Ph. D. Project
Title:
233 / 5000 Résultats de traduction Liquid biopsy for the evaluation of clonal heterogeneity, tumor evolution and survival in patients with hormone-dependent breast cancer treated with anti-CDK4 / 6 - CICLADES, CICLADES CE and ITMO evolution
Dates:
2022/09/01 - 2025/09/01
Supervisor(s): 
Description:
The estrogen-dependent nature of breast cancer was first described in 1896 with the publication of the observations by George
Beatson on regression of breast cancer after bilateral oophorectomy (Beatson, Trans Med Chir Soc Edinb, 1896).
About 75% of breast cancers express estrogen receptors (ER), a nuclear protein that functions as a ligand-dependent transcription
factor (Dunnwald et al., Breast Cancer Res, 2007). Direct treatments such as anti-estrogenic or indirect such as aromatase
inhibitors are available to treat these cancers, whether or not associated with CDK4 / 6 inhibitors.
Despite these important therapeutic advances, oncologists still face challenges such as the selection of patients for proper
maintenance treatment and early detection of relapses. Cancer progression can be detected by imaging or the appearance of clinical
symptoms, however imaging and clinical are sometimes insufficient to detect the earlier disease progression.
More recently, the interest of cfDNA (free circulating DNA) has been demonstrated in the treatment or monitoring of various solid
tumors as a surrogate marker for imaging or common nonspecific serum tumor markers. It was widely demonstrated that tumor
cells are able to release their DNA into the bloodstream or into biological fluids by mechanisms such as necrosis or apoptosis or by
the active excretion of vesicles (Thierry et al., Cancer Metastasis Rev, 2016). The presence in plasma of ctDNA (circulating tumor
DNA) has been described as of interest in assessment of minimal residual disease, efficacy of treatment, prognosis and early
detection of relapse in various solid tumors (Franczak et al., Arch Med Res, 2018).
Determining clonal heterogeneity and associated tumor evolution remains a major challenge in understanding and cancer treatment
(McGranahan et al., Cell, 2017).

Objectives and hypotheses
The main objective of the thesis will be to evaluate and validate the use of liquid biopsy as a substitute for tissue multisampling to
describe clonal heterogeneity, tumor development, response to treatment and survival in patients with hormone-dependent breast
cancer. We will also estimate the minimal residual disease in these patients using liquid biopsy.

We make the following assumptions:
- cfDNA extracted from plasma is a mirror of clonal heterogeneity
- The phylogenetic tree of the tumor can be constructed using the genomic data generated from the analysis of
cfDNA
- The clonal evolution subtype detected by analysis of cfDNA extracted from plasma is predictive of progression-free survival
- The clonal course subtype may progress over the course of the disease and may predict early resistance to treatment
- The course of the disease can be measured by determining the residual disease estimated by the liquid biopsy
- The occurrence of treatment resistance can be detected early by liquid biopsy

Positioning of the project in the context of current knowledge
Clonal heterogeneity and clonal evolution of tumors have been demonstrated using multisampling strategies tissue in various
cancers such as lung cancer (Jamal-Hanjani et al., N Engl J Med, 2017), kidney cancer (Turajlic et al., Cell, 2018) and more
recently ovarian cancer (Masoodi et al., Br J Cancer, 2020). The multisampling of tissue is difficult to transpose into routine care,
so new, less invasive strategies such as liquid biopsy are needed.
To our knowledge, there is little or no data in hormone-dependent breast cancers.
The recourse to tissue rebiopsy during the disease remains marginal given the invasive nature of the process, so liquid biopsy
monitoring should make possible the monitoring of reccurence or resistance to treatment earlier.

Expected results
- Biological data for 140 patients, showing clonal evolution during treatment.
- Detection of clones or subclones in circulating tumor DNA is expected in patients with progression tumor
- Design of phylogenetic trees of tumors of 140 patients studied in this research program
- Mathematical modeling of clonal evolution
- Determination of residual disease

Project strengths:
- This work is based on the analysis of biological samples already collected during the CICLADES study (ICL, PI promotion, Dr.
Vincent Massard).
- Collaborations between CRAN, researchers from the Elie Cartan Institute and the Nonacus company (Birmingham, UK).
- Continuity of the M2R's work which will begin in January 202
Keywords:
breast cancer, circulating tumor DNA, clonal evolution, tumor heterogeneity, residual disease
Conditions:
PhD 3 years
Thesis proposed to the 2022 CRAN doctoral candidate recruitment campaign
The internship will take place on the site Institut de Cancérologie de Lorraine (Department of Molecular Biology of Tumors) of
CRAN
Remuneration according to standard grids
Expected profile: Highly motivated student having validated his/her M2R with a research profile oriented towards oncology and with
strong experience in molecular biology of tumors.
Department(s): 
Biology, Signals and Systems in Cancer and Neuroscience
Funds:
Thesis proposed to the 2022 CRAN doctoral candidate recruitment campaign