HER-2 underexpression

The APIS kit accurately measures HER2/ERBB2 expression. The findings indicate that relying solely on IHC stratification may not be sufficient to predict responses to novel anti-HER2 treatments, like T-Dxd. By leveraging the dynamic range of RNA expression, a ΔCt semi-quantitative scale using additional cut-offs has been developed to enhance the stratification of ERBB2 mRNA expression.

P2, N=180, Recruiting, Fudan University Shanghai Cancer Center; Fudan University Shanghai Cancer Center

Within HR + HER2- breast cancer, HER2-low tumors are associated with high RS, especially for histologically invasive ductal carcinoma. A prognostic influence of HER2-low expression among HR + HER2- breast cancer remains as an area that requires further study.

For the treatment of breast cancer, there are three ADCs approved for breast cancer treatment: Trastuzumab emtansine (T-DM1), Trastuzumab Deruxtecan (T-Dxd) targeting HER-2, and Sacituzumab Govitecan (SG) targeting Trop-2. This review summarizes the efficacy and adverse effects of ADC therapies that have completed or are currently undergoing phase I-III clinical trials. Additionally, it analyzes potential combination strategies to overcome ADC resistance, aiming to provide clinicians with a comprehensive clinical guide to the use of ADCs in breast cancer treatment.

P2, N=66, Recruiting, Henan Cancer Hospital | Trial primary completion date: May 2024 --> Dec 2024

No abstract available

Our findings demonstrated a significant influence of HER2-low expression on the response to neoadjuvant chemotherapy among patients with hormone-positive HER2-low breast cancer within the studied cohort. Further studies are needed to evaluate the influence of hormonal expression on the response rate to NACT in the HER2-low patients in our population.

The radiomic signature and tumor descriptors from gray-scale US may predict distinct HER2 expressions of breast cancers with therapeutic implications.

Our study indicates that HER2-low status had no impact on pCR or DFS.

Kaplan-Meier survival curves showed that menstrual status, N staging, T staging, TNM staging, and pCR status affected the prognosis of HER2-low breast cancer patients (p < 0.05). HER2-low breast cancer exhibits distinct biological behaviors, suggesting personalized treatment approaches.

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 &lsqb;95%CI, 0.294-0.897], p = .019). 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.

The calibration curves showed satisfactory consistency, and DCA confirmed the clinical utility of the nomogram. The nomogram model based on ultrasound radiomics exhibited high prediction value for HER2-low BC.

Compared with those with high ERBB2 expression, tissues with low ERBB2 expression displayed greater immunogenicity and enrichment of immune pathways, particularly those related to B cells. These findings suggest that patients with low ERBB2 expression are likely to benefit from immunotherapy, especially B-cell-related immunotherapy.

P1, N=26, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Trial completion date: Aug 2024 --> Dec 2024 | Trial primary completion date: Aug 2024 --> Dec 2024

After HR stratification, there are unique clinical characteristics and prognostic outcomes in HER2-low expression breast cancer, which indicates the potential to become a specific molecular subtype of breast cancer. The significant instability of HER2-low expression status between primary tumor and residual invasive disease suggests that multiple detections of HER2 status should be emphasized in NAT strategies.

The APIS Breast Cancer Subtyping Kit accurately detects HER2/ERBB2 expression. The findings suggest that relying solely on IHC categorisation may not suffice for predicting response to novel anti-HER2 treatments. Utilising additional cut-offs could enhance the stratification of ERBB2 mRNA expression, distinguishing a ‘HER2- low’ group.

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.

This study revealed the incidence and clinical outcomes of HER2-low expression in de novo advanced breast cancer, suggesting favorable outcomes, particularly in HR-positive breast cancer. These findings may inform personalized treatment strategies. Further research into the mechanisms and implications of HER2-low expression in breast cancer is required.

No abstract available

The mutation frequency of PIK3CA in HER2 2+ was significantly higher than that in HER2 1+ group (P<0.05), and SLX4 gene was only mutated in HER2 1+ group. There are some differences of histological morphology and genetic variation between HER2-negative group and HER2-low group, and also differences in genetic variation between HER2 1+ and HER2 2+ in HER2-low group, which are helpful for more accurate stratification of TNBC and useful for finding the therapeutic target and precise treatment of HER2-low TNBC.

A high proportion of HER2-low expressors demonstrated HER2-CTC positivity. Monitoring CTC-HER2 status may offer prognostic value in patients with IBC.

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.

