HER2 Status Research Articles

Computational approach for counting of SISH amplification signals for HER2 status assessment

The human epidermal growth factor receptor 2 (HER2) gene is a critical biomarker for determining amplification status and targeting clinical therapies in breast cancer treatment. This study introduces a computer-aided method that automatically measures and scores HER2 gene status from invasive tissue regions of breast cancer using whole slide images (WSI) through silver in situ hybridization (SISH) staining. Image processing and deep learning techniques are employed to isolate untruncated and non-overlapping single nuclei from cancer regions. The Stardist deep learning model is fine-tuned on our HER2-SISH data to identify nuclei regions, followed by post-processing based on identified HER2 and CEP17 signals. Conventional thresholding techniques are used to segment HER2 and CEP17 signals. HER2 amplification status is determined by calculating the HER2-to-CEP17 signal ratio, in accordance with ASCO/CAP 2018 standards. The proposed method significantly reduces the effort and time required for quantification. Experimental results demonstrate a 0.91% correlation coefficient between pathologists manual enumeration and the proposed automatic SISH quantification approach. A one-sided paired t-test confirmed that the differences between the outcomes of the proposed method and the reference standard are statistically insignificant, with p-values exceeding 0.05. This study illustrates how deep learning can effectively automate HER2 status determination, demonstrating improvements over current manual methods and offering a robust, reproducible alternative for clinical practice.

Immune marker expression and prognosis of early breast cancer expressing HER3

IntroductionThere is a strong rationale for targeting HER3, as HER3 contributes to tumorigenesis and treatment resistance. However, the prognostic role of HER3 and their association with immunoregulatory protein expression has not been established. MethodsThe main objective of this study was to investigate the prognostic role of HER3 expression and identify immunoregulatory marker expression according to HER3 status. HER3 expression and 10 immunoregulatory protein (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/B7-H3/B7-H4) expression was identified in 320 stage I-III breast cancer patients who received curative surgery at Seoul National University Hospital in 2008. The median follow-up duration was 88.8 months. Criteria for HER3 IHC was adopted from HER2 IHC score and only those with 3 + was considered positive. ResultsAmong 320 patients, 213 (67.2 %) had luminal A disease, 30 (9.5 %) had luminal B disease, 28 (8.8 %) had HER2-positive disease, and 46 (14.5 %) had triple negative disease. HER3 expression was shown in 153 patients (47.8 %). Tumors with HER3-expression had more immunogenic tumor microenvironment compared to HER3-negative tumor. In addition, patients with HER3 expression had favorable 5-year relapse free survival compared to HER3-negative patients (5-year RFS 92.5 % vs. 85.2 %, p = 0.038). However, in the multivariate analysis, HER3 expression was not a prognostic factor, but expression of immunoregulatory protein was a prognostic factor. ConclusionsThis study identified immunoregulatory protein expression according to HER3 status in breast cancer patients. As tumor with HER3 expression have more immunogenic microenvironment, investigating combination treatment of HER3 targeting agent and immunotherapy in HER3 expressing breast cancer may be promising.

Discordance of human epidermal growth factor receptor 2-low status between breast primary and distant metastases with clinical-pathological correlation.

