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

• Published in: Oncotarget 2014-05, Vol.5 (10), p.3029-3038
• Main Authors: Wheler, Jennifer J, Moulder, Stacy L, Naing, Aung, Janku, Filip, Piha-Paul, Sarina A, Falchook, Gerald S, Zinner, Ralph, Tsimberidou, Apostolia M, Fu, Siqing, Hong, David S, Atkins, Johnique T, Yelensky, Roman, Stephens, Philip J, Kurzrock, Razelle
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Anastrozole; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Everolimus; Female; Genital Neoplasms, Female - drug therapy; Genital Neoplasms, Female - genetics; Genital Neoplasms, Female - mortality; Humans; Kaplan-Meier Estimate; Middle Aged; Nitriles - administration & dosage; Nitriles - adverse effects; Phosphatidylinositol 3-Kinases - genetics; Proto-Oncogene Proteins c-akt - genetics; Research Paper; Signal Transduction - genetics; Sirolimus - administration & dosage; Sirolimus - adverse effects; Sirolimus - analogs & derivatives; TOR Serine-Threonine Kinases - genetics; Treatment Outcome; Triazoles - administration & dosage; Triazoles - adverse effects; Young Adult
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.1799

Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was investigated. 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. 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. 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.