Oncotarget

Research Papers:

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

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

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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

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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