TEST:

HercepTest

Our findings support the adverse prognostic impact on HER2 in PCa. We propose the use of a modified scoring system to evaluate HER2 expression in PCa. The observed high prevalence of HER2 expression supports the consideration of novel HER2-targeted therapies addressing even low levels of HER2 expression in future PCa trials.

P2; Unknown status --> Completed

Background: DESTINY-Breast04 (DB-04) showed that trastuzumab deruxtecan improves survival vs chemotherapy in patients with human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry [IHC] 1+ or IHC 2+ with in situ hybridization negative) metastatic breast cancer (BC)... The degree of concordance between the CTA and non-CTAs varied among assay types and laboratory locations. A low NPA for some non-CTAs suggests the need for further assay optimization for HER2 IHC 0 evaluation.

P=N/A; Enrolling by invitation --> Completed

HER2 cytoplasmic granular staining was present in 29.7% of pure ACs using PATHWAY 4B5 platform. The rate of HER2 cytoplasmic granular staining on HercepTest platform was significantly lower than that of PATHWAY 4B5 and was only appeared in 2+ and 3+ cases, suggesting that the HercepTest platform is more suitable for the HER2 low expression cases. The IHC interpretation of HER2 3+ were highly consistent with FISH status.

There is a considerable overlap between mRNA values when correlated with HER2 IHC values regardless of the IHC scoring system used. Only a small percentage of cases fell in H-score category different from ASCO-CAP category, contributing to minimal difference seen in terms of correlation with mRNA scores suggesting that H-score has no advantage over ASCO-CAP scoring system.

Background: Anti-HER2 antibody-drug conjugate trastuzumab-deruxtecan has shown efficacy in patients with HER2-low metastatic breast cancer (BC)... These results are the evidence for the need of newly developed algorithms that are capable of distinguishing HER2-low from HER2-negative accurately.

Background: The DESTINY-Breast04(DB-04) trial has shown efficacy of breast cancer (BC) patients with HER2-low in the metastatic setting to Anti-HER2 antibody-drug conjugate trastuzumab-deruxtecan... We conclude that a significant number of patients will receive incorrect Anti-HER2-low therapy by simply taking the reported score on a historic sample. We recommend repeating the assay following the FDA-approved protocol on a large sample size such as excisional biopsy.

The current IHC assays are suboptimal in evaluating HER2-low breast cancers. RNAscope is a simple assay that can be objectively quantified. RNAscope is better than the current IHC assays in evaluating HER2 expression in HER2-low breast cancers and may identify patients who would benefit from T-DXd treatment.

ER and PR staining show a high level of concordance (97.3% and 87.1%, respectively) between IBC and DCIS. HER2 showed a slight trend toward increased staining in DCIS, however, only 4 of the 147 cases (2.7%) were 3+ with an associated HER2 negative IBC. Our findings suggest that ER, PR, and HER2 show concordance between IBC and DCIS, with only a slight increase in HER2 staining in DCIS.

Background: The DESTINY-Breast04(DB-04) trial has shown efficacy of breast cancer (BC) patients with HER2-low in the metastatic setting to Anti-HER2 antibody-drug conjugate trastuzumab-deruxtecan... We conclude that a significant number of patients will receive incorrect Anti-HER2-low therapy by simply taking the reported score on a historic sample. We recommend repeating the assay following the FDA-approved protocol on a large sample size such as excisional biopsy.

P1/2; Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Jul 2025 --> Oct 2026

The RNA levels were significantly higher (p=0.030) in responders (6.4±8.2 dots/cell, n=12) than in non-responders (2.6±2.2, n=20) to T-DXd. RNAscope is a simple assay that can be objectively quantified and is a promising alternative to current IHC assays in evaluating HER2 expression in breast cancers, especially HER2-low cases, and may identify patients who would benefit from T-DXd.

P1; Not yet recruiting --> Recruiting

This assay is linked to the use of the monoclonal antibody trastuzumab in the treatment of HER2 positive breast cancer...Currently, more than 60 drugs or drug combinations, primarily in hematology and oncology, have been approved by the FDA, with CDx assays linked to their use. The current article briefly discusses the subject of CDx and provides an overview of its evolution over the past 25 years, with particular emphasis on the United States.

In this large single institutional analysis of dual HER-2 testing, only 12% of cases demonstrate HER-2 amplification, and overall in our institutional pathology database, from 2001 – March 2023, 11.2% of cases are HER-2+ by either IHC or ISH. In our dual tested cohort, only 13.6% of IHC 2+ cases demonstrate amplification, and 13.8% are non-amplified, but have excess HER-2 copy number. We demonstrate a numerical increase in the rate of amplification, and copy number in non-amplified cases, associated with IHC score.

T-DXd has been approved by the FDA to treat patients with metastatic HER2-low and -positive breast cancer...There were significant differences of dots/cell comparing 1+, 2+ and 3+ cases. Note: ns not significant (p>0.05), * p<0.05, *** p<0.001, **** p<0.0001

We have reason to believe that the new antibody will reduce the diagnostic time and avoid unnecessary costs. Due to the small study group, further investigation is needed.

