myometrium. Involution of vessels was addressed by Rutherford and Hertig in 1945; however, involution of myometrium has received little attention in the modern literature. We suggest that the pathophysiology of myometrial involution may lead to uterine atony and postpartum hemorrhage. The myometrium dramatically enlarges due to gestational hyperplasia and hypertrophy of myocytes, caused by hormonal influences of the fetal adrenal cortex and the placenta. After delivery, uterine weight drops rapidly, with physiologic involution of myometrium associated with massive destruction of myometrial tissue. The resulting histopathology, supported by scientific evidence, may be termed "postpartum metropathy," and may explain the delay of postpartum menstrual periods until the completion of involution. When uterine atony causes uncontrolled hemorrhage, postpartum hysterectomy examination may be the responsibility of the perinatal pathologist.Postpartum metropathy may be initiated when delivery of the baby terminates exposure to the hormonal influence of the fetal adrenal cortex, and may be accelerated when placental delivery terminates exposure to human chorionic gonadotrophin (HCG). This hypothesis may explain why a prolonged third stage of labor, and delays in management, are risk factors for severe hemorrhage due to uterine atony.

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OBJECTIVES: Uterine cancer has the highest incidence and the second-highest mortality rate among gynecologic malignancies in the United States. Although uterine serous carcinoma (USC) represents less than 10% of endometrial carcinomas, it accounts for a disproportionate 50% of tumor relapses and 40% of endometrial cancer deaths. Over the past decade, clinical trials have focused on finding better treatments for this aggressive subtype of endometrial cancer, especially HER2-targeted therapy. METHODS: We conducted a literature search in PubMed to expand the understanding of HER2 in USC. RESULTS: HER2 has been established as an important biomarker with prognostic and therapeutic implications in USC. Intratumoral heterogeneity and lateral/basolateral membranous staining of HER2 as well as high discordance between HER2 immunohistochemistry and in situ hybridization are more common in USC than in breast carcinoma. Therefore, a universal HER2 testing and scoring system more suitable to endometrial cancer is needed and currently under investigation. CONCLUSIONS: This review discusses the clinical perspective of HER2 overexpression/gene amplification in USC, the distinct HER2 staining pattern and the evaluation of HER2 in USC, the resistance mechanisms of HER2-targeted therapy in HER2-positive cancers, and likely areas of future investigation.

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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.

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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.

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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.

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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.

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Breast cancer is the most common invasive cancer in women, with most deaths attributed to metastases. Neoadjuvant chemotherapy (NACT) may be prescribed prior to surgical removal of the tumor for subsets of breast cancer patients but can have diverse undesired and off-target effects, including the increased appearance of the 'tumor microenvironment of metastasis', image-based multicellular signatures that are prognostic of breast tumor metastasis. To assess whether NACT can induce changes in two other image-based prognostic/predictive signatures derived from tumor collagen, we quantified second-harmonic generation (SHG) directionality and fiber alignment in formalin-fixed, paraffin-embedded sections of core needle biopsies and primary tumor excisions from 22 human epidermal growth factor receptor 2-overexpressing (HER2+) and 22 triple-negative breast cancers. In both subtypes, we found that SHG directionality (i.e., the forward-to-backward scattering ratio, or F/B) is increased by NACT in the bulk of the tumor, but not the adjacent tumor-stroma interface. Overall collagen fiber alignment is increased by NACT in triple-negative but not HER2+ breast tumors. These results suggest that NACT impacts the collagenous extracellular matrix in a complex and subtype-specific manner, with some prognostic features being unchanged while others are altered in a manner suggestive of a more metastatic phenotype.

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Myometrial morphology and myometrial physiology have been considered to be separate entities; however, observations of myometrial morphology and associated dysfunctions suggest a relationship between myometrial morphology and myometrial physiology that deserves further exploration. Although myometrial electrical activity can be monitored by electrohysterogram, the association of increased myometrial contractions with an increase in electrical activity (due to an increase in gap junctions) is typically not evaluated. Although the association of increased myometrial contractions with increase in pain can be monitored by tocometry and intrauterine pressure catheters, respectively, this is generally not done in the non-pregnant uteri. Although standard morphologic evaluations routinely include evaluation with special stains and immunohistochemistry in other organ systems, such as skeletal and cardiac muscle, these evaluations are not standard or routine for myometrium in hysterectomies. The purpose of this review is to discuss non-neoplastic myometrial histology, with consideration of the potential value of using tools to measure variations in myometrial physiology, in order to reliably correlate myometrial histology with myometrial function (and dysfunction).

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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.

