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Figure 1.
Example of a False-Positive Finding
Example of a False-Positive Finding

A, Whole-body magnetic resonance imaging shows a bone lesion on the right femur. B, Magnetic resonance imaging shows an undetermined lesion in the medial femur condyle. C, Examination of a bone biopsy specimen reveals benign reactive tissue.

Figure 2.
Example of a True-Positive Finding
Example of a True-Positive Finding

A, Whole-body magnetic resonance imaging shows a lesion in the left axilla. B, Magnetic resonance imaging of the breast shows an axillary mass. C, Magnetic resonance imaging of the breast reveals multifocal breast cancer.

1.
Nichols  KE, Malkin  D, Garber  JE, Fraumeni  JF  Jr, Li  FP.  Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers.  Cancer Epidemiol Biomarkers Prev. 2001;10(2):83-87.PubMedGoogle Scholar
2.
Bougeard  G, Renaux-Petel  M, Flaman  JM,  et al.  Revisiting Li-Fraumeni syndrome from TP53 mutation carriers.  J Clin Oncol. 2015;33(21):2345-2352.PubMedGoogle ScholarCrossref
3.
Villani  A, Shore  A, Wasserman  JD,  et al.  Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study.  Lancet Oncol. 2016;17(9):1295-1305. doi:10.1016/S1470-2045(16)30249-2Google ScholarCrossref
4.
Villani  A, Tabori  U, Schiffman  J,  et al.  Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study.  Lancet Oncol. 2011;12(6):559-567.PubMedGoogle ScholarCrossref
5.
Hegenscheid  K, Seipel  R, Schmidt  CO,  et al.  Potentially relevant incidental findings on research whole-body MRI in the general adult population: frequencies and management.  Eur Radiol. 2013;23(3):816-826.PubMedGoogle ScholarCrossref
Research Letter
December 2017

Surveillance of Dutch Patients With Li-Fraumeni Syndrome: The LiFe-Guard Study

Author Affiliations
  • 1Family Cancer Clinic, Department of Clinical Genetics, the Netherlands Cancer Institute, Amsterdam, the Netherlands
  • 2Department of Radiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
  • 3Department of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
  • 4Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, the Netherlands
JAMA Oncol. 2017;3(12):1733-1734. doi:10.1001/jamaoncol.2017.1346

Li-Fraumeni syndrome is a rare cancer predisposition syndrome characterized by a high lifetime risk of developing different tumors including sarcomas, breast cancer, brain tumors, leukemia, and adrenal cortical carcinomas and is associated with germline mutations in the TP53 gene.1,2 An annual surveillance program including whole-body magnetic resonance imaging (WB-MRI) potentially benefits these patients.3,4 False-positive screening results, however, may pose a burden on patients and the health care system.

Being a national referral center for patients identified as TP53 mutation carriers, the Netherlands Cancer Institute initiated annual surveillance with WB-MRI in October 2011. In addition to WB-MRI, annual physical examination, complete blood cell count, renal function, and breast MRI in female patients identified as TP53 mutation carriers were part of the surveillance protocol. Additional investigations, such as brain MRI or colonoscopy, were performed according to the specific tumors occurring in each family.

We assessed the diagnostic yield and the false-positive rate of an annual surveillance program including WB-MRI in TP53 carriers.

Methods

All patients identified as TP53 mutation carriers visiting our institute between October 2011 and July 2016 participated in the surveillance program. The Netherlands Cancer Institute considers this program as standard of care in these patients. A 12 minute WB-MRI scan protocol consisted of noncontrast T1-weighted and T2-STIR (short τ inversion recovery) series in the coronal plane and a whole body diffusion DWIBS (diffusion-weighted whole-body imaging with background body signal suppression) series scanned in the axial plane and reconstructed in the coronal plane. The number of abnormal findings requiring subsequent diagnostic testing in the first surveillance round was counted, with the resulting rate of true malignancies and false-positive findings.

