TEST:

PATHWAY antiHer2/neu (4B5) Rabbit Monoclonal Primary Antibody

Among 22 HER2-positive/heterogenous cases with successful ISH testing, 100% (22/22) demonstrated amplification via ISH. Because the classification of tumors as HER2-positive/heterogenous by IHC correlated very closely with ISH positivity, our results suggest that ISH is likely unnecessary for CRCs with 3+ HER2 overexpression in 10-49% of neoplastic cells.

No abstract available

The advent of novel therapeutic molecules that require fewer membrane epitopes to be effective has prompted a reevaluation of the current immunohistochemistry testing protocols, with special emphasis on the detection limit. Here, we have used Boston Cell Standards technology to determine the sensitivity of 2 commercially available HER2 immunohistochemistry assays, including a lower limit of detection.

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.

This study reports an independent validation of a fully automated AI solution for HER2 scoring in BC. Our results show high accuracy for the AI, suggesting that AI can improve reproducibility and standardization of HER2 scoring in BC and additional validation studies are ongoing

HER2 IHC interpretation has a history of controversy due to competing scoring schema. Additionally, before 2022 no HER2 targeted treatment was available for the lower expression profiles (0, 1+, and 2+/ISH negative) and thus did not command the same level of interest as they do now. Here we demonstrate that the PATHWAY HER2 (4B5) assay is robust and reproducible in identifying HER2- ultralow tumours.

The overall consistency of HER2 expression between antibodies of different clone numbers was high, but the consistency of detecting HER2 low and ultra-low expression cases was poor, and there were differences in the detection rates, which still need to be validated by more subsequent studies.

Context: Human epidermal growth factor receptor 2 (HER2) overexpression in breast carcinomas offers the use of a targeted treatment approach with the monoclonal antibody trastuzumab... Manual immunohistochemical scoring of HER2 has high interobserver variability among the 0+ to 2+ categories. In the context of emerging HER2-low therapies and clinical trials, additional specific criteria are necessary for HER2 immunohistochemistry interpretation to improve reproducibility among pathologists.Fleiss κ Scores for HER2 IHC Agreement Among Categories 0+ to 2+

Recently, a new type of antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), has been approved for the treatment of metastatic breast cancer with low level of human epidermal growth factor receptor 2 (HER2) gene expression...The ability of pathologists to achieve acceptable diagnostic accuracy in identifying patients with HER2-low breast cancer could be enhanced by short-term training. Potential routes to improve the quality of HER2-low scoring in clinical practice have been identified.

As assays were validated for detecting HER2-amplified tumours, not all assays and antibodies proved suitable for HER2-low detection. Some tests showed distinct expression in the negative cell line. Dynamic range cell line controls and quantitative analysis using calibrators demonstrated more interlaboratory variability than commonly appreciated. Revalidation of HER2 tests by laboratories is needed to ensure clinical applicable HER2-low assays.

AI excels in automating the assessment of HER2 immunohistochemistry, showing promising results despite slight variations in performance across different HER2 status. While incorporating AI algorithms into the pathology workflow for HER2 assessment poses challenges in standardization, application patterns, and ethical considerations, ongoing advancements suggest its potential as a widely effective tool for pathologists in clinical practice in the near future.

While gastric and breast criteria demonstrated 96% concordance in identifying EEAs positive for HER2 overexpression, equivocal staining was more often documented with gastric scoring. This greater frequency of equivocal results may suggest a preference for gastric criteria in the assessment of EEA, matching trial inclusion criteria where clinical benefit of HER2 ADCs has been established in patients with HER2 equivocal tumors. Table: 739P Concordance and discordance of HER2 IHC calls by gastric and breast criteria

HER2-OE was relatively low across GTs, though certain histotypes and molecular features (HRD negative OCs, p53 abnormal EC and adenocarcinomas/CPS<1% CC) exhibited higher scores. The high CR suggests either scoring guideline may be suitable for GTs. HER2-OE's predictive/prognostic value in GTs requires further evaluation.

In March 2019, AstraZeneca entered into a global development and commercialization collaboration agreement with Daiichi Sankyo for trastuzumab deruxtecan (T-DXd; DS-8201)... Data show the gastric and breast algorithms are comparable in HER2 IHC 3+ identification; lower concordance was observed for IHC 2+ and 1+, and between the gastric and endometrial algorithms. Findings indicate greater awareness of best scoring practice is needed to ensure consistent assessment of HER2 IHC status in solid tumors. Table: 177P *Salivary gland tumors (n=18) and DP-02 other cohort; †PPA was 100% as no cases identified by gastric/breast algorithm

Local vs central HER2 agreement by standardized IHC techniques decreased for HER2-low compared to HER2 status. Monoclonal HercepTest proved higher agreement with gold standard than polyclonal HercepTest in terms of HER2 status and HER2-low BC identification, especially for 1+ and 2+ IHC cases. This highlights the need for standardized HER2 testing review, particularly when evaluating potential benefits of novel therapies for HER2-low BC patients.

