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.

Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if HER2-low status has an independent impact on prognosis.
A systematic literature research was carried out to identify studies comparing survival outcomes of patients affected by HER2-low versus HER2-zero breast cancer. Using random-effects models, pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for progression-free survival (PFS) and overall survival (OS) in the metastatic setting as well as disease-free survival (DFS), OS and pathological complete response (pCR) in the early setting. Subgroup analyses by hormone receptor (HoR) status were carried out. The study protocol is registered on PROSPERO (n.CRD42023390777).
Among 1916 identified records, 42 studies including 1 797 175 patients were eligible. In the early setting, HER2-low status was associated with significant improved DFS (HR 0.86, 95% CI 0.79-0.92, P < 0.001) and OS (HR 0.90, 95% CI 0.85-0.95, P < 0.001) when compared to HER2-zero status. Improved OS was observed for both HoR-positive and HoR-negative HER2-low populations, while DFS improvement was observed only in the HoR-positive subgroup. HER2-low status was significantly associated with a lower rate of pCR as compared to HER2-zero status both in the overall population (OR 0.74, 95% CI 0.62-0.88, P = 0.001) and in the HoR-positive subgroup (OR 0.77, 95% CI 0.65-0.90, P = 0.001). In the metastatic setting, patients with HER2-low breast cancers showed better OS when compared with those with HER2-zero tumours in the overall population (HR 0.94, 95% CI 0.89-0.98, P = 0.008), regardless of HoR status. No significant PFS differences were found.
Compared with HER2-zero status, HER2-low status appears to be associated with a slightly increased OS both in the advanced and early settings, regardless of HoR expression. In the early setting, HER2-low tumours seem to be associated to lower pCR rates, especially if HoR-positive.

BACKGROUND: The prognostic differences between HER2-zero and HER2-low breast cancer (BC) remain unclear. Purpose of this meta-analysis is to investigate the differences between HER2-low and HER2-zero in terms of clinicopathological factors and survival outcomes in early-stage BC.
METHODS: We searched major databases and congress proceedings until November 1, 2022 to identify studies comparing HER2-zero and HER2-low in early-stage BC. HER2-zero immunohistochemically (IHC) was defined as score 0, while HER2-low was defined as IHC 1+ or 2+/in situ hybridization negative.
RESULTS: A total of 23 retrospective studies involving 636,535 patients were included. HER2-low rate was 67.5% in the hormone receptor (HR)-positive group, while this rate was 48.6% in the HR-negative group. In the analysis of clinicopathological factors by HR status, the proportion of premenopausal patients within the HR-positive group was greater in the HER2-zero arm (66.5% vs 61.8%), whereas grade 3 tumors (74.2% vs 71.5%), patients younger than 50 years of age (47.3% vs 39.6%), and T3-T4 tumors (7.7% vs 6.3%) within the HR-negative group was higher in the HER2-zero arm. In both the HR-positive and HR-negative groups, the HER2-low arm showed significantly improved results for disease-free survival (DFS) and overall survival (OS). The hazard ratios for DFS and OS in the HR-positive group were 0.88 (95% CI 0.83-0.94) and 0.87 (95% CI 0.78-0.96), respectively. In the HR-negative group, the hazard ratios for DFS and OS were 0.87 (95% CI 0.79-0.97) and 0.86 (95% CI 0.84-0.89), respectively.
CONCLUSIONS: In early-stage BC, HER2-low is associated with better DFS and OS compared to HER2-zero, regardless of HR status.

UNASSIGNED: HER2-low expression breast cancer (BC) accounts for approximately 45%-55% of all BC cases. The purpose of this study was to investigate the prognostic difference between patients with HER2-low expression and HER2-zero BC.
UNASSIGNED: An electronic search of Pubmed, Embase, Cochrane Library, and Web of Science databases was performed to screen studies that included prognostic comparisons between HER2-zero and HER2-low expression groups. A total of 14 studies involving 52106 patients were included.
UNASSIGNED: Our results indicated that HER2-low expression was associated with a significant benefit in OS among all patients with early BC (HR, 0.83; 95% CI, 0.78-0.88), patients with hormone-receptor positive BC (HR, 0.83; 95% CI, 0.77-0.89), and patients with TNBC (HR, 0.78; 95% CI, 0.70-0.87). HER2-low expression was associated with a significant benefit in DFS among all patients (HR, 0.81; 95% CI, 0.71-0.93), patients with hormone receptor-positive BC (HR, 0.81; 95% CI, 0.72-0.90), but no significant difference in DFS was found in patients with TNBC (HR, 0.87; 95% CI, 0.65-1.17). HER2-low expression was associated with a significant benefit in RFS among all patients (HR, 0.90; 95% CI, 0.85-0.95), patients with hormone receptor-positive BC (HR, 0.90; 95% CI, 0.84-0.96), but no significant difference in RFS was found in patients with TNBC (HR, 0.80; 95% CI, 0.55-1.16).
UNASSIGNED: Among patients with early-stage BC, patients with HER2-low expression BC had better OS in the overall population, hormone receptor-positive and TNBC subgroups. Besides, favorable DFS and RFS were observed in both the overall population and hormone receptor-positive subgroup.
UNASSIGNED: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD 42022349458).