Surveillance in Germline TP53 Mutation Carriers Utilizing Whole-Body Magnetic Resonance Imaging

Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS).¹ Mutation carriers ascertained on family history have an extremely high lifetime risk of multiorgan cancers.² Unlike hereditary breast or bowel cancer syndromes, there are no consensus guidelines for screening in LFS, although emerging data suggest a benefit from surveillance.³ Herein, we report preliminary data from a prospective study of a whole-body screening program that includes whole-body magnetic resonance imaging (WBMRI) in carriers of germline mutations in TP53.

Eligible patients were TP53 mutation carriers, ages 18 to 70 years at the time of consent, Eastern Cooperative Oncology Group (ECOG) performance status 0-1 with no active cancer diagnosis. The protocol included annual WBMRI including brain, physical examination, breast MRI (for women), full blood evaluation, and colonoscopy and/or endoscopy every 2 or 5 years, dependent on family history, with fecal occult blood tests in the intervening years. The WBMRI scans were independently assessed by 2 radiologists (N.J.F. and K.M.). The study was approved by the human research ethics committee of the Peter MacCallum Cancer Centre. Written informed consent was obtained from all participants, and no payments were made.

Between July 2012 and October 2016, 30 eligible participants from 15 families were enrolled. The median (range) age was 38 (18-62) years. Eighteen (60%) were female. From 30 baseline WBMRIs, 16 lesions in 14 participants (47%) required follow-up (Table). On further investigation 11 of 16 lesions (69%) were benign, although ongoing surveillance was deemed warranted in 3 participants. Five lesions (31%) in 5 participants (17%) requiring further investigation were malignant. Three of these lesions were primary asymptomatic cancers, and 2 were recurrences of previous cancers. The new primary malignant neoplasms included a well-differentiated liposarcoma in the lumbar region and 2 prostate cancers (Gleason score 7 and 9), all treated with curative intent. With a median (SD) follow-up of 17.5 (12.8) months, 15 individuals have undergone 24 WBMRIs in subsequent years, with no additional malignant neoplasms identified. One participant withdrew from the WBMRI component owing to claustrophobia after completing 1 WBMRI. Physical examinations identified 1 squamous cell carcinoma on the lip, which was excised curatively. All other evaluation results have been within normal parameters.

There is an unmet need for surveillance strategies suitable for people at high risk of cancers at multiple sites. Li-Fraumeni syndrome is a rare syndrome, although TP53 mutation carriers are more often being identified in nontraditional settings, increasing the need for clinical management. Preliminary data from this small prospective study using WBMRI in TP53 mutation carriers identified 3 new primary malignant neoplasms in 30 participants at baseline. Further investigation was warranted for a further 13 lesions with targeted imaging resolving the diagnosis in most cases. Subsequent annual WBMRIs did not detect any additional tumors, nor were interval cancers diagnosed clinically. Interestingly, 2 prostate cancers were diagnosed, prompting the addition of annual prostate-specific antigen to the protocol.

This study is small, nonrandomized, and with short follow-up. Several assessments are precluded at this stage, including the ideal interval for WBMRI and false-negative rates. Participants have TP53 genotypes of varying penetrance, although several participants from a single family are included. These data contribute to international efforts to investigate surveillance in TP53 mutation carriers. The findings to date support continuation for longer-term evaluation.

Corresponding Author: Mandy L. Ballinger, PhD, Cancer Division, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, NSW, 2010, Australia (m.ballinger@garvan.org.au).

Accepted for Publication: December 5, 2016.

Published Online: August 3, 2017. doi:10.1001/jamaoncol.2017.1355

Author Contributions: Drs Ballinger and Thomas had full access to all of the data and take responsibility for the data integrity and analysis. Drs James and Thomas are equal last authors.

Study concept and design: Ballinger, Mitchell, James, Thomas.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Ballinger, Thomas.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Ballinger, Thomas.

Obtained funding: Ballinger, Mitchell, Thomas.

Study supervision: Mitchell, James, Shanley.

Conflict of Interest Disclosures: None reported.

Funding/Support: The Australasian Sarcoma Study Group provided indemnity cover for the study. Support was also received from the Johanna Sewell Research Foundation and Cancer Australia’s Priority-driven Collaborative Cancer Research Scheme (APP1067094).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study or the collection, management, analysis and interpretation of the data or preparation, review or approval of the manuscript or decision to submit for publication.

Meeting Presentations: Partial results from the study were presented at the Familial Aspects of Cancer Conference; August 12-15, 2014; Kingscliff, New South Wales Australia; the Connective Tissue Oncology Society; October 15-18, 2014; Berlin, Germany; the Familial Aspects of Cancer Conference; August 25-28, 2015; Kingscliff, New South Wales Australia; and the Human Genetics Society of Australasia Conference; August 6-9, 2016; Hobart, Tasmania, Australia.

Additional Contributions: We thank Marion Harris, FRACP, Monash Health, Melbourne Australia; Alison Trainer, FRACP, Bimal Parameswaran, FRANZCR, and Clair Shadbolt, DRANZCR, Peter MacCallum Cancer Center, Melbourne; and Mary-Anne Young, MSc, Garvan Institute of Medical Research, Sydney, Australia, for their invaluable contributions to reviewing scans, or clinical assessment of participants, contributions ordinarily worthy of authorship. They were not compensated for their assistance. Eveline Niedermayr, BSc, provided data management and Emma Galligan, BSc, coordinated recruitment and data collection. Both are paid employees of the Peter MacCallum Cancer Centre.