Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). Mutation carriers ascertained on family history have an extremely high lifetime risk of cancers arising from one or more of many possible sites. There is no established screening strategy for early detection and treatment of these cancers. Herein, we report preliminary data from a prospective study of a whole-body screening program that includes whole-body. Five new malignancies (3 de novo, 2 recurrent) have been identified in five of the first 30 participants, suggesting potentially significant benefits from screening in this population.
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.
WB MRI scans were performed on three scanners (one 1.5 T and two 3T), at two institutions. The WBMRI protocol involved scanning at 6 stations (vertex to soles of feet), with coronal Dixon T1, transverse 3D gradient echo T1, FSE T2 fat-suppressed or STIR (for the chest station), and diffusion-weighted EPI (with ADC map calculated by vendor software).
WBMR images were independently assessed by 2 radiologists, with findings scored on a 6-point rating scale of suspicion for malignancy. Findings scored 3 (equivocal for the presence of malignancy), or higher, were referred for further assessment. The study was approved by the human research ethics committee of the Peter MacCallum Cancer Centre. Written informed consent was obtained from all participants.
At the time of this submission, between July 2012 and October 2017, 41 eligible participants had been enrolled. Data from the most recent 11 of these participants is pending inclusion here. Analysis of the first 30 showed:
-The median (range) age was 38 (18-62) years. Eighteen (60%) were female.
-From 30 baseline WBMRI studies, 16 lesions in 14 participants (47%) required follow-up.
-On further investigation, 11 of 16 lesions (69%) were benign, although ongoing surveillance was deemed warranted in 3 participants.
-Five lesions (31%) of the 16 lesions, 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.
-Scan times have ranged up to 110 minutes (at 1.5 T), but generally been well tolerated.
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. This study is small, non-randomized, and with short followup. Participants have TP53 genotypes of varying penetrance, although several participants from a single family are included.
Several assessments are precluded at this stage, including the ideal time interval and imaging protocol for WBMRI, and false-negative rates. Quicker scan times would be highly desirable, and should be facilitated by newer equipment and streamlined protocols.
These data contribute to international efforts to investigate surveillance in TP53 mutation carriers. The findings to date support continuation for longer-term evaluation.
Cancer Australia.
SPHERE (Sydney Partnership for Health, Education, Research, and Enterprise)
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