Human epidermal growth factor receptor 2 (HER2)-low breast cancer has emerged as a subtype of breast cancer, defined by HER2 1+/2+ in immunohistochemistry (IHC) and absence of ERBB2 gene amplification on fluorescence in situ hybridization (FISH). Recent trials showed marked response of HER2-low breast cancer to novel anti-HER2 antibody-drug-conjugates. Data on characteristics of HER2-low breast cancer subtype is limited. Real-world data from the Anatomic Pathology Department of Hotel-Dieu de France, spanning 2017-2023, was retrospectively collected. HER2-positive patients were excluded to compare HER2-low to HER2-zero breast cancer subtypes. Clinicopathological characteristics between the groups were compared using a Chi-Squared test. Out of 1195 patients, we observed 341 (28.5 %) HER2-low breast cancers cases. HER2-positive breast cancer cases (n = 178; 14.9 %) were excluded. There was no significant difference in age and sex between HER2-low and HER2-zero group (p = 0.33 and 0.79, respectively). HER2-low breast cancer was associated with positive estrogen receptor status and positive progesterone receptor status (p < 0.001 and p = 0.01, respectively). Ductal adenocarcinomas were more commonly observed in HER2-low group (p < 0.001). When stratified by hormone (HR) status, 87.4 % of patients had HR-positive status and 12.6 % were HR-negative. Among the HR-negative group, HER2-low tumors tended to show lower proliferation index compared to HER2-zero tumors (25%vs.10 %, p = 0.04). This study showed that HER2-low is distinct from HER2-zero and is common among patients with breast cancer. Clinicopathological features such as histological type differ between HER2-zero and HER2-low breast cancer. Within HR-negative breast cancer, those with low HER2 expression exhibit a less aggressive profile compared to HER2-zero tumors.

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-low breast cancer (BC) is a new entity considered a biologically distinct subtype from HER2-zero BC. However, the importance of HER2 low expression on the activity of cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) remains unclear.
METHODS: We conducted a single-center retrospective study including hormone receptor-positive (HR +) /HER2- metastatic BC (mBC) patients treated with CDK4/6i plus endocrine treatment (ET) as first-line therapy. Clinical outcomes were analyzed according to HER2 expression.
RESULTS: 258 women were analyzed with a median follow-up of 25.4 months; 39.9% had HER2 low, and 60.1% had HER2 zero BC. Median progression-free survival (mPFS) in the HER2-low group was 27.6 months compared with 44.3 months in the HER2-zero group (p = 0.341). In patients receiving ribociclib, the mPFS in the HER2-low group was 24.2 months compared with 53.1 months in the HER2-zero group (multivariate-adjusted HR: 1.981, 95 Cl 1.094-3.586; p = 0.024). The survival probabilities at 24, 36 and 48 months for the HER2 low and HER2 zero groups were 82%, 69%, 69% and 83%, 75% and 69%, respectively (p = 0.336). Objective response rate (p = 0.179) and disease control rate (p = 0.338) did not significantly differ between HER-2-low and HER-2-zero groups.
CONCLUSIONS: 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.

BACKGROUND: The survival outcomes in HER2-low versus HER2-zero breast cancer (BC) after neoadjuvant chemotherapy (NACT) remain unclear. The meta-analysis was conducted to summarize current evidence about the survival outcomes in HER2-low versus HER2-zero BC.
METHODS: We conducted a systematic search in PubMed and EMBASE databases to identify relevant studies.
RESULTS: A total of 14 studies with 53,714 patients were included. Overall, 34,037 patients (63.37%) were HER2-low, and 19,677 patients (36.63%) were HER2-zero. Patients with HER2-low tumors had a significantly lower pathological complete response (pCR) rate than patients with HER2-zero tumors, regardless of the hormone receptor status. Compared with HER2-zero breast cancer, the overall survival (OS) and disease-free survival (DFS) of HER2-low BC were longer in the overall cohort (HR = 0.72; 95% CI = 0.61-0.85; P < 0.0001; HR = 0.83; 95% CI = 0.75-0.92; P = 0.0002); however, no differences were observed in terms of OS and DFS between HER2-low and HER2-zero BC in the HR-negative group. In the HR-positive group, HER2-low status had no significant impact on OS, while significantly associated with increased DFS (HR = 0.85; 95% CI = 0.76-0.96; P = 0.007).
CONCLUSIONS: These results suggest that although HER2-low BC has a poor response to NACT, it is correlated with favorable OS and DFS after NACT in the overall cohort as well as longer DFS in the HR-positive group.

Background: Recently, the classification of HER2 status evolves from binary to ternary, and HER2-low expression may exhibit prognostic significance. We aimed to investigate whether HER2-low tumor is distinct from HER2-zero or HER2-positive tumors, and then to develop a modified staging system (mNeo-Bioscore) that incorporates HER2-low status into Neo-Bioscore. Patients and Methods: This cohort study was conducted using data from the prospective database on breast cancer patients between January 2014 and February 2019. Results: Among 259 patients enrolled in the study, the HER2-low tumor exhibited significantly lower histological grade, pathological staging and Ki-67 level than the other two groups. HER2-low patients and HER2-positive patients receiving concurrent HER2-directed therapy may have similar LRFS (p = 0.531) and OS (p = 0.853), while HER2-zero peers may have significantly worse LRFS (p = 0.006) and OS (p = 0.017). In particular, a similar trend was also found in the patients without pathological complete response after surgery. Incorporation of HER2-low status made improvement in fit: 5-year OS rate estimates ranged from 33.33% to 100% for mNeo-Bioscore vs 61.36% to 100% for Neo-Bioscore. Conclusions: 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.

