Is the risk of brain metastasis and prognosis different in HER2-low breast cancer?

We aimed to evaluate whether brain metastases, which are one of the most critical factors that have a poor prognostic value and make treatment difficult in breast cancer cases, differ in HER2-low breast cancer and to evaluate the prognosis of HER2-low breast cancer.

This retrospective study included 1134 female patients diagnosed with breast cancer between June 2012 and June 2023 from two tertiary healthcare centers in Türkiye. Molecular groups were examined in six categories according to hormone receptor (HR) and human epidermal growth factor receptor (HER2) status (HR(+) HER2(-), HR(+) HER2-low, HR(+) HER2(+), HR(-) HER2(-), HR(-) HER2-low, and HR(-) HER2(+)).

The median follow-up period was 56.6 months (IQR 29.9-90.5). We detected HER2-low disease in 155 (13.7%) cases. Among the six molecular groups, the highest brain metastasis rate was observed in the HR(-) HER2-low group (22.2%) (p = 0.001). In the HR(+) HER2-low group, the brain metastasis rate was 3.8%, with no statistically significant difference (p = 0.13). In the multivariate binary logistic regression model, there was a 32.4-fold increase in the risk of brain metastasis for the HR(-) HER2-low group compared to the HR(+) HER2(-) group (OR: 12.4, 95% CI 6.70-156.2, p < 0.001). The analysis reveals no significant increase in risk for the HR(+) HER2-low group (OR: 1.68, CI: 0.42-6.67, p = 0.46). In the Cox's regression model, the highest risk for poor BMFS was found in the HR(-) HER2-low group compared to the HR(+) HER2(-) group, with a 32.8-fold increased risk (HR: 32.82, CI: 7.80-138.3, p < 0.001). In the Cox's regression model, the highest risk for poor DFS was detected in the HR(-) HER2-low group compared to the HR(+) HER2(-) group, with a fourfold increase in risk (HR: 4.05, CI 1.34-12.30, p = 0.013). Shorter BMSS times were observed in the triple-negative and HR(-) HER2-low groups (1.33 and 3.9 months, respectively; p = 0.001).

Our study found that the risk of brain metastasis and disease recurrence increased significantly in the HR(-) HER2-low group, and contrary to some literature data, the risk of brain metastasis in the HR(+) HER2-low group did not differ from the HR(+) HER2(-) group. Both in our study and in many existing studies in the literature, it seems that the HR(+) HER2-low group has a similar prognosis with the HR(+) HER2(-) group, and the HR(-) HER2-low group is in an intermediate form between the HR(-) HER2(+) and HR(-) HER2(-) groups. Recurrence with brain metastasis and general disease recurrence were more common in the HR(-) HER2-low group. The study's retrospective design and the limited number of patients, especially in the HR(-) HER2-low group, along with potential underreporting in 1 + HER2 cases, are notable limitations.