Abstract Book - PDF - San Antonio Breast Cancer Symposium

December 4-8, 2012 Abstracts: Poster Session 2
P2-14-05
A phase II study of combined fulvestrant and RAD001
(everolimus) in metastatic estrogen receptor (ER) positive breast
cancer after aromatase inhibitor (AI) failure.
Croley JJ, Black EP, Romond E, Chambers M, Waynick S, Slone
S, Waynick C, Stevens M, Weiss HL, Massarweh SA. University of
Kentucky and Markey Cancer Center, Lexington, KY
Background: Fulvestrant is used to treat women with metastatic
ER-positive breast cancer after AI failure, but has a short duration
of benefit. Pi3K/mTOR signaling has been implicated in preclinical
models of fulvestrant resistance and recent trials suggest that
everolimus, an oral inhibitor of mTOR, can overcome resistance to
other forms of endocrine therapy. We hypothesized that everolimus
may delay resistance to fulvestrant and prolong time to progression
(TTP).
Methods: We designed a phase II clinical trial of combined fulvestrant
and everolimus in postmenopausal women with ER-positive breast
cancer who relapsed or experienced metastatic disease progression
within 6 months of AI use. Fulvestrant was given at 500 mg
IM on day1, 250 mg d14, 250 mg d28, and monthly thereafter.
Everolimus was given at 10 mg po daily. Patients were required to
have measurable or evaluable disease with preserved performance
status and adequate organ function. Primary endpoint is TTP, and
secondary endpoints are safety, response rate, clinical benefit rate,
and biomarker analysis. A sample size of 40 patients was calculated
to meet a median TTP of 7.0 vs. 3.7 months for fulvestrant alone
as reported in the EFECT trial. Patients were followed monthly for
clinical and toxicity assessment and imaging was obtained every 2
months. Tumor blocks were collected when available and biopsies
were offered if disease was accessible.
Results: To date, 30 patients enrolled on study with a median age of 56
years (range 39-85). Most common metastatic disease sites were bone
in 26 patients (87%), liver in 19 (63%), and lung in 16 (53%). Prior
therapy included tamoxifen in 21 patients (70%), and chemotherapy
in 20 (67%), of those 17 were in the adjuvant/neoadjuvant setting.
6 patients (20%) received more than one AI. 2 patients were ruled
ineligible immediately after enrollment and starting study treatment,
one because of a creatinine level outside the reference range and
one because of the need for palliative radiation. Of the remaining
28 patients, 18 discontinued therapy because of disease progression,
3 because of toxicity, 2 upon patient request, and 1 because of
unrelated intercurrent illness, with 4 patients currently on therapy.
Most common adverse events reported were mucositis in 13 patients
(43%) and rash in 11 (36%). Most common laboratory abnormalities
were elevated ALT/AST in 18 patients (60%), elevated cholesterol in
13 (43%), and hypokalemia in 13 (43%). The majority of toxicities
were grade I/II. Most common grade III toxicities, regardless of
attribution, were infection requiring hospitalization in 3 patients
(10%), hypokalemia in 3 (10%) and mucositis in 2 (7.4%). There was
one grade 4 toxicity reported-hypokalemia. Overall, treatment was
reasonably tolerated and toxicities manageable. Efficacy findings,
including the primary endpoint of TTP, will be analyzed and presented
at the meeting.
Conclusions: Combined everolimus with fulvestrant is feasible and
has manageable toxicities in this cohort of women with metastatic
ER-positive breast cancer. Detailed efficacy analysis along with
updated toxicity data will be presented at the meeting.
P2-14-06
A phase II trial of low dose estradiol in postmenopausal women
with advanced breast cancer and acquired resistance to an
aromatase inhibitor.
Howell SJ, Seif MW, Armstrong AC, Cope J, Wilson G, Welch RS,
Misra V, Ryder D, Blowers E, Palmieri C, Wardley AM. University of
Manchester, United Kingdom; The Christie NHS Foundation Trust,
Manchester, United Kingdom; Imperial College, London, United
Kingdom
Background High dose estrogen (HDE) is an effective but toxic
treatment for postmenopausal women with advanced breast
cancer (ABC). In vitro, prolonged periods of estrogen deprivation
(ED) sensitises cancers to the inhibitory effects of estrogen. We
hypothesised that the profound ED seen with third generation
aromatase inhibitor (AI) would sensitise cancers to LDE which would
be better tolerated.
Methods Single arm phase II study in postmenopausal women
with measurable ER+ ABC and demonstrated clinical benefit (CB)
with a third generation AI. Treatment: estradiol valerate 2mg daily.
Primary endpoint: CB rate (CBR) was correlated with baseline and
dynamic LH/FSH levels and on-treatment estradiol levels. Secondary
endpoints included TTF, PFS, toxicity and QoL. If LDE was effective,
retreatment with the AI on which the cancer had progressed prior
to study entry was offered on progression. If LDE was ineffective
HDE was offered.
Results 21/50 patients were recruited before early closure due to slow
accrual. 19 were assessable for efficacy and toxicity (1 ineligible; 1
no LDE). CBR was 5/19 (26%; 95%CI 9.1%,51.2%). Median TTF
2.8months (range 0.5-29.8). CBR durations were 11.1, 16.8, 17.3*,
19.8, 29.8 months (*censored). 4 stopped treatment early due to
toxicity (G4 hypercalcaemia/ G2 vaginal bleeding (VB) plus G4
hyponatraemia/ G2 mucositis/ G2 headaches) 1 with SD at 3 months
and 3 before response assessment. Other common toxicities were all
G1/2 and mainly limitted to nausea (8/19), breast pain (7/19) and
tumour flare (7/19). VB occurred in 8/11 without prior hysterectomy.
Baseline LH correlated with CBR by logistic regression (p=0.01). Of
3 retreated with the same AI post LDE; 1 had PR, 1 SD ≥6months
and 1 PD. One woman received HDE after failure of LDE and
achieved a PR.
Conclusion LDE is an effective and largely well tolerated treatment
in women with acquired resistance to AI. VB is common without
prior hysterectomy. Rechallenge with the same AI post LDE seems
effective and may offer an extra line of endocrine therapy. This should
be tested in future trials.
P2-14-07
Evaluation of Aromatase Inhibitor failure and total healthcare
expenditures among post-menopausal women with metastatic
ER+/HER2- breast cancer in the US
Namjoshi M, Landsman-Blumberg P, Thomson E, Chu BC. Novartis
Pharmaceuticals Corporation, East Hanover, NJ; Thomson Reuters,
Washington, DC
Aromatase Inhibitors (AIs) have replaced tamoxifen as first-line
therapy for post-menopausal women with metastatic, ER+ breast
cancer (BC). However, little information is available on the realworld
use of AIs. This retrospective administrative claims study
compared healthcare expenditures of post-menopausal women with
metastatic ER+/HER2- BC treated with AIs and experiencing 0 or
≥ 1 AI failures (AIF).
Women ≥ 55 years of age newly diagnosed with stage IV BC (index)
were identified in the 2006-2010 Thomson Reuters MarketScan
www.aacrjournals.org 281s
Cancer Res; 72(24 Suppl.) December 15, 2012