The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early Metastasis to Lymph Nodes

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is a clinically, phenotypically, and molecularly heterogeneous disease. This heterogeneity is a factor that negatively impacts therapy response. To analyze evolutionary patterns and the genomic alterations in patients with clinically aggressive disease who did not respond to treatment, we performed whole-exome sequencing in multiple longitudinal samples from diagnosis to distant metastasis. We found an extensive intrapatient and interpatient genetic heterogeneity, mutational signature composition at different stages, and, interestingly, an early lymph node metastasis formation during the evolution of aggressive TNBC. This study provides detailed insights into the genomic complexity, and the phylogenetic and evolutionary development of TNBC, as well as identifying specific mutations associated with targeted treatments in TNBC. ABSTRACT: In triple-negative breast cancer (TNBC), only 30% of patients treated with neoadjuvant chemotherapy achieve a pathological complete response after treatment and more than 90% die due to metastasis formation. The diverse clinical responses and metastatic developments are attributed to extensive intrapatient genetic heterogeneity and tumor evolution acting on this neoplasm. In this work, we aimed to evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease. We sequenced the whole exome of 16 lesions from four patients who did not respond to therapy, and took several follow-up samples, including samples from tumors before and after treatment, as well as from the lymph nodes and skin metastases. We found substantial intrapatient genetic heterogeneity, with a variable tumor mutational composition. Early truncal events were MCL1 amplifications. Metastatic lesions had deletions in RB1 and PTEN, along with TERT, AKT2, and CCNE1 amplifications. Mutational signatures 06 and 12 were mainly detected in skin metastases and lymph nodes. According to phylogenetic analysis, the lymph node metastases occurred at an early stage of TNBC development. Finally, each patient had three to eight candidate driving mutations for targeted treatments. This study delves into the genomic complexity and the phylogenetic and evolutionary development of aggressive TNBC, supporting early metastatic development, and identifies specific genetic alterations associated with a response to targeted therapies.