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Background Accurately assessing HER2-low (immunohistochemistry [IHC] 1 + and IHC 2+/in situ hybridization [ISH]–) and HER2-ultralow (IHC > 0 < 1+) is essential given the emergence of novel therapies. Thorough understanding of the reproducibility of rescoring IHC stained slides or re-staining archived tissue slides is essential. Methods 2,869 breast cancer patients diagnosed between July 2021 and July 2022 from 10 hospitals in China were included in this multicentre study. The prevalence of different HER2 expression levels and distribution of HER2 IHC scores were assessed by HER2 status determination from rescored historical slides. Concordance was evaluated across historical results versus rescored results, historical results versus re-stained results, and leading center results versus local site results. Clinicopathological characteristics were retrospectively analyzed as well. Results HER2 IHC 0, IHC 1+, IHC 2+, and IHC 3 + were identified in 682 (23.8%), 871 (30.4%), 801 (27.9%), and 515 (18.0%) cases, respectively. HER2-positive, HER2-low, and HER2 IHC 0 (HER2-ultralow and IHC null) were identified in 21.7%, 54.5%, and 23.8% of cases, respectively. The prevalence of HER2-ultralow and IHC null was 10.6% and 13.2%, respectively. The concordance for HER2-ultralow was 43.3%; 30% of cases that were scored as HER2-ultralow at local sites were rescored as HER2-null and 26.7% of cases were rescored as IHC 1 + at the leading site. Overall, there was substantial agreement (83.1%) between rescored and historical IHC results. A high concordance rate of 91.7% was observed for HER2-low classification. Conclusions This is the first multicenter study to determine the prevalence of HER2-low and HER2-ultralow based on rescored results in the Chinese breast cancer population. The concordance analysis carries important implications for the diagnosis of HER2-low and HER2-ultralow cases in clinical practice. The relatively low concordance in identifying HER2-ultralow suggested that the reproducibility of scoring HER2-ultralow needed to be improved through training. Trial registration ClinicalTrials.gov identifier NCT05203458.

Abstract Background A deeper understanding of the molecular and clinical characteristics of HER2-low and ultralow breast cancer (BC) subtypes is essential for advancing therapeutic strategies. Methods Three independent GEO datasets with microarray and IHC/FISH data from 510 BC patients were analyzed to establish reliable HER2 expression cutoff values (>3034 for HER2-positivity and <1780 for HER2-ultralow), defining HER2-positive (HER2+), HER2-low, and HER2-ultralow cohorts. Combined with hormone receptor status, six distinct BC subgroups were identified. Prognosis was evaluated using univariate and multivariate survival analysis in a dataset of 7830 BC patients, alongside correlative analysis of 17 immune-related gene signatures across subgroups. A PubMed literature review compared our findings with existing studies. Results In hormone receptor-positive (HR+) patients, HER2-low tumors were associated with better prognosis than HER2-ultralow and HER2+ subgroups (P = .0048 for relapse-free survival (RFS) and P = .0015 for distant-metastasis-free survival (DMFS)). No prognostic significance was observed in HR-negative (HR−) patients. Immune gene activation was consistently higher in HR− tumors, with HER2-low (HR+ and HR−) and HR-/HER2+ patients showing significant immune signature overlap. While HR+/HER2-ultralow and HR+/HER2+ patients had modest immune activation, HR-/HER2-ultralow patients exhibited the strongest association with immune signaling, including IFN signaling, T cell-activating cytokines, and cytotoxic effector molecules. Conclusions These findings, supported by a comprehensive literature review, indicate that patients with HER2-low and HER2-ultralow BC exhibit distinct immune patterns, which supports their classification as unique BC subgroups.

