title: Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study.
abstract: BACKGROUND
  Carriers of a germline TP53 pathogenic variant have a substantial lifetime risk of developing cancer. In 2011, we did a prospective observational study of members of families who chose to either undergo a comprehensive surveillance protocol for individuals with Li-Fraumeni syndrome or not. We sought to update our assessment of and modify the surveillance protocol, so in this study we report both longer follow-up of these patients and additional patients who underwent surveillance, as well as update the originally presented surveillance protocol.
  
  
  METHODS
  A clinical surveillance protocol using physical examination and frequent biochemical and imaging studies (consisting of whole-body MRI, brain MRI, breast MRI, mammography, abdominal and pelvic ultrasound, and colonoscopy) was introduced at three tertiary care centres in Canada and the USA on Jan 1, 2004, for carriers of TP53 pathogenic variants. After confirmation of TP53 mutation, participants either chose to undergo surveillance or chose not to undergo surveillance. Patients could cross over between groups at any time. The primary outcome measure was detection of asymptomatic tumours by surveillance investigations. The secondary outcome measure was 5 year overall survival established from a tumour diagnosed symptomatically (in the non-surveillance group) versus one diagnosed by surveillance. We completed survival analyses using an as-treated approach.
  
  
  RESULTS
  Between Jan 1, 2004, and July 1, 2015, we identified 89 carriers of TP53 pathogenic variants in 39 unrelated families, of whom 40 (45%) agreed to surveillance and 49 (55%) declined surveillance. 19 (21%) patients crossed over from the non-surveillance to the surveillance group, giving a total of 59 (66%) individuals undergoing surveillance for a median of 32 months (IQR 12-87). 40 asymptomatic tumours have been detected in 19 (32%) of 59 patients who underwent surveillance. Two additional cancers were diagnosed between surveillance assessments (false negatives) and two biopsied lesions were non-neoplastic entities on pathological review (false positives). Among the 49 individuals who initially declined surveillance, 61 symptomatic tumours were diagnosed in 43 (88%) patients. 21 (49%) of the 43 individuals not on surveillance who developed cancer were alive compared with 16 (84%) of the 19 individuals undergoing surveillance who developed cancer (p=0·012) after a median follow-up of 46 months (IQR 22-72) for those not on surveillance and 38 months (12-86) for those on surveillance. 5 year overall survival was 88·8% (95% CI 78·7-100) in the surveillance group and 59·6% (47·2-75·2) in the non-surveillance group (p=0·0132).
  
  
  CONCLUSIONS
  Our findings show that long-term compliance with a comprehensive surveillance protocol for early tumour detection in individuals with pathogenic TP53 variants is feasible and that early tumour detection through surveillance is associated with improved long-term survival. Incorporation of this approach into clinical management of these patients should be considered.
  
  
  BACKGROUND
  Canadian Institutes for Heath Research, Canadian Cancer Society, Terry Fox Research Institute, SickKids Foundation, and Soccer for Hope Foundation.
authors: Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Hematology/Oncology, University of Toronto, Toronto, ON, Canada; Genetics & Genomic Biology Program, University of Toronto, Toronto, ON, Canada.
authors: Anita
authors: A
authors: Villani
authors: Genetics & Genomic Biology Program, University of Toronto, Toronto, ON, Canada.
authors: Ari
authors: A
authors: Shore
authors: Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Endocrinology, University of Toronto, Toronto, ON, Canada; Genetics & Genomic Biology Program, University of Toronto, Toronto, ON, Canada.
authors: Jonathan D
authors: JD
authors: Wasserman
authors: Division of Biostatistics, Design and Analysis, University of Toronto, Toronto, ON, Canada.
authors: Derek
authors: D
authors: Stephens
authors: The Hospital for Sick Children, and Department of Medicine and Division of Medical Oncology and Hematology, Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada.
authors: Raymond H
authors: RH
authors: Kim
authors: Division of Hematology/Oncology, University of Toronto, Toronto, ON, Canada; Department of Genetic Counselling and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors: Harriet
authors: H
authors: Druker
authors: Genetics & Genomic Biology Program, University of Toronto, Toronto, ON, Canada; Department of Genetic Counselling and Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
authors: Bailey
authors: B
authors: Gallinger
authors: Division of Pediatric Hematology/Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors: Anne
authors: A
authors: Naumer
authors: Division of Pediatric Hematology/Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors: Wendy
authors: W
authors: Kohlmann
authors: Division of Hematology/Oncology, University of Toronto, Toronto, ON, Canada; Genetics & Genomic Biology Program, University of Toronto, Toronto, ON, Canada.
authors: Ana
authors: A
authors: Novokmet
authors: Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Hematology/Oncology, University of Toronto, Toronto, ON, Canada; Genetics & Genomic Biology Program, University of Toronto, Toronto, ON, Canada.
authors: Uri
authors: U
authors: Tabori
authors: Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
authors: Marta
authors: M
authors: Tijerin
authors: Department of Medical Imaging, University of Toronto, Toronto, ON, Canada.
authors: Mary-Louise C
authors: ML
authors: Greer
authors: Division of Hematology/Oncology, Nationwide Children's Hospital, The Ohio State University, Columbus, OH, USA.
authors: Jonathan L
authors: JL
authors: Finlay
authors: Division of Pediatric Hematology/Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
authors: Joshua D
authors: JD
authors: Schiffman
authors: Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Division of Hematology/Oncology, University of Toronto, Toronto, ON, Canada; Genetics & Genomic Biology Program, University of Toronto, Toronto, ON, Canada. Electronic address: david.malkin@sickkids.ca.
authors: David
authors: D
authors: Malkin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016864:Li-Fraumeni Syndrome / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging / Q000379:methods*; D009367:Neoplasm Staging; D009369:Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011159:Population Surveillance; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53