Abstract
Purpose
The objective of the current research was to assess the clinicopathological characteristics and long-term prognosis of triple-negative breast cancer (TNBC) patients with human epidermal growth factor receptor 2 (HER2)-low status following breast surgery.
Methods
A total of 202 TNBC patients treated at Qingdao Central Hospital from January 2010 to December 2019 were included, comprising 71 HER2-low and 131 HER2-zero patients. Propensity score matching (PSM) was applied to minimize differences between the cohorts.
Results
HER2-low TNBC patients had lower histological grade, lower Ki-67 expression levels, and a higher prevalence of hypertension compared to HER2-zero TNBC patients. Before and after PSM, the HER2-low group consistently exhibited a lower recurrence rate and longer RFS compared to HER2-zero TNBC patients. HER2-low status was validated as an independent low-risk factor for RFS both pre-PSM (HR 0.354, 95% CI 0.178–0.706, p = 0.003) and post-PSM (HR 0.405, 95% CI 0.185–0.886, p = 0.024). No statistically significant differences in mortality rate and OS were observed, both before and after PSM.
Conclusions
HER2-low and HER2-zero TNBC patients show significant clinicopathological differences. Compared to HER2-zero, HER2-low status is linked to better long-term prognosis and serves as an independent low-risk factor for RFS in TNBC patients.
Supplementary Information
The online version contains supplementary material available at 10.1007/s00432-024-06069-7.
Keywords: Triple-negative breast cancer, HER2-Low, Clinicopathological characteristics, Long-term prognosis
Introduction
Breast cancer is the most commonly diagnosed malignancy and the leading cause of cancer-related mortality in women (Bray et al. 2024). Triple-negative breast cancer (TNBC) is defined by the lack of expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2), and thereby has limited options for effective therapies other than surgery, chemotherapy and immunotherapy, which further accounts for the stronger aggressiveness, higher risk of recurrence, and the least favorable outcomes of TNBC compared to other subtypes. (Weng et al. 2024; Bianchini et al. 2022; Liu et al. 2023). HER2-low breast cancer is defined as tumors with a HER2 immunohistochemistry (IHC) score of 1 + or 2 + combined with a negative in situ hybridization (ISH) (Tarantino et al. 2020, 2023; Wolff et al. 2023). HER2-low tumors represent a subgroup with potential therapeutic value, and precision medicine targeting this subgroup could offer new treatment options for patients, particularly those with TNBC (Dent et al. 2007; Chen et al. 2023). Trastuzumab deruxtecan has shown enhanced efficacy over standard chemotherapy in advanced HER2-low breast cancer patients, highlighting the clinical importance of this subgroup and emphasizing the need to refine classifications within HER2-negative breast cancer (Modi et al. 2022).
HER2-low tumors exhibit differences in biology, clinicopathological characteristics, treatment response, and prognosis (Berrino et al. 2022; Dai et al. 2023; Tuluhong et al. 2023; Shao et al. 2024; Li et al. 2023; Almstedt et al. 2022). However, the current clinical and biological understanding of HER2-low breast cancer remains limited due to the frequent combination of HER2-zero and HER2-low (Chen et al. 2023). Currently, there is no established consensus on the molecular characteristics, clinicopathological features, and prognostic impact of HER2-low breast cancer. This is especially true for the TNBC subtype, which has a lower proportion in breast cancer, resulting in even fewer studies related to HER2-low in this subtype. Several studies have found no prognostic significance associated with HER2-low expression (Schettini et al. 2021; Horisawa et al. 2022; Tarantino et al. 2022; Gampenrieder et al. 2023). However, according to the study conducted by Carsten et al. (Denkert et al. 2021), HER2-low tumors may be considered a distinct breast cancer subgroup, with patients having HER2-low, hormone receptor (HR)-negative tumors showing better survival and more favorable clinicopathological features compared to those with HER2-zero tumors. In contrast, some studies present differing or even opposite viewpoints, suggesting that patients with HER2-low TNBC exhibit more aggressive clinicopathological features and are associated with poorer prognosis (Hu et al. 2023; Sanomachi et al. 2023).
Therefore, the clinical and prognostic significance of HER2-low expression in TNBC, as well as whether it should be defined as a distinct molecular entity, remain unclear. This study aims to investigate the clinicopathological features and long-term prognosis of HER2-low TNBC patients, providing new evidence to optimize personalized treatment and improve diagnostic and therapeutic strategies for TNBC.
Materials and methods
Clinical patients
This is a retrospective study that included the clinical data of 202 female patients who underwent surgery for primary invasive TNBC at Qingdao Central Hospital between January 2010 and December 2019. Patients were stratified by HER2 status into two groups: HER2-low (n = 71, 35.1%) and HER2-zero (n = 131, 64.9%). Patients with concurrent bilateral breast cancer (bilateral tumors diagnosed less than 6 months apart), a prior history of recurrent breast cancer, other combined malignancies, those treated with neoadjuvant chemotherapy, incomplete or missing clinical data, M1 disease, or those lost to follow-up were excluded.
Clinical and pathological variables
Clinical and pathological information, including age, age of menarche, menstrual status, history of abortion, comorbidities, Body Mass Index (BMI), tumor location, TNM stage, tumor size, nodal stage, lymphatic invasion, cancer embolus, histological subtype, grade, Ki-67 index, type of surgery, and adjuvant treatments, were gathered from medical records and pathology databases. The TNM stage was determined by the eighth edition of the American Joint Committee on Cancer (AJCC) staging system (Giuliano et al. 2018). According to the ASCO/CAP guidelines (Allison et al. 2020; Wolff et al. 2023), HR (ER/PR) negative was defined as < 1% of tumor cell nuclei exhibiting positive staining on IHC analysis. HER2-zero was defined as IHC 0, while HER2-low was defined as IHC 1 + or 2 + with a negative fluorescence in situ hybridization (FISH) assay.
Follow-up and study endpoints
Follow-up was conducted based on the principles used for general breast cancer. Regular follow-ups were performed through outpatient visits and telephone consultations. Postoperative tumor recurrence monitoring included pathology and physical examinations, tumor markers, chest computed tomography (CT) scans, pelvic and breast ultrasound, mammography, and whole-body bone scans for high-risk patients with more than four positive lymph nodes. Additionally, MRI and PET-CT were performed when necessary to confirm the recurrence sites. The time and type of the first recurrence were recorded. Recurrence-free survival (RFS) was defined as the period from the date of surgery to the first occurrence of disease progression (including ipsilateral or contralateral breast cancer recurrence, local or distant metastasis) or the last follow-up. Overall survival (OS) was defined as the time from surgery or pathological diagnosis to death or the last follow-up. The follow-up work concluded in May 2024.