Purpose HER2-low breast cancer (BC) is a novel entity with relevant therapeutic implications, especially in hormone receptor (HR) positive BC. This study examines whether HER2 mRNA through the 21-gene assay, Oncotype DX (ODX), can refine the diagnosis of HER2-low and HER2- zero , obtained by immunohistochemistry (IHC). Methods Between Jan 2021 and Jan 2023, 229 consecutive HR-positive HER2-negative early BC (T1-3 N0-1) have been characterised by IHC and ODX. HER2 status by IHC was either zero (IHC-0) or low (IHC-1 + and IHC-2 + /ISH-negative) while HER2-zero was further divided into HER2-null (IHC-0) and HER2-ultralow (IHC-1–10%). HER2 gene expression by ODX was negative if lower 10.7. Results The distribution of HER2 IHC was as follows: 53.3% HER2-0, 29.25% HER2-1 + , and 17.5% HER2-2 + . The clinicopathological characteristics were similar in the three groups, with higher PgR-negative rate in HER2-zero (13.9% vs 3% vs 5%). The distribution of RS was homogeneous in the three groups with the median HER2 gene expression of 9.20 [IQR: 8.70–9.60]. HER2 gene expression gradually increased as the IHC score, with substantial overlap. After adjusting for confounders, HER2-1 + and HER2 2 + had a significant positive correlation between HER2 gene expression and IHC [OR 1.42, 95% CI 1.21 to 1.68, p  < 0.001; OR 1.96, 95% CI 1.61 to 2.37, p  < 0.001] compared to the HER2- zero group. HER2 gene expression did not differ between HER2-null and HER2-ultralow subgroups. Conclusion Due to the substantial overlap, the HER2 gene expression is unable to properly distinguish HER2-low and HER2- zero IHC whose accurate identification is critical in the context of HER2-negative BC.

Background Breast cancer was previously categorized as human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry [IHC] 3+, IHC 2+ / in situ hybridization [ISH]–positive) or HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH−). Recent studies of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, have explored the spectrum of HER2 expression in tumors categorized as HER2-negative, including HER2-low (IHC 1+, IHC 2+/ISH−) and HER2-ultralow (IHC 0 with membrane staining). Clinical relevance of HER2-low and HER2-ultralow is reinforced by encouraging efficacy findings in these populations. Objective To assess HER2-low and HER2-ultralow scoring performance by pathologists, and compare real-world HER2-low scoring with centralized scoring by trained pathologists. Methods Formalin-fixed, paraffin-embedded breast cancer samples stained by the VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Roche) assay were selected to ensure adequate representation across all HER2 IHC scores ( N  = 500). Samples were rescored in a central laboratory by three pathologists trained in HER2-low scoring, and a majority consensus generated. Agreement between consensus and historical real-world HER2 scores was assessed by Fleiss’ kappa across HER2 scores (IHC 0, 1+, 2+, 3+). Results Substantial agreement was observed among central pathologists across HER2 scores (κ = 0.69), for the HER2-low cutoff (IHC 0 vs. IHC 1+, 2+, 3+; κ = 0.79), and the HER2-ultralow cutoff (IHC 0 absent membrane staining vs. IHC 0 with membrane staining, 1+, 2+, 3+; κ = 0.68). Substantial agreement was observed between real-world pathologists and central consensus for the HER2-low cutoff (κ = 0.72). Conclusions Pathologists can reproducibly score HER2-low and HER2-ultralow when supported by training. Findings may aid decision-making for patients with breast cancer who are potentially eligible for HER2-directed therapy.

Breast cancer was previously categorized as human epidermal growth factor receptor 2 (HER2)-positive (immunohistochemistry [IHC] 3+, IHC 2+ / in situ hybridization [ISH]-positive) or HER2-negative (IHC 0, IHC 1+, IHC 2+/ISH-). Recent studies of trastuzumab deruxtecan, a HER2-directed antibody-drug conjugate, have explored the spectrum of HER2 expression in tumors categorized as HER2-negative, including HER2-low (IHC 1+, IHC 2+/ISH-) and HER2-ultralow (IHC 0 with membrane staining). Clinical relevance of HER2-low and HER2-ultralow is reinforced by encouraging efficacy findings in these populations. To assess HER2-low and HER2-ultralow scoring performance by pathologists, and compare real-world HER2-low scoring with centralized scoring by trained pathologists. Formalin-fixed, paraffin-embedded breast cancer samples stained by the VENTANA anti-HER2/neu (4B5) Rabbit Monoclonal Primary Antibody (Roche) assay were selected to ensure adequate representation across all HER2 IHC scores (N = 500). Samples were rescored in a central laboratory by three pathologists trained in HER2-low scoring, and a majority consensus generated. Agreement between consensus and historical real-world HER2 scores was assessed by Fleiss' kappa across HER2 scores (IHC 0, 1+, 2+, 3+). Substantial agreement was observed among central pathologists across HER2 scores (κ = 0.69), for the HER2-low cutoff (IHC 0 vs. IHC 1+, 2+, 3+; κ = 0.79), and the HER2-ultralow cutoff (IHC 0 absent membrane staining vs. IHC 0 with membrane staining, 1+, 2+, 3+; κ = 0.68). Substantial agreement was observed between real-world pathologists and central consensus for the HER2-low cutoff (κ = 0.72). Pathologists can reproducibly score HER2-low and HER2-ultralow when supported by training. Findings may aid decision-making for patients with breast cancer who are potentially eligible for HER2-directed therapy.