BACKGROUND: A new concept of HER2-low has emerged in recent years. However, the prognostic value and the relapse pattern of HER2-low is unclear.
METHODS: Our study included patients diagnosed with HER2-negative/hormone receptor-positive breast cancer to explore the differences in survival outcomes between the HER2-low group and the HER2-zero group. More importantly, we explored different recurrence patterns, including the comparison of metastatic sites and recurrence time curve between the two groups.
RESULTS: A total of 797 patients with hormone receptor-positive breast cancer were analyzed. Similar disease-free survival (DFS) was observed between the HER2-low group and HER2-zero group (HR 0.84, 95% CI: 0.61-1.16, p = 0.290). There was also no significant difference in OS between the HER2-low group and the HER2-zero group (HR 0.77, 95% CI: 0.46-1.28, p = 0.310). When IHC 1+ and 0 were taken as a group, the IHC 2+ group had significantly better DFS than the IHC 1+ and 0 group in some subgroups. The risk of bone metastasis in patients with HER2 IHC 1+ and 0 was significantly higher than that of patients with HER2 IHC 2+ (12.7% vs. 4.7%, p < 0.001). Compared with the HER2-zero group, we found that the HER2-low group had a more obvious peak in mortality at the time of postoperative 80th-100th month.
CONCLUSIONS: No significant difference in DFS and OS between the HER2-low group and the HER2-zero group was observed. Patients with HER2 IHC 1+ and 0 tend to develop bone metastasis. The HER2-low group had a more obvious second peak in mortality.

OBJECTIVE: The cyclin-dependent kinase (CDK) 4/6 inhibitors significantly altered the treatment landscape of hormone-positive (HR+), HER2- metastatic breast cancer (MBC). However, biomarkers predicting long-term benefit and early progression are yet to be defined. Several studies suggested the possibility of diminished efficacy in patients with HER2-low disease. Therefore, we conducted a systematic review and meta-analysis to evaluate the association between low-level HER2 expression and efficacy outcomes (PFS, OS, ORR) with CDK 4/6 inhibitors.
METHODS: The Pubmed, Web of Science, and Scopus databases were used to systematically filter the published studies from inception to 08 August 2023 for this systemic review. Studies including MBC patients treated with CDK 4/6 inhibitors and reported survival outcomes according to HER2 expression were included. We performed the meta-analyses with the generic inverse-variance method with a fixed-effects model and used HRs with 95% two-sided CIs as the principal summary measure.
RESULTS: Nine studies encompassing 2705 patients were included in the analyses. In the pooled analysis of nine studies, the risk of progression and/or death was higher in patients with HER2-low tumors compared to HER2-zero (HR: 1.22, 95% CI 1.10-1.35, p < 0.001). In the pooled analysis of five studies, although the median follow-up was short, the risk of death was higher in the HER2-low group compared to the HER2-zero group (HR: 1.22, 95% CI 1.04-1.44, p = 0.010).
CONCLUSIONS: The available evidence demonstrates a significantly higher risk of progression or death with CDK 4/6 inhibitors in HER2-low tumors. Further research is needed to improve outcomes in patients with HR+-HER2-low tumors.

OBJECTIVE: To investigate potential differences in pathological complete response (pCR) rates and overall survival (OS) between HER2-low and HER2-zero patients with early-stage hormone receptor (HR)-positive and triple-negative breast cancer (TNBC), in the neoadjuvant chemotherapy setting.
METHODS: We identified early-stage invasive HER2-negative BC patients who received neoadjuvant chemotherapy diagnosed between 2010 and 2018 in the National Cancer Database. HER2-low was defined by immunohistochemistry (IHC) 1+ or 2+ with negative in situ hybridization, and HER2-zero by IHC0. All the methods were applied separately in the HR-positive and TNBC cohorts. Logistic regression was used to estimate the association of HER2 status with pCR (i.e. ypT0/Tis and ypN0). Kaplan-Meier method and Cox proportional hazards model were applied to estimate the association of HER2 status with OS. Inverse probability weighting and/or multivariable regression were applied to all analyses.
RESULTS: For HR-positive patients, 70.9% (n = 17,934) were HER2-low, whereas 51.1% (n = 10,238) of TNBC patients were HER2-low. For both HR-positive and TNBC cohorts, HER2-low status was significantly associated with lower pCR rates [HR-positive: 5.0% vs. 6.7%; weighted odds ratio (OR) = 0.81 (95% CI: 0.72-0.91), p < 0.001; TNBC: 21.6% vs. 24.4%; weighted OR = 0.91 (95% CI: 0.85-0.98), p = 0.007] and improved OS [HR-positive: weighted hazard ratio = 0.85 (95% CI: 0.79-0.91), p < 0.001; TNBC: weighted hazard ratio = 0.91 (95% CI: 0.86-0.96), p < 0.001]. HER2-low status was associated with favorable OS among patients not achieving pCR [HR-positive: adjusted hazard ratio = 0.83 (95% CI: 0.77-0.89), p < 0.001; TNBC: adjusted hazard ratio = 0.88 (95% CI 0.83-0.94), p < 0.001], while no significant difference in OS was observed in patients who achieved pCR [HR-positive: adjusted hazard ratio = 1.00 (95% CI: 0.61-1.63), p > 0.99; TNBC: adjusted hazard ratio = 1.11 (95% CI: 0.85-1.45), p = 0.44].
CONCLUSIONS: In both early-stage HR-positive and TNBC patients, HER2-low status was associated with lower pCR rates. HER2-zero status might be considered an adverse prognostic factor for OS in patients not achieving pCR.

