BACKGROUND: Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors in combination with traditional endocrine therapy (ET) are now the recommended first-line treatment for hormone receptor (HR)-positive and HER2-negative metastatic breast cancer (MBC). However, the benefits of adding CDK4/6 inhibitors to ET in HER2-low-positive and HER2-0 subgroups remain unclear. We aimed to assess the effectiveness of CDK4/6 inhibitors in combination with ET in patients with HR-positive, HER2-low-positive and HER2-0 MBC.
METHODS: This secondary analysis assessed progression-free survival (PFS) among HER2-low-positive and HER2-0 patients enrolled in the double-blind, placebo-controlled randomised clinical trials PALOMA-2 and PALOMA-3. The study included 1186 HER2-negative, HR-positive female patients, with available immunohistochemistry (IHC) and/or in situ hybridization (ISH) results, across 17 countries enrolled between February 2013 and August 2014. HER2-low-positive status was defined by IHC 1+ or 2+ with negative ISH, and HER2-zero by IHC 0. Data analyses were conducted between March and May 2023. In the PALOMA-2 trial, patients were randomly assigned to receive either palbociclib or placebo, in combination with letrozole in the first-line treatment for HR-positive MBC. Patients in the PALOMA-3 study, who had progression or relapse during previous ET, were randomly allocated to receive either palbociclib plus fulvestrant or placebo plus fulvestrant. The primary endpoint was investigator-assessed PFS. Kaplan-Meier approach and Cox proportional hazards model were applied to estimate the association of treatment strategies with PFS among HER2-0 and HER2-low-positive populations. The two trials are registered with ClinicalTrials.gov, number NCT01740427 and NCT01942135.
RESULTS: Of the 666 patients with MBC from the PALOMA-2 study, there were 153 HER2-0 and 513 HER2-low-positive patients. In the HER2-0 population, no significant difference in PFS was observed between the palbociclib-letrozole and placebo-letrozole groups (hazard ratio = 0.79, 95% confidence interval [CI] 0.48-1.30, p = 0.34). In the HER2-low-positive population, palbociclib-letrozole demonstrated a significantly lower risk of PFS than placebo-letrozole group (hazard ratio = 0.52, 95% CI 0.41-0.66, p < 0.0001). The PALOMA-3 study analysed 520 patients with MBC. Within the 153 HER2-0 patients, the palbociclib-fulvestrant group showed a significantly longer PFS than the placebo-fulvestrant group (hazard ratio = 0.54, 95% CI 0.30-0.95, p = 0.034). Among the 367 HER2-low-positive patients, palbociclib-fulvestrant improved PFS (hazard ratio = 0.39, 95% CI 0.28-0.54, p < 0.0001).
CONCLUSIONS: The combination of a CDK4/6 inhibitor with ET significantly improved PFS in HER2-low-positive patients, while for HER2-0 patients, benefits were primarily observed in patients who had progressed on previous ET. Furthermore, HER2-0 patients may derive limited benefits from first-line CDK4/6 inhibitor treatment. Further work is needed to validate these findings and to delineate patient subsets that are most likely to benefit from the combination of CDK4/6 inhibitors and ET as first-line treatments.
BACKGROUND: None.

In our study, we observed the long-term survival outcomes investigated for HER2-0 and HER2-low-positive breast cancer patients who received neoadjuvant chemotherapy. Between 1998 and 2020, 10,333 patients with primary breast cancer were treated, including 1373 patients with HER2-0 or HER2-low-positive disease with neoadjuvant chemotherapy. Descriptive analyses were performed, and logistic regression models and survival analyses were calculated for disease-free survival (DFS) and overall survival (OS). Among the 1373 patients, 930 (67.73%) had HER2-low-positive and 443 (32.27%) had HER2-0 tumors. Patients with HER2-0 tumors had a significantly better pathological complete response, 29.25% vs. 20.09%, and pathological complete response/in situ, 31.97% vs. 24.08%, than patients with HER2-low-positive tumors (p < 0.001; p = 0.003), regardless of the hormone receptor (HR) status. No statistically significant differences were observed for the HR-positive (p = 0.315; p = 0.43) or HR-negative subgroups (p = 0.573; p = 0.931). DFS and OS were significantly longer for HR-positive, HER2-low-positive patients (log-rank p = 0.02; p = 0.012). OS was significantly longer for HR-negative, HER2-0 patients (log-rank p = 0.032). No significant DFS differences were found for the HR-negative cohort (log-rank p = 0.232). For the overall cohort, no significant differences were noted between HER2-low-positive and HER2-0 patients, either for DFS (log-rank p = 0.220) or OS (log-rank p = 0.403). These results show different survival outcomes for HER2-0 and HER2-low-positive tumors relative to HR status. These different cohorts can be identified using standardized immunohistochemistry, even retrospectively.

