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

Schmid, Peter, Pinder, Sarah E., Wheatley, Duncan, Macaskill, Jane, Zammit, Charles, Hu, Jennifer, Price, Robert, Bundred, Nigel, Hadad, Sirwan, Shia, Alice, Sarker, Shah-Jalal, Lim, Louise, Gazinska, Patrycja, Woodman, Natalie, Korbie, Darren, Trau, Matt, Mainwaring, Paul, Gendreau, Steven, Lackner, Mark R., Derynck, Mika, Wilson, Timothy R., Butler, Hannah, Earl, Gemma, Parker, Peter, Purushotham, Arnie and Thompson, Alastair (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. doi:10.1200/JCO.2015.63.9179

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Author Schmid, Peter
Pinder, Sarah E.
Wheatley, Duncan
Macaskill, Jane
Zammit, Charles
Hu, Jennifer
Price, Robert
Bundred, Nigel
Hadad, Sirwan
Shia, Alice
Sarker, Shah-Jalal
Lim, Louise
Gazinska, Patrycja
Woodman, Natalie
Korbie, Darren
Trau, Matt
Mainwaring, Paul
Gendreau, Steven
Lackner, Mark R.
Derynck, Mika
Wilson, Timothy R.
Butler, Hannah
Earl, Gemma
Parker, Peter
Purushotham, Arnie
Thompson, Alastair
Title 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 name Journal of Clinical Oncology   Check publisher's open access policy
ISSN 1527-7755
0732-183X
Publication date 2016-06-10
Year available 2016
Sub-type Article (original research)
DOI 10.1200/JCO.2015.63.9179
Open Access Status File (Publisher version)
Volume 34
Issue 17
Start page 1987
End page 1994
Total pages 8
Place of publication Alexandria, VA, United States
Publisher American Society of Clinical Oncology
Language eng
Subject 2730 Oncology
1306 Cancer Research
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.
Formatted 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.
Keyword PI3K pathway
Estrogen receptor–positive breast cancer
Primary breast cancer
Combination therapy
Endocrine therapy
PI3K inhibitors
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID CG-12-07
Institutional Status UQ

 
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