Breast cancer with human epidermal growth factor receptor 2 (HER2) immunohistochemistry (IHC) 1+ or 2+ with negative in-situ hybridisation (ISH) (HER2-low) can now be targeted by HER2 antibody drug conjugates. We set out to compare HER2 status between matched primary invasive breast carcinoma (IBC) and distant metastases (DM) with clinical-pathological correlation, with specific interest in HER2-low. Biomarker studies and clinical-pathological features of primary IBC with matched DM diagnosed between 2021 and 2022 were retrospectively analysed. HER2 status was assessed per 2023 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for IHC (4B5) and ISH (IQFISH pharmDX). Bilateral breast primaries were excluded. HER2 IHC 0 to 1+ were reassessed. One hundred and forty-seven cases of primary IBC with matched DM were identified. Biomarkers were performed on core biopsy (n = 74) and resection (n = 73). One hundred and twenty-six (86%) were initially classified as 'HER2-negative'; of these, 67 (46%) were reclassified as HER2-low. Patients with HER2-positive primaries were younger (P = 0.01) and had an increased incidence of micropapillary carcinoma (P = 0.02). HER2-low primaries also had an increased incidence of micropapillary carcinoma (P = 0.02) and oestrogen receptor (ER) positivity (P = 0.02) compared to HER2 0. One hundred and sixty-nine matched DM cases excluding bone metastasis were identified (range = one to seven metastases per IBC). The most common sites of metastases were liver (50 of 169, 30%), lung (36 of 169; 21%), distant lymph node (26 of 169, 15%); 138 DM cases (82%) were previously classified as 'HER2-negative', and 62 (37%) were reclassified as HER2-low. Like HER2-low primaries, HER2-low metastases were frequently ER-positive (52 of 62; 84%) (P = 0.02). Brain metastases were more frequently HER2-positive (five of 32; 16%) (P = 0.04). Comparing HER2 status in matched primaries and DM, HER2 status was discordant in 62 cases (37%). Most changes occurred from HER2-low to HER2 0 (33 of 169, 20%), HER2 0 to HER2-low (17 of 169, 10%) and HER2-low to positive (10 of 169, 6%). All HER2-low to HER2 0 changes were HER2 1+ to 0. In 30 patients with multiple DM sites (47 cases), HER2 status among different DM samples was discordant in 16 patients (53%), mainly from HER2-low to HER2 0 (16 of 47, 34%). A significant proportion of previous 'HER2-negative' primaries and DM cases were reclassified as HER2-low. Discordant HER2 status between IBC primary and metastasis and between different DM sites demonstrated tumour heterogeneity and highlights the need for HER2 retesting in distant metastasis.

Correlation of tumor budding with a novel and other established prognostic parameters in patients with invasive breast carcinoma.

Breast cancer is the most common malignancy among women. Established prognostic markers in breast carcinomas include tumor size, histologic grade, nodal status, lymphovascular invasion, perineural invasion, hormone receptor status, HER-2 status, and age. To correlate peripheral tumor budding (pTB) with stromal tumor-infiltrating lymphocytes (sTILs) and established prognostic factors in invasive breast carcinoma. It is a retrospective study conducted at multiple centers including a tertiary care center. 100 cases were included over a period of 2.5 years. All cases of invasive breast carcinoma (IBC) in which excision specimens with lymph node dissection were available were studied. Slides were reviewed for pTB and sTILs. Tumor budding of ≤20/10 hpf was considered low tumor budding, and >20 buds/10 hpf was considered high tumor budding. Tumor budding was correlated with age, tumor size, lymphovascular invasion, perineural invasion, tumor stage (pT, pN), stromal tumor-infiltrating lymphocytes, tumor grade, ductal carcinoma in situ, hormonal receptors, and HER2neu. Fisher exact test and Chi-square test were used. We found that high tumor budding was seen in 34 cases and low tumor budding in 66 cases. There was a statistically significant association between high tumor budding and tumor size (P = 0.007), lymphovascular invasion (P < 0.001), perineural invasion (P = 0.004), tumor staging/pT (P = 0.006), nodal staging/pN (P = 0.001), and low sTILs (P < 0.001). However, the association of high tumor budding with parameters like age (P = 0.979), histological type (P = 0.243), tumor grade (P = 0.052), DCIS (P = 0.478), and ER (P = 0.633), and PR (P = 0.544), HER2Neu status (P = 0.171) was not significant. This study suggests tumor budding score can be used as a prognostic indicator for breast cancer.

Adaptive enrichment trial designs using joint modelling of longitudinal and time-to-event data.

Adaptive enrichment allows for pre-defined patient subgroups of interest to be investigated throughout the course of a clinical trial. These designs have gained attention in recent years because of their potential to shorten the trial's duration and identify effective therapies tailored to specific patient groups. We describe enrichment trials which consider long-term time-to-event outcomes but also incorporate additional short-term information from routinely collected longitudinal biomarkers. These methods are suitable for use in the setting where the trajectory of the biomarker may differ between subgroups and it is believed that the long-term endpoint is influenced by treatment, subgroup and biomarker. Methods are most promising when the majority of patients have biomarker measurements for at least two time points. We implement joint modelling of longitudinal and time-to-event data to define subgroup selection and stopping criteria and we show that the familywise error rate is protected in the strong sense. To assess the results, we perform a simulation study and find that, compared to the study where longitudinal biomarker observations are ignored, incorporating biomarker information leads to increases in power and the (sub)population which truly benefits from the experimental treatment being enriched with higher probability at the interim analysis. The investigations are motivated by a trial for the treatment of metastatic breast cancer and the parameter values for the simulation study are informed using real-world data where repeated circulating tumour DNA measurements and HER2 statuses are available for each patient and are used as our longitudinal data and subgroup identifiers, respectively.

