Abstract OT1-2-04: TP53 mutants in circulating tumor DNA and follow-up of BRCA1 mutation carriers: The CirCA01 study
Authors: Bidard Francois-Clement , Stoppa-Lyonnet Dominique , Nogues Catherine , Caron Olivier , Delaloge Suzette , Dugast Catherine , Lasset Christine , Berger Frederique , Asselain Bernard , Lantz Olivier , Stern Marc-Henri , Pierga Jean-Yves 
Published: May 2015

Abstract
Background:
Circulating tumor DNA (ctDNA) has been proposed as a biological surrogate of the repertoire of molecular aberrations in cancer patients. The genetic information derived from the analysis of ctDNA may be therefore employed as biomarker for diagnosis, prognostication, therapy response monitoring and assessment of genetic mechanisms of resistance. We have initiated a prospective study in a population of BRCA1-mutation carrier at high risk of either relapse and/or new cancer growth. The CirCA01 study is based on the combination of (i) on the clinical side, the systematic inactivation of the TP53 gene by mutations in BRCA1-related cancers, whatever the histological type and the organ of origin, and (ii) on the bench side, an original assay that allows to detect any TP53 mutation in plasma with exquisite sensitivity.
Methods:
CirCA01 is a national prospective study, opened in several cancer centers in France (Institut Curie, Gustave Roussy, Centre Léon Bérard, Centre Eugène Marquis) and funded by the French Ministry of Health (PHRCK1369250N). Inclusion criteria are: patients with no evidence of any invasive tumor mass at inclusion (clinical and, if any, radiological exams), carriers of known germline BRCA1 deleterious mutation (a personal history of cancer being not mandatory), age ≥ 30 years for patient with previous history of cancer or age ≥ 40 years for patient without previous history of cancer, written informed consent. Main exclusion criteria are: patient presenting with invasive tumor masses (e.g. stage IV cancer or localized cancer not yet surgically removed), carriers of germline BRCA1 variant of unknown significance, carriers of germline BRCA2 deleterious mutation or variant, individuals with a low risk of BRCA1-related tumor growth, i.e. women who underwent prophylactic bilateral mastectomy, annexectomy or controlateral prophylactic mastectomy after breast cancer. 200 BRCA1 mutation carriers will be enrolled and followed up regularly, as per national guideline for high-risk patients. Fresh plasma samples will be collected at each follow-up visit to the hospital and will be used to detect any mutation in TP53 exons and flanking non-translated regions by a "digital NGS"-based technique. (NCT registration ongoing).
Results: Correlation with patients outcome will allow to report whether TP53 ctDNA detection may be used as (i) a new screening test that can be repeated easily in BRCA1-carriers with no evidence of tumor growth (ii) a new diagnostic test in BRCA1-carriers who present a clinical or radiological abnormality (typically ACR class 3 mammograms): (A) diagnosis of the malignant vs benign nature of the abnormality, based on TP53 mutation levels, (B) differential diagnosis of a new cancer growth vs relapse of a previously treated cancer based on TP53 mutation characterization (different vs similar TP53 mutations).
Citation Format: Francois-Clement Bidard, Dominique Stoppa-Lyonnet, Catherine Nogues, Olivier Caron, Suzette Delaloge, Catherine Dugast, Christine Lasset, Frederique Berger, Bernard Asselain, Olivier Lantz, Marc-Henri Stern, Jean-Yves Pierga. TP53 mutants in circulating tumor DNA and follow-up of BRCA1 mutation carriers: The CirCA01 study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-2-04.