The rate of identifiable tumors with HER2 low or HER2 ultra-low expression varies depending on assay parameters that can easily be modified. Irrespective of assay sensitivity, our data identify various tumor entities with significant fractions of "HER2-low" cases that might benefit from therapy with new antibody drug conjugates.

Furthermore, C-erbB-2 and SP3 were used with different antibody concentrations showing inconsistent HER2-expression. Overall, HER2 antibodies need to be re-validated and the use of a standardized reference material (e.g. cell lines) with AI is a promising method to determine HER2-low for clinical use.

P2; N=55 --> 0 | Trial completion date: Oct 2009 --> Jul 2023 | Completed --> Withdrawn | Trial primary completion date: Oct 2009 --> Jul 2023

Conclusions In this study, there was no prognostic difference based on HER2 expression status in HER2-negative early-stage BC, but there was a frequency difference in determining HER2-low and HER2-0 depending on the immunostaining kits. While there are many assays for HER2 evaluation approved in the practice, an appropriate companion diagnosis for HER2-low seems to be critical to select patients who may benefit from newer treatment such as Trastuzumab Deruxtecan.

Detection of HER2 amplification in plasma was accurate, as indicated by the low rate of false positives; however, sensitivity was poor. This suggests that ctDNA testing may help identify pts with HER2 amplification but is not yet a substitute for tissue-based HER2 ISH and IHC testing.

As clinical consequences in HER2-low group are not yet fully established, different segregation profiles among different IHC-based assays should be acknowledged. Probability of a case being overscored in one assay or underscored in another should be considered while therapeutic translations are made from pathology reports.

P=N/A; N=10; Enrolling by invitation; Sponsor:Tomsk National Research Medical Center of the Russian Academy of Sciences

P1; N=10; Not yet recruiting; Sponsor:Tomsk National Research Medical Center of the Russian Academy of Sciences

TBA.

P2; Trial completion date: Dec 2024 --> Apr 2025 | Trial primary completion date: Dec 2023 --> Apr 2024

Low level HER2 expression occurs commonly in many cancer types. The rate of identifiable tumors with HER2 low or HER2 ultra-low expression greatly varies depending on assay parameters that can easily be modified. Clinical trials are needed to identify the HER2 expression thresholds to identify patients who may benefit from anti-HER2-low therapies.

There was a wide range of quantitative HER2 gene expression using Oncotype DX assay across all IHC categories; continuous HER2 expression is independently associated with recurrence. Quantitative HER2 expression may be useful for identification of HER2-low breast cancer. Further studies are needed.

P=N/A; Recruiting --> Completed

P1; Enrolling by invitation --> Completed

P2; Recruiting --> Completed | Trial completion date: Dec 2023 --> Dec 2022

P1; Active, not recruiting --> Completed | N=19 --> 9

P=N/A; Enrolling by invitation --> Completed

P=N/A; N=58; Active, not recruiting; Sponsor:Fondazione Policlinico Universitario Agostino Gemelli IRCCS

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.

The HercepTest was approved 20+ years ago as the companion diagnostic test for trastuzumab in human epidermal growth factor 2 (HER2) or ERBB2 gene-amplified/overexpressing breast cancers...Conversely, at the task of scoring HER2 IHC as 3+ or not 3+ pathologists' concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding the patients in whom the ERBB2 gene is amplified but unacceptably discordant in assigning HER2-low or HER2-negative status for the emerging HER2-low therapies.

P1; Recruiting --> Active, not recruiting

P=N/A; N=24; Enrolling by invitation; Sponsor:Tomsk National Research Medical Center of the Russian Academy of Sciences

To our knowledge, this study is the first to compare the performance of the two most commonly-used HER2 IHC methods to HER2 gene amplification by FISH. Both HercepTest and 4B5 HER2 IHC had 100% specificity for detecting HER2 gene amplification in USC, while HercepTest has superior sensitivity. Therapeutic targeting of HER2 is among the most significant advancements in this disease in decades, specifically for patients with HER2 positive advanced stage and recurrent USC.

Background : With the advent of antibody-drug conjugate (ADC) therapy such as trastuzumab deruxtecan, further elucidation of the HER2-low category of invasive breast cancer (IBC) is necessary given the promising benefits of ADCs in this newly defined group (IHC score 1+ or 2+ and FISH negative)... In our cohort, a majority of cases (84%; 294/350) that were originally classified as HER2 negative by the 2018 ASCO/CAP guidelines were classified as HER2-low, qualifying them for HER2-targeted ADC therapy in the appropriate clinical setting. As triple-negative IBC (TN; ER/PR/HER2 negative by current guidelines) has limited treatment options, the observation that a majority of TN IBC in this cohort (69.4%; 25/36) were classified as HER2-low raises the possibility that these patients may derive clinical benefit from HER2-targeted ADCs. This study adds to the limited literature available for this newly defined category.