Abstract P3-13-04: Change in oncotype DX variables and Ki67 response and outcome in women with ER positive early breast cancer treated with neo-adjuvant anastrozole and fulvestrant
Authors: Khan QJ , Fabian CJ , Kimler BF , O'Dea AP , Mamen J , Amin A , Wagner J , Springer M , Baccaray S , Sharma P 
Published: February 2018

Abstract
Neo-adjuvant endocrine therapy (NAET) provides opportunity for on-treatment assessment of endocrine responsiveness and need for adjuvant chemotherapy (C) in ER+/HER2 negative breast cancer (BC). We investigated Ki67-IHC response to NAET, the 21-gene Recurrence Score (RS; Oncotype DX), and Postoperative Endocrine Prognostic Index (PEPI) as predictors of response and recurrence in a neoadjuvant trial of fulvestrant (F) + anastrozole (A). The combination had been shown to improve survival compared to A alone in ER+ metastatic breast cancer.
Design: Single arm phase II trial of postmenopausal women with clinical stage II/III ER+/HER2 negative BC and RS &lt;25. Following initial biopsy (CNB) women received NAET for 4 months: A 1mg (PO) daily continuously from day 1 until surgery + F 500mg IM on day 1, 14 and 28 of cycle 1, and on the last day of 3 subsequent 28 day cycles (total 6 doses of F) followed by surgery. Ki67-IHC and RS (weighted heavily by gene expression of ESR1, HER-2, Ki67, and PR) were assessed at baseline and at surgical resection (3-4 weeks after last F). Chemotherapy was allowed at physician discretion and recommended for PEPI&gt;0. All patients received adjuvant A.
Results: 51 patients were screened and RS was performed on initial CNB with a success rate of 96%. 7 were not eligible due to RS&gt;25. 42 patients were enrolled. 18 (49%) had PEPI score of 0 at surgery. Median RS was 12 at baseline and 17 at surgery for the 36 patients with evaluable tissue at both time points. 28/36 (78%) patients had numeric increase in RS at surgery and 5/36 had RS &gt; 25 at surgery. Increase in RS is likely driven by decrease in ESR1 gene expression (p=0.063). Median RS at surgery but not at baseline was associated with PEPI score of 0 (p=0.02). Ki67 gene expression at surgery was lower in patients with PEPI 0 (p=.003) whereas ESR1 expression was higher (p=.024). Median Ki67-IHC was 5% (mean 7.6%) at baseline and 1% (mean 2.8%) at surgery for the 37 patients with evaluable tissue at both time points. 35 of these 37 (94%) had decrease in Ki67-IHC from baseline to surgery; only 2/37 had an increase in Ki67-IHC at surgery. 22% of women received adjuvant chemotherapy. At median follow up of 61 months, only 3/42 patients have had a recurrence: the two patients with an increase in Ki67-IHC from baseline to surgery had a recurrence; plus a third who was taken off trial during therapy due to clinical progression and received C prior to surgery.
Conclusions: 4 months of neo-adjuvant anastrozole + fulvestrant results in decrease in Ki67-IHC in 94% of women with stage II/III ER+ HER2 negative breast cancer. No patients with decrease in Ki67-IHC at surgery have had a breast cancer recurrence. The majority of patients treated with this regimen do not need chemotherapy. A small number of patients with on-therapy increase in Ki67-IHC are at high risk of recurrence. Oncotype DX RS and expression of some of the component genes (ESR1 and Ki67) change with NAET. Expression of ESR1 and Ki67 genes at surgery after NAET is associated with PEPI score of 0 and should be explored as potential response biomarkers in NAET trials.
Citation Format: Khan QJ, Fabian CJ, Kimler BF, O'Dea AP, Mamen J, Amin A, Wagner J, Springer M, Baccaray S, Sharma P. Change in oncotype DX variables and Ki67 response and outcome in women with ER positive early breast cancer treated with neo-adjuvant anastrozole and fulvestrant [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-13-04.