Work

Anastrozole and everolimus in advanced gynecologic and breast malignancies: activity and molecular alterations in the PI3K/AKT/mTOR pathway

Year: 2014

Type: article

Abstract: // Jennifer J. Wheler 1 , Stacy L. Moulder 2 , Aung Naing 1 , Filip Janku 1 , Sarina A. Piha-Paul 1 , Gerald S. Falchook 1 , Ralph Zinner 1 , Apostolia M. Tsimberidou 1 , Siqing Fu 1 , David S. Hong 1 , Johnique T. Atkins 1 , Roman Yelensky 3 , Philip J. Stephens 3 , Razelle Kurzrock 4 1 Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 2 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 3 Foundation Medicine, Cambridge, MA 4 Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, La Jolla, CA Correspondence: Jennifer J Wheler, email: // Keywords : Anastrozole, Breast Cancer, Everolimus, Gynecologic Cancer, Hormone therapy Received : January 22, 2014 Accepted : March 12, 2014 Published : March 14, 2014 Abstract Background: Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was investigated. Patients and Methods: We evaluated anastrozole and everolimus in 55 patients with metastatic estrogen (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates. Results: Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Twelve of 50 evaluable patients (24%) (median = 3 prior therapies) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR) (n = 5 (10%) with PR/CR): 9 of 32 (28%) with breast cancer (n=5 (16%) with PR/CR); 2 of 10 (20%), ovarian cancer; and 1 of 6 (17%), endometrial cancer. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. 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: mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All three responders (CR (n = 1); PR (n=2)) who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC. Conclusions: Combination anastrozole and everolimus is well tolerated at full approved doses, and is active in heavily-pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Responses were observed in patients with multiple molecular aberrations. Clinical Trails Included: NCT01197170

Source: Oncotarget

DOI: 10.18632/oncotarget.1799