Oncotarget

Research Papers:

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

Jennifer J. Wheler _, Stacy 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, Roman Yelensky, Philip J. Stephens and Razelle Kurzrock

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Oncotarget. 2014; 5:3029-3038. https://doi.org/10.18632/oncotarget.1799

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Abstract

Jennifer J. Wheler1, Stacy L. Moulder2, Aung Naing1, Filip Janku1, Sarina A. Piha-Paul1, Gerald S. Falchook1, Ralph Zinner1, Apostolia M. Tsimberidou1, Siqing Fu1, David S. Hong1, Johnique T. Atkins1, Roman Yelensky3, Philip J. Stephens3, Razelle Kurzrock4

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


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