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

Peter Schmid (Lead / Corresponding author), Sarah E. Pinder, Duncan Wheatley, Jane Macaskill, Charles Zammit, Jennifer Hu, Robert Price, Nigel Bundred, Sirwan Hadad, Alice Shia, Shah Jalal Sarker, Louise Lim, Patrycja Gazinska, Natalie Woodman, Darren Korbie, Matt Trau, Paul Mainwaring, Steven Gendreau, Mark R. Lackner, Mika DerynckTimothy R. Wilson, Hannah Butler, Gemma Earl, Peter Parker, Arnie Purushotham, Alastair Thompson

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Abstract

Purpose: Preclinical data support a key role for the PI3K pathway in estrogen receptor-positive breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. This preoperative window study assessed whether adding the PI3K inhibitor pictilisib (GDC-0941) can increase the antitumor effects of anastrozole in primary breast cancer and aimed to identify the most appropriate patient population for combination therapy. Patients and Methods: In this randomized, open-label phase II trial, postmenopausal women with newly diagnosed operable estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers were recruited. Participants were randomly allocated (2:1, favoring the combination) to 2 weeks of preoperative treatment with anastrozole 1 mg once per day (n = 26) or the combination of anastrozole 1 mg with pictilisib 260 mg once per day (n = 49). The primary end point was inhibition of tumor cell proliferation as measured by change in Ki-67 protein expression between tumor samples taken before and at the end of treatment. 

Results: There was significantly greater geometric mean Ki-67 suppression of 83.8% (one-sided 95% CI, ≥ 79.0%) for the combination and 66.0% (95% CI, ≤ 75.4%) for anastrozole (geometric mean ratio [combination: anastrozole], 0.48; 95% CI, ≤ 0.72; P = .004). PIK3CA mutations were not predictive of response to pictilisib, but there was significant interaction between response to treatment and molecular subtype (P =.03);for patients with luminal B tumors, the combination:anastrozole geometric mean ratio of Ki-67 suppression was 0.37 (95% CI, ≤ 0.67; P = .008), whereas no significant Ki-67 response was observed for pictilisib in luminal A tumors (1.01; P = .98). Multivariable analysis confirmed Ki-67 response to the combination treatment of patients with luminal B tumors irrespective of progesterone receptor status or baseline Ki-67 expression. Conclusion: Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer.

Original languageEnglish
Pages (from-to)1987-1994
Number of pages8
JournalJournal of Clinical Oncology
Volume34
Issue number17
Early online date14 Mar 2016
DOIs
Publication statusPublished - 10 Jun 2016

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    Schmid, P., Pinder, S. E., Wheatley, D., Macaskill, J., Zammit, C., Hu, J., Price, R., Bundred, N., Hadad, S., Shia, A., Sarker, S. J., Lim, L., Gazinska, P., Woodman, N., Korbie, D., Trau, M., Mainwaring, P., Gendreau, S., Lackner, M. R., ... Thompson, A. (2016). 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. Journal of Clinical Oncology, 34(17), 1987-1994. https://doi.org/10.1200/JCO.2015.63.9179