Propensity score matching (PSM) analyses
We performed PSM using R software version 4.2.2. Propensity scores were calculated using a logistic regression model including factors such as age, menopause, menarche, BMI, comorbid conditions, surgery type, tumor location, TNM stage, T stage, N stage, cancer embolus, histological grade, histological type, Ki-67, and adjuvant therapy. We employed 1:1 nearest neighbor matching without replacement, using a greedy algorithm to pair each HER2-low patient with the closest HER2-zero patient based on propensity scores. Various caliper widths were tested during the matching process, and standardized mean differences were used to evaluate covariate balance between different groups. A caliper width of 0.1 was ultimately selected to enhance homogeneity and reduce sample loss.
Statistical methods
Statistical analysis was conducted using IBM SPSS version 29.0 (SPSS, Inc., Chicago, IL, USA). Categorical variables were reported as counts and percentages and compared using Pearson’s chi-squared test or Fisher’s exact test. Kaplan-Meier and log-rank tests were employed to compare OS and RFS among different groups. Independent clinical risk factors for OS and RFS were identified using a Cox proportional hazards model. In the univariate Cox proportional hazards regression analysis, variables with p < 0.1 were considered for inclusion in the multivariate Cox proportional hazards model. P < 0.05 considered statistically significant in this study.
Results
Comparison of clinicopathological characteristics
A total of 202 female patients with TNBC who met the criteria for this study were included (Fig. 1). In the overall cohort, HER2 status was HER2-zero in 131 patients (64.9%) and HER2-low in 71 patients (35.1%). Among the HER2-low patients, 37 (52.1%) had HER2 IHC 1 + expression, and 34 (47.9%) had HER2 IHC 2 + with non-amplified FISH results. The clinical and pathological characteristics of the two HER2 subgroups were compared in Table 1. Hypertension was less common in HER2-low patients compared to HER2-zero patients (4.2% vs. 13.7%, p = 0.034). Histological grade differed significantly between the two groups. Patients with HER2-low status exhibited a lower histological grade compared to those with HER2-zero status (p = 0.021), with Grade I (9.9% vs. 2.3%), Grade II (39.4% vs. 32.1%), and Grade III (50.7% vs. 65.6%). Additionally, Ki-67 expression levels were lower in HER2-low patients compared to HER2-zero, with a significantly lower proportion of Ki-67 > 30% (62.0% vs. 80.2%, p = 0.02). Through PSM, we successfully generated 61 matched pairs of patients. After PSM, clinical and pathological characteristics were re-evaluated, showing that the two groups were effectively matched in terms of these characteristics, with no statistically significant differences.
Fig. 1.
Flow chart of study cohort selection
Table 1.
Patient clinical and pathological characteristics before and after PSM
| Before PSM (N = 202) | After PSM (N = 122) | ||||||
|---|---|---|---|---|---|---|---|
| HER2-low patients (N = 71) |
HER2-zero patients (N = 131) | p value | HER2-low patients (N = 61) | HER2-zero patients (N = 61) | p value | ||
| Age | 0.543 | 0.55 | |||||
| < 40 years | 11 (15.5%) | 18 (13.7%) | 8 (13.1%) | 10 (16.4%) | |||
| 40 years-60 years | 43 (60.6%) | 72 (55.0%) | 37 (60.7%) | 31 (50.8%) | |||
| > 60 years | 17 (23.9%) | 41 (31.3%) | 16 (26.2%) | 20 (32.8%) | |||
| Menarche | 0.369 | 0.855 | |||||
| ≥ 15 years | 41 (57.7%) | 67 (51.1%) | 35 (57.4%) | 34 (55.7%) | |||
| < 15 years | 30 (42.3%) | 64 (48.9%) | 26 (42.6%) | 27 (44.3%) | |||
| Menopause | 0.776 | 0.706 | |||||
| Yes | 43 (60.6%) | 82 (62.6%) | 38 (62.3%) | 40 (65.6%) | |||
| No | 28 (39.4%) | 49 (37.4%) | 23 (37.7%) | 21 (34.4%) | |||
| Abortion | 38 (53.5%) | 68 (51.9%) | 0.827 | 33 (54.1%) | 31 (50.8%) | 0.717 | |
| Diabetes | 3 (4.2%) | 8 (6.1%) | 0.75 | 2 (3.3%) | 5 (8.2%) | 0.439 | |
| Hypertension | 3 (4.2%) | 18 (13.7%) | 0.034* | 2 (3.3%) | 7 (11.5%) | 0.163 | |
| Heart disease | 5 (7.0%) | 11 (8.4%) | 0.734 | 4 (6.6%) | 2 (3.3%) | 0.68 | |
| Comorbid conditions ≥ 2 | 2 (2.8%) | 9 (6.9%) | 0.335 | 2 (3.3%) | 3 (4.9%) | 1 | |
| BMI | 0.418 | 0.585 | |||||
| ≤ 24 | 31 (43.7%) | 65 (49.6%) | 29 (47.5%) | 26 (42.6%) | |||
| > 24 | 40 (56.3%) | 66 (50.4%) | 32 (52.5%) | 35 (57.4%) | |||
| Tumor location | 0.425 | 0.865 | |||||
| UOQ | 43 (60.6%) | 82 (62.6%) | 40 (65.6%) | 41 (67.2%) | |||
| UIQ | 8 (11.3%) | 21 (16.0%) | 7 (11.5%) | 8 (13.1%) | |||
| LIQ | 8 (11.3%) | 9 (6.9%) | 5 (8.2%) | 2 (3.3%) | |||
| LOQ | 6 (8.5%) | 14 (10.7%) | 6 (9.8%) | 6 (9.8%) | |||
| Central | 6 (8.5%) | 5 (3.8%) | 3 (4.9%) | 4 (6.6%) | |||
| Surgery type | 0.636 | 0.555 | |||||
| Mastectomy | 50 (70.4%) | 88 (67.2%) | 41 (67.2%) | 44 (72.1%) | |||
| BCS | 21 (29.6%) | 43 (32.8%) | 20 (32.8%) | 17 (27.9%) | |||
| Tumor size | 0.833 | 1 | |||||
| ≤ 2 cm | 28 (39.4%) | 57 (43.5%) | 24 (39.3%) | 23 (37.7%) | |||
| 2–5 cm | 39 (54.9%) | 68 (51.9%) | 34 (55.7%) | 34 (55.7%) | |||
| > 5 cm | 4 (5.6%) | 6 (4.6%) | 3 (4.9%) | 4 (6.6%) | |||
| T stage | 0.569 | 1 | |||||
