Abstract P4-15-06: Results of a randomized double blind trial of neoadjuvant anastrozole plus placebo vs anastrozole plus saracatinib for ER+ postmenopausal breast cancer
Authors: Slingerland JM , Mark P , Hurley J , Net J , Collado-Mesa F , Lippman M , Avisar E , Yepes M , Jorda M , Gomez C 
Published: May 2019

Abstract
Antiestrogen mediated cell cycle arrest requires the CDK inhibitor, p27. Src kinase mediates p27 loss and antiestrogen resistance in ER+ breast cancer lines in vitro. In ER+ xenografts, the Src inhibitor, saracatinib, restored antiestrogen responses in resistant tumors. This led to a Phase I/randomized double-blind Phase II trial to test effects of saracatinib with anastrozole for ER+ and/or PR+ postmenopausal breast cancer.
Phase I accrued 12 subjects and showed 175 mg po saracatinib is safely given with 1 mg po daily anastrozole with good PK . In Phase II, postmenopausal women with new ER+ and/or PR+, HER2- breast cancers ≥ 2 cm were randomized 2:1 to either neoadjuvant anastrozole with saracatinib or anastrozole/placebo over 6 months. Response was assayed by clinical 2D measurements each cycle and by MRI pre-study, at 10 weeks and prior to surgery. The Phase II primary endpoint was to test if tumor volume decrease (from 2D clinical measures) with dual therapy (dual) exceeded that of monotherapy (mono) by &gt;20%. Secondary endpoints included tumor response by 3D MRI measures and by RECIST, PK and toxicity, and molecular predictors of drug efficacy in pre-/ post-therapy tumors. Of 58 subjects, 15% were Black, 5% Asian and 79% White. 61% were Hispanic. Dual therapy was well tolerated, with the following grade 1 toxicities: flu-like syndrome 20%, non-pruritic rash 48% (17% for mono), self-limited diarrhea in 55% (33% mono). Transaminasemia with dual therapy was 52.5% and 17% with mono. 6/59 stopped dual due to drug related AEs: 2 had gr 3 hepatitis, one gr 3 anemia, 3 had grade 3 urticarial rash. Dual Rx increased mean anastrozole levels to 50 ng/ml vs 38 ng/ml for mono (T test p= 5.45201 E-05). Mean saracatinib level, 269 ng/ml, was similar to prior studies. All of 50 evaluable subjects showed clinical and MRI tumor responses. 17% in both groups progressed, usually after 16 weeks. Mean tumor vol (calculated from 2D clinic measures) declined more rapidly (by 63% in dual vs 55% in mono at 8 weeks), but both groups showed an 89% mean tumor volume decrease by 20 weeks. Clinical RECIST showed size reductions of 61% in dual and 62% after monotherapy. Tumor volumes based on 3D MRI show a non-significant trend to greater response to dual therapy, with mean volume decreased by 64% vs 45% at the end of dual vs monotherapy. RECIST response by MRI also showed a trend to greater % decrease tumor size post treatment by 34% vs 25% in dual vs mono. Thus, clinical volumetric assessment of response to this neoadjuvant endocrine therapy may overestimate response compared to volumes calculated by MRI, while RECIST may underestimate it. Pathologic responses based on initial and residual tumor burden calculated from initial and final tumor volumes and % cellularity in biopsy and surgical specimens will be presented.
Citation Format: Slingerland JM, Mark P, Hurley J, Net J, Collado-Mesa F, Lippman M, Avisar E, Yepes M, Jorda M, Gomez C. Results of a randomized double blind trial of neoadjuvant anastrozole plus placebo vs anastrozole plus saracatinib for ER+ postmenopausal breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-15-06.