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collected from all patients for determination of predictors of response and
mechanisms of resistance to treatment. Patients are treated with ganetespib
150 mg/m 2 is given twice weekly of a 4-week cycle for up to 12 weeks. A total of
70 patients are planned for accrual. At the time of submission, the study is receiving
IRB approvals in several centers.
Disclosure: All authors have declared no conflicts of interest.
348P HGFK1 INHIBITS BONE METASTASIS IN BREAST CANCER
THROUGH THE TAK1/P38 MAPK SIGNALING PATHWAY
Y-Z. Bu 1 , Z. Shen 2
1 Department of Surgery, Lianshui People’s Hospital, Jiangsu Province, CHINA,
2 Department of Oncology, Shanghai 6th People’s Hospital, Shanghai Jiao Tong
University, Shanghai, CHINA
Background: Breast cancer metastasis to bone represents a devastating complication
of advanced breast cancer, frequently resulting in significant increases in morbidity
and mortality. An understanding of the mechanisms that govern breast cancer
metastasis at the molecular level should lead to more effective therapies. Recently, the
kringle 1 domain of human hepatocyte growth factor (HGFK1) was identified as a
candidate metastasis suppressor gene.
Methods: Here, we investigated whether HGFK1 is a key regulator of breast cancer
bone metastasis.
Results: Of the 193 human breast carcinoma tissue samples examined, HGFK1
expression was positive in 82 (42.4%). The positive expression of HGFK1 was
significantly associated with a better prognostic value (P < 0.001) and inversely
correlated with bone metastasis (P = 0.003). The efficacy of adeno-associated virus
carrying HGFK1 (AAV-HGFK1) in osteolytic bone metastasis was then evaluated
using an in vivo bone metastasis model. AAV-HGFK1 significantly inhibited
osteolytic bone metastasis and prolonged the survival of mice in this model (P <
0.01). In vitro, HGFK1 expression resulted in significant anti-invasion effects,
enhanced the phosphorylation of TAK1, p38 MAPK and MAPKAPK2, and
decreased the expression of receptor activator of NF-κB (RANK), which was
abrogated by the p38 MAPK inhibitor SB203580.
Conclusions: This study shows for the first time that HGFK1 significantly inhibits
the metastasis of breast cancer to bone by activating the TAK1/p38 MAPK signaling
pathway and inhibiting RANK expression. Thus, AAV-HGFK1 treatment represents
a potential therapy for bone metastasis in breast cancer.
Disclosure: All authors have declared no conflicts of interest.
349P IMPACT OF DIABETES AND HYPERGLYCEMIA ON SURVIVAL
IN ADVANCED BREAST CANCER PATIENTS
R.J. Shaw Dulin 1 , C. Villarreal-Garza 1 , F. Lara 1 , L. Bacon 2 , D. Rivera 2 , A.D.
Rivera Salceda 2 , L. Urzua 2 , L. Herrera 3 , C. Aguila 2 , J.E. Bargallo-Rocha 1
1 Breast Tumor Department, Instituto Nacional de Cancerología Mexico, Mexico
City, MEXICO, 2 Medical Oncology, Instituto Nacional de Cancerología Mexico,
Mexico City, MEXICO, 3 Department of Biomedical Research In Cancer, Instituto
Nacional de Cancerologia, Mexico City, MEXICO
Background: Clinical experience and previous studies suggest that women with
diabetes and breast cancer have worse outcomes than their non-diabetic counterparts.
The purpose of this study was to examine the impact of diabetes and hyperglycemia
on cancer-specific survival of patients with metastatic or recurrent breast cancer.
Methods: We performed a retrospective analysis of patients with advanced breast
cancer receiving palliative chemotherapy from 2006 to 2011 at the National Cancer
Institute in Mexico, and compared breast cancer-specific mortality in diabetic and
non-diabetic patients, as well as in patients that presented hyperglycemia during
palliative treatment.
