Abstract
This prospective study of surveillance strategies uses a whole-body screening program, including whole-body magnetic resonance imaging, in carriers of germline mutations in TP53.
Germline TP53 mutations are associated with Li-Fraumeni syndrome (LFS). Mutation carriers ascertained on family history have an extremely high lifetime risk of multiorgan cancers. Unlike hereditary breast or bowel cancer syndromes, there are no consensus guidelines for screening in LFS, although emerging data suggest a benefit from surveillance. 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.
Methods
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.
Results
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.
Table. Investigable Lesions Arising From WBMRI Surveillance in 30 TP53 Mutation Carriers.
| Patient No./Sex/Age at Consent, y | Genotype | Cancer History (Age at Diagnosis, y) | Subsequent Investigations | Diagnosis | Treatment |
|---|---|---|---|---|---|
| Benign Findings on Further Investigation | |||||
| 3/M/55a | p.Arg110Pro | Sarcoma (37), sarcoma (44) | Left calf: thallium scan | Benign nodule | NA |
| 3/M/55a | p.Arg110Pro | Sarcoma (37), sarcoma (44) | Prostate: PSA | Lesion of uncertain significance | Surveillance |
| 5/F/39 | p.Arg158His | Breast (26), sarcoma (36), pheo (37) | Pelvic: US | Ovarian cysts | NA |
| 12/F/52a | p.Arg337His | Breast (49) | Thyroid: US | Multiple thyroid nodules | Surveillance |
| 14/M/40 | p.Gly245Ser | NA | Shoulder: US | Normal | NA |
| 15/M/22 | p.Arg213a | Sarcoma (<1), sarcoma (13) | Mandible: MRI | Metal artifact | NA |
| 17/F/45 | p.Pro152Leu | Left breast (34), right DCIS (44), 3 melanomas | Brain: MRI | Normal | NA |
| 24/F/36 | p.Arg181His | NA | Breast: MRI | Benign cysts | NA |
| 28/F/52 | p.Arg181His | NA | Breast: MRI | Benign cysts | NA |
| 31/F/33 | p.Arg337Cys | Right breast DCIS (33) | Chest: CT, PET, and MRI | Mediastinal cyst | NA |
| 34/M/19 | p.Arg158His | NA | Prostate: PSA | Lesion of uncertain significance | Surveillance |
| Malignant Findings on Further Investigation | |||||
| 6/M/41 | p.His168Leu | Leiomyosarcoma (39) | Liver: MRI and biopsy | Met leiomyosarcoma | Palliation |
| 12/F/52a | p.Arg337His | Breast (49) | Lumbar: MRI and biopsy | WDLPS | Curative intent |
| 18/M/41 | p.Arg273Cys | Osteosarcoma (12) | Prostate: MRI and biopsy | Prostate cancer | Curative intent |
| 19/M/46 | p.Arg273Cys | Gastric (42), melanoma (42) | Prostate: MRI and biopsy | Prostate cancer | Curative intent |
| 29/F/40 | p.Arg248Gln | Left breast (35), DFSP (36), right breast (39) | Upper body: PET scan | Met breast cancer | Palliation |
Abbreviations: CT, computed tomography; DCIS, ductal carcinoma in situ; DFSP, dermatofibrosarcoma protuberans; F, female; M, male; met, metastatic; MRI, magnetic resonance imaging; NA, not applicable; PET, positron emission tomography; pheo, pheochromocytoma; PSA, prostate-specific antigen; US, ultrasonography; WBMRI, whole-body magnetic resonance imaging; WDLPS, well-differentiated liposarcoma.
Two lesions in participant.
Discussion
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.
References
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