TP53 Gene Mutation and Breast Cancer Risk

• The TP53 gene:
  • Is a key tumor-suppressor gene:
    • That acts as a checkpoint control for DNA damage
  • Due to its critical role in controlling cellular damage:
    • A TP53 germline mutation predisposes patients to multiple malignancies, including:
      • Breast cancer and soft tissue sarcomas
• The associated familial syndrome was first observed in 1969 and is known as the Li-Fraumeni syndrome:
  • The penetrance of breast cancer related to TP53 mutations is higher than seen in the more common BRCA 1 or BRCA 2 mutations:
    • With a cumulative incidence reported for TP53 of:
      • 85% by age 60.
    • TP53-associated breast cancers:
      • Present at an early age:
        • Median age of diagnosis is 34
      • The majority are:
        • Hormone receptor positive and / or HER-2 positive
    • Due to this high penetrance and associated increased risk for a secondary breast cancer:
      • Bilateral prophylactic mastectomy is recommended:
        • For management of an early-stage breast cancer in patients with a mutation in TP53
      • This is especially true in younger women:
        • As contralateral breast cancer risk inversely correlates with the patient’s age
      • The recommendation for mastectomy is further supported by the concern regarding radiation use in this patient population already at increased risk for soft tissue sarcomas:
        • Radiation should be used with extreme caution and careful consideration of the risk / benefit
  • For patients presenting with a known TP53 germline mutation and without a diagnosis of breast cancer:
    • NCCN guidelines recommend:
      • Annual breast MRI at 20 to 29 years
      • Annual MRI and mammography at 30 to 75 years for high-risk breast cancer screening
      • Consideration of prophylactic risk-reducing mastectomy should be made in context of the age of presentation:
        • As breast cancer risk increases significantly after the second decade of lifein these patients:
          • Bilateral mastectomy should be considered:
            • Starting at age 20
        • The risk of breast cancer peaks at age 40 to 45 and then decreases:
          • Therefore bilateral mastectomy offers significantly less benefit in women over 60 years of age

• References:
• Mai PL, Best AF, Peters JA, DeCastro RM, Khincha PP, Loud JT, Bremer RC, Rosenberg PS, Savage SA Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016 Dec 1; 122(23):3673-3681.
• Masciari S, Dillon DA et al. Breast cancer phenotype in women with TP53 germline mutations: a Li Fraumeni syndrome consortium effort. Breast Cancer Res Treat. 2012;133(3):1125–1130.
• Schon, K, Tischkowitz, M. Clinical implications of germline mutations in breast cancer: TP53 Breast Cancer Res Treat. 2018; 167(2): 417–423.
• National Comprehensive Cancer Network (2014) Genetic/familial high risk assessment: breast and ovarian. Li Fraumeni syndrome management. NCCN Clinical Practice Guidelines in Oncology. Version 1.2018.

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