Authors:
Emma Zattarin, Teresa Beninato, […], and Marta Brambilla, +5 (View all authors)
Abstract
The distinction between a metastatic recurrence and the onset of a second primary malignancy can be diagnostically challenging. Precision medicine can offer valuable support in this context.
A 34-year-old woman was diagnosed in 2012 with hormone-receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer in the left breast, with homolateral axillary node involvement but no distant metastases. Following neoadjuvant chemotherapy, surgery (pathological stage was ypT1b ypN2a M0), adjuvant endocrine therapy and radiotherapy, she remained disease-free until 2021, when a positron emission tomography scan showed a mediastinal mass. Histology revealed a high-grade large cell neuroendocrine carcinoma (LCNEC) lacking breast cancer-specific markers (GATA3-, HR-, HER2-, mammoglobin-, GCDFP15-), with PD-L1 expression at 10% and a tumor mutational burden (TMB) of 9.54 mut/MB. Chemotherapy (cisplatin plus etoposide) led to rapid disease progression, whereas second-line pembrolizumab led to a remarkable and prolonged disease response. Treatment was discontinued in 2023 due to grade 3 immune-related colitis and, as of November 2024, the patient shows no clinical evidence of disease.
Next-generation sequencing identified shared tumor PIK3CA pathogenic variants in both breast cancer and LCNEC tissues, suggesting a potential relationship as primary tumor and metastasis, rather than two distinct malignancies.
Molecular characterization of cancer enabled the identification of potential causal links between tumors with distinct histologies and locations, offering a deeper insight into an atypical clinical scenario.