Abstract PD7-03: Characterization of Li-Fraumeni syndrome diagnosed using a 25-gene hereditary cancer panel
Authors: Rich T , Lotito M , Kidd J , Saam J , Lancaster J 
Published: May 2016

Background: Clinical diagnostic criteria for Li-Fraumeni syndrome (LFS) have evolved with increased utilization of TP53 germline testing and subsequent improved understanding of the diversity of the associated cancer phenotypes. However, data on LFS still suffer from ascertainment bias as patients are typically selected to undergo TP53 testing based on the presence of hallmark features of LFS. Analyzing TP53 mutation carriers identified from multi-gene panel testing, for which the diagnosis of LFS may not have been suspected or was included in a longer differential diagnosis, affords an opportunity to characterize additional TP53 carriers who might not otherwise have been ascertained.

Methods: Patients with a deleterious or suspected deleterious germline TP53 mutation were identified from 80,748 consecutive cases that underwent a 25-gene hereditary cancer panel test between September 2013 and March 2015 at a commercial diagnostic laboratory. Patient clinical data were obtained by healthcare provider report on test requisition forms. Each TP53 mutation carrier was evaluated to determine whether the National Comprehensive Cancer Network's (NCCN) guidelines were met for TP53 testing.

Results: Eighty-one TP53 mutation carriers were identified and had a total of 115 cancers (0.1% overall prevalence). Among the 76 carriers with at least one cancer, the average age at first diagnosis was 42 years (range 11-76 years) and 24% were first diagnosed older than age 50 years. The most common first cancers were of the breast (n=45), ovary (n=9), and gastrointestinal tract (n=8). Fifty-two of the 75 (69%) women had breast cancer, 44% of which were first diagnosed at 35 years or younger, and 21% were first diagnosed at 50 years or older. Only 27 TP53 carriers met NCCN criteria for TP53 testing, 14 of whom only met based on having early-onset breast cancer. An additional 8 did not meet criteria themselves but had a first- or second-degree relative who did. Among the 28 individuals with more than one primary cancer, 21 (75%) developed their second primary at a site for which increased surveillance is recommended in LFS, but only 4 would have met NCCN criteria for TP53 testing at their first cancer diagnosis. The most common second cancers were of the breast (n=16), gastrointestinal tract (n=4), or kidney (n=2) and occurred an average of 11 years after the first cancer (range 0-36 years).

Conclusion: In this analysis, a large proportion of carriers would not have been identified as TP53 testing candidates based on NCCN guidelines. Our data are consistent with other studies demonstrating high second primary cancer risks in LFS, and highlight the value of multigene panel testing in identifying individuals who may be candidates for increased surveillance and/or cancer risk-reducing management options.

Citation Format: Rich T, Lotito M, Kidd J, Saam J, Lancaster J. Characterization of Li-Fraumeni syndrome diagnosed using a 25-gene hereditary cancer panel. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD7-03.