Navigating the HER2 Frontier: Advancing Gastrointestinal Adenocarcinoma Diagnosis through Updated NCCN Guidelines

Abstract Introduction/Objective HER2-status is routinely tested in breast and upper-gastrointestinal (GI) cancers. Studies have shown the importance of anti-HER2 therapy with HER2 being a negative predictive marker in advanced colorectal cancer (CRC). Thus, recent NCCN-guidelines recommend screening for HER2-status in such cases. To increase compliance with the NCCN recommendations, we performed a quality assurance project to screen for HER2 status by immunohistochemistry (IHC) in GI adenocarcinomas. Methods/Case Report We conducted a validation of HER2 IHC for GI adenocarcinomas. Surgical pathologists were informed via email discussing the criteria and significance of HER2 IHC in GI adenocarcinomas. A total of 50 GI adenocarcinoma cases were evaluated in our surgical-pathology service, from June to December 2023. Pathologists were periodically reminded, either through email or in-person meetings, to ensure HER2 IHC assessment, especially for cases initially missed. Results (if a Case Study enter NA) Out of 50 GI adenocarcinomas, HER2 IHC was performed on 27 out of 50 cases (54%) without any reminder. The pathologists were reminded to perform HER2 IHC on the remaining 23 cases, resulting in the IHC performance on an additional 22 cases, giving a yield of 98%. Of 49 cases, HER2 was negative in 46 cases and was positive (3+) in one case, and equivocal (2+) in two cases. Subsequent HER2 FISH analysis of equivocal cases showed HER2 amplification in one case. Thus, HER2 expression/amplification was present in 2 out of 50 cases (4%) including one case each in upper and lower GI tracts. Conclusion While we have long recognized importance of HER2 Status in upper GI adenocarcinomas, it’s now clear that understanding HER2 status is crucial in CRC too. New evidence highlights how anti-HER2 therapy can make a difference, especially for advanced cases. By screening for HER2 early, clinicians can enroll such patients in appropriate clinical trials and also guide them on the appropriate treatment options, offering hope and targeted care.

The prognostic impact of Her2 status in early triple negative breast cancer: a Turkish Oncology Group (TOG) study

The studies evaluating the impact of Her2 levels in neoadjuvant setting have conflicting data. The aim of the study was to evaluate the prognostic impact of Her2 status in early triple negative breast cancer(TNBC). In the study TNBC patients who were treated with neoadjuvant chemotherapy (NAC) and surgery were analyzed retrospectively. The primary aim of the study was to analyze the impact of Her2 status(Her2-0 and Her2-low) on pathological complete response (pCR). The secondary objectives were disease free survival (DFS) and overall survival (OS). 620 female triple negative breast cancer patients were evaluated. 427 patients (68.9%) had Her2-0 and 193(31.1%) had her2-low pathology. The pCR rates were similar between Her2-0 and Her2-low patients (33.0% vs. 27.5%, p = 0.098). Although Her2-0 group has better DFS (106 vs. 50 months, p = 0.002), in multivariate analysis it had a HR of 0.74 (p = 0.06). In addition, OS was similar (131 vs. 105 months, p = 0.13) with a HR of 0.88 (p = 0.61). In multivariate analysis; presence of LVI (HR:2.2 (95% CI 1.1–3.5) p = 0.001), Clinical stage T1/T2 (HR:0.39 (95% CI 0.2–0.6) p < 0.001) and lymph node negativity (HR:0.35 (95% CI 0.1–0.9) p = 0.03) were independent factors for OS. Although there were pathological and clinical differences, the pCR, DFS and OS were similar between Her2-0 and Her2-low TNBC patients. The importance of Her2 status of TNBC in neoadjuvant setting should be further studied.

