Stage IV triple-negative invasive lobular breast cancer with HER2 mutations: complete metabolic response to trastuzumab deruxtecan

What happened, in summary

This 72-year-old patient had a prior history of breast cancer at age 35 and a negative germline next-generation sequencing panel. In October 2021, she was diagnosed with metastatic breast cancer. Biopsy showed triple-negative invasive lobular carcinoma with pleomorphic features. HER2 immunohistochemistry showed dubious staining, but HER2 FISH was negative. At the outside facility where she first received treatment, iliac bone lesions were not initially considered metastatic, so she underwent a curative-intent pathway: neoadjuvant chemotherapy, breast-conserving surgery with sentinel lymph node biopsy, and adjuvant radiation. Her first follow-up PET/CT in April 2022 showed residual cancer in the breast, and the iliac bone lesions became lytic, confirming metastatic disease. She transferred to Hospital Israelita Albert Einstein and began capecitabine as first-line metastatic therapy. After palmar-plantar erythrodysesthesia and bone progression, she switched to cyclophosphamide 50 mg/day plus methotrexate 2 x 2.5 mg/day. The bone lesions continued to progress, and tumor biomarkers rose. Somatic tumor sequencing found 2 ERBB2/HER2 activating mutations, V842I and L755S, despite HER2 FISH negativity. A molecular tumor board recommended trastuzumab deruxtecan. She started T-DXd 5.4 mg/kg every 21 days, later reduced to 4.4 mg/kg because of neutropenia. Follow-up imaging showed no pulmonary toxicity and a sustained complete metabolic response. As of January 2026, the response had lasted 20 months, supporting strong disease control on third-line targeted antibody-drug conjugate therapy. The response was particularly meaningful because she had already progressed through capecitabine and low-dose cyclophosphamide plus methotrexate. The ongoing complete metabolic response supported continued T-DXd despite dose reduction, with monitoring for neutropenia and pulmonary toxicity.