title: 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.
  
  
  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.affiliation: Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: Ralph
authors.initials: R
authors.lastname: Zinner
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Johnique T
authors.initials: JT
authors.lastname: Atkins
authors.affiliation: Foundation Medicine, Cambridge, MA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.affiliation: Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, La Jolla, CA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077384:Anastrozole; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D000068338:Everolimus; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000235:genetics; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D000077384:Anastrozole; D000068338:Everolimus; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014230:Triazoles; C546842:MTOR protein, human