Abstract 3514: A dose-escalation study of anastrozole and everolimus in patients with advanced gynecologic and breast malignancies: tolerance, biological activity, and molecular alterations in the PI3K/AKT/mTOR pathway

Background Combining aromatase inhibitors with PI3K/AKT/mTOR inhibitors is synergistic and may overcome hormone resistance. Patients and Methods We evaluated anastrozole and everolimus in patients with metastatic estrogen receptor (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates. Results Fifty-five patients were enrolled. Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Fifty patients were evaluable for response with a median age of 57 (range: 24-82) and a median number of prior therapies of 3 (range: 0-13). Twelve of 50 patients (24%) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR), including 9 of 32 patients (28%) with breast cancer, 2 of 9 patients (22%) with ovarian cancer and 1 of 6 patients (17%) with uterine cancer. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway including mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All 3 patients who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. Conclusion Combination anastrozole and everolimus is well tolerated at full approved doses and active in heavily pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Patients with SD ≥ 6 months/PR/CR frequently had alterations in the PI3K/AKT/mTOR pathway. Citation Format: Jennifer J. Wheler, Stacey L. Moulder, Aung Naing, Filip Janku, Sarina A. Piha-Paul, Gerald S. Falchook, Ralph Zinner, Apostolia M. Tsimberidou, Siqing Fu, David S. Hong, Johnique T. Atkins, Maureen Cronin, Roman Yelensky, Phil Stephens. A dose-escalation study of anastrozole and everolimus in patients with advanced gynecologic and breast malignancies: tolerance, biological activity, and molecular alterations in the PI3K/AKT/mTOR pathway. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3514. doi:10.1158/1538-7445.AM2013-3514