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

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.

• Authors: 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, Razelle Kurzrock
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 10 Pg. 3029-38 (May 30 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24912489 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Nitriles
• Triazoles
• Anastrozole
• Everolimus
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• Sirolimus

Topics

• Adult
• Aged
• Aged, 80 and over
• Anastrozole
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Breast Neoplasms (drug therapy, genetics, mortality)
• Everolimus
• Female
• Genital Neoplasms, Female (drug therapy, genetics, mortality)
• Humans
• Kaplan-Meier Estimate
• Middle Aged
• Nitriles (administration & dosage, adverse effects)
• Phosphatidylinositol 3-Kinases (genetics)
• Proto-Oncogene Proteins c-akt (genetics)
• Signal Transduction (genetics)
• Sirolimus (administration & dosage, adverse effects, analogs & derivatives)
• TOR Serine-Threonine Kinases (genetics)
• Treatment Outcome
• Triazoles (administration & dosage, adverse effects)
• Young Adult