Efficacy of pyrotinib and capecitabine in recurrent breast cancer with a HER2-negative genetic switch following systemic therapy: A case report and literature review

Despite the demonstrated safety and efficacy of pyrotinib and capecitabine in treating human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer, their efficacy in recurrent breast cancer in which the HER2 status has changed to negative remains unexplored. Here, we report a case of a 38-year-old female diagnosed with invasive ductal adenocarcinoma of the left breast, staged as mcT2N0M0. Fluorescence in situ hybridization (FISH) confirmed that the tumor was hormone receptor (HR) positive with low HER2 expression (2+) and a HER2/CEP17 ratio of 3.56. Following neoadjuvant targeted therapy and chemotherapy, she underwent a modified radical mastectomy. Post-surgical histopathological examination revealed a non-pathological complete response, classified as ypT1cypN1M0. The tumor remained HR positive with low HER2 expression (2+), but the FISH result was negative (HER2/CEP17 ratio of 1.65). For 1 year, she was administered dual-targeted therapy with goserelin and exemestane. Sequential therapy with neratinib was initiated; however, it was discontinued due to grade IV diarrhea. Despite ongoing endocrine therapy, she experienced tumor recurrence on the left chest wall. A biopsy of the recurrent lesion revealed it to be HR positive with low HER2 expression (2+) and a negative FISH result (HER2/CEP17 ratio of 1.33). The recurrent lesion responded to combination therapy consisting of pyrotinib and capecitabine, with tolerable adverse events. This case highlights the potential advantages of combining pyrotinib and capecitabine when the HER2 status changes to negative following systemic therapy.

Whole‑exome sequencing insights into synchronous bilateral breast cancer with discordant molecular subtypes.

The incidence of synchronous bilateral breast cancer (SBBC) is very low, and SBBC with discordant molecular subtypes is even more uncommon. As such, little is known about the pathogenesis of SBBC with discordant molecular subtypes, and reports about this entity are scarce. In the present study, the case of a 72-year-old female patient who presented with SBBC with discordant molecular subtypes is reported, with a stage IA hormone receptor negative {human epidermal growth factor receptor-2 [HER2(+)]} tumor in the left breast and a stage IIIA hormone sensitive tumor [HER2(-)] in the right breast. Whole-exome sequencing was performed to identify the differential genetic variations in the BBC tissues. A total of 8 key mutated cancer susceptibility genes (ALK, BRCA1, FAT1, HNF1A, KDR, PTCH1, SDHA and SETBP1) were screened, and mutations were found in 10 vital cancer driver genes, including BRCA1, EBF1, MET, NF2, NUMA1 RALGAPA1, ROBO2, SMYD4, UBR5 and ZNF844. The high-frequency mutated genes mainly contained missense mutations, among which single nucleotide variants were the most common mutations, with C > T and C > A as the main forms. The pathways associated with the high frequency mutated genes were further elucidated by functional category and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses. Heterogeneity in the hormone receptor and HER2 status of SBBC poses unique therapeutic challenges. Future studies should aim to identify the optimal management strategy for this disease.

Clinical and Molecular Characteristics of High-Risk, Recurrent, or Metastatic Endometrial Cancer That Is Human Epidermal Growth Factor Receptor 2-Low.

Recent success of human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug-conjugate trastuzumab-deruxtecan in HER2-low and HER2-positive tumors has sparked interest in examining the HER2 status of tumors not traditionally associated with HER2 amplification. Despite the increasing number of systemic treatment options, patients with advanced endometrial cancer (EC) still face a poor prognosis. This study evaluates HER2-low status in over 800 EC, correlating HER2 with both molecular and clinical features. HER2 status was determined by immunohistochemistry (IHC) and dual in situ hybridization (DISH) on four studies of previously classified high-risk EC (PORTEC-3 and Medical Spectrum Twente cohort), recurrent or metastatic EC (DOMEC), and a primary stage IV cohort. EC was classified as HER2-negative (IHC 0), HER2-low (IHC 1+/2+ without amplification), or HER2-positive (IHC 3+ or DISH-confirmed amplification). Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazards models assessed the independence of any prognostic impact of HER2 status. HER2 status was determined in 806 EC: 74.8% were HER2-negative, 17.2% HER2-low, and 7.9% HER2-positive. HER2-low was found across all molecular classes and histotypes. The highest rates of HER2-low and HER2-positive tumors were in recurrent or metastatic EC (35.6% and 15.6%), followed by primary stage IV EC (29.9% and 12.4%) and high-risk EC (14.2% and 6.8%). HER2 status had no independent prognostic value. A quarter of high-risk, metastatic, or recurrent EC exhibited HER2 overexpression. The presence of HER2 overexpression in all clinical and molecular categories highlights the need for broad testing and offers treatment options for a wide range of patients.

