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Impact of reproductive history and pregnancy on breast cancer biology

par Nguyen, Bastien
Président du jury Casimir, Georges
Promoteur Sotiriou, Christos
Publication Non publié, 2018-11-15

Thèse de doctorat

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Résumé :

It is estimated that four in five women will give birth while one in eight women will be diagnosed with breast cancer at some point in her lifetime. It is also known that pregnancy at a young age is associated with a marked decrease in the risk of breast cancer and that this protection is different according to breast cancer subtypes. This thesis explores the impact of reproductive history on breast cancer biology and provides the molecular characterization of breast cancer diagnosed during pregnancy. The last part investigates the effect of RANKL inhibition on the biology of breast cancer in young women. In the first study, we investigated the impact of parity and age at first pregnancy on the clinicopathological features, the genomic and transcriptomic landscape, and the immune microenvironment of 313 breast cancers. For the first time, we highlighted a link between reproductive history and the genomic landscape of subsequent breast cancer. We demonstrated that, independently of clinicopathological features, age at first birth is associated with specific genomic alterations that could explain the differences in risk reduction associated with pregnancy according to breast cancer subtypes. This study represents a first step toward the recognition that reproductive factors matter in order to fully understand breast cancer biology and advocates that reproductive history should be routinely collected in future studies addressing the biology of breast cancer but also of other female cancers. The second study is focused on the molecular characterization of breast cancer diagnosed during pregnancy (BCP). We conducted a comparative analysis of a unique cohort of BCP patients and non-pregnant control patients by integrating gene expression, copy number alterations, and whole-genome sequencing data. We showed that BCP has unique molecular characteristics including an enrichment of non-silent mutations, a higher frequency of mutations in mucin gene family and an enrichment of mismatch repair deficiency mutational signature. This provides important insights into the biology of BCP and suggests that these features may be implicated in promoting tumor progression during pregnancy. In addition, it provides an unprecedented resource for further understanding of the biology of breast cancer in young women and how pregnancy could modulate tumor biology. In a previous study, the laboratory had reported up-regulation of RANKL in young and pregnant breast cancer patients. Therefore, in the last chapter, we investigated the biological effect of denosumab, a RANKL inhibitor, in a preoperative study including 27 young primary breast cancer patients. We demonstrated evidence that denosumab induces modulation of the tumor immune microenvironment with an increased level of tumor-infiltrating lymphocytes. This effect was likely due to upregulation of inflammatory cytokines and depletion of immunosuppressive regulatory T cells within the tumor microenvironment. These findings suggest a role for denosumab in reshaping the tumor immune microenvironment of breast cancer and that its use in combination could improve immunotherapy efficacy.