Abstract
Background/Aim: This study investigated the prognostic impact of human epidermal growth factor-2 receptor (HER2) status on the survival of patients with metastatic triple-negative breast cancer (TNBC).
Patients and Methods: This multicenter, retrospective study included 168 patients diagnosed with recurrent or de novo
metastatic TNBC between April 2013 and September 2024. Patients were categorized into two groups: HER2-negative (n=121, 72%) and HER2-low (n=47, 28%). Clinicopathological features and survival outcomes were compared between groups.
Results: The median follow-up was 44 months [95% confidence interval (CI)=35.7-52.2]. All patients received systemic chemotherapy as part of their first-line treatment. The median progression-free survival (PFS) in all patients was 9 months (95%CI=7.7-10.3 months). The median overall survival (OS) in all patients was 22 months (95%CI=17.4-26.5 months). Higher Ki67 value at diagnosis was a significant poor prognostic factor for median OS (29 months vs. 15 months, p<0.001). HER2-negative patients had significantly worse median OS than HER2-low patients (19 months vs. 33 months, p=0.026). In multivariate analysis, the HER2-low group had significantly longer median OS than the HER2-negative group [hazard ratio=0.64 (95%CI=0.42-0.98), p=0.040].
Conclusion: HER2-low expression was associated with significantly improved survival compared with HER2-negative status in metastatic TNBC. These findings highlight HER2 status as a potential prognostic factor, particularly relevant in settings with limited access to novel therapies such as immunotherapy or antibody-drug conjugates.
Introduction
Breast cancer is the most common malignancy in women worldwide and remains the leading cause of cancer-related mortality (1). It is a heterogeneous disease comprising subtypes with distinct biological behaviors and prognostic characteristics (1, 2). Triple-negative breast cancer (TNBC) constitutes approximately 15-20% of all breast cancers (3). It is defined as a subgroup with an aggressive course and poor prognosis. Treatment options for TNBC, especially for metastatic ones, were quite limited until the 2000s. Immunotherapy and targeted treatments have emerged as transformative treatment strategies in TNBC. Immune checkpoint inhibitors such as programmed death-1 (PD-1) inhibitors (4) and antibody-drug conjugates (ADCs) such as sacituzumab govitecan (5) and trastuzumab deruxtecan (T-DXd) have been shown to provide better survival outcomes in TNBC, including human epidermal growth factor receptor-2 (HER2)-low cases (6). All of these significant advances have lighted a new era in the treatment of metastatic TNBC.
The concept of “HER2-low” in breast cancer has led to significant developments and new treatment approaches in recent years. The prevalence of HER2-low expression is relatively high, occurring in 45-55% of all breast cancer cases and in approximately 30-35% of TNBC cases (7, 8). Clinical trial outcomes suggest that HER2-low breast cancer may represent a distinct entity with unique clinical and prognostic features compared to HER2-negative disease. However, no consensus has yet been reached. Moreover, most published studies have focused on early-stage breast cancer, with relatively few addressing the metastatic setting.
This study aimed to compare the clinical, prognostic factors, and survival outcomes of HER2-negative and HER2-low subgroups in metastatic TNBC.
Patients and Methods
Study design. This is a multicenter retrospective study that included 168 patients with de novo metastatic or recurrent metastatic TNBC diagnosed between April 2013 and September 2024. The study was approved by the Ethics Committee of the University of Health Sciences Ankara Dr. Abdurrahman Yurtaslan Oncology Training and Research Hospital (2024-05/72). In de novo metastatic patients, the diagnosis of TNBC was confirmed based on the results of the initial biopsy. In recurrent metastatic patients, the diagnosis was confirmed based on the initial biopsy and biopsy taken from the metastatic region. TNBC was defined as estrogen receptor-negative (ER <1%), progesterone receptor-negative (PR <1%), and human epidermal growth factor receptor-2 (HER2) negative or HER2-low. HER2 negativity was defined as CerbB2 immunohistochemical (IHC) score 0. HER2-low status was defined as patients with a CerbB2 IHC score of 1 or 2, in whom HER2 amplification could not have been demonstrated by in situ hybridization (ISH). The inclusion criteria for the study were: age over 18 years, metastatic disease, and more than one line of systemic treatment at an advanced stage. Patients with a secondary primary malignancy and inadequate complete access to past medical records were excluded from the study.