Results: A total of 265 patients receiving palliative therapy were eligible for inclusion.
Previous diagnosis or detection of diabetes at recurrence was recorded in 40 patients
(15%). No difference was observed between diabetic and non-diabetic patients in
terms of OS. A statistically significant difference in OS was observed between patients
without diabetes and diabetic patients who had hyperglycemia (p = 0.003). OS in
diabetic patients with proper metabolic control was shown to be superior compared
to diabetics with hyperglycemia (p = 0.01) Hyperglycemia was identified in 14% of
non-diabetics at some point while receiving palliative treatment. For patients that
experienced hyperglycemia during treatment or who had a mean glucose level above
130, either in the diabetic or non-diabetic subgroups, a worse outcome was noted
compared to normoglycemic patients, with a HR of 1.5 (p = 0.029) and HR of 2.04
(p = 0.006) for death, respectively.
Conclusions: Elevated glucose levels confer a poor outcome in diabetic and
non-diabetic patients in contrast with patients with normoglycemic levels, conferring
an elevated risk of death. According to these results, clinicians must monitor glucose
levels during treatment for advanced breast cancer disease, and should take action in
order to maintain normal glucose levels.
Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
350P ANTITUMOR ACTIVITY OF DUAL PI3K AND ER BLOCKADE
IN ER POSITIVE BREAST CANCER MODELS
J. Tao 1 , M. Scaltriti 1 , S. Marlow 1 , M. Elkabets 1 , N. Morse 1 , D. Sgroi 2 , J. Baselga 1
1 Cancer Center, Massachusetts General Hospital, Charlestown, MA, UNITED
STATES OF AMERICA, 2 Molecular Pathology Unit, Massachusetts General
Hospital, Charlestown, MA, UNITED STATES OF AMERICA
Background: Activation of the phosphoinositide 3-kinase (PI3K) pathway, either by
receptor tyrosine kinase overexpression or PI3K/Akt/mTOR axis dysregulation, has
been implicated in endocrine therapy resistance, prompting combination of PI3K
inhibitors and antiestrogen therapy in the clinical setting such as in the recent
BOLERO-2 study. We hypothesize that dissecting the molecular crosstalk between
the PI3K and estrogen receptor (ER) pathways will help define the subset of patients
most responsive to combined PI3K/antiestrogen therapy.
Methods: ER+ cell lines MCF7, MCF7-long term estrogen deprived (LTED),
MCF7-fulvestrant resistant clones Fslx64 and Fslx70, T47D, ZR75-1, CAMA1,
MDA361, KPL-1, BT474, EFM19, HCC1428, UACC812, were treated with the ER
degrader, fulvestrant, and the p110α-specific PI3K inhibitor BYL719 in vitro. Cell
viability was measured by CellTiter-Glo and Crystal Violet. MCF7 and ER+
patient-derived xenografts were treated with fulvestrant, BYL719 or the combination
in vivo. Protein expression was measured by Western blot and
immunohistochemistry.
Results: Fulvestrant or BYL719 treatment resulted in variable inhibition of cell
viability in all ER+ cell lines. Combination treatment was significantly superior to
monotherapy in MCF7, MCF7-LTED, MCF7-Fslx64 and MCF7-Fslx70. While MCF7
clones Fslx64 and Fslx70 were resistant to >1 µM of fulvestrant, they were exquisitely
sensitive to BYL719. Moreover, PI3K inhibition led to ER upregulation in ER+ cell
lines, including those most sensitive to combination treatment. Total ER levels also
increased in MCF7 xenografts treated with therapeutic doses of BYL719.
Conclusions: Combined treatment with BYL719 and fulvestrant in vitro was superior to
single-agent treatment in 4 of 13 ER+ cell lines. Importantly, dual PI3K/ER blockade was
effective in cells resistant to ER deprivation and/or degradation. Induced ER levels
following PI3K suppression may represent a feedback mechanism by which ER+ cells
escape PI3K inhibition. We are currently studying whether this phenomenon predicts
sensitivity to dual PI3K/ER blockade in ER+ breast cancer models.