Impact of low HER2 expression on response to CDK4/6 inhibitor treatment in advanced HR + /HER2- breast cancer: a multicenter real-world data analysis.

CDK4/6 inhibitors (CDK4/6i) represent the first-line therapy approach of choice for patients with hormone receptor-positive, HER2-negative advanced breast cancer (HR + /HER-ABC). Approximately 50% of HR + /HER2-ABC displays low HER2 expression (HER2 low). Recent data emerging from the DESTINY-Breast04 trial demonstrated practice-changing efficacy of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in patients with low HER2 expression. Here, we aimed to analyze the impact of low HER2 expression on CDK4/6i therapy response in a well-characterized multicenter HR + /HER-ABC cohort. Patients diagnosed with HR + /HER2-ABC who were treated with CDK4/6i in clinical routine between November 2016 and December 2020 at four certified German Breast Cancer Centers were retrospectively identified. The cohort was stratified according to graduation of positivity in HER2 immunohistochemistry (IHC; HER2 zero = IHC score 0 and HER2 low = IHC score 1 + , 2 + /fluorescence in situ hybridization negative). Subgroups were analyzed with regard to progression-free survival (PFS) following CDK4/6i initiation. The study cohort comprised n = 448 patients. For n = 311 patients, HER2 status from the metastatic site was available. n = 91 (29.3%) cases were HER2 zero and n = 220 cases (70.7%) were HER2 low. There was no significant difference in PFS between the two groups (PFS: 17months versus 18months, log-rank p = 0.42). Further, we examined the influence of HER2 expression changes between primary and metastatic tissue (n = 171; HER2 gain/HER2 loss/HER2 stable expression) on CDK4/6i treatment response. Again, there was no significant difference between these three groups, respectively (PFS: 16months versus 13months versus 17months, log-rank p = 0.86). In our analysis, HER2 status did not have a significant impact on treatment response to CDK4/6i.

Clinical characterization, prognostic, and predictive values of HER2-low in patients with early breast cancer in the PALLAS trial (ABCSG-42/AFT-05/BIG-14–13/PrE0109)

BackgroundBidirectional crosstalk between HER2 and estrogen receptor (ER) pathways may influence outcomes and the efficacy of endocrine therapy (ET). Low HER2 expression levels (HER2-low) have emerged as a predictive biomarker in patients with breast cancer (BC).MethodsPALLAS is an open, international, phase 3 study evaluating the addition of palbociclib for 2 years to adjuvant ET in patients with stage II-III ER-positive/HER2-negative BC. To assess the impact of HER2 expression on patient outcomes in the phase III PALLAS trial, we analyzed (1) the association between rate of HER2-low with demographic and clinicopathological parameters, (2) the prognostic value of HER2-low status on invasive disease-free survival (iDFS), distant relapse-free survival (DRFS), and overall survival (OS) and (3) HER2 expression’s value as a predictive biomarker of response to palbociclib. HER2-low was defined as HER2 immunohistochemistry (IHC) 1 + or IHC 2 + with negative in situ hybridization (ISH). All pathologic evaluation was performed locally. Prognostic and predictive power of HER2 were assessed with Cox models.ResultsFrom the original PALLAS intention-to-treat population (N = 5753), 5304 patients (92.2%) were included in this analysis. Among these, 2254 patients (42.5%) were classified as having HER2 IHC 0 (HER2-0), and 3050 (57.5%) as having HER2-low disease (1838 with IHC 1 + and 1212 with IHC 2 +). Median follow-up was 59.8 months. HER2-low prevalence varied significantly across 21 participating countries (range 16.7% to 75.6%; p < 0.001) and was more frequent in patients enrolled in North America (63.1%) than in Europe (53.4%) or other regions (53.4%) (p < 0.001). HER2 status was not significantly associated with iDFS in a multivariable Cox model (hazard ratio 0.93, 95% confidence interval 0.81 – 1.06). No significant interaction was observed between treatment arm and HER2 status for iDFS (p = 0.43). Similar results were obtained for DRFS and OS.ConclusionsIn this large, prospective, global patient cohort, no differences were observed in clinical parameters, prognosis, or differential benefit from palbociclib between HER2-0 and HER2-low tumors. Significant geographic variability was observed in the prevalence of HER2-low status, suggesting a high degree of variation in pathologic assessment of HER2 expression without impact on outcomes.

