Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer 
susceptibility syndromes, characterized by early age at tumor onset and a wide 
spectrum of malignant tumors. Identifying LFS in patients with cancer is 
clinically imperative because they have an increased sensitivity to ionizing 
radiation and are more likely to develop radiation-induced secondary 
malignancies. This case report describes a young woman whose initial 
presentation of LFS was early-onset breast cancer and whose treatment of this 
primary malignancy with breast conservation likely resulted in a secondary 
malignancy arising in her radiation field. As seen in this case, most breast 
cancers in patients with LFS exhibit a triple-positive phenotype (estrogen 
receptor-positive/progesterone receptor-positive/HER2-positive). Although this 
patient met classic LFS criteria based on age and personal and family history of 
cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial 
High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for 
TP53 mutations in a subset of patients with early-onset breast cancer, even in 
the absence of a suggestive family history, because of the potential for de novo 
TP53 mutations.