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AIMS: Management of anal dysplasia relies upon the accurate diagnosis of anal biopsy specimens. As institutions move towards subspecialty signout (SSSO), decisions must be made regarding whether to assign anal biopsies to the gastrointestinal (GI) or gynaecological (GYN) pathology service. MATERIALS AND RESULTS: We identified 200 archival tissue biopsies of anal mucosa and circulated them among three GI pathologists and three GYN pathologists. Each pathologist separately scored each biopsy as normal, atypical, low-grade squamous intra-epithelial lesion (LSIL) or high-grade squamous intra-epithelial lesion (HSIL). Every case that was called HSIL by at least one pathologist was stained with p16 immunostain and a 'gold standard' interpretation of whether or not a case represented HSIL was made. The GI pathologists agreed on 97 (49%) cases prior to consensus; the GYN pathologists agreed on 33 (17%). The sensitivities of the three GI pathologists in detecting HSIL against the 'gold standard' were 47, 100 and 21% and for the GYN pathologists the sensitivities were 74, 89 and 84%; the sensitivities of the GI and GYN consensus diagnoses were 74% each. The specificities of the three GI pathologists in detecting HSIL were 99, 90 and 100% and for the GYN pathologists the specificities were 99, 92 and 91%; the specificities of both the GI and GYN consensus diagnoses were 100%. CONCLUSIONS: A mild to moderate degree of interobserver variability exists in the diagnosis of anal dysplasia among pathologists. Our study indicates the utility of some form of consensus conference, as overall agreement among GI pathologists and among GYN pathologists improved following in-person consensus.

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Apoplectic leiomyomas-benign uterine leiomyomas with morphologic changes including hemorrhage, hypercellularity, mitotic activity, nuclear atypia, and even necrosis-can be difficult to distinguish from uterine leiomyosarcomas. Apoplectic leiomyomas have been associated with hormonal therapy; however, the relationship between apoplectic leiomyomas, hormones, and ethnicity has not received much attention in the literature. We evaluated the relationship of hormonal therapy and ethnicity in 869 women with uterine leiomyomas, 136 of which qualified as apoplectic leiomyomas.Apoplectic leiomyomas were observed in 23.3% (49/210) of women exposed to hormonal therapy compared to 13.2% (87/659) of women not exposed to hormonal therapy (p < 0.0001). Women taking ethinyl estradiol/norethindrone (Lo-Estrin), leuprolide, and medroxyprogesterone were significantly more likely to have apoplectic leiomyomas compared to women taking other hormonal therapies. Apoplectic leiomyomas were observed in 28.9% (44/152) of African-American women compared to 12.4% (79/639) of Caucasian women (p < 0.0001), and this difference remained statistically significant regardless of hormone use. Apoplectic leiomyomas were observed in 22.1% (77/349) of women ≤ 45 years of age compared to 11.3% (59/520) of women > 45 years of age (p < 0.0001), and this difference remained statistically significant regardless of hormone use.This is the largest study to date examining apoplectic leiomyomas in women on known hormonal therapy compared to women with uterine leiomyomas, but not on hormonal therapy. Information about hormonal therapy, ethnicity, and age can be helpful in the diagnostic interpretation of apoplectic leiomyoma.

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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.

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We investigate L1 cell adhesion molecule (L1CAM) expression in estrogen receptor (ER)-positive/human epidermal growth factor receptor (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. 304 cases comprising 152 cases of ER-positive, progesterone receptor (PR)-positive/negative, and HER2-negative recurrent/metastatic breast carcinomas and 152 nonrecurrent 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. L1CAM positive cases showed increased specificity for recurrence and these patients were significantly younger than L1CAM negative ones. Compared with 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 with 67.3% of the L1CAM negative cases. 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.

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It has been suggested that impaired venous drainage and endometrial vascular ectasia (EMVE), secondary to increased intramural pressure, explains abnormal bleeding in fibroid uteri. Striking EMVE with extravasated red blood cells (ecchymosis) has also been seen in uteri with grossly obvious myometrial hyperplasia (MMH), suggesting that increased intramural pressure can cause EMVE in the absence of fibroids. EMVE with MMH may explain the century old association of clinically enlarged uteri with abnormal bleeding, and this same mechanism may be operative in myopathic uteri with grossly obvious adenomyosis. EMVE with associated thrombosis, ecchymosis, and/or stromal breakdown is commonly seen in random sections of hysterectomies for bleeding. EMVE may also be associated with endothelial hyperplasia, consistent with a reaction to endothelial injury due to impaired venous drainage. This further supports the theory that EMVE bleeds when thrombosis occurs, due to Virchow's Triad (stasis, endothelial injury, and hypercoagulability). EMVE may be "the lesion for which surgery was performed" in hysterectomies with otherwise unexplained bleeding.

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