Stable or at least once HER2-low status during neoadjuvant chemotherapy confers survival benefit in patients with breast cancer

Background Temporal heterogeneity in human epidermal growth factor receptor 2 (HER2) status may be associated with the prognosis of breast cancer. We aimed to clarify the relationship of HER2-low transition during neoadjuvant therapy with survival outcomes under the new classification of HER2 status. Methods This retrospective study was conducted based on the prospective database of breast cancer patients treated with neoadjuvant therapy from September 2013 to August 2020. Results This analysis enrolled 185 patients, including 44 patients with HER2-zero tumours, 93 patients with HER2-low tumours and 48 patients with HER2-positive tumours after neoadjuvant therapy. Nearly, 57.6% of HER2-zero tumours turned into HER2-low tumours after neoadjuvant therapy, while 25.0% of HER2-low patients changed to HER2-zero or HER2-positive tumours. We found that at least once diagnosis as HER2-low breast cancer was related to hormone receptor status (p < .001) and Ki-67 expression (p = .036). Patients ever diagnosed as HER2-low tumours had favourable clinicopathological features (less Ki-67 expression, lower pathological staging, etc.) as well as significantly better locoregional relapse-free survival (LRFS; p = .007) and overall survival (OS; p = .026) compared with those never exhibiting HER2-low expression. Furthermore, the 6-year OS rates were 94.2% (95% confidence interval (CI) 83.1–98.1), 88.7% (74.4–95.2) and 78.1% (65.4–86.6) for patients with stable, once and none HER2-low expression, respectively (adjusted HR, 0.514 [95%CI, 0.294–0.897], p = .019). Conclusions Our study first indicated in patients across all expression levels of HER2 that stable or at least once HER2-low status may confer favourable attributes including less malignant biological behaviour and long-term survival benefit for breast cancer receiving neoadjuvant therapy.

Expression of histone methyltransferase WHSC1 in invasive breast cancer and its correlation with clinical and pathological data

BackgroundThe WHSC1 protein facilitates specific dimethylation of histone H3 at the K36 position, enhancing gene transcription and expression. Studies have confirmed its high expression in diverse malignant tumors. We aimed to identify novel molecular markers to assess the biological behavior of breast cancer cells. MethodsWe conducted a comprehensive analysis of mRNA expression in breast cancer and adjacent tissues based on TCGA data. We enrolled 141 breast cancer patients treated at the First Affiliated Hospital of Fujian Medical University between 2012 and 2016. Patient clinical information and pathological specimens were obtained. We utilized tissue microarray (TMA) technology. We employed the chi-square test for between-group comparisons, with p < 0.05 indicating statistical significance. Furthermore, we analyzed the associations between WHSC1 expression and clinical or pathological data. ResultsWHSC1 mRNA expression was significantly higher in breast cancer tissues than in adjacent tissues (p < 0.001). Moreover, high WHSC1 protein expression in breast cancer was associated with several important clinical parameters, such as pathological type (p = 0.007), high Ki67 expression(Ki67＞20 %) (p < 0.001), lymph node metastasis (p < 0.001), T stage (p = 0.011), N stage (p < 0.001), postoperative pathological stage (p < 0.001), premenopausal status (p = 0.004), and positive HER2 status (p < 0.001). Multivariate regression analysis showed that high WHSC1 expression, elevated Ki67 levels, and positive HER2 status were independent risk factors for axillary lymph node metastasis in breast cancer patients. ConclusionWHSC1 protein expression is upregulated in breast cancer patients and represents an independent risk factor influencing axillary lymph node metastasis, highlighting its potential significance as a strong candidate biomarker.

Prognostic Impact of HER2 Low Status in Male Breast Cancer: Prospective Cohort Analysis.

Male breast cancer (MBC) is a rare disease, and the potential influence of low expression of human epidermal growth factor receptor 2 (HER2 low) remains unexplored. In this prospective cohort study, we evaluated 870 patients treated for MBC between May 2009 and June 2023 to assess HER2 low status and its prognostic implications. With a median follow-up of 43 months (range 1-175 months), 659 eligible patients were categorized into three groups based on HER2 status: 501 (76%) HER2 low, 81 (12.3%) HER2 zero, and 77 (11.7%) HER2 positive. HER2 positivity correlated with younger age, higher proliferation index, non-specific type histology, lymphovascular invasion (LVSI), and low differentiation grade. Notably, all these parameters were equally distributed between the HER2 zero and HER2 low groups. Additionally, HER2 positivity was significantly associated with increased occurrences of regional and distant lymph nodes and pulmonary metastases. However, no statistically significant difference was observed between HER2 zero and HER2 low. Disease-free and overall survival showed no significant disparities between the groups. Our findings suggest that HER2 low status is frequently detected in MBC. Despite this, HER2 low did not correlate with clinical and pathological parameters, nor did it impact patients' survival.

