Abstract:The introduction of novel anti-HER2 antibody-drug conjugates (ADC) for the treatment of HER2-low breast cancers has transformed the traditional dichotomy of HER2 status to an expanded spectrum. However, the identification of HER2-low (i.e., immunohistochemistry (IHC) score 1 + or IHC score 2+, without gene amplification) tumors is challenged by methodological and analytical variables that might influence the sensitivity and reproducibility of HER2 testing. To open all possible therapeutic opportunities for HER… Show more
“…AI algorithms are not yet widely used in the clinical setting for the identification of HER2-low breast cancer, and further research is required to refine them. 37 Nevertheless, change is imminent, and despite current uncertainties and challenges, laboratories are expected to benefit from preparing for this sooner rather than later. 21 …”
“…AI algorithms are not yet widely used in the clinical setting for the identification of HER2-low breast cancer, and further research is required to refine them. 37 Nevertheless, change is imminent, and despite current uncertainties and challenges, laboratories are expected to benefit from preparing for this sooner rather than later. 21 …”
“…Moreover, although not currently recommended for routine practice outside of clinical trials, providing the percentage (10% or less) of immunostained cells in samples with an IHC score of 0 could hold future value. This approach may prove beneficial for investigating the potential advantages of new ADCs in the context of HER2-ultra low BC (defined as a score of 0 with incomplete and faint staining in >0 and ≤ 10% of tumor cells) in forthcoming studies [ 61 ]. Methodological information, including the primary antibody used (e.g., 4B5, HercepTest GE001), should be provided, along with a statement confirming adherence to the ASCO/CAP guidelines.…”
Section: Improving the Detection And Reporting Of Her2-low Breast Can...mentioning
confidence: 99%
“…Until recently, effective HER2-targeted therapies for these tumors were lacking [ 60 ]. Nonetheless, the advent of novel antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan (T-DXd), which deliver cytotoxic agents to cells with low HER2 levels, has opened a new therapeutic option for this substantial BC patient population [ 60 ]. Fig.…”
Since the release of the DESTINY-Breast04 (DB-04) trial findings in June 2022, the field of pathology has seen a renaissance of HER2 as a predictive biomarker in breast cancer. The trial focused on patients with metastatic breast cancer who were classified as “HER2-low,” i.e., those with immunohistochemistry (IHC) HER2 1 + or 2 + and negative in situ hybridization (ISH) results. The study revealed that treating these patients with trastuzumab deruxtecan (T-DXd) instead of the oncologist’s chosen chemotherapy led to outstanding improvements in survival. This has challenged the existing binary HER2 pathological classification system, which categorized tumors as either positive (overexpression/amplification) or negative, as per the ASCO/CAP 2018 guideline reaffirmed by ASCO/CAP 2023 guideline update. Given that DB-04 excluded patients with HER2 IHC score 0 status, the results of the ongoing DB-06 trial may shed further light on the potential benefits of T-DXd therapy for these patients. Roughly half of all breast cancers are estimated to belong to the HER2-low category, which does not represent a distinct or specific subtype of cancer. Instead, it encompasses a diverse group of tumors that exhibit clinical, morphological, immunohistochemical, and molecular variations. However, HER2-low offers a distinctive biomarker status that identifies a specific therapeutic regimen (i.e., T-DXd) linked to a favorable prognosis in breast cancer. This unique association emphasizes the importance of accurately identifying these tumors. Differentiating between a HER2 IHC score 0 and score 1 + has not been clinically significant until now. To ensure accurate classification and avoid misdiagnosis, it is necessary to adopt standardized procedures, guidelines, and specialized training for pathologists in interpreting HER2 expression in the lower spectrum. Additionally, the utilization of artificial intelligence holds promise in supporting this endeavor. Here, we address the current state of the art and unresolved issues in assessing HER2-low status, with a particular emphasis on the score 0. We explore the dilemma surrounding the exclusion of HER2-zero patients from potentially beneficial therapy based on traditional HER2 testing. Additionally, we examine the clinical context, considering that DB-04 primarily involved heavily pretreated late-stage metastatic breast cancers. We also delve into emerging evidence suggesting that extrapolating HER2-low status from the original diagnosis may lead to misleading results. Finally, we provide recommendations for conducting high-quality testing and propose a standardized pathology report in compliance with 2023 ASCO/CAP updates and 2023 ESMO consensus statements on HER2-low breast cancer.
“…The emergence of antibody-drug conjugates (ADCs) has shown efficacy in not only tumors with HER2 overexpression but also low HER2 tumors [ 6 ]. Conventional HER2 IHC assays have challenges, including not being calibrated to detect low HER2 levels and poor reproducibility of low HER2 expression diagnoses among pathologists [ 7 , 8 ]. Therefore, HER2 expression quantification is becoming increasingly important.…”
HER2 expression in breast cancer is evaluated to select patients for anti-HER2 therapy. With the advent of newly approved HER2-targeted drugs for low HER2 expression breast cancer, more solid evidence on the whole spectrum of HER2 expression is needed. In this study, we quantitatively assessed HER2 expression from the whole core by combining high-intensity phosphor-integrated dot (PID) immunostaining and whole slide imaging (WSI) analysis. Two types of staining were performed using a 170-core tissue microarray of invasive breast cancer. First, HER2 was stained by immunohistochemistry (IHC), and IHC scores were determined by two practicing pathologists according to the ASCO/CAP HER2 guideline. Second, HER2 was stained with PID, and tentative PID scores were determined by quantitative analysis. The results show that PID can numerically classify HER2 expression status into scores 3+, 2+, 1+, and 0. The HER2 value quantified by PID strongly correlated with the 3, 3’-diaminobenzidine (DAB) IHC score determined by pathologists (R2 = 0.93). PID IHC score 1+ cases included both DAB IHC score 1+ and 0 cases, and low HER2 expression cases appeared to be often evaluated as DAB IHC score 0. Therefore, digital image analysis by PID and WSI can help stratify HER2 IHC. It may also help classify low HER2 expression.
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