Trastuzumab deruxtecan shows limited efficacy in HER2-positive breast squamous cell carcinoma following standard therapy failureNew Treatment Options for Rare HER2-Positive Breast Squamous Cell Carcinoma

Primary breast squamous cell carcinoma (PBSCC) with HER2-positive status is exceptionally rare, with fewer than 100 cases reported globally, and HER2 positivity occurring in only 5.8-7.1% of these cases. No established treatment standards exist for this entity. We present the case of a 43-year-old woman with HER2-positive PBSCC who exhibited a poor response to neoadjuvant TCHP therapy (Miller-Payne grade 2). Local recurrence occurred just 3 months after mastectomy. Second-line therapy with pyrotinib plus capecitabine provided 9 months of disease control before lung metastasis emerged. Subsequent molecular profiling revealed a PIK3CA E545K mutation (VAF 40.3%), co-amplified with FGF3/4/19 and CCND1. Although third-line treatment with trastuzumab deruxtecan (T-DXd) achieved a partial response, the progression-free survival (PFS) was limited to only 5 months. A repeat biopsy confirmed HER2 downregulation (from 3+ to 2+), identifying antigen loss as a key mechanism of acquired resistance. A review of the literature indicates that the pathological complete response rate of HER2-positive PBSCC to standard HER2-targeted therapy is remarkably low, far inferior to the 50-60% pCR rates achieved with dual HER2 blockade in HER2-positive invasive ductal carcinoma. This case underscores that upon failure of HER2-targeted therapy accompanied by HER2 antigen loss, the treatment strategy should pivot towards molecularly-guided precision therapy. Based on evidence such as that from the TRIUMPH trial, priority should be given to agents targeting the detected alterations, such as PIK3CA or FGFR inhibitors, rather than persisting with HER2-targeted approaches.