Approximately 80% of invasive breast cancers are classified as human epidermal growth factor receptor 2 (HER2)-negative; however, many of these tumors have detectable levels of HER2 surface expression. Trastuzumab deruxtecan (T-DXd) is a HER2-directed antibody-drug conjugate with a membrane-permeable payload that is cytotoxic to both HER2-expressing tumor cells and neighboring cells via the bystander antitumor effect. T-DXd has shown significant antitumor activity in clinical trials for patients with HER2-positive (immunohistochemistry [IHC] 3+ or IHC 2+/in situ hybridization [ISH]+) breast cancer. In addition, the results of the DESTINY-Breast04 trial demonstrated the clinical benefit of T-DXd in patients with HER2-low (IHC 1+ or IHC 2+/ISH−) breast cancer after receiving prior chemotherapy. DESTINY-Breast06 demonstrated the clinical benefit of T-DXd in patients with hormone receptor (HR)-positive, HER2-low (IHC 1+ or IHC 2+/ISH−), and HER2-ultralow (IHC 0 with membrane staining) metastatic breast cancer who had not received prior chemotherapy in the advanced setting. These results validate the need for a standard-of-care diagnostic test to identify HER2-low and HER2-ultralow expression levels in patients with metastatic breast cancer to guide therapeutic decision-making. Furthermore, effective treatment sequencing strategies and adverse event management are essential for maximizing patient benefit. This review presents the identification of HER2-low and HER2-ultralow breast cancer, sequencing of T-DXd with other treatments, and management of common or clinically significant adverse events reported with T-DXd.

Background: HER2-ultralow is an emerging subgroup of metastatic breast cancer (mBC). However, despite an increasing interest, limited data exist on its prevalence and outcomes, especially among patients receiving standard first-line chemotherapy. Objectives: This study assessed the prevalence and outcomes of HER2-ultralow mBC in a real-world cohort of hormone receptor-positive (HR+)/HER2-negative patients receiving first-line standard-of-care (SOC) chemotherapy. Design: A retrospective, single-center cohort study. Methods: We included HR+/HER2-negative mBC patients treated with SOC between January 2016 and February 2023. Patient data were reviewed from electronic health records. HER2-zero tumors (immunohistochemistry 0) were rescored by expert pathologists using the American Society of Clinical Oncology/College of American Pathologists guidelines to distinguish HER2-ultralow from HER2-null cases. Real-world progression-free survival (rwPFS) and real-world overall survival (rwOS) were estimated using Kaplan–Meier and multivariable Cox regression models. Results: Among 320 patients (median age, 62.4 years), 72.8% had visceral metastases, and 17.5% had bone-only disease. Previous CDK4/6 inhibitor treatment was reported in 43.4%. Rescoring identified 15.6% with HER2-ultralow, 61.9% with HER2-low, and 22.5% with HER2-null tumors. The median follow-up was 39.4 months (95% confidence interval (CI), 37.1–47.6). Median rwPFS was 7.9 months (95% CI, 4.6–19.0), 7.3 months (95% CI, 6.4–9.1), and 6.2 months (95% CI, 4.6–8.9) for HER2-ultralow, HER2-low, and HER2-null groups, respectively. Median rwOS was 19.5 months (95% CI, 10.7–33.4), 21.5 months (95% CI, 19.0–25.8), and 16.6 months (95% CI, 11.9–23.6). In patients previously treated with CDK4/6 inhibitors, median rwPFS was 4.6 months (95% CI, 2.7–21.4), 6.1 months (95% CI, 5.5–7.3), and 5.6 months (95% CI, 3.8–8.7). Conclusion: HER2-ultralow accounts for 15.6% of HR+/HER2-negative mBC cases and demonstrates outcomes comparable to HER2-low with SOC chemotherapy.