Correlation of Androgen Receptor Expression With Ki67 Proliferative Index and Other Clinicopathological Characteristics in Invasive Mammary Carcinomas.

Introduction The clinical importance of androgen receptor (AR) status in breast cancer is uncertain. The existing knowledge regarding the association of androgen receptor expression with clinicopathological factors of breast cancer is also limited. The main aim of this study is to evaluate the AR expression in breast cancer and to correlate it with the Ki67 proliferative index and other clinicopathological prognostic factors. Methods Theexpression of AR was evaluated in 192 invasive mammary carcinoma cases and the expression patterns were correlated with various clinicopathological prognostic factors such as age, tumor size, pathological primary tumor (pT) stage, nodal status,histological grade, estrogen receptor (ER) expression, progesterone receptor (PgR) expression, human epidermal growth factor receptor 2 (Her2) status, molecular subtype, and Ki67 labeling index. Immunohistochemistry was performed to assess AR, ER, PgR, Her2, and Ki67 expression. The clinicopathological data required for the analysis were obtained from the laboratory information system. Results Out of the 192 breast carcinoma cases, 139 (72.4%) showed AR-positive expression. The average age of the AR-positive cases was slightly higher than the AR-negative cases. AR-positive tumors tended to have a lower histological grade and positive ER and PgR expression. The expression of ARdid not correlate with tumor size, pT stage, nodal status, Her2 status, and Ki67 labeling index. Conclusion The expression of AR is noted in a significant proportion of breast carcinoma cases. AR expression may be related to good prognostic factors such as ER expression, PgR expression, and lower histologic grade. We also observed that AR expression did not have any association with the Ki67 proliferative index.

Predicting HER2 Status Associated with Breast Cancer Aggressiveness Using Four Machine Learning Models.

Breast cancer (BC) is a heterogeneous disease with various biological and clinical subtypes. HER2 status (human epidermal growth factor receptor 2) is a crucial biomarker, associated with aggressive tumor behavior and poor prognosis. Advanced algorithmic models can aid in predicting cancer growth and metastasis, serving as valuable clinical tools for classification and treatment. Effective treatment strategies in oncology rely on accurate decision-making and early identification of factors associated with positive outcomes. Breast cancer (BC) presents challenges in understanding its contributing factors and establishing precise diagnostic methods. Our research introduces a novel method utilizing machine learning (ML) techniques to explore the relationship between various clinical and molecular variables focusing on predicting the status of the human epidermal growth factor receptor 2 (HER2), a key aggressiveness biomarker in BC. This objective aligns with leveraging artificial intelligence (AI) to support decision-making and address diagnostic considerations during treatment. Four ML models, namely logistic regression, random forest, LightGBM, and CatBoost, were implemented and evaluated using Python. The dataset was compiled by extracting medical records of BC patients, covering the period from 2018 to 2020. The model's predictive performance was evaluated using accuracy, precision, recall, and F1-score as performance metrics. The models achieved varying accuracies between 86.36 and 95.45%. The logistic regression model achieved an accuracy of 90.90% while the random forest and LightGBM models achieved an accuracy of 86.36%. The CatBoost model outperformed others with a greater accuracy of 95.45%, indicating its superior predictive capabilities for HER2 status. The ML models demonstrated potential in predicting HER2 status, enabling early detection and facilitating personalized treatment strategies. Our findings emphasize the significance of AI and ML techniques in improving BC outcomes and guiding decision-making. Further research is required to explore the broader applications of ML in predicting comprehensive BC outcomes in diverse healthcare settings and among heterogeneous populations.