Survival analyses. Descriptive statistical methods were used to analyze the clinical and histopathological characteristics of the patients. The chi-square test was used to compare categorical data. The unpaired student’s t-test was used to compare two groups for data normally distributed. The Kolmogorov-Smirnov test was also used for normality.
The Kaplan-Meier method was used for survival analysis [median progression-free survival (PFS) and median overall survival (OS)]. PFS was defined as the time from diagnosis to recurrence, metastasis, or the last contact date. OS was defined as the interval between the date of diagnosis and the date of death or last contact. The reverse Kaplan-Meier test was used to determine the median follow-up.
A p-value less than 0.05 was considered as statistically significant. All statistical analyses were performed using the Statistical Package for Social Science (SPSS) for personal computers, version 21.0, Chicago, IL, USA.
Results
Patient baseline characteristics. A total of 168 patients were included in the study. All patients were female. The mean age of the patients was 50.2 (±11.3). Sixty-nine (41.1%) patients were premenopausal, 15 (8.9%) were perimenopausal, and 84 (50%) were postmenopausal. Forty-two (28%) patients had hypertension, 31 (18.5%) had diabetes mellitus, and 10 (6%) had heart disease as comorbid diseases. Upon examination of the pathological features, 121 (72%) patients were HER2-negative, and 47 (28%) patients were classified as HER2-low. Forty-one (24.4%) patients had grade 2 disease, and 127 (75.6%) had grade 3. The mean Ki67 value was 52.7% (±24.7), and the median Ki67 value was 50%. Fifty-eight (34.5%) of the patients had de novo metastatic disease, while 110 (65.5%) had recurrent metastatic disease (Table I).
Comparison of baseline characteristics of HER2-negative and HER2-low groups.
The most common sites of metastasis were the bone, lung, and liver. The patients’ de novo metastasis and recurrence sites are detailed in Table II and Table III. Baseline characteristics of HER2-negative and HER2-low patients were similar in terms of demographic and clinicopathological features (Table I).
Metastasis sites in patients with de novo metastasis.
Metastasis sites in patients with recurrent metastasis.
Treatment regimens. Systemic treatment regimens in the first-line setting were examined. Thirty-four (20.2%) of the patients received capecitabine, 29 (17.3%) carboplatin plus paclitaxel, 24 (14.3%) single-agent paclitaxel, 21 (12.5%) cisplatin plus gemcitabine, 18 (10.7%) carboplatin plus gemcitabine, and 16 (9.5%) adriamycin plus cyclophosphamide. Less common treatment regimens and all first-line treatment regimens are detailed in Table IV. The mean number of treatment cycles in first-line treatment was 7.42 (±4.9). Of the 168 patients included in the study, 121 (72%) had any grade of treatment-related adverse events. Of these, 38 (31.4%) were grade 1, 56 (46.3%) were grade 2, 23 (19%) were grade 3, and three (2.4%) were grade 4. The most common treatment-related side effect was hematological toxicity (n=82, 48.8%), followed by neuropathy (n=36, 21.4%). Hepatotoxicity, nephrotoxicity, and pulmonary thromboembolism were observed less frequently as treatment-related side effects.
First-line treatment regimens.
Of the patients who received first-line therapy, 115 (68.4%) also received second-line therapy. Twenty-two (19.1%) patients received capecitabine, 16 (14%) patients received paclitaxel, 14 (12.1%) patients received carboplatin plus gemcitabine, 14 (12.1%) patients received cisplatin plus gemcitabine, and 13 (11.3%) patients received sacituzumab govitecan as second-line therapy. The treatment regimens as second-line therapy are detailed in Table V. The mean number of treatment cycles in second-line therapy was 5.9 (±3.6). Of the 115 patients who received second-line therapy, 83 (72.1%) had treatment-related adverse events of any grade. The most common treatment-related adverse event was hematologic toxicity (n=50, 43.4%). The second most common treatment-related adverse event was neuropathy (n=24, 20.8%). Hepatotoxicity and nephrotoxicity were less common.
Second-line treatment regimens.