| 1 | 28 (39.4%) | 57 (43.5%) | 24 (39.3%) | 23 (37.7%) | |||
| 2 | 38 (53.5%) | 68 (51.9%) | 33 (54.1%) | 34 (55.7%) | |||
| 3 | 4 (5.6%) | 6 (4.6%) | 3 (4.9%) | 4 (6.6%) | |||
| 4 | 1 (1.4%) | 0 (0.0%) | 1 (1.6%) | 0 (0.0%) | |||
| N stage | 0.667 | 0.758 | |||||
| 0 | 46 (64.8%) | 91 (69.5%) | 41 (67.2%) | 41 (67.2%) | |||
| 1 | 20 (28.2%) | 27 (20.6%) | 16 (26.2%) | 13 (21.3%) | |||
| 2 | 4 (5.6%) | 10 (7.6%) | 3 (4.9%) | 5 (8.2%) | |||
| 3 | 1 (1.4%) | 3 (2.3%) | 1 (1.6%) | 2 (3.3%) | |||
| TNM stage | 0.387 | 0.499 | |||||
| I | 20 (28.2%) | 46 (35.1%) | 18 (29.5%) | 19 (31.1%) | |||
| II | 44 (62.0%) | 68 (51.9%) | 37 (60.7%) | 32 (52.5%) | |||
| III | 7 (9.9%) | 17 (13.0%) | 6 (9.8%) | 10 (16.4%) | |||
| Lymphatic invasion | 25 (35.2%) | 40 (30.5%) | 0.497 | 20 (32.8%) | 20 (32.8%) | 1 | |
| Cancer embolus | 11 (15.5%) | 29 (22.1%) | 0.258 | 11 (18.0%) | 13 (21.3%) | 0.649 | |
| Histological type | 0.308 | 0.623 | |||||
| Ductal | 54 (76.1%) | 112 (85.5%) | 47 (77.0%) | 50 (82.0%) | |||
| Lobular | 3 (4.2%) | 2 (1.5%) | 3 (4.9%) | 1 (1.6%) | |||
| Mixed | 2 (2.8%) | 3 (2.3%) | 1 (1.6%) | 2 (3.3%) | |||
| Other | 12 (16.9%) | 14 (10.7%) | 10 (16.4%) | 8 (13.1%) | |||
| Histological grade | 0.021* | 0.694 | |||||
| Grade I | 7 (9.9%) | 3 (2.3%) | 4 (6.6%) | 3 (4.9%) | |||
| Grade II | 28 (39.4%) | 42 (32.1%) | 23 (37.7%) | 28 (45.9%) | |||
| Grade III | 36 (50.7%) | 86 (65.6%) | 34 (55.7%) | 30 (49.2%) | |||
| Ki-67 | 0.02* | 0.396 | |||||
| ≤ 5% | 5 (7.0%) | 5 (3.8%) | 2 (3.3%) | 4 (6.6%) | |||
| 5-30% | 22 (31.0%) | 21 (16.0%) | 19 (31.1%) | 13 (21.3%) | |||
| ≥ 30% | 44 (62.0%) | 105 (80.2%) | 40 (65.6%) | 44 (72.1%) | |||
| Adjuvant therapy | 0.867 | 0.841 | |||||
| None | 6 (8.5%) | 9 (6.9%) | 5 (8.2%) | 6 (9.8%) | |||
| CT | 40 (56.3%) | 77 (58.8%) | 33 (54.1%) | 35 (57.4%) | |||
| RT | 1 (1.4%) | 4 (3.1%) | 1 (1.6%) | 2 (3.3%) | |||
| Combination therapy | 24 (33.8%) | 41 (31.3%) | 22 (36.1%) | 18 (29.5%) | |||
Note:* p < 0.05. HER2-zero was defined as immunohistochemistry 0, while HER2-low was defined as immunohistochemistry 1 + or 2 + with a negative fluorescence in situ hybridization assay
Abbreviation: PSM, propensity score matching; BMI, body mass index; UOQ, upper-outer quadrant; UIQ, upper-inner quadrant; LOQ, lower-outer quadrant; LIQ, lower-inner quadrant; BCS, breast-conserving surgery; HER2, human epidermal growth factor receptor-2; CT, chemotherapy; RT, radio therapy
Comparison of long-term outcomes
The median follow-up time for all patients was 111 (95% CI: 106–116) months. Comparisons of RFS are presented in Table 2. Before PSM, during the follow-up period, the HER2-low cohort exhibited a lower recurrence rate compared to the HER2-zero cohort (14.1% vs. 32.1%, p = 0.005). RFS was significantly longer in the HER2-low patients than in the HER2-zero patients (p = 0.005) (Fig. 2A). The 1-year RFS rates were 98.6% for the HER2-low group and 91.6% for the HER2-zero group (p = 0.06). The 3-year RFS rate was significantly higher in the HER2-low group at 91.5%, compared to 77.1% in the HER2-zero group (p = 0.01). Similarly, a significant difference was observed in the 5-year RFS rates, with the HER2-low group at 88.7% and the HER2-zero group at 70.1% (p = 0.003). Likewise, the 10-year RFS rates were higher in the HER2-low group at 83.3% compared to 67.5% in the HER2-zero group (p = 0.015). After PSM, HER2-low patients continued to show a significantly lower recurrence rate than HER2-zero patients (14.8% vs. 34.4%, p = 0.012). The RFS for HER2-low patients remained significantly longer than for HER2-zero patients (p = 0.011) (Fig. 2B). No significant difference in 1-year RFS rates (98.4% vs. 90.2%, p = 0.114). The 3-year RFS rate was 90.2% in the HER2-low group, significantly higher than 75.4% in the HER2-zero group (p = 0.031). Similarly, the 5-year RFS rate was 86.6% for the HER2-low group versus 67.1% for the HER2-zero group (p = 0.01). At 10 years, the RFS rate remained higher in the HER2-low group at 81.8%, compared to 65.3% in the HER2-zero group (p = 0.04).
Table 2.
Long-term RFS outcomes before and after PSM
| Before PSM (N = 202) | After PSM (N = 122) | ||||||
|---|---|---|---|---|---|---|---|
| HER2-low patients (N = 71) | HER2-zero patients (N = 131) | p value | HER2-low patients (N = 61) | HER2-zero patients (N = 61) | p value | ||
| Recurrence during the follow-up | 10 (14.08%) | 42 (32.06%) | 0.005** | 9 (14.8%) | 21 (34.4%) | 0.012* | |
| RFS | 0.005** | 0.011* | |||||
| 1-year RFS rate, % | 98.6% | 91.6% | 0.06 | 98.4% | 90.2% | 0.114 | |
| 3-year RFS rate, % | 91.5% | 77.1% | 0.01* | 90.2% | 75.4% | 0.031* | |
| 5-year RFS rate, % | 88.7% | 70.1% | 0.003** | 86.6% | 67.1% | 0.01* | |
| 10-year RFS rate, % | 83.3% | 67.5% | 0.015* | 81.8% | 65.3% | 0.04* | |
Note* p < 0.05; ** p < 0.01. HER2-zero was defined as immunohistochemistry 0, while HER2-low was defined as immunohistochemistry 1 + or 2 + with a negative fluorescence in situ hybridization assay
Abbreviations: RFS, recurrence-free survival; PSM, propensity score matching; HER2, human epidermal growth factor receptor-2
Fig. 2.
