Investigation of the prevalence of HER2-ultralow and the effects of HER2 status (HER2-null vs. HER2-ultralow) on survival in HER2-negative early-stage breast cancer.

[PURPOSE] Investigation of 'HER2-ultralow' prevalence and the effects of HER2 status (HER2-null vs. HER2-ultralow) on prognosis in patients with early-stage (non-metastatic) breast cancer.

[METHODS/PATIENTS] This single-center, retrospective study analyzed 424 patients with early-stage, CerbB2 immunohistochemistry (IHC) score 0 breast cancer. Pathological re-review classified tumors as HER2-ultralow (≤ 10% of tumor cells with faint, incomplete membrane staining) or HER2-null (no staining). The cohorts were stratified by estrogen receptor (ER) status into ER + (≥ 1%) and triple-negative breast cancer (TNBC) groups.

[RESULTS] This study included 235 ER + and 189 TNBC patients. HER2-ultralow frequency was 30.6% (n = 72) in the ER + group and 18% (n = 34) in the TNBC group. In the ER + group, higher Ki67 and increasing stage were associated with worse 5 year disease-free survival (DFS) (p = 0.006 and p < 0.001, respectively), while HER2 status had no significant effect on 5-year DFS (p = 0.269). In the TNBC group, HER2-ultralow patients had worse 5-year DFS than HER2-null patients (67% vs. 74.1%, p = 0.048). In multivariate analysis, HER2 status was a statistically significant prognostic factor [(HR: 0.34 (0.145-0.841), p = 0.019)]. Despite a numerically worse 5 year overall survival (OS) rate in HER2-ultralow versus HER2-null patients (73.2% vs. 79.5%), the difference was statistically insignificant (p = 0.114).

[CONCLUSIONS] In TNBC, HER2-ultralow was a poor prognostic factor associated with inferior 5 year DFS compared to HER2-null, while no difference was observed in the ER + cohort. These findings suggest that HER2-ultralow status may identify a TNBC subgroup that warrants novel therapies, such as T-DXd, although validation in larger studies is needed.