Overcoming endocrine resistance in neoadjuvant endocrine therapy for early breast cancer

Mené sur 334 patientes atteintes d'un cancer du sein de stade précoce ER+ HER2- après la ménopause, cet essai de phase II évalue l'efficacité, du point de vue de la proportion de patientes obtenant une réponse objective et une réponse pathologique complète au niveau du sein et de l'aisselle au moment du traitement chirurgical, et la toxicité de l'ajout du tasélisib au létrozole dispensé en traitement néoadjuvant (durée médiane de suivi : 4,9 mois)

Résumé en anglais

Endocrine therapy is the mainstay of treatment for oestrogen receptor-positive breast cancer, now classified as either the luminal A (HER2-negative with low levels of Ki67) or luminal B (HER2 positive or negative, with high levels of Ki67) phenotype. Historically, endocrine therapy has included the approach of targeting the oestrogen receptor itself, either by means of selective oestrogen receptor modulators such as tamoxifen, or fulvestrant, a selective oestrogen receptor degrader. Another mode of action is the inhibition of oestrogen production so that no ligand is available to activate the receptor. This is the mode of action of aromatase inhibitors, which block the aromatase enzyme and lower oestrogen levels in postmenopausal women; whereas in premenopausal women, luteinising hormone-releasing hormone agonists reduce oestrogen production in the ovaries by interacting via the regulatory axis from the pituitary gland to the ovary. Since the 1990s, data have suggested that aromatase inhibitors might be the optimal neoadjuvant endocrine therapy treatment approach in postmenopausal women with breast cancer, resulting in better overall responses, improved pathological complete responses, and increased breast conservation at surgery. More empirically, a 3-month period for neoadjuvant endocrine therapy was introduced as the standard of care in postmenopausal women with breast cancer in the mid-1990s. However, compared with neoadjuvant chemotherapy, neoadjuvant endocrine therapy has always yielded inferior results in terms of pathological complete responses. Once introduced in the metastatic breast cancer setting, combinations of endocrine therapy plus mTOR inhibitors or CDK4/6 inhibitors instantly changed the standard treatment approach. However, resistance and disease progression while on treatment have occurred in both the adjuvant and metastatic settings.