PMID- 24327334
OWN - NLM
STAT- MEDLINE
DCOM- 20140828
LR  - 20211203
IS  - 1573-7217 (Electronic)
IS  - 0167-6806 (Linking)
VI  - 143
IP  - 2
DP  - 2014 Jan
TI  - A phase II study of combined fulvestrant and everolimus in patients with 
      metastatic estrogen receptor (ER)-positive breast cancer after aromatase 
      inhibitor (AI) failure.
PG  - 325-32
LID - 10.1007/s10549-013-2810-9 [doi]
AB  - Fulvestrant, which degrades ER, is used after AI failure in metastatic breast 
      cancer but resistance develops quickly. We hypothesized that using everolimus to 
      inhibit mTOR, a key signaling pathway in endocrine resistance, may delay 
      fulvestrant resistance in patients and thus improve its efficacy. We conducted a 
      phase II trial of combined fulvestrant and everolimus in postmenopausal women 
      with disease progression or relapse after an AI. Primary endpoint was time to 
      progression (TTP) and secondary endpoints included objective response rate, 
      clinical benefit rate (CBR), safety, and biomarker correlates. Tumor blocks were 
      collected and biopsy of accessible tumor was done for future biomarker analysis. 
      Of 33 patients enrolled two were ruled ineligible after enrollment and were 
      excluded from study analysis, for a total of 31 evaluable patients. Median age 
      was 54 years (range 45-85). Prior therapy included tamoxifen (81 %), chemotherapy 
      (71 %), with 26 % of patients having received 3 or more endocrine agents. Median 
      TTP was 7.4 months (95 % CI 1.9-12.1) with an objective response rate of 13 % and 
      CBR of 49 %. Of particular note, 32 % of patients exhibited de novo resistance to 
      study treatment with disease progression as their best response. Most common 
      adverse events (AEs) were elevated AST (87 %) and ALT (77 %), anemia (74 %), 
      hyperglycemia (71 %), and hypercholesterolemia (68 %). Prominent clinical 
      toxicities were mucositis (58 %), weight loss (48 %), and rash (42 %). Most AEs 
      were grade 1 or 2 and largely reversible with infrequent need for everolimus dose 
      reduction. To conclude, everolimus plus fulvestrant is effective after AI failure 
      in heavily pretreated metastatic ER-positive breast cancer and has manageable 
      toxicity. Further study of this combination is warranted in randomized studies. 
      Since not all patients experience benefit, and in view of potential toxicities, 
      biomarker examination is critical to help select patients most likely to benefit 
      from this strategy in future studies.
FAU - Massarweh, Suleiman
AU  - Massarweh S
AD  - The Department of Internal Medicine, University of Kentucky, Lexington, KY, USA, 
      massarweh@uky.edu.
FAU - Romond, Edward
AU  - Romond E
FAU - Black, Esther P
AU  - Black EP
FAU - Van Meter, Emily
AU  - Van Meter E
FAU - Shelton, Brent
AU  - Shelton B
FAU - Kadamyan-Melkumian, Vera
AU  - Kadamyan-Melkumian V
FAU - Stevens, Mark
AU  - Stevens M
FAU - Elledge, Richard
AU  - Elledge R
LA  - eng
SI  - ClinicalTrials.gov/NCT00570921
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131211
PL  - Netherlands
TA  - Breast Cancer Res Treat
JT  - Breast cancer research and treatment
JID - 8111104
RN  - 0 (Antineoplastic Agents, Hormonal)
RN  - 0 (Aromatase Inhibitors)
RN  - 0 (Immunosuppressive Agents)
RN  - 0 (Receptors, Estrogen)
RN  - 22X328QOC4 (Fulvestrant)
RN  - 4TI98Z838E (Estradiol)
RN  - 9HW64Q8G6G (Everolimus)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
EIN - Breast Cancer Res Treat. 2015 Jan;149(2):565
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents, Hormonal/adverse effects/therapeutic use
MH  - Antineoplastic Combined Chemotherapy Protocols/adverse effects/therapeutic use
MH  - Aromatase Inhibitors/*therapeutic use
MH  - Breast Neoplasms/*drug therapy
MH  - Estradiol/adverse effects/*analogs & derivatives/therapeutic use
MH  - Everolimus
MH  - Female
MH  - Fulvestrant
MH  - Humans
MH  - Immunosuppressive Agents/adverse effects/therapeutic use
MH  - Middle Aged
MH  - Neoplasm Recurrence, Local/drug therapy
MH  - Receptors, Estrogen/metabolism
MH  - Sirolimus/adverse effects/*analogs & derivatives/therapeutic use
MH  - TOR Serine-Threonine Kinases/antagonists & inhibitors
MH  - *Treatment Failure
EDAT- 2013/12/12 06:00
MHDA- 2014/08/29 06:00
CRDT- 2013/12/12 06:00
PHST- 2013/10/28 00:00 [received]
PHST- 2013/12/04 00:00 [accepted]
PHST- 2013/12/12 06:00 [entrez]
PHST- 2013/12/12 06:00 [pubmed]
PHST- 2014/08/29 06:00 [medline]
AID - 10.1007/s10549-013-2810-9 [doi]
PST - ppublish
SO  - Breast Cancer Res Treat. 2014 Jan;143(2):325-32. doi: 10.1007/s10549-013-2810-9. 
      Epub 2013 Dec 11.