Lung Metastasis of HER2-positive Breast Cancer with Squamous Cell Differentiation Phenotype: A Case Report

Drug resistance, recurrence, and metastasis are the main challenges that can lead to treatment failure and deteriorate outcomes of patients with breast cancer. Breast cancer metastasizes to different organs and may present with different phenotypic features. However, the underlying mechanisms of phenotypic plasticity of breast cancer still remain unclear. We herein report a case of HER2-positive breast cancer in which the patient developed acquired therapeutic resistance following standard postoperative adjuvant chemotherapy combined with anti-HER2 targeted therapy. The patient initially responded to treatment; however, one year after completion of therapy, new bilateral pulmonary nodules emerged. Subsequent pathological examination confirmed metastatic carcinoma with a transdifferentiated squamous cell phenotype. Comprehensive biomarker analyses, including immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and next-generation sequencing (NGS), were performed on matched samples from the primary breast tumor and the corresponding lung metastatic lesions. Integrated diagnostic results confirmed that the pulmonary lesions were metastatic in origin from the breast, harboring HER2 amplification as well as PIK3CA and TP53 mutations. In contrast to the primary lesion, the metastatic lung lesions demonstrated acquisition of a squamous phenotype, accompanied by multiple chromosomal heterozygous/homozygous deletions and copy-number gain that may have contributed to this phenotypic transformation. Despite HER2 amplification, the pulmonary metastases showed negative HER2 protein expression, possibly reflecting tissue-specific gene expression differences. These findings provide new insights for the clinical management of HER2-positive breast cancer.