原发性HER2低表达晚期乳腺癌患者原发灶和复发/转移灶HER2状态异质性的真实世界研究:一项回顾性队列研究OA

Background and purpose:With the publication of the DESTINY-Breast04 trial results,human epidermal growth factor receptor 2(HER2)-low expression has emerged as a subtype with independent therapeutic value.However,HER2 expression status exhibits heterogeneity between primary and metastatic lesions,and thus its alteration may affect the accuracy of treatment decision-making.Many studies have indicated that approximately 7%to 30%of breast cancer patients experience changes in HER2 status during disease progression.Our study aimed to investigate the heterogeneity of HER2 status between primary and recurrent/metastatic lesions in metastatic breast cancer patients with HER2-low expression in the primary lesion in a real-world setting,and further analyze whether there is a survival difference between breast cancer patients with HER2 1+and those with HER2 2+/fluorescence in situ hybridization(FISH)-negative status.Methods:We conducted a retrospective cohort study.Clinical data of 261 breast cancer patients with HER2-low expression in the primary lesion who developed recurrence/metastasis and were treated at Jiangsu Cancer Hospital from January 2012 to February 2025 was collected.The changes in HER2 expression levels between primary and recurrent/metastatic lesions were compared to clarify the HER2 heterogeneity in recurrent/metastatic lesions of metastatic breast cancer with primary HER2-low expression in a real-world setting.Furthermore,the clinicopathological features of these patients were analyzed,and univariate and multivariate analyses were performed to identify prognostic factors and independent risk factors.Patients were eligible for inclusion if they had pathologically confirmed HER2-low expression in the primary tumor,had advanced breast cancer,and had documented recurrent/metastatic lesions confirmed by pathological biopsy.The primary exclusion criterion was missing pathological data.This study has been approved by the Ethics Committee of Jiangsu Cancer Hospital(KY-2025-043)and is conducted in accordance with the Declaration of Helsinki.Results:Among the 261 patients,151 cases(57.9%)had HER2 1+status in the primary lesion,and 110 cases(42.1%)had HER2 2+/FISH-negative status.Regardless of HER2 expression level,more than 70%of the patients were hormone receptor-positive,and the proportion of patients with Ki-67 proliferation index≥20%exceeded half.The two groups with primary HER2 1+and HER2 2+/FISH-negative status had consistent baseline characteristics.The study found that although there was consistency in HER2 status between primary and recurrent/metastatic lesions regardless of hormone receptor status,the consistency was poor(κ=0.145,P<0.001),especially in hormone receptor-negative patients.In addition,there was no significant difference in median first-line progression-free survival(PFS)between patients with primary HER2 1+and those with primary HER2 2+/FISH-negative status(P>0.05).However,among breast cancer patients with primary HER2 1+,those whose recurrent/metastatic lesions converted to HER2-positive status had a significantly higher risk of disease progression than those whose recurrent/metastatic lesions converted to HER2 0 status[hazard ratio(HR)=2.44,P=0.032].In contrast,for patients with primary HER2 2+/FISH-negative status,the difference in HER2 levels in recurrent/metastatic lesions had no significant effect on disease progression,while the hormone receptor status of the primary lesion,surgical stage,Ki-67 proliferation index,and the advanced first-line treatment regimen had a significant impact on the survival outcomes of patients with HER2 2+/FISH-negative status.Conclusion:Breast cancer patients with HER2-low expression in the primary lesion exhibit heterogeneity in HER2 status in recurrent/metastatic lesions.In addition,for patients with primary HER2 1+status,those with recurrent/metastatic lesions converting to HER2-positive status have a significantly higher risk of disease progression than those converting to HER2 0 status.Therefore,retesting HER2 status in recurrent/metastatic lesions is extremely necessary,which can provide more precise treatment strategies for patients.