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Clinical Trial
. 2016 Dec 1;122(23):3673-3681.
doi: 10.1002/cncr.30248. Epub 2016 Aug 6.

Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort

Phuong L Mai  1 , Ana F Best  2 , June A Peters  1 , Rosamma M DeCastro  1 , Payal P Khincha  1 , Jennifer T Loud  1 , Renée C Bremer  1 , Philip S Rosenberg  2 , Sharon A Savage  1
Affiliations
Clinical Trial

Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort

Phuong L Mai et al. Cancer. .

Abstract

Background: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome characterized by a very high lifetime cancer risk and an early age at diagnosis of a wide cancer spectrum. Precise estimates for the risk of first and subsequent cancers are lacking.

Methods: The National Cancer Institute's Li-Fraumeni Syndrome Study includes families meeting the diagnostic criteria for LFS or Li-Fraumeni-like syndrome, and individuals with a germline TP53 mutation, choroid plexus carcinoma, adrenocortical carcinoma, or ≥3 cancers. Herein, we estimated the cumulative risk and annual hazards for first and second cancers among TP53 mutation carriers (TP53 positive [TP53+]) using MATLAB statistical software.

Results: This study evaluated 286 TP53+ individuals from 107 families. The cumulative cancer incidence was 50% by age 31 years among TP53+ females and 46 years among males, and nearly 100% by age 70 years for both sexes. Cancer risk was highest after age 20 years for females, mostly due to breast cancer, whereas among males the risk was higher in childhood and later adulthood. Among females, the cumulative incidence rates by age 70 years for breast cancer, soft tissue sarcoma, brain cancer, and osteosarcoma were 54%, 15%, 6%, and 5%, respectively. Among males, the incidence rates were 22%, 19%, and 11%, respectively, for soft tissue sarcoma, brain cancer, and osteosarcoma. Approximately 49% of those with 1 cancer developed at least another cancer after a median of 10 years. The average age-specific risk of developing a second cancer was comparable to that of developing a first cancer.

Conclusions: The cumulative cancer risk in TP53 + individuals was very high and varied by sex, age, and cancer type. Additional work, including prospective risk estimates, is needed to better inform personalized risk management. Cancer 2016;122:3673-81. © 2016 American Cancer Society.

Keywords: Li-Fraumeni syndrome; TP53; cumulative cancer risk; second cancer; second cancer risk.

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Conflict of interest statement

The authors report no conflict of interest

Figures

Figure 1
Figure 1
Overall and cancer-free survival among TP53+ females (A) and TP53+ males (B)
Figure 1
Figure 1
Overall and cancer-free survival among TP53+ females (A) and TP53+ males (B)
Figure 2
Figure 2
Cumulative incidence of first cancer diagnosis among TP53+ females (A) and TP53+ males (B)
Figure 3
Figure 3
Overall estimated product-limit and hazard curves for brain cancer, STS, osteosarcoma, and breast cancer (Note: Hazard curve for breast cancer is on a different scale). STS: soft-tissue sarcoma; OS: osteosarcoma
Figure 4
Figure 4
Estimated Kaplan-Meier curve of time from first cancer to second cancer, product-limit for age at second cancer, and hazard curves for age at second cancer. All cancers included (A–C) and with breast and prostate cancer excluded (D–F). BC: breast cancer; PC: prostate cancer
Figure 5
Figure 5
Kaplan-Meier Curves of time from first cancer to second cancer, stratified by age at first cancer diagnosis; A: Females, B: Females, with breast cancer excluded, C: Males
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