Kaplan–Meier curves of recurrence-free survival. (A) Before propensity score matching (p = 0.005). (B) After propensity score matching (p = 0.011)
Supplementary Table 1 presents comparisons of OS. Before PSM, the mortality rate during follow-up showed no statistically significant difference between HER2-low and HER2-zero patients (9.9% vs. 16.8%, p = 0.18). Additionally, OS did not significantly differ between the two groups of patients (p = 0.171) (Supplementary Fig. 1A). The 1-year OS rate in the HER2-low group was 98.6%, marginally lower than the 99.2% observed in the HER2-zero group. The 3-, 5-, and 10-year OS rates for HER2-low group were 97.2%, 94.3%, and 88.9%, respectively, which were higher than that for HER2-zero (91.6%, 84.6%, and 82.9%, respectively). However, except for the 5-year OS rate (p = 0.043), the differences in the 1-, 3-, and 10-year OS rates were not statistically significant. After PSM, HER2-low patients still exhibited no statistically significant difference in the mortality rate compared to HER2-zero patients (9.8% vs. 18.0%, p = 0.191). In the PSM cohort, the OS for HER2-low patients remained not significantly different from that of HER2-zero patients (p = 0.193) (Supplementary Fig. 1B). The 1-year OS rate was the same for the two groups, at 98.4%. The 3-, 5-, and 10-year OS rates for HER2-low patients were 96.7%, 93.3%, and 89.3%, respectively, which were higher than those for HER2-zero patients (88.5%, 83.6%, and 81.7%, respectively), though the differences were not statistically significant.
Prognostic analyses
In the pre-PSM cohort, univariate and multivariate Cox proportional hazards regression analyses revealed that HER2-low status was an independent low-risk factor for patient RFS (HR = 0.354, 95% CI: 0.178–0.706, p = 0.003). Surgery type and tumor size were also identified as independent prognostic factors for RFS (Table 3). In the OS analysis, HER2-low status did not emerge as an independent prognostic factor (HR 0.557, 95% CI 0.238–1.304, p = 0.178). Independent prognostic factors for OS of patients included TNM stage and adjuvant therapy (Supplementary Table 2). In the cohort after PSM, HER2-low status remained an independent low-risk factor for RFS (HR 0.405, 95% CI 0.185–0.886, p = 0.024). Additional independent prognostic factors for RFS included surgery type, tumor size, and cancer embolus (Table 4). For OS, HER2-low status remained not an independent prognostic factor (HR 0.523, 95% CI 0.193–1.414, p = 0.201), with independent prognostic factors including TNM stage, Ki-67, and adjuvant therapy (Supplementary Table 3).
Table 3.
Univariate and multivariate Cox regression analyses of RFS before PSM
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |||
| Age | ||||||
| < 40 years | Reference | 0.669 | ||||
| 40 years-60 years | 0.725 (0.341–1.541) | 0.403 | ||||
| > 60 years | 0.865 (0.382–1.959) | 0.729 | ||||
| Menarche | ≤ 15 years vs. > 15 years | 0.977 (0.566–1.686) | 0.934 | |||
| Menopause | Yes vs. No | 0.726 (0.407–1.296) | 0.279 | |||
| Abortion | Yes vs. No | 1.232 (0.712–2.129) | 0.456 | |||
| Comorbid conditions | ≥ 2 vs. < 2 | 0.677 (0.165–2.784) | 0.589 | |||
| BMI | > 24 vs. ≤ 24 | 0.749 (0.434–1.292) | 0.299 | |||
| Tumor location | ||||||
| UOQ | Reference | 0.335 | ||||
| UIQ | 1.73 (0.893–3.351) | 0.104 | ||||
| LIQ | 0.624 (0.191–2.035) | 0.434 | ||||
| LOQ | 0.688 (0.244–1.942) | 0.48 | ||||
| Central | NA | 0.973 | ||||
| Surgery type | BCS vs. Mastectomy | 0.154 (0.056–0.427) | < 0.001*** | 0.196 (0.068–0.566) | 0.003** | |
| Tumor size | ||||||
| ≤ 2 cm | Reference | < 0.001*** | Reference | 0.015* | ||
| 2–5 cm | 2.645 (1.34–5.221) | 0.005** | 1.727 (0.855–3.487) | 0.128 | ||
| > 5 cm | 6.657 (2.577–17.194) | < 0.001*** | 4.187 (1.584–11.072) | 0.004** | ||
| T stagea | ||||||
| 1 | Reference | 0.001** | NA | NA | ||
| 2 | 2.59 (1.309–5.126) | 0.006** | NA | NA | ||
| 3 | 6.662 (2.579–17.209) | < 0.001*** | NA | NA | ||
| 4 | 8.857 (1.138–68.92) | 0.037* | NA | NA | ||
| N stage | ||||||
| 0 | Reference | 0.123 | ||||
| 1 | 1.638 (0.878–3.056) | 0.121 | ||||
| 2 | 2.334 (0.969–5.624) | 0.059 | ||||
| 3 | 2.573 (0.614–10.788) | 0.196 | ||||
| TNM stage | ||||||
| I | Reference | 0.001** | Reference | 0.302 | ||
| II | 2.985 (1.321–6.75) | 0.009** | NA | 0.934 | ||
| III | 5.832 (2.295–14.822) | < 0.001*** | NA | 0.423 | ||
| Lymphatic invasion | Yes vs. No | 1.84 (1.064–3.18) | 0.029* | NA | 0.249 | |
| Cancer embolus | Yes vs. No | 2.201 (1.232–3.93) | 0.008** | NA | 0.138 | |
| Histological type | ||||||
| Ductal | Reference | 0.72 | ||||
| Lobular | 1.373 (0.332–5.67) | 0.661 | ||||
| Mixed | 1.64 (0.397–6.773) | 0.495 | ||||
| Other | 0.697 (0.276–1.761) | 0.446 | ||||
| Histological grade | I/II vs. III | 1.28 (0.723–2.266) | 0.397 | |||
| HER2 | Low vs. Zero | 0.383 (0.192–0.764) | 0.006** | 0.354 (0.178–0.706) | 0.003** | |
| Ki-67 | ≥ 30% vs. < 30% | 1.849 (0.901–3.794) | 0.094 | NA | 0.394 | |
| Adjuvant therapy | ||||||
| None | Reference | 0.013* | Reference | 0.306 | ||
| CT | 0.784 (0.331–1.855) | 0.58 | NA | 0.439 | ||
| RT | 0.422 (0.051–3.508) | 0.425 | NA | 0.495 | ||
| Combination therapy | 0.219 (0.074–0.653) | 0.006** | NA | 0.161 | ||
Note* p < 0.05; ** p < 0.01; *** p < 0.001. HER2-zero was defined as immunohistochemistry 0, while HER2-low was defined as immunohistochemistry 1 + or 2 + with a negative fluorescence in situ hybridization assay. aDue to the duplication between clinical T stage and tumor size, tumor size was included in the multivariate Cox regression analysis instead of clinical T stage
Abbreviations: RFS, recurrence-free survival; PSM, propensity score matching; HR, hazards ratio; CI, confidence interval; BMI, body mass index; UOQ, upper-outer quadrant; UIQ, upper-inner quadrant; LOQ, lower-outer quadrant; LIQ, lower-inner quadrant; BCS, breast-conserving surgery; TNBC, triple-negative breast cancer; HER2, human epidermal growth factor receptor-2; CT, chemotherapy; RT, radio therapy; NA, not applicable
Table 4.
