Abstract S2-03: Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study)
Authors: Schmid Peter , Pinder Sarah E , Wheatley Duncan , Macaskill Jane , Zammit Charles , Hu Jennifer , Price Robert , Bundred Nigel , Hadad Sirwan , Shia Alice , Lim Louise , Sarker Shah-Jalal , Gazinska Patrycja , Woodman Natalie , Korbie Darren , Trau Matt , Mainwaring Paul , Parker Peter , Purushotham Arnie , Thompson Alastair M 
Published: May 2015

Abstract
Background: Preclinical and clinical data support a key role for the PI3K pathway in resistance to endocrine therapy in patients with ER+ breast cancer and suggest that combining PI3K inhibitors with endocrine therapy may overcome resistance. Short-term preoperative window of opportunity (WOO) studies are a validated strategy for novel treatments to provide proof-of-concept and define the most appropriate patient population by directly assessing treatment effects in tumour tissue before and after treatment. This is the first WOO study with the PI3K inhibitor pictilisib (GDC-0941) in combination with anastrozole (ANA).
Methods: 73 postmenopausal patients (pts) have been randomized (2:1 in favour of the combination) to receive 2-week preoperative treatment with ANA plus pictilisib (n=50, "ANA+PIC" arm) or ANA alone (n=23, "ANA" arm). Pts had newly diagnosed, operable, ER+, HER2-negative breast cancer of ≥1 cm size. Pts receiving HRT were excluded. Treatment effects and correlative studies were assessed using FFPE and frozen tumour biopsies taken before and after 14 days of study treatment.
The primary endpoint was inhibition of tumour-cell proliferation, as measured by change in Ki67 expression, determined centrally by 2 investigators. Secondary endpoints include induction of apoptosis (Caspase3) and safety. Comprehensive biomarkers analyses include targeted NGS of a comprehensive cancer panel of &gt;400 genes, copy number analyses, and pre- and post-treatment reverse-phase protein arrays (RPPA) and RNA profiling.
Results: Baseline (BL) disease characteristics were similar between both study arms. PAM50 analysis showed that 53% and 47% of tumors were Luminal (Lum) A and B, respectively. 65% of tumors had &gt;14% Ki67-positive cells. Observed treatment-emergent AEs were consistent with those previously described for single-agent pictilisib and anastrozole.
Mean post-treatment percentage reduction of Ki67 was 84% (95% CI, 75%-89%) for ANA+PIC and 72% (54%-87%) for ANA. Ki67-response (≥50% drop in % of Ki67+ cells) was 86% for ANA+PIC and 60% for ANA. By using the definition that pts with a natural logarithm of %Ki67+ cells of ≤1 or 1-2 have a day 15 anti-proliferative response, 93% [ln(ki67): &lt;1, 46%; 1-2, 46%] of ANA+PIC were responders compared with 60% [&lt;1, 47%; 1-2, 13%] of ANA-treated pts (p = 0.01).
Preplanned subgroup analyses showed a significant interaction of response to ANA+PIC with molecular subtype and Ki67 levels. Patients with LumB tumors or high BL Ki67 (&gt;14%) had a higher Ki67 response with ANA+PIC compared to ANA (LumB, 83% vs 38%; Ki67&gt;14%, 94% vs 55%), whereas Ki67 response was similar for both treatments for LumA tumors (ANA, 75%; ANA+PIC, 73%) or tumors with low BL Ki67. Mean post-treatment % reduction of Ki67 in LumB tumors was 87% (95% CI, 49%-96%) for ANA+PIC and 56% (16%-77%) for ANA (p=0.03).
Additional data on apoptosis and comprehensive pre- and post-treatment biomarkers analyses will be presented.
Conclusions: This first report of a preoperative WOO study evaluating a PI3K inhibitor in early breast cancer demonstrated addition of pictilisib to ANA was associated with increased anti-proliferative response over single-agent ANA.
Citation Format: Peter Schmid, Sarah E Pinder, Duncan Wheatley, Jane Macaskill, Charles Zammit, Jennifer Hu, Robert Price, Nigel Bundred, Sirwan Hadad, Alice Shia, Louise Lim, Shah-Jalal Sarker, Patrycja Gazinska, Natalie Woodman, Darren Korbie, Matt Trau, Paul Mainwaring, Peter Parker, Arnie Purushotham, Alastair M Thompson. Preoperative window of opportunity study of the PI3K inhibitor pictilisib (GDC-0941) plus anastrozole vs anastrozole alone in patients with ER+, HER2-negative operable breast cancer (OPPORTUNE study) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S2-03.