Pts with HR+ mBC determined as HER2-low or HER2-ultralow using the VENTANA HER2 (4B5) assay (and ISH when applicable) derived clinical benefit from T-DXd, irrespective of sample type used to determine HER2 status. Of note, 64% of pts with a local HER2 IHC 0 score were classed as HER2-low or HER2-ultralow by central test. It may be advisable for pts with HR+ HER2 IHC 0 mBC to be reassessed to determine T-DXd eligibility.

The real-world data on HER2 assessment concordance, in the spectrum of HER2-low BC, although substantial, are not perfect even among experienced breast pathologists. Concordance was significantly better with the Ventana 4B5 clone, which provided a majority of score 0 cases. On the contrary, with the Novacastra/Leica CB11 clone the 2+ score prevailed.

HER2 scores vary markedly between different clinically approved HER2 antibodies, both in primary tumours and their corresponding metastasis, and across different antibodies. Especially DG44 deviated from the other antibodies. Discrepancies in testing methods could impact patient selection for Trastuzumab-deruxtecan treatment.

The HER2 “ultra-low� category is not currently recognized as a target for new HER2 anti-ADCs. However, this could change soon depending on the results of ongoing clinical trials. If this becomes the case, HER2 assays must provide supporting evidence on their capability to accurately differentiate HER2 null from HER2 “ultra-low�.

After administering a total of 17 courses of eribulin, she was evaluated as having PD due to pleural dissemination. She then administered 3 courses of paclitaxel-bevacizumab therapy, but developed aphasia...After that, five courses of the drug were administered as outpatients, and both brain metastasis and pleural dissemination achieved partial response, and tumor markers gradually decreased. Conclusion In cases where symptom improvement can be expected by surgical local treatment of the brain metastasis responsible lesion, as in this case, treatment aimed at improving ADL with an eye on the application of the drug may also be considered

The median age was 59 years (range 47 to 66 years), all patients were female, and the subtypes were luminal B in three cases and triple-negative in one case. The median number of chemotherapy regimens administered was 3.5 (range 3 to 6), and the breakdown of metastatic lesions was lung pleura in two cases, regional lymph nodes in two cases, bone in two cases, liver in one case, chest wall in two cases, and skin in one case. Clinical efficacy was PR in one case, SD in one case, and PD in two cases, with one case of death due to multiple organ failure and one case of death from current disease.

[Cases] (Onset, CDK4/6 inhibitor, and Enhertz use start date are listed) Case 1: Right-sided breast cancer treated with conservative therapy (BCT) on 2013/3/13, pleural metastasis on 2016/3, 2019/2/7 ~ Faslodex (FAS) + Verzenio, 2023/11/8 ~ Enhertz, tumor markers decreasing Case 2: 2001/6/29 BCT for right breast cancer, 2012/12 pleural and abdominal wall metastases, 2018/6/14 ~ Ibrance + Letrozole (LET), 2019/1/31 ~ FAS + Verzenio, 2023/9/27 ~ Enhertz, tumor markers decreasing Case 3: 2011/2/4 Right stage IV breast cancer, lymph node and bone metastases, 2022/11/16 mastectomy after chemotherapy (Bt + Ax), 2019/2/7-2019/9/12 Exemestane (EXE) + Verzenio, 2021/10/20 ~ 2021/12/15EXE Ibrance, 2023/7/19 ~ Enhertz, Tumor marker decreased, but after 6 cycles interstitial pneumonia developed, improved with pulse therapy, treatment for recurrence ended, transitioned to palliative care Case ④: 2014/6/18Bilateral breast cancer, bilateral BCT, 2019/3Pleural dissemination and bone metastasis, 2020/4/16 ~ 2020/8/5EXE + Vergenio, 2021/12/1 ~ 2023/1FAS + Ibrance, 2023/10 ~ Enhertz, under observation Case ⑤: 2012/9/19Left breast cancer, Bt + Ax (with FISH amplification), 2018/7Resection due to chest wall recurrence, then chest wall recurrence + supraclavicular metastasis, No FISH amplification in repeat biopsy, 2019/11/28 ~ 2021/5 FAS + Verzenio, 2023/10/4 recurrence in precordial area, 2023/11/8 ~ Enhertz, under observation Case ⑥: 2007/11/21 Left breast cancer, preoperative chemotherapy followed by Bt + Ax, 2010/12 liver metastasis, 2019/2/7 ~ 2021/4/13 LET + Verzenio, 2021/4/14 ~ FAS + Verzenio, 2023/1/15 ~ Nolvadex (TAM) + Verzenio, recent tumor marker increase, scheduled to switch to Enhertz from 2024/1. &lsqb;Results] Enhertz therapy is effective, but under observation. One patient developed interstitial pneumonia, but it improved