Univariate and multivariate Cox regression analyses of RFS after PSM
| Variables | Univariate | Multivariate | ||||
|---|---|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |||
| Age | ||||||
| < 40 years | Reference | 0.514 | ||||
| 40 years-60 years | 0.717 (0.258–1.99) | 0.523 | ||||
| > 60 years | 1.126 (0.391–3.242) | 0.826 | ||||
| Menarche | ≤ 15 years vs. > 15 years | 0.966 (0.469–1.989) | 0.925 | |||
| Menopause | Yes vs. No | 0.47 (0.202–1.097) | 0.081 | NA | 0.286 | |
| Abortion | Yes vs. No | 0.816 (0.398–1.673) | 0.578 | |||
| Comorbid conditions | ≥ 2 vs. < 2 | 0.046 (0-96.076) | 0.431 | |||
| BMI | > 24 vs. ≤ 24 | 1.109 (0.539–2.284) | 0.778 | |||
| Tumor location | ||||||
| UOQ | Reference | 0.619 | ||||
| UIQ | 1.25 (0.475–3.291) | 0.651 | ||||
| LIQ | 0.472 (0.064–3.495) | 0.462 | ||||
| LOQ | 0.255 (0.034–1.891) | 0.181 | ||||
| Central | NA | 0.979 | ||||
| Surgery type | BCS vs. Mastectomy | 0.067 (0.009–0.494) | 0.008** | 0.1 (0.013–0.77) | 0.027* | |
| Tumor size | ||||||
| ≤ 2 cm | Reference | 0.002** | Reference | 0.034* | ||
| 2–5 cm | 2.964 (1.112-7.9) | 0.03* | 1.521 (0.558–4.146) | 0.413 | ||
| > 5 cm | 9.18 (2.651–31.786) | < 0.001*** | 4.795 (1.345–17.093) | 0.016* | ||
| T stagea | ||||||
| 1 | Reference | 0.003** | NA | NA | ||
| 2 | 2.855 (1.066–7.649) | 0.037* | NA | NA | ||
| 3 | 9.192 (2.655–31.827) | < 0.001*** | NA | NA | ||
| 4 | 10.86 (1.259–93.668) | 0.03* | NA | NA | ||
| N stage | ||||||
| 0 | Reference | 0.031** | Reference | 0.516 | ||
| 1 | 2.721 (1.233–6.001) | 0.013* | NA | 0.665 | ||
| 2 | 3.837 (1.255–11.731) | 0.018* | NA | 0.223 | ||
| 3 | 1.746 (0.229–13.297) | 0.591 | NA | 0.367 | ||
| TNM stage | ||||||
| I | Reference | 0.002** | Reference | 0.828 | ||
| II | 3.491 (1.028–11.855) | 0.045* | NA | 0.884 | ||
| III | 9.173 (2.477–33.976) | 0.001** | NA | 0.707 | ||
| Lymphatic invasion | Yes vs. No | 2.823 (1.376–5.793) | 0.005** | NA | 0.51 | |
| Cancer embolus | Yes vs. No | 3.353 (1.612–6.973) | 0.001** | 2.795 (1.334–5.855) | 0.006** | |
| Histological type | ||||||
| Ductal | Reference | 0.134 | ||||
| Lobular | 1.815 (0.429–7.686) | 0.418 | ||||
| Mixed | 3.636 (0.852–15.524) | 0.081 | ||||
| Other | 0.397 (0.094–1.681) | 0.21 | ||||
| Histological grade | I/II vs. III | 1.417 (0.682–2.942) | 0.35 | |||
| HER2 | Low vs. Zero | 0.377 (0.172–0.823) | 0.014* | 0.405 (0.185–0.886) | 0.024* | |
| Ki-67 | ≥ 30% vs. < 30% | 2.519 (0.964–6.585) | 0.059 | NA | 0.151 | |
| Adjuvant therapy | ||||||
| None | Reference | 0.056 | Reference | 0.114 | ||
| CT | 0.89 (0.306–2.584) | 0.83 | NA | 0.092 | ||
| RT | 0.794 (0.089–7.107) | 0.837 | NA | 0.946 | ||
| Combination therapy | 0.17 (0.038–0.761) | 0.02* | NA | 0.018* | ||
Note* p < 0.05; ** p < 0.01; *** p < 0.001. HER2-zero was defined as immunohistochemistry 0, while HER2-low was defined as immunohistochemistry 1 + or 2 + with a negative fluorescence in situ hybridization assay. aDue to the duplication between clinical T stage and tumor size, tumor size was included in the multivariate Cox regression analysis instead of clinical T stage
Abbreviations: RFS, recurrence-free survival; PSM, propensity score matching; HR, hazards ratio; CI, confidence interval; BMI, body mass index; UOQ, upper-outer quadrant; UIQ, upper-inner quadrant; LOQ, lower-outer quadrant; LIQ, lower-inner quadrant; BCS, breast-conserving surgery; TNBC, triple-negative breast cancer; HER2, human epidermal growth factor receptor-2; CT, chemotherapy; RT, radio therapy; NA, not applicable
Discussion
It is well known that TNBC neither express ER nor PR, nor do they produce high levels of HER2 protein, which makes them unresponsive to hormonal therapies or trastuzumab treatment (Li et al. 2021). Additionally, TNBC exhibits significant biological and clinical heterogeneity and frequently develops resistance to treatment, making it the breast cancer subtype with the poorest prognosis (Li et al. 2022; So et al. 2022). Recent research suggests that HER2-low breast cancer has distinct biological characteristics and differences in treatment response and prognostic outcomes, which is especially significant in HR-negative tumors that are resistant to therapy (Corti et al. 2023). Therefore, detailed classification and investigation of TNBC based on HER2 expression levels are crucial for gaining a deeper comprehension of its underlying biological characteristics and advancing personalized treatment strategies. Our study aimed to compare the clinicopathological characteristics and prognostic outcomes of HER2-low and HER2-zero TNBC patients, both before and after PSM, with a primary focus on evaluating the impact of HER2-low expression on TNBC prognosis.
