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J Clin Oncol. 2016 Jun 10;34(17):1987-94. doi: 10.1200/JCO.2015.63.9179. Epub 2016 Mar 14.

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.

Author information

1
Peter Schmid, Alice Shia, Shah-Jalal Sarker, and Louise Lim, Queen Mary University London; Sarah E. Pinder, Patrycja Gazinska, Natalie Woodman, Peter Parker, and Arnie Purushotham, Kings College London; Robert Price, Kings College Hospital; Jennifer Hu, Barts Health National Health Service (NHS) Trust, London; Duncan Wheatley, Royal Cornwall Hospital, Truro; Jane Macaskill, Ninewells Hospital Dundee, Dundee; Charles Zammit, Hannah Butler, and Gemma Earl, Brighton & Sussex University Hospitals NHS Trust, Brighton; Nigel Bundred, University Hospital of South Manchester, Manchester; Sirwan Hadad, Royal Hallamshire Sheffield, Sheffield; Darren Korbie and Matt Trau, Australian Institute for Bioengineering and Nanotechnology, and Matt Trau, University of Queensland; Paul Mainwaring, Mater Research Centre; Brisbane, Australia; Steven Gendreau, Mark R. Lackner, Mika Derynck, and Timothy R. Wilson, Genentech, South San Francisco, CA; and Alastair Thompson, MD Anderson Cancer Centre, Houston, TX. p.schmid@qmul.ac.uk.
2
Peter Schmid, Alice Shia, Shah-Jalal Sarker, and Louise Lim, Queen Mary University London; Sarah E. Pinder, Patrycja Gazinska, Natalie Woodman, Peter Parker, and Arnie Purushotham, Kings College London; Robert Price, Kings College Hospital; Jennifer Hu, Barts Health National Health Service (NHS) Trust, London; Duncan Wheatley, Royal Cornwall Hospital, Truro; Jane Macaskill, Ninewells Hospital Dundee, Dundee; Charles Zammit, Hannah Butler, and Gemma Earl, Brighton & Sussex University Hospitals NHS Trust, Brighton; Nigel Bundred, University Hospital of South Manchester, Manchester; Sirwan Hadad, Royal Hallamshire Sheffield, Sheffield; Darren Korbie and Matt Trau, Australian Institute for Bioengineering and Nanotechnology, and Matt Trau, University of Queensland; Paul Mainwaring, Mater Research Centre; Brisbane, Australia; Steven Gendreau, Mark R. Lackner, Mika Derynck, and Timothy R. Wilson, Genentech, South San Francisco, CA; and Alastair Thompson, MD Anderson Cancer Centre, Houston, TX.

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.

PMID:
26976426
PMCID:
PMC6075966
DOI:
10.1200/JCO.2015.63.9179
[Indexed for MEDLINE]
Free PMC Article

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