Clinicopathologic Features and Digital Imaging Analysis of HER2 Protein in Breast Carcinomas With Different HER2 Fluorescence in Situ Hybridization Patterns

BackgroundHER2-targeted therapies have significantly improved outcomes for patients with HER2-positive breast cancer (BC), which represents 15% to 20% of all BC cases. HER2 status is assessed via immunohistochemistry (IHC) and/or in situ hybridization (ISH), dividing BCs into five groups (G1-G5). Patients and methodsIn a study of 2,702 primary BC cases, comprising 12.7% G1, 0.2% G2, 2.8% G3, 8.5% G4, and 75.9% G5, we analyzed clinicopathologic features and HER2 protein expression digitally for each ISH group. ResultsNotably, G5 cases had a higher proportion of lobular carcinoma (13.9%) compared to other groups. G3 cases showed the highest percentage of grade 3 tumors (56.9%), while G5 cases had the lowest (21.4%). Additionally, G5 cases had the highest rate of estrogen receptor (ER) positivity (84.6%), while G1-HC (high copy number) cases had the lowest (70.4%). Most G1-HC cases were HER2 IHC 3+ (76.1%), while most G5 cases were IHC 0/1+ (75.7%). IHC 2+ was most common in G1-LC (low copy number) and G3 cases (83.8% and 90.7%, respectively), with G4 cases predominantly IHC 2+ (56.3%) and IHC 1+ (30.1%). Discordant HER2 IHC and ISH results were observed in 12 cases (0.4%), including 7 G1-HC (2.3%), 4 G1-LC (10.8%), and 1 G5 case (0.1%). Digital quantification of HER2 IHC levels in all groups except G5 revealed that G1-HC tumors had the highest HER2 protein expression, followed by G3, with G4 showing the lowest. ConclusionThese findings offer valuable insights into the clinicopathologic characteristics and future management for different HER2 ISH groups.

Time-Dependent Diffusion MRI Helps Predict Molecular Subtypes and Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer.

Background Time-dependent diffusion MRI has the potential to help characterize tumor cell properties; however, to the knowledge of the authors, its usefulness for breast cancer diagnosis and prognostic evaluation is unknown. Purpose To investigate the clinical value of time-dependent diffusion MRI-based microstructural mapping for noninvasive prediction of molecular subtypes and pathologic complete response (pCR) in participants with breast cancer. Materials and Methods Participants with invasive breast cancer who underwent pretreatment with time-dependent diffusion MRI between February 2021 and May 2023 were prospectively enrolled. Four microstructural parameters were estimated using the IMPULSED method (a form of time-dependent diffusion MRI), along with three apparent diffusion coefficient (ADC) measurements and a relative ADC diffusion-weighted imaging parameter. Multivariable logistic regression analysis was used to identify parameters associated with each molecular subtype and pCR. A predictive model based on associated parameters was constructed, and its performance was assessed using the area under the receiver operating characteristic curve (AUC) and compared by using the DeLong test. The time-dependent diffusion MRI parameters were validated based on correlation with pathologic measurements. Results The analysis included 408 participants with breast cancer (mean age, 51.9 years ± 9.1 [SD]). Of these, 221 participants were administered neoadjuvant chemotherapy and 54 (24.4%) achieved pCR. The time-dependent diffusion MRI parameters showed reasonable performance in helping to identify luminal A (AUC, 0.70), luminal B (AUC, 0.78), and triple-negative breast cancer (AUC, 0.72) subtypes and high performance for human epidermal growth factor receptor 2 (HER2)-enriched breast cancer (AUC, 0.85), outperforming ADC measurements (all P < .05). Progesterone receptor status (odds ratio [OR], 0.08; P = .02), HER2 status (OR, 3.36; P = .009), and the cellularity index (OR, 0.01; P = .02) were independently associated with the odds of achieving pCR. The combined model showed high performance for predicting pCR (AUC, 0.88), outperforming ADC measurements and the clinical-pathologic model (AUC, 0.73 and 0.79, respectively; P < .001). The time-dependent diffusion MRI-estimated parameters correlated well with the pathologic measurements (n = 100; r = 0.67-0.81; P < .001). Conclusion Time-dependent diffusion MRI-based microstructural mapping was an effective method for helping to predict molecular subtypes and pCR to neoadjuvant chemotherapy in participants with breast cancer. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Partridge and Xu in this issue.

120 - The value of T1ρ mapping in preoperatively predicting the status of ER, PR, HER-2 and Ki-67 in breast cancer

120 - The value of T1ρ mapping in preoperatively predicting the status of ER, PR, HER-2 and Ki-67 in breast cancer