Several studies have indicated that the clinicopathological and prognostic distinctions between the two HER2 status are largely attributable to the levels of HR expression, with no significant differences observed after adjusting for HR status (Peiffer et al. 2023; Jin et al. 2023; Zhang et al. 2022b). However, our study, along with several others, presents a different perspective, suggesting that HER2-low may show a more favorable prognosis, particularly in the HR-negative subtype (Denkert et al. 2021; Zheng et al. 2023). The study by Katrin et al. (Almstedt et al. 2022) showed that HR-negative breast cancer patients with HER2-low expression had better disease-free survival (DFS) compared to those with HER2-zero expression, with significant differences in histological grade and Ki-67 levels between groups. Several studies from Asia (Won et al. 2022; Tan et al. 2022; Zhou et al. 2023) have shown that, regardless of HR status, HER2-low patients generally have a more favorable prognosis. HER2-low patients tend to have a higher proportion of grade I/II tumors and lower Ki-67 expression, suggesting potentially lower aggressiveness compared to HER2-zero patients. The observed survival advantage in HER2-low patients could be attributed to the reduced prevalence of factors linked to poor prognosis in this group. Our study revealed that the HER2-low group, in comparison to the HER2-zero group, showed a lower occurrence of unfavorable clinicopathological features, such as reduced Ki-67 expression and lower histological grades (with a higher proportion of grade I and II tumors). These findings align with those reported in previous studies. Meanwhile, our study demonstrated that the HER2-low group showing a longer RFS compared to the HER2-zero group. HER2-low status was identified as an independent prognostic factor for RFS in TNBC patients. Additionally, the OS of the HER2-low group tended to be better than that of the HER2-zero group, although the difference was not statistically significant. This finding may be constrained by our limited sample size, and increasing the sample size may yield a more definitive conclusion regarding OS. Furthermore, this outcome may also be attributed to differences in the response to postoperative adjuvant treatment between HER2-low and HER2-zero patients. While direct evidence is limited, some studies have noted that HER2-low patients have a significantly lower pathological complete response rate to neoadjuvant chemotherapy compared to those with HER2-zero expression (Zhang et al. 2022a; Tang et al. 2023; Li et al. 2024). The HER2-low group had a lower frequency of Grade III tumors and lower Ki-67 levels, which may explain their reduced responsiveness to adjuvant treatments.
By employing PSM to balance other confounding factors that could influence the prognosis between the two cohorts, we achieved a more precise assessment of the effect of HER2 status on the outcome of TNBC patients. The results indicated that, the HER2-low group still had longer RFS and OS compared to the HER2-zero group, though the difference in OS did not reach statistical significance. Furthermore, following PSM, HER2-low status remained an independent predictor of RFS in TNBC patients. Shi et al. (Shi et al. 2024) found that although TNBC patients with HER2-low and HER2-zero statuses had no significant clinicopathological differences, those with HER2-low status had notably longer OS. The survival differences may be attributable to tumor heterogeneity (Li et al. 2023). A clinical sequencing study revealed that, in HR-negative cases, HER2-low status had a higher incidence of PIK3CA mutations and exhibited better DFS compared to HER2-zero status (Han et al. 2024). Research on breast cancer in women aged 40 years or younger with germline pathogenic variants (PVs) in the BRCA1/2 genes indicated that HER2-low expression is linked to better patient outcomes compared to HER2-zero expression. This difference in long-term prognosis appears to be more pronounced in TNBC. Moreover, germline BRCA2 and BRCA1 PVs were observed to be more common in HER2-low tumors (Schettini et al. 2024). However, the study by Hu et al. (Hu et al. 2023) reached an opposite conclusion, finding that HER2-low TNBC had high expression of tumor invasion-related genes, whereas HER2-zero TNBC exhibited high expression of immune-related genes, indicating a better prognosis compared to HER2-low TNBC. In conclusion, the classification of HER2-low breast cancer as an independent subtype is still under investigation, and its clinical and prognostic significance remains unclear, requiring further research for clarification. Our study used PSM to compare the clinicopathological characteristics and prognostic outcomes of HER2-low and HER2-zero TNBC patients, demonstrating that the HER2-low group exhibited distinct clinicopathological characteristics and better long-term prognosis, with more reliable results after controlling for confounding factors. These findings further emphasize the importance of HER2-low expression in TNBC and provide new support for redefining subgroups within HER2-negative breast cancer. By combining clinicopathological analysis with prognostic assessment, this study offers valuable insights into the heterogeneity of TNBC and lays the foundation for the development of future personalized treatment strategies.
However, our present study has some limitations. First, its single-center, retrospective design may introduce selection bias, and the inclusion of only Asian patients limits the generalizability of the findings to other ethnic groups. Future studies should be multicenter and include a more diverse patient population. Second, although PSM was used to reduce the impact of confounding factors, the small sample size may still affect statistical power and increase the risk of Type I and Type II errors. Furthermore, the lack of independent internal and external validation may lead to model overfitting, reducing its predictive accuracy. Future research should increase the sample size, incorporate cross-validation, and use independent datasets to enhance the reliability of the findings. Third, this study did not perform biological experiments to explore the molecular tumor heterogeneity between the two groups, and future studies should conduct corresponding experiments to further investigate the differences between the two groups. Fourth, the pathology data used in this study were retrospective and not centrally reassessed, which may affect the accuracy of the results. Future studies should adopt standardized centralized pathology analysis processes to improve reliability. Fifth, although BRCA1/2 gene testing is typically recommended for TNBC patients, the low completion rate of BRCA1/2 testing in this study limited its analysis, reducing the comprehensiveness of the findings. Future studies should consider including this factor. Sixth, our study did not include patients receiving neoadjuvant chemo-immunotherapy, whereas HER2-low status may have a different role in TNBC patients undergoing standard neoadjuvant chemo-immunotherapy. Future research should further explore the impact of HER2 status on treatment responses to neoadjuvant chemo-immunotherapy and its subsequent effect on patient prognosis. Finally, studies have found that instability in HER2 expression during breast cancer progression may contribute to tumor heterogeneity, including differences in HER2 status between primary tumors and advanced or recurrent/metastatic samples (Tarantino et al. 2022; Miglietta et al. 2021 Löb et al. 2023). Therefore, future prospective studies are needed to dynamically monitor HER2 expression levels at various stages of cancer progression and perform stratified comparisons to comprehensively evaluate the evolution of HER2 status and its clinical, pathological, and prognostic significance in TNBC.