After postoperative radiation therapy, the patient took capecitabine for 10 months...After 13 sessions of eribulin as chemotherapy, 8 sessions of fulvestrant + abemaciclib were administered, resulting in PR. After that, eribulin + palbociclib was administered due to bone metastasis progression, but the patient did not progress, resulting in PD...Furthermore, by using T-DXd, which has a different therapeutic mechanism, it was possible to shrink the tumor and improve the patient's quality of life, despite its late use as the seventh regimen. Conclusion We have observed a case in which changing the treatment method in accordance with the change in subtype of recurrent breast cancer produced an antitumor effect

Eight patients were hormone receptor (HR) positive and HER2 negative, four were HR negative and HER2 negative, four were stage IV, and eight were recurrent cases. The median number of lines of T-Dxd treatment for metastatic or recurrent breast cancer was five (2-12), with only one patient receiving the second line and 11 receiving the third line or later. The maximum therapeutic effect was PR in 3 patients, SD in 3 patients, PD in 3 patients, and NE in 3 patients.

After starting pembrolizumab + carboplatin (CBDCA) + weekly-paclitaxel (wPTX), she developed fatigue, nausea, and loss of appetite...When using them, it is necessary to pay close attention to immune-related adverse events, which are a concept different from the adverse events of conventional cytotoxic antitumor drugs. In addition, in cases such as Case 2, it is difficult to choose the postoperative therapy

Background Trastuzumab decrustecan has been shown to be effective in treating patients with HER2 low-expressing breast cancer. All 18 patients were female, with a median age of 62 years (44-75 years), 2 patients (11.1%) were premenopausal, and 16 patients (88.9%) were postmenopausal. Thirteen cases (72.2%) were recurrent, five cases (27.8%) were de novo Stage IV, 16 cases (88.9%) had visceral metastases, and three cases (16.7%) had brain metastases. Biology: 14 cases (77.8%) were hormone receptor (HR) positive, four cases (22.2%) were HR negative, and 14 cases (77.8%) were HER2 1+ and four cases (22.2%) were HER2 2+ by companion diagnosis using HER2 4B5.

Background In the DESTINY-Breast04 (DB-04) study, trastuzumab plus deruxtecan therapy was administered to patients with HER2-low expressing breast cancer. Adverse events were almost the same as when used in HER2 positive cases. Conclusion In clinical practice, T-DXd therapy for HER2-low expressing breast cancer does not have a high response rate, but the clinical benefit rate is relatively good, and it is considered to be a new treatment option

Background Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC), has shown favorable PFS and OS for HER2-positive unresectable or metastatic breast cancer in a series of DESTINY trials, and can now be said to be a key drug in the treatment of metastatic breast cancer.In March 2023, its indications were expanded to include "inoperable or recurrent breast cancer with low HER2 expression and a history of chemotherapy." The diagnosis of HER2 low expression requires confirmation by Ventana ultraView Pathway HER2 (4B5) as a companion diagnostic, and specimens stained after March 27, 2023 must be evaluated for past specimens...&lsqb;Discussion] In this study, no difference was found in the low expression rate at the time of specimen collection, but the HER2 low expression rate in in-hospital IHC staining and 4B5 evaluation differed greatly. There was also a large discrepancy in diagnosis between pathologists, and it was considered important to resubmit 4B5 regardless of the IHC judgment at the time of initial onset, or to re-evaluate HER2 by aggressive re-biopsy in metastatic lesions

Of the 51 cases, 15 (29%) were HER2 0, 30 (59%) were 1+, and 6 (12%) were 2+. Of the 36 cases with low HER2 expression, 18 (60%) were ER positive/ER negative/12 (40%). One case was originally HER2 0 but changed to HER2 low expression, and conversely, 8 cases changed from low expression to HER2 0, with a concordance rate of HER2 status of 87.5% for HER2 0 and 73% for low expression.

The subjects consisted of 9 advanced breast cancers and 14 recurrent breast cancers, with 11 (47.8%) patients with high HER2 expression and an average age of 65.7 years, and 12 (52.2%) patients with low HER2 expression and an average age of 64.1 years. The patients with low HER2 expression showed a score of 1 on the Ventana Ultra View Pathway HER2 (4B5). Sixteen patients were HR positive and seven were negative, with HR positive accounting for 83.3% of the patients with low HER2 expression.