Results

Fifty-six patients identified as TP53 mutation carriers were included in the surveillance program; 34 patients (61%) were women and 27 patients (48%) had a prior history of malignancy. Thirty-two abnormal findings were detected in 24 patients, giving rise to additional imaging or referral in all 24 patients (Figure 1 and Figure 2). Four of these abnormal findings were malignant (12.5%; 95% CI, 1.0%-24.0%), whereas 28 of the abnormal findings were false positives (87.5%; 95% CI, 76.0%-99.0%). One woman (age 66 years) was diagnosed with early-stage breast cancer visible on breast MRI and WB-MRI, and she was treated successfully. Another woman (age 38 years) had locoregional breast cancer recurrence diagnosed with WB-MRI and was also treated successfully without further evidence of disease activity since. A third woman (age 33 years) had a solitary liver metastasis after prior breast cancer. She received metastasectomy and repetitive lines of systemic treatment, but she died 30 months later. Finally, another woman (age 61 years) showed evidence of chronic lymphatic leukemia without need for treatment 3 years after diagnosis.

Twenty-six of 28 false-positive findings were detected by WB-MRI (93%). Detailed MRI and ultrasonography comprised 23 of 29 (79%) of the additional diagnostic procedures. Benign liver lesions (5 of 28 [18%]) and benign bone lesions (5 of 28 [18%]) were the most common false-positive findings.

Discussion

The initial round of our annual surveillance program in patients identified as TP53 mutation carriers detected malignancies in approximately 7% of patients. This detection rate comes at the expense of many false-positive findings and additional diagnostic procedures in almost half of the patients. The high frequency of incidental findings at the first surveillance is well known from other screenings studies.5

Given the short follow-up, it is uncertain whether detecting asymptomatic malignancies will improve the prognosis of these patients. Extending the number of screened individuals, screening episodes, and follow-up time in the LiFe-Guard study and combining our data with other cohorts of TP53 mutation carriers in a meta-analysis will provide additional insight into the value of a surveillance program in this population. In addition, the LiFe-Guard study is currently collecting data on patient reported outcomes regarding the perceived benefits and limitations of a surveillance program including cancer worries.

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Article Information

Corresponding Author: Marielle Ruijs, MD, PhD, Family Cancer Clinic, Department of Clinical Genetics, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX, Amsterdam, the Netherlands (m.ruijs@nki.nl).

Accepted for Publication: January 4, 2017.

Published Online: August 3, 2017. doi:10.1001/jamaoncol.2017.1346

Author Contributions: Drs Ruijs and Sonke had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: All authors.

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

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Loo, Bleiker, Sonke.

Statistical analysis: van Buchem, Sonke.

Administrative, technical, or material support: Ruijs, Loo, Bleiker.

Study supervision: Bleiker, Sonke.

Conflict of Interest Disclosures: None reported.

Additional Contributions: We thank Annemiek Cats, MD, PhD; Sabine Linn, MD, PhD; and Sjoerd Rodenhuis, MD, PhD, who were involved in the management of patients and collection of the data. They were not compensated for their contributions.

References
1.
Nichols  KE, Malkin  D, Garber  JE, Fraumeni  JF  Jr, Li  FP.  Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers.  Cancer Epidemiol Biomarkers Prev. 2001;10(2):83-87.PubMedGoogle Scholar
2.
Bougeard  G, Renaux-Petel  M, Flaman  JM,  et al.  Revisiting Li-Fraumeni syndrome from TP53 mutation carriers.  J Clin Oncol. 2015;33(21):2345-2352.PubMedGoogle ScholarCrossref
3.
Villani  A, Shore  A, Wasserman  JD,  et al.  Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study.  Lancet Oncol. 2016;17(9):1295-1305. doi:10.1016/S1470-2045(16)30249-2Google ScholarCrossref
4.
Villani  A, Tabori  U, Schiffman  J,  et al.  Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study.  Lancet Oncol. 2011;12(6):559-567.PubMedGoogle ScholarCrossref
5.
Hegenscheid  K, Seipel  R, Schmidt  CO,  et al.  Potentially relevant incidental findings on research whole-body MRI in the general adult population: frequencies and management.  Eur Radiol. 2013;23(3):816-826.PubMedGoogle ScholarCrossref
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