The Evolution of Clinically Aggressive Triple-Negative Breast Cancer Shows a Large Mutational Diversity and Early...

Area of Science:

• Genomics
• Cancer Research
• Oncology

Background:

• Triple-negative breast cancer (TNBC) has poor outcomes, with low pathological complete response rates to neoadjuvant chemotherapy and high rates of metastasis.
• Intrapatient genetic heterogeneity and tumor evolution contribute to diverse clinical responses and metastatic progression in TNBC.

Purpose of the Study:

• To evaluate genomic alterations and tumor evolution in TNBC patients with aggressive disease who did not respond to therapy.
• To identify potential driving mutations for targeted treatments in aggressive TNBC.

Main Methods:

• Whole-exome sequencing of 16 lesions from four TNBC patients with aggressive disease.
• Analysis of tumor samples before and after treatment, lymph node, and skin metastasis samples.
• Phylogenetic analysis to understand tumor evolution and metastatic development.

Main Results:

• Substantial intrapatient genetic heterogeneity and variable tumor mutational composition were observed.
• Early truncal events included MCL1 amplifications; metastatic lesions showed RB1 and PTEN deletions, with TERT, AKT2, and CCNE1 amplifications.
• Mutational signatures 06 and 12 were prevalent in skin metastases and lymph nodes, suggesting early metastatic spread.

Conclusions:

• Aggressive TNBC exhibits significant genomic complexity and early metastatic development, as supported by phylogenetic analysis.
• Specific genetic alterations, including gene amplifications and deletions, are associated with metastatic lesions.
• Each patient presented multiple candidate driving mutations, highlighting opportunities for targeted therapy development in TNBC.