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

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.

Fig 1.

Trial CONSORT diagram. AE, adverse event; HER2, human epidermal growth factor receptor 2.

Fig 2.

Individual Ki-67 changes from baseline to day 15. (A) Individual changes in percentage Ki-67 expression from baseline to day 15; the number and percentage of patients achieving an end-of-treatment (EOT) Ki-67 score of > 10% or ≤ 10% are provided for each group. (B) Individual relative Ki-67 suppression sorted from low to high; relative Ki-67 suppression is defined as Ln(Ki-67_{day 15}) – Ln(Ki-67_baseline); results are displayed on their original scale by back transformation. Individual PTEN status, PIK3CA status, progesterone receptor (PgR) status, luminal A/B status, tumor grade, baseline and EOT Ki-67 expression are indicated by colored boxes under each patient. IHC, immunohistochemistry; mut, mutant; Wt, wild-type.

Fig 3.

Antiproliferative response to study treatment. (A) Antiproliferative response expressed as the geometric mean Ki-67 suppression from baseline to day 15. (B) Antiproliferative response by luminal subtype. (C) Antiproliferative response by PIK3CA mutation status; e9: exon 9 domain mutations (helical domain); e20: exon 20 domain mutations (kinase domain). (D) Antiproliferative response at day 15 compared with baseline. The cumulative proportion (by percentage) of patients who had tumors with percentage positive Ki-67 (expressed as the natural logarithm) less than the value on the x-axis is illustrated at baseline and at day 15 for each treatment arm. Error bars indicate 95% CI. wt, wild-type.

Fig 4.

Ratio (combination:ANA) of geometric mean of Ki-67 proportional changes in prespecified subgroups. Pgr, progesterone; WT, wild type.