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Phase II Randomized Preoperative Window-of-Opportunity Study of the PI3K Inhibitor Pictilisib Plus Anastrozole
Peter Schmid1, Sarah E Pinder2, Duncan Wheatley2
1Peter 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.
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.
Insights
Adding pictilisib to anastrozole significantly enhances antitumor effects in estrogen receptor-positive breast cancer, particularly in luminal B subtypes. This combination therapy shows promise for overcoming endocrine resistance.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Preclinical studies indicate the PI3K pathway is crucial in estrogen receptor-positive breast cancer.
- Combining PI3K inhibitors with endocrine therapy may overcome treatment resistance.
- This study investigates the efficacy of pictilisib combined with anastrozole in primary breast cancer.
Purpose of the Study:
- To assess if adding the PI3K inhibitor pictilisib to anastrozole enhances antitumor effects in primary breast cancer.
- To identify patient populations most likely to benefit from this combination therapy.
- To evaluate the impact on tumor cell proliferation via Ki-67 suppression.
Main Methods:
- A randomized, open-label phase II trial involving postmenopausal women with operable ER+/HER2- breast cancer.
- Participants received either anastrozole alone or anastrozole plus pictilisib for two weeks preoperatively.
- Primary endpoint: change in Ki-67 protein expression as a measure of tumor cell proliferation.
Main Results:
- The combination of anastrozole and pictilisib demonstrated significantly greater Ki-67 suppression (83.8%) compared to anastrozole alone (66.0%).
- PIK3CA mutations did not predict response, but a significant interaction was observed with molecular subtype.
- Luminal B tumors showed significant Ki-67 suppression with the combination (geometric mean ratio 0.37), unlike luminal A tumors.
Conclusions:
- Adding pictilisib to anastrozole significantly increases tumor cell proliferation suppression in luminal B primary breast cancer.
- The combination therapy is effective in luminal B breast cancer, irrespective of progesterone receptor status or baseline Ki-67.
- This combination warrants further investigation for treating specific subtypes of estrogen receptor-positive breast cancer.
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