UNASSIGNED: It has been reported that breast cancer (BC) with low expression of human epidermal growth factor receptor 2 (HER2) might be a distinct subtype of BC. However, the prognostic effect of low HER2 expression on BC patients remains controversial. We aim to conduct this single-institution retrospective analysis to assess HER2-low-positive BC outcomes in Chinese women and the prognostic role of TILs in HER2-low-positive early-stage BC.
UNASSIGNED: We retrospectively enrolled 1,763 BC patients treated in a single institution from 2017 to 2018. TILs are regarded as continuous variables and are divided into low TILs (≤10%) and high TILs (>10%) for statistical analysis. Univariate and multivariable Cox proportional hazards regression models were used to test the associations between TILs and disease-free survival (DFS) with adjustment for clinicopathologic characteristics.
UNASSIGNED: High TIL levels (>10%) were associated with tumor size (>2 cm, p = 0.042), age at diagnosis (p = 0.005), Ki-67 index (>25%; p <0.001), HR (hormone receptor) status (positive, p <0.001), advanced pathological stage (p = 0.043), subtype (p <0.001), and HER2 status (p <0.001). The Kaplan-Meier analysis indicated that no significant difference in DFS (p = 0.83) could be found between HER2-positive, HER2-low-positive, and HER2-0 BC. The DFS of HER2-low-positive BC and HER2-nonamplified BC with high levels of TILs was statistically better than that of patients with low levels of TILs (p = 0.015; p = 0.047). In HER2-low-positive BC patients with high TIL levels (>10%), DFS was significantly improved in both the univariate (HR = 0.44, 95% CI 0.22-0.87, P = 0.018) and multivariate (HR = 0.47, 95% CI 0.23-0.95, P = 0.035) Cox models. For further subgroup analysis, HR (+)/HER2-low-positive BC with high TIL (>10%) levels was associated with improved DFS in both the univariate (HR = 0.41, 95% CI 0.19-0.90, P = 0.025) and multivariate (HR = 0.42, 95% CI 0.19-0.93, P = 0.032) Cox models. The HR (-)/HER2-0 BC with high TIL (>10%) level was not statistically significant in the univariate Cox model, but it was statistically significant in the multivariate (HR = 0.16, 95% CI 0.28-0.96, P = 0.045) Cox model.
UNASSIGNED: Among early-stage BC, no significant survival difference could be found between the HER2-positive, HER2-low-positive, and HER2-0 cohorts. High levels of TILs were significantly associated with improved DFS in HER2-low-positive patients, especially in the HR (+)/HER2-low-positive subtype.

OBJECTIVE: With the release of promising data from clinical trials of novel anti-HER2 antibody-drug conjugates, there is a new therapeutic direction in HER2-low expression breast cancer (BC). This study aims to evaluate the differences in clinicopathological characteristics of HER2-low-positive and HER2-zero BC, including response to neoadjuvant chemotherapy (NACT) and prognosis.
METHODS: Records of HER2-negative (immunohistochemistry [IHC] 0, + 1, or + 2 non-amplified by in situ hybridization [ISH]) patients who received NACT at our cancer center between January 2017 and December 2017 were retrospectively collected. HER2-low-positive was defined as immunohistochemistry (IHC) 1 + or IHC2 + /in-situ hybridization negative and HER2-zero was defined as IHC0. The coprimary objectives were to compare pathological complete response (pCR) and relapse-free survival (RFS) and overall survival (OS) between the two groups. Univariate and multivariable logistic regression models and Cox-proportional hazards models were performed for analysis of the endpoints pCR, RFS, and OS.
RESULTS: A total of 239 [84.5%] of 283 tumors were HER2-low-positive (including 132 [55.2%] HER2-1 + and 107 [44.8%] HER2-2 + /ISH non-amplified) and 44 [15.5%] were HER2-zero. Patients in the HER2-low-positive group had more commonly hormone receptor positivity than HER2-zero patients (188 [78.7%] vs. 19 [43.2%], P = 0.000), but there was no difference between HER2-1 + and HER2-2 + / ISH non-amplified (99 [75.0%] vs. 89 [83.2%], P = 0.125). HER2-zero tumors had a significantly higher pCR rate than HER2-low-positive tumors (15 [34.1%] of 44 vs. 22 [9.2%] of 239, P = 0.000). Pathological complete response was also significantly higher in HER2-zero tumors versus HER2-low-positive tumors in the hormone receptor-negative subgroup (13 [52.0%] of 25 vs. 14 [27.5%] of 51, P = 0.036), but not in the hormone receptor-positive subgroup (2 [10.5%] of 19 vs 8 [4.3%] of 188, P = 0.231). No significant difference was observed in 5-year RFS between the two groups (HR 0.577, 95% CI 0.298-1.118, P = 0.103). However, HER2-low-positive tumors showed significantly better OS than HER2-zero tumors (HR 0.280, 95% CI 0.122-0.697, P = 0.006).
CONCLUSIONS: These results suggest that HER2-low-positive tumors have specific biological characteristics according to the hormone receptor status and exhibit different responses to NACT and prognosis.

Previous studies have observed that human epidermal growth factor receptor 2 (HER2)-low-positive patients and HER2-zero patients have different prognoses. This study was conducted to investigate whether there are differences in clinicopathological characteristics and the response to neoadjuvant systemic therapy (NST) defined as systemic treatment prior to surgery between HER2-low-positive patients and HER2-zero patients. We retrospectively analyzed the data of patients with HER2-negative breast cancer who received NST at the First Affiliated Hospital of Nanjing Medical University from 2014 to 2021. There were 238 patients with HER2-low-positive status and 198 patients with HER2-zero status. The proportion of hormone receptor (HR)-positive patients in the HER2-low-positive group was significantly higher than that in the HER2-zero group (82.8% vs 52.0%, p < 0.001). The HER2-low-positive group had more patients with low Ki67 expression (23.9% vs 16.2%, p = 0.045), higher mastectomy rate (94.5% vs 88.9%, p = 0.031), and larger pathological tumor size (21.6 vs 17.8 mm, p = 0.028) than the HER2-zero group. However, no significant differences were found in pathologic complete response (pCR) rates between the two groups. We draw a conclusion that patients with HER2-low status and HER2-zero status were not found to have different pCR rates after NST, irrespective of HR status. However, differences were observed in some clinicopathological characteristics between the two groups.