OBJECTIVE: 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.
CONCLUSIONS: 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.

UNASSIGNED: Metastatic breast cancers (MBC) with no expression of human epidermal growth factor receptor-2 (HER2) are recently classified into two groups; HER2-zero [HER2-immunohistochemistry (IHC) score of 0 (IHC-0)] and HER2-low, defined as those with IHC score of 1+ or 2+ with negative in situ hybridization (ISH) assay. We investigate differences in treatment outcomes between both groups treated with endocrine therapy (ET) and the CDK4/6 inhibitor ribociclib.
UNASSIGNED: Data were retrospectively collected for patients with HR-positive+/HER2-negative MBC who received ribociclib with an aromatase inhibitor (AI) or fulvestrant and were divided into two groups: HER2-zero and HER2-low.
UNASSIGNED: A total of 257 patients, median age 48 (22-87) years, all with MBC who were treated with ET and ribociclib were enrolled. One hundred and thirty-seven (53.3%) patients had de novo MBC, and majority (n = 162, 63.0%) received ribociclib as a first-line therapy. In total, 114 (44.4%) patients had HER2-zero (IHC-0), while 143 (55.6%) others had HER2-low disease. The overall response rate (ORR) was 52.0% for the HER2-zero group compared to 39.4% for the HER2-low group, p = 0.005. The median PFS was 22.2 (95% confidence interval [CI], 19.4-NR) months for HER2-zero versus 17.3 (95% CI, 14.1-20.6) months for HER2-low, P = 0.0039. In multivariable analysis, HER2-low expression remained significant determinant of inferior PFS after adjusting for other factors, including the site of metastasis, prior chemotherapy, and the line of treatment.
UNASSIGNED: In patients with MBC treated with ET and ribociclib, level of HER2 negativity may affect treatment outcomes; patients with HER2-zero had better response rate and PFS compared to those with HER2-low disease. These findings, if confirmed in larger studies, may help oncologists select patients with HER2-low for better treatment options.

BACKGROUND: HER2-low has emerged as a new predictive biomarker in metastatic breast cancer. However, its prognostic value in early-stage carcinomas needs to be revisited. We aimed to evaluate the association of HER2-low carcinomas with PAM50 risk groups combined with clinicopathological variables in early breast cancer.
METHODS: We conducted a retrospective analysis of 332 patients with early-stage breast cancer that underwent PAM50 signature analysis between 2015 and 2021at Hospital Universitario 12 de Octubre (Madrid, Spain). Clinical and pathological variables were collected from medical records. After adjusting for potential confounders, we estimated Odds Ratio (OR) and 95% confidence interval for high-risk PAM50 subgroup, comparing HER2-low versus HER2-zero carcinomas by multivariable logistic regression. P values below 0.05 were deemed statistically significant.
RESULTS: 192 (57%) patients were classified as HER2-low carcinomas. Median follow-up was 34 months. Adjusted OR for high-risk PAM50 when comparing HER2-low versus HER2-zero carcinomas was 1.31 (95% CI: 0.75-2.30, p = 0.33). The multivariable model detected significant associations for Ki-67% (≥20% vs. <20%: OR = 4.03, 95% CI: 2.15-7.56, p < 0.001), T staging category (T2/T3 vs. T1: OR = 3.44, 95% CI: 1.96-6.04, p < 0.001), progesterone receptor (PR ≥ 20% vs. <20%: OR = 0.44, 95% CI: 0.23-0.83, p = 0.01), nodal staging category (N+ vs. N0: OR = 3.8, 95% CI: 1.89-7.62, p < 0.001) and histological grade (grade 2 vs. 1: OR = 2.41, 95% CI: 1.01-5.73, p = 0.04; grade 3 vs 1: OR = 5.40, 95%CI: 1.98-14.60, p = 0.001).
CONCLUSIONS: In this early-stage breast cancer cohort, HER2-low was not associated with a high-risk PAM50 compared to HER2-zero carcinomas. Ki-67 ≥ 20%, T2/T3, histological grade 2/3, N+ and PR<20% were significantly associated to a high-risk PAM50.