Survival analyses. The median follow-up was 44 months (95%CI=35.7-52.2). The median PFS in all patients was 9 months (95%CI=7.7-10.3 months). The median OS in all patients was 22 months (95%CI=17.4-26.5 months). Possible factors were age, menopausal status, de novo metastasis status, Ki67 value at diagnosis, grade at diagnosis, and HER2 status. In the univariate analyses, the median PFS was significantly worse in patients with de novo metastasis than in those with recurrent disease (8 months vs. 9 months, p=0.010). However, there was no difference in median OS between the two groups (22 months vs. 21 months, p=0.562). Higher Ki67 value at diagnosis was a significant poor prognostic factor for median OS (29 months vs. 15 months, p<0.001) (Figure 1).
Kaplan-Meier curve for overall survival according to Ki67 values.
When the groups were evaluated according to HER2 status, the median PFS for HER2-negative patients was eight months, and the median PFS for HER2-low patients was 11 months (p=0.167). HER2-negative patients had significantly worse median OS than HER2-low patients (19 months vs. 33 months, p=0.026) (Figure 2). Older age and postmenopausal status seemed to have numerically better OS; however, the differences were not statistically significant. Median OS was 25 months versus 19 months for age and 25 months versus 19 months for menopausal status (p=0.651 and p=0.654, respectively). Survival outcomes for other factors are detailed in Table VI.
Kaplan-Meier curve for overall survival according to HER2 status.
Univariate analysis of possible prognostic factors for survival.
Multivariate analysis was performed to examine the effects of age, menopausal status, Ki67 value, and HER2 status. Univariate analysis evaluated these factors as prognostic factors for median OS. The HER2 low group had significantly longer median OS than the HER2 negative group [HR=0.64 (95%Cl=0.42-0.98), p=0.040]. Other statistically significant prognostic factors are presented in Table VII.
Multivariate analysis of clinical characteristics affecting overall survival.
Discussion
TNBC has an aggressive tumor biology. Until recently, the mainstay of treatment for metastatic TNBC was systemic chemotherapy. However, ADCs and immunotherapy have demonstrated improved survival outcomes, leading to a novel practice-changing strategy (4, 9)
There are several studies investigating the prognostic role of HER2-low status in both hormone receptor-positive (HR+) and HR-negative (HR−) patients with breast cancer, with different outcomes (10-14). However, there is no well-established consensus on this subject in the current literature.
In a study conducted using pooled analysis from three prospective clinical trials, including 350 patients with metastatic TNBC, the prognostic impact of HER2 status was investigated, and 34.9% of the patients were HER2-low (15). The HER2-low rate was lower in our study, at 28%. In a prior study, patients with HER2-low tumors were older and had fewer premenopausal patients than those with HER2-negative tumors. We found no difference between these two groups, regarding age and menopausal status in our study. In survival analysis, there was no significant difference in PFS and OS according to HER2 status (i.e., HER2-low vs. HER2−), consistent with other studies in the literature (15). However, we found that HER2-low patients had significantly longer OS than HER2-negative ones (p=0.026). The survival advantage in HER2-low breast cancer patients is a novel addition to the literature, as there is currently no consensus on the effect of HER2 status. We believe that this study should be supported by prospective trials.
Carsten et al. investigated the prognostic significance of HER2 status in patients with early-stage breast cancer by pooling data of a total of 2,310 patients from four prospective trials (16). In this analysis, both HR+ and HR-patients were evaluated in subgroups, as HER2-low and HER2-negative. In the HR−/TNBC group (n=1,162), the HER2-low subgroup had longer DFS and OS than the HER2-negative subgroup. The 3-year DFS was 84.5% vs. 74.4%, and 3-year OS was 90.2% vs. 84.3% (p=0.0076, p=0.016), respectively (16). However, that study was conducted in patients with early-stage breast cancer, whereas all patients in our study had metastatic disease.
In another study conducted by Jiang et al. using the National Cancer Database in the United States, 30,929 patients with de novo metastatic HER2-low breast cancer were analyzed (17). Both HR+ and HR− patients were included, and 16.2% of the patients had TNBC. HER2-low rate in the TNBC group was 51.4%. It was higher than that in our study. The HER2-low group had longer OS than the HER2-negative group. Median OS for HR+/HER2 low patients was 39.0 months vs. 37.1 months (HR=0.95, 95%CI=0.91-0.98), and it was 15.8 months vs. 14.1 months for HR−/HER2 low ones (HR=0.92, 95%CI=0.86-0.98) (17). Li et al. compared the clinicopathological features and survival outcomes of patients with HER2-low and HER2-negative metastatic breast cancer (18). Three hundred eighty-eight (27.1%) of 1,433 patients had TNBC, and 35.3% of patients with TNBC were in the HER2-low group. The HER2-low group had longer OS, similar to the outcomes of our study. In our study, median OS was 19 months in the HER2-low group and 33 months in the HER2-negative group (p=0.026). Li et al. mentioned that the median OS was longer in both the overall population and HR+ patients, but there was no OS difference for either HER2-low or HER2-negative patients in the TNBC population (29.5 months vs. 29.9 months, p=0.718) (18).