Disclosure: J. Baselga: J. Baselga is a consultant/advisory board member for Aragon,
AstraZeneca, Sanofi, Bayer, Onyx, Chugai, Constellation, Exelixis, Intellikine, Merck,
Novartis, and Roche Genentech. All other authors have declared no conflicts of interest.
351P SAFETY OF EVEROLIMUS FOR WOMEN OVER 65 YEARS OF
AGE WITH ADVANCED BREAST CANCER: 18-MO FOLLOW-UP
OF BOLERO-2
M. Gnant 1 , S. Noguchi 2 ,Y.Ito 3 , M. Piccart 4 , J. Baselga 5 , A. Panneerselvam 6 ,
T. Taran 6 , T. Sahmoud 6 , G.N. Hortobagyi 7 , K. Pritchard 8
1 Deparment of Surgery, Medical University of Vienna, Vienna, AUSTRIA,
2 Department of Breast and Endocrine Surgery, Osaka University, Osaka, JAPAN,
3 Department of Medical Oncology, Cancer Institute Hospital, Japanese
Foundation for Cancer Research, Tokyo, JAPAN, 4 Institut Jules Bordet, Institut
Jules Bordet, Brussels, BELGIUM, 5 Massachusetts General Hospital Cancer
Center and Harvard Medical School, Massachusetts General Hospital Cancer
Center and Harvard Medical School, Boston, MA, UNITED STATES OF
AMERICA, 6 Novartis Pharmaceuticals Corporation, East Hanover, NJ, UNITED
STATES OF AMERICA, 7 The University of Texas Md Anderson Cancer Center,
The University of Texas MD Anderson Cancer Center, Houston, TX, UNITED
STATES OF AMERICA, 8 Medical Oncology, Sunnybrook Odette Cancer Center,
Toronto, CANADA
Background: Hormone-receptor–positive (HR + ) breast cancer (BC) refractory/
resistant to nonsteroidal aromatase inhibitor (NSAI) may be treated with the
steroidal AI exemestane (EXE), although there is no approved treatment standard.
The BOLERO-2 trial showed that adding everolimus (EVE) to EXE significantly
improved clinical benefit beyond that of EXE alone (Hortobagyi et al, SABCS 2011,
Abstract S3-7). As many women with advanced BC are elderly (≥ 65 years), the
efficacy and tolerability of EVE + EXE in this population are of interest.
Methods: BOLERO-2 is a phase 3, randomized trial comparing EVE (10 mg once
daily) vs placebo (PBO), both plus EXE (25 mg once daily) in postmenopausal
women with advanced HR + BC progressing or recurring after NSAIs.
Results: Baseline disease and prior treatment characteristics were balanced between
study arms (N = 724). At 18 months’ median follow-up, adding EVE to EXE
significantly improved progression-free survival in patients < 65 (n = 449; 8.3 vs 2.9
mo; HR = 0.38; 95% CI = 0.30, 0.47) and ≥ 65 years (n = 275; 6.8 vs 4.0 mo; HR =
0.59; 95% CI = 0.43, 0.80). Overall incidence of adverse events (AEs) was marginally
higher in patients ≥ 65 years (n = 272, safety population) compared with those < 65
years. Grade 3/4 AEs occurred in 50% of patients ≥ 65 years compared with 42% of
patients < 65 years. Incidences of grade 3/4 stomatitis, rash, pneumonitis, and
hyperglycemia in EVE-treated patients ≥ 65 years and those < 65 years were similar.
Additional analysis using an age cutoff of 70 years also showed no meaningful
differences in the efficacy/safety profile of EVE. Grade 3/4 AEs in patients ≥ 65 years
ix126 | Abstracts Volume 23 | Supplement 9 | September 2012