Conclusion
Compared to HER2-zero TNBC patients, HER2-low TNBC have a higher prevalence of hypertension, lower histological grade, and lower Ki-67 expression levels. HER2-low TNBC patients exhibited a significantly lower recurrence rate and markedly longer RFS compared to the HER2-zero. HER2-low status can be considered an independent low-risk factor for RFS in TNBC patients. Compared to the HER2-zero TNBC patients, the HER2-low TNBC patients may have a better OS, but further studies are required to confirm this.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary Material 1: Supplementary Figure 1. Kaplan–Meier curves of overall survival. (A) Before propensity score matching (p = 0.171). (B) After propensity score matching (p = 0.193).
Acknowledgements
None.
Abbreviations
- PSM
Propensity score matching
- BMI
Body mass index
- UOQ
Upper-outer quadrant
- UIQ
Upper-inner quadrant
- LOQ
Lower-outer quadrant
- LIQ
Lower-inner quadrant
- BCS
Breast-conserving surgery
- HER2
Human epidermal growth factor receptor-2
- CT
Chemotherapy
- RT
Radio therapy
- RFS
Recurrence-free survival
- OS
Overall survival
- HR
Hazards ratio
- CI
Confidence interval
- TNBC
Triple-negative breast cancer
- NA
Not applicable
- HR
Hormone receptor
- ER
Estrogen receptor
- PR
Progesterone receptor
- IHC
Immunohistochemistry
- ISH
In situ hybridization
- AJCC
American Joint Committee on Cancer
- FISH
Fluorescence in situ hybridization
- CT
Computed tomography
- DFS
Disease-free survival
- PVs
Pathogenic variants
Author contributions
X.Z. and H.W.C. contributed to the study conception and design. Z.Y.Z. and M.Y.L. conducted the data collection. X. L. and K.H.Z. performed the data analysis and wrote the first draft of the manuscript, with all authors commenting on previous versions of the manuscript. All authors read and approved the final manuscript.
Funding
The authors received no funding for this work.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethical approval
The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Qingdao Central Hospital. Written informed consent requirement was waived by the Ethics Committee.
Consent to publish
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Xin Liu and Kaihua Zhao have contributed equally to this work.
Contributor Information
Hongwu Chu, Email: chuhw5@mail2.sysu.edu.cn.
Xiao Zou, Email: 18660229101@qq.com.
References
- Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL et al (2020) Estrogen and progesterone receptor testing in breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol 38(12):1346–1366. 10.1200/jco.19.02309 [DOI] [PubMed] [Google Scholar]
- Almstedt K, Heimes AS, Kappenberg F, Battista MJ, Lehr HA, Krajnak S et al (2022) Long-term prognostic significance of HER2-low and HER2-zero in node-negative breast cancer. Eur J Cancer 173:10–19. 10.1016/j.ejca.2022.06.012 [DOI] [PubMed] [Google Scholar]
- Berrino E, Annaratone L, Bellomo SE, Ferrero G, Gagliardi A, Bragoni A et al (2022) Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas. Genome Med 14(1):98. 10.1186/s13073-022-01104-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bianchini G, De Angelis C, Licata L, Gianni L (2022) Treatment landscape of triple-negative breast cancer - expanded options, evolving needs. Nat Rev Clin Oncol 19(2):91–113. 10.1038/s41571-021-00565-2 [DOI] [PubMed] [Google Scholar]
- Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229–263. 10.3322/caac.21834 [DOI] [PubMed] [Google Scholar]
- Chen L, Liu CC, Zhu SY, Ge JY, Chen YF, Ma D et al (2023) Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase-relevant subgroup with therapeutic prospects. JCI Insight 8(22). 10.1172/jci.insight.172366 [DOI] [PMC free article] [PubMed]
- Corti C, Giugliano F, Nicolò E, Tarantino P, Criscitiello C, Curigliano G (2023) HER2-Low breast Cancer: a New Subtype? Curr Treat Options Oncol 24(5):468–478. 10.1007/s11864-023-01068-1 [DOI] [PubMed] [Google Scholar]
- Dai LJ, Ma D, Xu YZ, Li M, Li YW, Xiao Y et al (2023) Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer. Nat Commun 14(1):5112. 10.1038/s41467-023-40715-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- Denkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M et al (2021) Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol 22(8):1151–1161. 10.1016/s1470-2045(21)00301-6 [DOI] [PubMed] [Google Scholar]
- Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434. 10.1158/1078-0432.Ccr-06-3045 [DOI] [PubMed] [Google Scholar]
- Gampenrieder SP, Dezentjé V, Lambertini M, de Nonneville A, Marhold M, Le Du F et al (2023) Influence of HER2 expression on prognosis in metastatic triple-negative breast cancer-results from an international, multicenter analysis coordinated by the AGMT Study Group. ESMO Open 8(1):100747. 10.1016/j.esmoop.2022.100747 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Giuliano AE, Edge SB, Hortobagyi GN (2018) Eighth Edition of the AJCC Cancer staging Manual: breast Cancer. Ann Surg Oncol 25(7):1–3. 10.3389/fonc.2023.1157789 [DOI] [PubMed] [Google Scholar]
- Han BY, Chen C, Luo H, Lin CJ, Han XC, Nasir J et al (2024) Clinical sequencing defines the somatic and germline mutation landscapes of Chinese HER2-Low breast Cancer. Cancer Lett 588:216763. 10.1016/j.canlet.2024.216763 [DOI] [PubMed] [Google Scholar]
- Horisawa N, Adachi Y, Takatsuka D, Nozawa K, Endo Y, Ozaki Y et al (2022) The frequency of low HER2 expression in breast cancer and a comparison of prognosis between patients with HER2-low and HER2-negative breast cancer by HR status. Breast Cancer 29(2):234–241. 10.1007/s12282-021-01303-3 [DOI] [PubMed] [Google Scholar]
- Hu XE, Yang P, Chen S, Wei G, Yuan L, Yang Z et al (2023) Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low. Breast Cancer Res 25(1):34. 10.1186/s13058-023-01639-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jin J, Li B, Cao J, Li T, Zhang J, Cao J et al (2023) Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer. J Transl Med 21(1):360. 10.1186/s12967-023-04076-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li Y, Sun Y, Kulke M, Hechler T, Van der Jeught K, Dong T et al (2021) Targeted immunotherapy for HER2-low breast cancer with 17p loss. Sci Transl Med 13(580). 10.1126/scitranslmed.abc6894 [DOI] [PMC free article] [PubMed]
- Li Y, Zhang H, Merkher Y, Chen L, Liu N, Leonov S et al (2022) Recent advances in therapeutic strategies for triple-negative breast cancer. J Hematol Oncol 15(1):121. 10.1186/s13045-022-01341-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li Y, Tsang JY, Tam F, Loong T, Tse GM (2023) Comprehensive characterization of HER2-low breast cancers: implications in prognosis and treatment. EBioMedicine 91:104571. 10.1016/j.ebiom.2023.104571 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li H, Plichta JK, Li K, Jin Y, Thomas SM, Ma F et al (2024) Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis. Breast Cancer Res Treat 204(1):89–105. 10.1007/s10549-023-07171-z [DOI] [PubMed] [Google Scholar]
