Cyclin E1 Expression Predicts Poorer Outcome in HER2-positive Breast Cancer with Residual Disease after Neoadjuvant...

Among HER2-positive breast cancer patients, those who do not achieve pathological complete response (non-pCR) after neoadjuvant chemotherapy (NAC) generally have poorer outcomes. Although additional postoperative therapies have been developed, it remains unclear which patients truly require treatment intensification. This study aimed to identify prognostic factors in non-pCR patients.

Of 283 patients with HER2-positive invasive breast cancer treated with NAC, including anti-HER2 therapy between 2006 and 2023, 174 were classified as non-pCR. Of these, 37 patients developed distant metastases (Met group) and 137 remained metastasis-free (non-Met group). Gene expression profiling was performed by using pretreatment biopsies from six Met and six non-Met cases. Immunohistochemical validation was conducted in an independent cohort of 101 patients who did not achieve pCR.

Gene expression analysis identified multiple genes with differential expression between the Met and non-Met groups; MYCN, CCNE1, and IL6 were upregulated in the Met group, whereas KIT and ERBB4 were downregulated. Among these, MYCN and cyclin E1 showed concordant results at the protein level. Immune-related gene set analysis further suggested increased regulatory T-cell infiltration in the Met group. In the validation cohort, cyclin E1 positivity was significantly higher in the Met group (50% vs. 20%, P = 0.005), and cyclin E1-positive patients had significantly shorter disease recurrence-free survival (P = 0.005). Cyclin E1 expression was thus associated with poorer outcomes in HER2-positive breast cancer patients with non-pCR.

These findings support cyclin E1 as a prognostic biomarker that may contribute to risk stratification and individualized postoperative treatment strategies.