Trainee Project
Liquid biopsy for evaluation of clonal heterogeneity and tumor development in patients with hormone-dependent breast cancer treated with anti-CDK4 / 6
2022/01/03 - 2022/07/01

The estrogen-dependent nature of breast cancer was first described in 1896 with the publication of George Beatson's observations
of breast cancer regression 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 antiestrogens or indirect treatments such as aromatase
inhibitors are available to treat these cancers, associated or not with CDK4 / 6 inhibitors.
Despite these important therapeutic advances, oncologists still face challenges such as selecting patients for the right maintenance
treatment and early detection of relapses. Cancer progression can be detected by imaging or by the appearance of clinical
symptoms, however imaging and clinical findings are sometimes insufficient to detect disease early 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 for common nonspecific serum tumor markers. It has been widely demonstrated that
tumor cells are capable of releasing 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 the evaluation of residual disease, treatment efficacy, 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 treating cancer
(McGranahan et al., Cell, 2017).

The main objective of the CICLADES-CE study is to assess the feasibility of using liquid biopsy as a substitute for tissue
multisampling to describe clonal heterogeneity and tumor evolution in patients with a hormone-dependent breast cancer.

We make the following assumptions:
- cfDNA extracted from plasma is the mirror of clonal heterogeneity
- The phylogenetic tree of the tumor can be built 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

Positioning of the project in the context of current knowledge
Clonal heterogeneity and clonal evolution of tumors have been demonstrated using tissue multisampling strategies in different
cancers such as lung cancer (Jamal-Hanjani et al., N Engl J Med, 2017), the kidney cancer (Turajlic et al., Cell, 2018) and more
recently ovarian cancer (Masoodi et al., Br J Cancer, 2020). Multisampling of tissues is difficult to transpose into routine care, and
less invasive strategies such as liquid biopsy need to be evaluated. To our knowledge, there is little or no data in hormone-
dependent breast cancers.

Expected results
- Biological data for 20 patients, showing clonal evolution during treatment.
- Detection of clones or subclones in circulating tumor DNA is expected in patients with tumor progression
- Design of phylogenetic trees of the tumors of the 20 patients studied in this research program
breast cancer, circulating tumor DNA, clonal evolution, tumor heterogeneity
Biology, Signals and Systems in Cancer and Neuroscience