- Liu Y, Hu Y, Xue J, Li J, Yi J, Bu J et al (2023) Advances in immunotherapy for triple-negative breast cancer. Mol Cancer 22(1):145. 10.1186/s12943-023-01850-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Löb S, Linsmeier E, Herbert SL, Schlaiß T, Kiesel M, Wischhusen J et al (2023) Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases. J Cancer Res Clin Oncol 149(8):5417–5428. 10.1007/s00432-022-04486-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Miglietta F, Griguolo G, Bottosso M, Giarratano T, Lo Mele M, Fassan M et al (2021) Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer 7(1):137. 10.1038/s41523-021-00343-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E et al (2022) Trastuzumab Deruxtecan in previously treated HER2-Low advanced breast Cancer. N Engl J Med 387(1):9–20. 10.1056/NEJMoa2203690 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Peiffer DS, Zhao F, Chen N, Hahn OM, Nanda R, Olopade OI et al (2023) Clinicopathologic characteristics and prognosis of ERBB2-Low breast Cancer among patients in the National Cancer Database. JAMA Oncol 9(4):500–510. 10.1001/jamaoncol.2022.7476 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sanomachi T, Okuma HS, Kitadai R, Kawachi A, Yazaki S, Tokura M et al (2023) Low HER2 expression is a predictor of poor prognosis in stage I triple-negative breast cancer. Front Oncol 13:1157789. 10.3389/fonc.2023.1157789 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schettini F, Chic N, Brasó-Maristany F, Paré L, Pascual T, Conte B et al (2021) Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer 7(1):1. 10.1038/s41523-020-00208-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Schettini F, Blondeaux E, Molinelli C, Bas R, Kim HJ, Di Meglio A et al (2024) Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: results of a large international retrospective cohort study. Cancer 130(16):2746–2762. 10.1002/cncr.35323 [DOI] [PubMed] [Google Scholar]
- Shao Y, Guan H, Luo Z, Yu Y, He Y, Chen Q et al (2024) Clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy. Breast 73:103666. 10.1016/j.breast.2023.103666 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shi Z, Liu Y, Fang X, Liu X, Meng J, Zhang J (2024) Efficacy and prognosis of HER2-Low and HER2-Zero in triple-negative breast cancer after neoadjuvant chemotherapy. Sci Rep 14(1):16899. 10.1038/s41598-024-67795-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- So JY, Ohm J, Lipkowitz S, Yang L (2022) Triple negative breast cancer (TNBC): non-genetic tumor heterogeneity and immune microenvironment: emerging treatment options. Pharmacol Ther 237:108253. 10.1016/j.pharmthera.2022.108253 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tan R, Ong WS, Lee KH, Lim AH, Park S, Park YH et al (2022) HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis. BMC Med 20(1):105. 10.1186/s12916-022-02284-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tang Y, Shen G, Xin Y, Li Z, Zheng Y, Wang M et al (2023) The association between HER2-low expression and prognosis of breast cancer: a systematic review and meta-analysis. Ther Adv Med Oncol 15:17588359231156669. 10.1177/17588359231156669 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tarantino P, Hamilton E, Tolaney SM, Cortes J, Morganti S, Ferraro E et al (2020) HER2-Low breast Cancer: pathological and clinical Landscape. J Clin Oncol 38(17):1951–1962. 10.1200/jco.19.02488 [DOI] [PubMed] [Google Scholar]
- Tarantino P, Gandini S, Nicolò E, Trillo P, Giugliano F, Zagami P et al (2022) Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer 163:35–43. 10.1016/j.ejca.2021.12.022 [DOI] [PubMed] [Google Scholar]
- Tarantino P, Viale G, Press MF, Hu X, Penault-Llorca F, Bardia A et al (2023) ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer. Ann Oncol 34(8):645–659. 10.1016/j.annonc.2023.05.008 [DOI] [PubMed] [Google Scholar]
- Tuluhong D, Li X, Gao H, Zhu Y, Li Q, Wang S (2023) Molecular characteristics and prognosis of breast cancer patients with different level of HER2 positivity after adjuvant and neoadjuvant chemotherapy. Eur J Cancer Prev 32(4):377–387. 10.1097/cej.0000000000000813 [DOI] [PubMed] [Google Scholar]
- Weng L, Zhou J, Guo S, Xu N, Ma R (2024) The molecular subtyping and precision medicine in triple-negative breast cancer—based on Fudan TNBC classification. Cancer Cell Int 24(1):120. 10.1186/s12935-024-03261-0 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wolff AC, Somerfield MR, Dowsett M, Hammond MEH, Hayes DF, McShane LM et al (2023) Human epidermal growth factor receptor 2 testing in breast Cancer: ASCO-College of American Pathologists Guideline Update. J Clin Oncol 41(22):3867–3872. 10.1200/jco.22.02864 [DOI] [PubMed] [Google Scholar]
- Won HS, Ahn J, Kim Y, Kim JS, Song JY, Kim HK et al (2022) Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean breast Cancer Society. Breast Cancer Res 24(1):22. 10.1186/s13058-022-01519-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang H, Katerji H, Turner BM, Audeh W, Hicks DG (2022a) HER2-low breast cancers: incidence, HER2 staining patterns, clinicopathologic features, MammaPrint and BluePrint genomic profiles. Mod Pathol 35(8):1075–1082. 10.1038/s41379-022-01019-5 [DOI] [PubMed] [Google Scholar]
- Zhang G, Ren C, Li C, Wang Y, Chen B, Wen L et al (2022b) Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status. BMC Med 20(1):142. 10.1186/s12916-022-02346-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zheng L, Zhang Y, Wang Z, Wang H, Hao C, Li C et al (2023) Comparisons of clinical characteristics, prognosis, epidemiological factors, and genetic susceptibility between HER2-low and HER2-zero breast cancer among Chinese females. Cancer Med 12(14):14937–14948. 10.1002/cam4.6129 [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhou S, Liu T, Kuang X, Zhen T, Shi H, Lin Y et al (2023) Comparison of clinicopathological characteristics and response to neoadjuvant chemotherapy between HER2-low and HER2-zero breast cancer. Breast 67:1–7. 10.1016/j.breast.2022.12.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1: Supplementary Figure 1. Kaplan–Meier curves of overall survival. (A) Before propensity score matching (p = 0.171). (B) After propensity score matching (p = 0.193).
Data Availability Statement
No datasets were generated or analysed during the current study.