Bone-Induced HER2 Promotes Secondary Metastasis in HR⁺/HER2⁻ Breast Cancer

Bone metastases can disseminate to secondary sites and promote breast cancer progression, creating additional clinical challenges. The mechanisms contribut-ing to secondary metastasis are barely understood. Here, we evaluate the prediction power of HER2-expressing (HER2E) circulating tumor cells (CTC) after analyzing over 13,000 CTCs from a cohort of 137 patients with metastatic breast cancer with initial HR⁺ /HER2⁻ status and use pre-clinical models of bone metastasis (BM) to validate the role of HER2E CTCs in multiorgan metas-tases. Although HER2 expression was higher in patients with BM, experimental analyses revealed that HER2E CTCs derived from bone lesions were more dependent on HER2 activity and more susceptible to anti-HER2 therapy. Targeting the bone-mediated HER2 induction reduces CTC detection and abrogates secondary metastasis from the bone. Overall, we elucidate that HER2E CTCs can serve as a noninvasive biomarker for BM formation with high therapeutic benefit for patients with HR⁺ metastatic breast cancer. Significance: Given the urgent need for alternative strategies to block metastasis progression, we demonstrate that blocking HER2-mediated secondary metastasis improves clinical outcome and establish HER2 as a biomarker for bone metastasis in patients with initial HR⁺ /HER2⁻ breast cancer, which represents ~70% of all cases.