Patients with ‘de novo’ metastatic breast cancer, including TNBC, were reported to have better OS than relapsed ones (19). In our study, there was no difference in OS, but patients with ‘de novo’ metastatic disease had significantly worse PFS (p=0.562, p=0.01).
There are novel therapeutic options, such as ADCs, for many solid tumors, including breast cancer. In the DESTINY-Breast04 study, trastuzumab deruxtecan (T-DXd), an ADC, was shown to have efficacy in patients with metastatic HER2-low breast cancer. Most (89%) of the patients had HR+/HER2 low breast cancer. T-DXd provided a significant OS improvement in both the whole population and the HR+/HER2 low subgroup (6). In this study, only 11.3% of the patients had HR−/HER2-low (TNBC) disease; therefore, there was no direct comparison of HR−/HER2-low patients with HR+/HER2-low ones due to the small number of HR−/HER2-low patients. However, the T-DXd survival advantage, observed in almost all populations, including HR+ and HR− HER2-low ones, supports its clinical utility in daily routine, as a recommended second-line treatment option in metastatic HER2-low TNBC.
In current clinical practice for metastatic TNBC, assessment of PD-L1 combined positive score (CPS), BRCA mutation status, and HER2-low expression for eligibility to trastuzumab deruxtecan (T-DXd) is recommended for second-line and later therapies. Although chemoimmunotherapy is the standard of care for patients with metastatic TNBC with a PD-L1 CPS score ≥10, systemic chemotherapy without immunotherapy is still used as a first-line treatment in many developing countries, including our own, due to limited access to immunotherapy, primarily because of reimbursement issues and/or other factors. Except for two patients who had chemotherapy with atezolizumab, almost all of the patients in our study received systemic chemotherapy as 1st-line treatment. The survival analyses determined that the HER2-low subgroup had a significantly longer OS than the HER2-negative subgroup (33 months vs. 19 months, p=0.026). As mentioned earlier, this outcome may inform treatment decisions for patients with limited access to current treatment options, such as immunotherapy or PARP inhibitors (PARPi), particularly for those with metastatic HER2-low disease.
The limitations of our study include its retrospective nature, small sample size, lack of knowledge regarding PDL1 status, and the addition of immunotherapy for possible PDL1 CPS >10, BRCA mutation status, and PARPi usage. PDL1 and BRCA mutation status have significant clinical implications here, as none of our patients received immunotherapy, PARPi, and/or ADCs, including patients who could have potentially benefited from them. Despite all these limitations, we demonstrated a survival advantage with only systemic chemotherapy as the first-line treatment.
Conclusion
In our study, we evaluated the prognostic significance of HER2 status in patients with metastatic TNBC retrospectively. We found that the HER2-low subgroup had significantly longer OS than the HER2-negative subgroup. There is conflicting data for both HR+/HER2 negative and TNBC patients in the literature. Some of them agree with our study, showing a survival benefit with systemic chemotherapy, even without immunotherapy, for patients with a PDL1 CPS >10. Additionally, PARPi is recommended for patients with BRCA mutations and/or ADCs for those with HER2-low tumors. This may represent an advantage for patients with limited access to novel therapeutics such as immunotherapy or ADCs. Nevertheless, prospective randomized clinical trials are needed to validate these findings.
Footnotes
Authors’ Contributions
Conceptualization: AT and MD; Data curation: AT; Formal analysis: AT and RM; Investigation: AT and SA; Methodology: MD and DÇ; Project administration: MD; Resources: all authors; Software: AT; Supervision: MD and FS; Roles/Writing – original draft: AT and MD; Writing – review & editing: all authors.
Conflicts of Interest
The Authors declare that they have no conflicts of interest in relation to this study.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received July 25, 2025.
- Revision received August 19, 2025.
- Accepted August 22, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
