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

• Published in: Journal of clinical oncology Vol. 34; no. 17; pp. 1987 - 1994
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States American Society of Clinical Oncology 10.06.2016
• Subjects: Aged; Aged, 80 and over; Anastrozole; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - surgery; Combined Modality Therapy; Drug Synergism; Female; Humans; Indazoles - administration & dosage; Middle Aged; Neoplasms, Hormone-Dependent - drug therapy; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - surgery; Nitriles - administration & dosage; Nitriles - therapeutic use; ORIGINAL REPORTS; Phosphoinositide-3 Kinase Inhibitors; Postmenopause; Preoperative Care - methods; Protein Kinase Inhibitors - administration & dosage; Receptor, ErbB-2 - biosynthesis; Receptors, Estrogen - biosynthesis; Sulfonamides - administration & dosage; Triazoles - administration & dosage; Triazoles - therapeutic use
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2015.63.9179

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. 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. 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. Adding pictilisib to anastrozole significantly increases suppression of tumor cell proliferation in luminal B primary breast cancer.