Background This study aims to analyze potential differences in clinicopathology, efficacy of neoadjuvant therapy (NAT), and clinical outcome among HER2-null, HER2-ultralow and HER2-low breast cancers. Methods Consecutive cases of HER2-negative breast cancer that received NAT were included. They were classified as HER2-null (no staining), HER2-ultralow (incomplete faint staining in ≤ 10% of tumour cells) and HER2-low (HER2-1 + or HER2-2+, in situ hybridisation negative). Subgroup analysis was performed based on the HER2 expression level. Results Out of 302 patients, 215 (71.19%) were HER2-low, 59 (19.54%) were HER2-ultralow, and 28 (9.27%) were HER2-null. In comparison to the HER2-ultralow group, the HER2-low group exhibited higher expression frequencies of ER ( p  < 0.001), PR ( p  < 0.001), and AR ( p  = 0.004), along with a greater prevalence of the luminal subtype ( p  < 0.001). The HER2-ultralow group also demonstrated a higher prevalence of lymph node metastasis compared to the HER2-null group ( p  = 0.026). Varied rates of pathologic complete response (pCR) were observed among the three subgroups: HER2-null, HER2-ultralow, and HER2-low, with rates of 35.71%, 22.03%, and 12.56%, respectively. Only the HER2-low subgroup exhibited a significant difference compared to HER2-null ( p  = 0.001). Despite variations in pCR rates, the three subgroups exhibited comparable disease-free survival (DFS) ( p  = 0.571). Importantly, we found HER2-low patients with better treatment response (RCB-0/I) exhibited significantly better DFS than those with significant residual disease (RCB-II/III) ( P  = 0.036). The overall rate of HER2 immunohistochemical score discordance was 45.24%, mostly driven by the conversion between HER2-0 and HER2-low phenotype. Notably, 32.19% of cases initially classified as HER2-0 phenotype on baseline biopsy were later reclassified as HER2-low after neoadjuvant therapy, and it is noteworthy that 22 out of these cases (78.57%) originally had an HER2-ultralow status in the pretreatment biopsy sample. Conclusions Our results demonstrate the distinct clinicopathological features of HER2-low and HER2-ultralow breast tumors and confirm that RCB is an effective predictor of prognosis in HER2-low populations for the first time. Notably, our findings demonstrate high instability in both HER2-low and HER2-ultralow expression from the primary baseline biopsy to residual disease after NAT. Furthermore, this study is the first to investigate the clinicopathological feature and the effectiveness of NAT for HER2-ultralow breast cancer.

The concept of binary classification of HER2 status has recently been challenged following the DESTINY-Breast trial data showing a clinically meaningful response to antibody–drug conjugates (ADCs) in invasive breast cancer expressing low levels of HER2. HER2-low breast cancer is defined as an immunohistochemistry (IHC) score of 1+ and 2+ without HER2 gene amplification. While HER2-low breast cancer does not represent a biological entity, it encompasses both hormone receptor-positive and triple-negative breast cancer. Differences exist between this group and HER2-null breast cancer. In this review, we provide an update on HER2-low and HER2-ultralow breast cancer, including background trial data, the evolution of HER2-low expression, current clinical guidelines, quality issues, and future directions.

Background and Objectives: A recent clinical trial has demonstrated that breast cancer with low-HER2 expression levels responds to trastuzumab deruxtecan treatment. This has prompted a re-evaluation of HER2-targeted therapies in the HER2-negative group. Further research is required in the form of more detailed information about HER2-negative breast cancers with HER2-null, HER2-ultralow, and HER2-low subgroups. This study represents a novel approach to this field. Materials and Methods: HER2-negative breast cancer patients were classified into three groups as HER2-null, HER2-ultralow, and HER2-low. A comparison of clinicopathological features was analyzed retrospectively. Results: Of 722 patients, 22.3% were HER2-null, 23.7% were HER2-ultralow, 54.0% were HER2-low. While two-thirds of all the patients were evaluated as having T2 tumors, T4 tumors constituted 2.4%. Among HER2-negative cases, 11.8% were triple-negative and 88.2% were hormone-positive. The mean tumor diameter was 0.57 cm larger in the HER2-ultralow group than in the HER2-null group and 0.34 cm larger in the HER2-low group than in the HER2-null group. HER2-null tumors tend to be smaller. The HER2-low group was more likely to relapse than the HER2-null group. There were no significant differences in the distribution of hormone positivity or negativity (TNBC) among the groups; they accounted for 89.2% and 10.8% of all cases, respectively. Conclusions: HER2-negative breast cancer is a heterogeneous disease and deserves a detailed review in terms of diagnosis and treatment. HER2-ultralow tumors are larger in size and have a prognosis comparable to HER2-null tumors. HER2-low tumors tend to recur much more frequently and with poorer outcomes. In this field, new therapeutic approaches may result in better outcomes.