ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the efficacy of CDK4/6 inhibitors and develop a gene expression signature of CDK4/6 inhibition. CDK4/6 inhibition robustly suppressed cell cycle progression of ER+/HER2- models and complements the activity of limiting estrogen. Chronic treatment with CDK4/6 inhibitors results in the consistent suppression of genes involved in cell cycle, while eliciting the induction of a comparable number of genes involved in multiple processes. The CDK4/6 inhibitor treatment shifted ER+/HER2- models from a high risk (luminal B) to a low risk (luminal A) molecular-phenotype using established gene expression panels. Consonantly, genes repressed by CDK4/6 inhibition are strongly associated with clinical prognosis in ER+/HER2- cases. This gene repression program was conserved in an aggressive triple negative breast cancer xenograft, indicating that this is a common feature of CDK4/6 inhibition. Interestingly, the genes upregulated as a consequence of CDK4/6 inhibition were more variable, but associated with improved outcome in ER+/HER2- clinical cases, indicating dual and heretofore unknown consequence of CDK4/6 inhibition. Interestingly, CDK4/6 inhibition was also associated with the induction of a collection of genes associated with cell growth; but unlike suppression of cell cycle genes this signaling was antagonized by endocrine therapy. Consistent with the stimulation of a mitogenic pathway, cell size and metabolism were induced with CDK4/6 inhibition but ameliorated with endocrine therapy. Together, the data herein support the basis for profound interaction between CDK4/6 inhibitors and endocrine therapy by cooperating for the suppression of cell cycle progression and limiting compensatory pro-growth processes that could contribute to therapeutic failure.

Le traitement systémique adjuvant du cancer du sein infiltrant repose sur la chimiothérapie et l’hormonothérapie. Certains facteurs sont connus pour être pronostiques (âge, taille tumorale, statut ganglionnaire, grade tumoral, emboles vasculaires, statut des récepteurs hormonaux (RH) et de HER2) ou prédictifs de réponse aux traitements (RH et HER2) et influent sur nos décisions thérapeutiques. Cependant, certaines patientes récidivent malgré un traitement complet alors que d’autres vont recevoir un traitement qui aurait pu être évité de par leur bon pronostic « intrinsèque ». Nous avons cherché à identifier dans ce travail d’autres facteurs pronostiques et / ou prédictifs dans le cancer du sein infiltrant en situation néoadjuvante / adjuvante. Premièrement, nous montrons que le type histologique lobulaire, réputé pour être une histologie de cancer du sein de bon pronostic et peu chimiosensible, ne doit pas être un facteur décisionnel quant aux traitements systémiques. En situation adjuvante et concernant la chimiothérapie, la validité et l’utilité cliniques des tests génomiques nécessitent d’être évaluées spécifiquement dans ce sous-groupe. Ensuite, nous avons étudié la validité analytique, la validité clinique et l’utilité clinique de 2 classifications moléculaires des cancers du sein selon PAM50 et l’analyse immunohistochimique de biomarqueurs : récepteur œstrogène, HER2 et Ki67 avec un cut-off à 14%. Selon nos conclusions, il n’y a actuellement pas de données suffisamment robustes pour que ces 2 classifications modifient les décisions de traitement systémique. Nous avons mis en évidence un sous-groupe de tumeurs triples négatives exprimant le récepteur androgène et FOXA1 et se comportant comme des tumeurs luminales. Enfin, nous avons montré sur une large série néoadjuvante que la réponse histologique complète est un critère substitutif de survie pour les tumeurs RH négatifs / The adjuvant systemic treatment of invasive breast cancer is based on chemotherapy and endocrine therapy. Several prognostic factors (age, tumoral size, nodal status, tumoral grade, vascular embols, hormonal receptors (HR), HER2) and predictive factors of response to treatment (HR and HER2) are described and have an impact on our therapeutic decisions. However, recurrences are frequent after a complete treatment and patients could avoid such treatment because of the good “intrinsic” prognosis. In this work, we aimed to identify other prognostic and / or predictive factors for the invasive breast cancer in the neoadjuvant / adjuvant settings. Firstly, we showed that the lobular histology, considered as histology of good prognosis and low chemo sensitive, should not be a decisive factor regarding systemic therapy. In the adjuvant setting, regarding chemotherapy, clinical validity and utility of the genomic tests need to be specifically evaluated in this subgroup. Then, we studied analytical validity, clinical validity and clinical utility of 2 molecular classification of breast cancer: PAM50 and a panel of 3 biomarkers in immunohistochemistry (estrogen receptor, HER2 and Ki-67 with a cut-off of 14%). We concluded that the data were not strong enough and that the therapeutic decisions should not be influenced by these classifications. We identified a subgroup of triple negative breast cancer that express androgen receptor and FOXA1 and which behave like luminal tumors. At last, we showed in a large neoadjuvant population, that the pathological complete response is a surrogate marker of survival in RH negative tumors