Background and Objective: Breast cancers that overexpress the HER2 receptor tend to exhibit more
aggressive behavior compared to other breast cancer subtypes. As a result, HER2 status plays a critical role
in prognosis and treatment planning. Recently, increasing attention has been given to differences among
HER2 -Negative cases, which include three subgroups: 0, 1+, and 2+ (with Negative results on FISH or CISH
tests), collectively referred to as “HER2-low.” Emerging evidence suggests that these subgroups may differ
biologically. This study aimed to investigate the clinical and pathological characteristics of these three HER2-
Negative subgroups, with a particular focus on tumor features.
Materials & Methods: This retrospective, cross-sectional analytical study included data from 3,745
patients with HER2-Negative breast cancer. Categorical variables were analyzed using the Chi-Square test,
while continuous variables were assessed based on normality with appropriate test.
Results: The mean age of the patients was 50.96 ± 11.37 years. Comparative analysis showed that
patients in the HER2-intermediate ISH-Negative group were significantly younger than those in the other
two groups (p = 0.03). Tumor size was smaller, and the mean Ki-67 index was higher in this group compared
to the others (p < 0.001). Additionally, grade 3 tumors (22.1%), positive surgical margins (9%), and
metastasis (11.1%) were more common in the HER2-intermediate ISH-Negative group. This group also had
the highest recurrence (26.1%) and mortality rates (24.7%). Conversely, the HER2-zero group had the largest
average tumor size (28.74 ± 19.59 mm), the highest lymph node involvement (53.2%), and the greatest
incidence of lymphovascular invasion (58.6%). The HER2-low 1+ group appeared to be the least aggressive,
showing the lowest rates of grade 3 tumors (13.7%), positive margins (4.3%), and recurrence (11.5%).
Regarding treatment, the majority of HER2-zero and HER2-low 1+ patients received adjuvant chemotherapy
(62.3% and 51.3%, respectively), while neoadjuvant chemotherapy was more commonly administered to
patients in the HER2-intermediate ISH-Negative group (52%).
Conclusion: Based on the findings of this study, patients in the HER2-intermediate ISH-Negative group
exhibited more aggressive tumor characteristics and poorer outcomes compared to the other HER2 -
Negative subgroups. In contrast, the HER2-low 1+ group demonstrated the most favorable prognosis. These
results suggest that patients with HER2-intermediate ISH-Negative status may benefit from closer
monitoring and more frequent follow-up to improve clinical outcomes.