Pictilisib Plus Anastrozole Reduces Proliferation in ER⁺ Breast Cancer

PI3K–mTOR pathway genes are commonly mutated in estrogen receptor (ER)–positive breast cancer, and preclinical and clinical data have indicated that PI3K–mTOR pathway inhibition may enhance endocrine therapy, prompting Schmid and colleagues to perform a phase II preoperative window-of-opportunity study investigating the effects of the PI3K inhibitor pictilisib in combination with the aromatase inhibitor anastrozole on tumor cell proliferation. This study randomly assigned 75 postmenopausal women with newly diagnosed operable ER⁺, HER2⁻ breast cancer to receive anastrozole alone (26 patients) or anastrozole plus pictilisib (49 patients). Treatment was given for 14 days prior to surgical resection and adjuvant therapy. At least two tumor biopsies were taken at baseline and at the end of treatment, and used for immunohistochemistry. The primary end point was inhibition of tumor cell proliferation measured by change in Ki67 staining before and after treatment. Ki67 staining decreased in all but 3 patients, and the group receiving pictilisib and anastrozole had a greater mean suppression (83.8%) than the group receiving anastrozole alone (66.0%). Subanalysis of the molecular subtypes revealed that anastrozole plus pictilisib reduced luminal B tumor proliferation, whereas there was no effect on luminal A tumor proliferation. There were no significant correlations observed between PI3K mutation status and pictilisib response. Treatment-related adverse events for pictilisib and anastrozole were consistent with previous studies, with the anastrozole plus pictilisib group having more adverse events than the anastrozole-alone group, including fatigue, rash, nausea, and diarrhea. All adverse events were rapidly reversible, and reducing the dose of pictilisib reduced skin toxicity. The results of this phase II trial indicate that the addition of pictilisib to preoperative anastrozole hormone therapy reduces tumor proliferation in patients with luminal B breast cancer, but further insight is needed to understand why the effects were independent of PI3K mutation status and specific to luminal B subtype tumors.

Schmid P, Pinder SE, Wheatley D, Macaskill J, Zammit C, Hu J, et al. Phase II randomized preoperative window-of-opportunity study of the PI3K inhibitor pictilisib plus anastrozole compared with anastrozole alone in patients with estrogen receptor–positive breast cancer. J Clin Oncol 2016 Mar 14 [Epub ahead of print].

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