Significant associations between ERBB2 alterations and HER2 low-expressing tumors were observed. High prevalence of ERBB2 alterations was observed in some uncommonly tested tumors. Median OS of HER2 low-expressors was better than non-expressors in this heterogenous group.

Early-stage HR-positive breast carcinomas have low TIL levels regardless of the recurrence risk, molecular subtype, and HER2- low status. These cancers are markedly enriched by HER2-low phenotype, which might have therapeutic implications due to the recently approved anti-HER2 antibody-drug conjugate.

In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.

This has provoked many discussions on HER2-low breast cancer, such as quality control prior to HER2-low expression detection, the latest progress of tumor heterogeneity, and the application of AI. In this paper, we discuss the latest testing guidelines and advances on HER2-low breast cancer, aiming to standardize and improve the pathological testing of HER2-low breast cancer.

This study supports the interpretation of HER2 status as a possible prognostic and predictive biomarker for HER2-negative eBC, especially among patients with ER+ disease.

After progression on treatment with CDK4/6 inhibitors for HR-positive/HER2-low expression metastatic breast cancer, both chemotherapy and endocrine therpy combined with targeted drugs are viable treatment options. However, for patients with PR negative or ≥2 lines of endocrine therapy previously, priority should be accorded to chemotherapy.

The mPFS in the Her2-zero group was almost twice that of the Her2-low group, but the difference was not statistically significant. mPFS was significantly longer in the HER2-zero group compared to the HER2-low group in patients receiving ribociclib. More prospective studies are needed to understand the actual consequences of this biomarker.

However, the ROC AUCs were still over 0.90 for both primary tumours and mALNs. Thus, lesion-to-spleen ratios should be further evaluated to find if these could be applied to imaging using stand-alone SPECT cameras that do not permit SUV calculations.

RT-qPCR-based assessment of the mRNA expression of ESR1, PGR, ERBB2, and MKI67 showed high concordance with IHC, suggesting that the MammaTyper test on core needle biopsies represents a reliable, efficient, and reproducible alternative for breast cancer classification and refining HER2 low categorisation.

This study demonstrated that HER2-low tumor may exhibit prognostic significance. The innovative mNeo-Bioscore, based on a new classification of HER2 status, may serve as a prognostic staging system superior to Neo-Bioscore.

Our results suggest that a significant number of MBC patients could benefit from ADCs, as shown in FBC. Further studies are required to better understand HER2 low breast cancer, both generally and in MBC.

Additionally, patients with ERBB2-low and low TILs tumors had better BCSM (subdistribution HR, 0.36; 95% CI, 0.14-0.92; P = .03). These findings suggest that there were clinical, pathological, and epidemiological differences between ERBB2-low and ERBB2-negative BC, raising the possibility that ERBB2-low might be a unique biologic entity.

The prognostic value of HER2-low status remains controversial. Our study showed no significant effect of HER2 low expression on survival in patients receiving CDK 4/6i plus ET.

P1, N=115, Recruiting, Daiichi Sankyo | Trial completion date: Mar 2024 --> Aug 2025 | Trial primary completion date: Feb 2024 --> Dec 2024

A total of 25 common and stable differential metabolites may hold promise as liquid non-invasive indicators for GCA diagnosis. HER2 may function as a tumor suppressor gene in GCA, as its overexpression is associated with improved survival. The downregulation of bile acid metabolism in GCA may offer valuable theoretical insights and innovative approaches for precision-targeted treatments in GCA patients.

Results confirm that IHC stratification may not be an adequate method for predicting the response to novel anti-HER2 therapies, such as T-DXd. Implementation of additional cut offs could allow further stratification of ERBB2 mRNA expression, however, additional studies are required to validate this approach.

This study suggested that HER2-low expression may predict the efficacy of ET but not that of CDK4/6 inhibitor plus ET in HR-positive/HER2-negative MBC patients. The results of this study highlight the importance of integrating HER2 status in tailoring personalized treatment strategies for HR-positive MBC.

P1/2, N=42, Recruiting, Sichuan Baili Pharmaceutical Co., Ltd. | Not yet recruiting --> Recruiting

The strengths of evidence and recommendation were determined through a quantitative and qualitative systematic review using multiple outcomes, including efficacy and safety. We conclude that trastuzumab deruxtecan is recommended for this patient population (strength of recommendation: 1; strength of evidence: moderate; CQ34) and that HER2-low expression for the indication of trastuzumab deruxtecan should be diagnosed using companion diagnostics based on appropriate criteria (FRQ7).

P2, N=80, Not yet recruiting, RemeGen Co., Ltd. | Initiation date: Dec 2023 --> Dec 2024