Introduction The DESTINY-Breast04 study demonstrated the high therapeutic effect of trastuzumab deruxtecan (TDXd) against TPC in patients with HER2-low expressing inoperable or recurrent breast cancer (MBC) who had previously been treated with chemotherapy...There is a good possibility that HER2 0 cases will be judged to be low expression (HER2 1+, 2+), which will increase the number of treatment options (34% in this study). Therefore, all cases targeted for companion diagnostics for TDXd should be reevaluated with 4B5

Background HER2 low-expressing breast cancer has attracted attention due to the expansion of indications of trastuzumab deruxtecan... The HER2low group included 28 cases of non-specific ductal carcinoma (24 luminal, 4 triple negative) and 3 cases of mucinous carcinoma, while the HER2zero group included 16 cases of non-specific ductal carcinoma (12 luminal, 2 triple negative), 5 cases of lobular carcinoma, and 1 case of mucinous carcinoma. The coexistence of DCIS was more frequent in the HER2low group (87.5%) than in the HER2zero group (36.4%), and vascular invasion was also more frequent in the HER2low group (25%) than in the HER2zero group (0%). There was no significant difference in the rate of axillary lymph node metastasis.

Four cases (5.3%) were upgraded to HER2 non-expression (score 0) in biopsy and low expression (score 1+) in surgical specimen. On the other hand, there was one case (1.3%) in which HER2 expression was low in biopsy and non-expression in surgical specimen. There was a tendency for HER2 expression to be underestimated in biopsy specimens.

Of the 327 cases, 51 (16%) were HER2 negative, 200 (61%) were HER2 low expression, 58 (18%) were HER2 positive, and 18 (5%) were HER2 low expression or positive. By hormone receptor status, of the 243 HR positive cases, 29 (12%) were HER negative, 171 (70%) were HER2 low expression, 27 (11%) were HER2 positive, and 16 (7%) were HER2 low expression or positive. Of the 84 HR-negative cases, 22 (26%) were HER2-negative, 29 (35%) were HER2-low expressing, 31 (37%) were HER2-positive, and 2 (2%) were either HER2-low expressing or positive.

Introduction Approximately 60% of breast cancers classified as HER2-negative are said to have low HER2 expression (IHC 1+ or IHC 2+/ISH-), and the DESTINY-Breast04 study demonstrated the efficacy of trastuzumab deruxtecan (T-Dxd) for metastatic recurrent breast cancer with low HER2 expression...No clear pathological characteristics were observed in the HER2 low expression and negative groups, but bone metastasis was common as a clinical feature. As demand for testing increases in the future, it will be necessary to accumulate more cases and reexamine the clinical and pathological characteristics

There were 9 cases of changes in ER expression before and after needle biopsy. 5 cases (1.2%) had ER expression before needle biopsy but not after surgery. 4 cases (1%) had no ER expression before biopsy but had ER expression after surgery.

Background Anti-HER2 therapy was not indicated for HER2-negative metastatic or recurrent breast cancer, but the indications of trastuzumab deruxtecan have been expanded to include cases with low HER2 expression (IHC 1+, 2+ and ISH negative)... Age at the time of surgery ranged from 31 to 90 years (median 62 years). 555 were female and 2 were male. 350 were cStage I, 170 were cStage II, and 37 were cStage III.

Patient background: median age 55.5 years, 16 hormone positive cases, 8 triple negative cases, median treatment history after recurrence 4.5 regimens. HER2 low expression of metastatic lesions was 1+ in 18 cases and 2+/ISH negative in 6 cases. Changes in HER2 expression were negative to low expression in 9 cases, low expression to low expression in 12 cases, and positive to low expression in 3 cases.

The results showed that the amount of mRNA in Oncotype DX is not useful as an auxiliary diagnostic result for distinguishing between HER2 low (score 1) and HER2 null (score 0) using Dako Herceptest II. In the future, we would like to conduct similar studies with HER2 (4B5), a companion diagnostic for HER2 low

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that combines trastuzumab, an anti-human epidermal growth factor receptor type 2 (HER2) humanized monoclonal antibody, with deruxtecan, a topoisomerase I inhibitor...There were 6 cases of IHC 0, and all cases were judged to be 4B5 0. Previous reports have shown that 59.3-66.7% of HER2-negative breast cancers have low HER2 expression, which is generally consistent with the results

It was also suggested that the FISH method may be useful in determining not only "HER2 positive" but also "HER2 low expression". However, it seemed difficult to distinguish between 0 and 1+, which is the most troublesome point in the IHC method, using the FISH method

Recently, trastuzumab deruxtecan (T-DXd) has become eligible for insurance coverage for advanced recurrent breast cancer with low HER2 expression (HER2 low), and it is expected that the prognosis of HR+HER2- breast cancer will be further improved...The fixation conditions of the CNB specimen and the postoperative specimen may be one of the reasons why there were more cases of HER2 negative evaluation after surgery. It is thought that the timing of collection of the specimen affects the evaluation of HER2 low