Annual Meeting Proceedings Part 1 - American Society of Clinical ...

1097 General Poster Session (Board #30A), Sat, 8:00 AM-12:00 PM
Prevention of chemotherapy-induced damage to ovarian reserve by sphingosine-1-phosphate
Presenting Author: Fang Li, Laboratory of Molecular
Reproduction and Fertility Preservation, New York Medical College, Valhalla,
NY
Background: Chemotherapy agents such as cyclophosphamide (Cy) and
doxorubicin (D) are known to compromise ovarian function. We have
previously shown that these agents alter ovarian function by causing
apoptotic death of primordial follicles and thereby causing diminishment of
ovarian reserve (Cancer Research 2007; Aging 2011). While assisted
reproduction techniques exist to preserve fertility there has been no proven
approach to pharmacologic preservation of ovarian function. Sphingosine-
1-Phosphate (S1P) is a naturally occurring ceramide-induced death pathway
inhibitor. Here we investigated whether S1P can prevent Cy or
D-induced apoptotic follicle death in mouse ovaries. Methods: Eight wk old
NOD mice (n�23) were treated with Cy (75 mg/kg), Cy�S1P (200 �M), D
(10 mg/kg), D�S1P or vehicle only (Control). S1P was administered via
continuous infusion using a mini-osmotic pump beginning 3 hours prior to
single dose chemotherapy injection for 72 hours. Ovaries were removed
72h later and serially sectioned, and stained with anti-caspase 3 (AC-3)
antibody for the detection of apoptosis in primordial follicles. The ratio of
apoptotic to total follicles was expressed as percentage in each group.
Results: Both Cy and D resulted in significant increase in apoptotic follicle
death compared to controls (48.2�11.6 vs. 28.2�8.9, p�0.016 and
46.4�5.4 vs. 24.8�5.2, p�0.004, respectively). Percentages of apoptotic
follicles were similar between Cy and D-treated groups (48.2�11.6 vs.
46.4�5.4, P�NS) indicating that these agents were equally gonadotoxic.
S1P treatment resulted in a significant decrease in the percentage of
apoptotic follicles both in the Cy (25.6�3.5, P�0.011) and the D group
(32.2�10.8, P� 0.013) compared to controls. In the S1P-treated groups,
the percentages of apoptotic follicles were similar to those in untreated
controls indicating that S1P completely blocked Cy and D-induced apoptotic
follicle death. Conclusions: S1P can block apoptotic follicle death
induced by highly cytotoxics agents. In addition, we showed that S1P can
block follicle death by chemotherapy agents that act through different
molecular mechanisms. If targeted delivery systems can be developed, S1P
may hold significant promise in preserving fertility by pharmacological
means.
1099 General Poster Session (Board #30C), Sat, 8:00 AM-12:00 PM
Phase II trial of sorafenib (S) and vinorelbine (V) in metastatic breast
cancer (mBC) with pharmacokinetics (PK) analysis. Presenting Author:
Cristiano Ferrario, Department of Oncology, McGill University, Montreal,
QC, Canada
Background: S inhibits pathways involved in cancer resistance to treatments
(Raf, VEGFR, PDGFR). This phase 2 trial aimed to define tolerability
and efficacy of full doses of S and V in mBC. Toxicity data were previously
reported: frequent dose reductions were noted, for which we investigated a
possible PK interaction. Indeed, the metabolism of both S and V depends
on hepatic CYP3A isoenzymes. Methods: Patients with measurable (RE-
CIST), HER2 negative mBC received first-line therapy with V (30 mg/m2 days 1, 8 every 21) � S (400 mg bid). After 8 cycles patients could be
switched to S alone. For PK analysis 6 patients started S on day 4 of cycle
1, to compare plasma levels of V, S and M2 (N-oxide active metabolite of S)
when V and S were administered apart from each other versus concomitantly.
Plasma samples were collected at time 0 (oral intake of S or right
before V infusion), at completion of V infusion and after 0.5, 1, 2.5, 5, 7,
24, 48 and 72 hours from time 0 (cycle 1 day 1 for V and day 21 for S�M2;
cycle 2 day 1 for both). Samples were analyzed using validated LC-MS/MS
assays. Results: 27 patients (median age 57, 35-71) received a median of 8
cycles (1-28), with one patient still on treatment. With repeated cycles
48% of patients required at least 1 dose reduction and 3 patients
discontinued therapy for toxicity. 30% of patients had a partial response,
85% had clinical benefit (including stable disease � 4 cycles). Median
progression-free survival was 5.7 months (95% CI 4.4-7.6). Plasma levels
of V were influenced by S, with a mean Cmax right after the infusion of
1301 ng/mL for V administered alone (cycle 1 day 1) versus 2039 ng/mL
with concomitant S (cycle 2 day 1; paired t-test, p�0.004). Plasma levels
of S and M2 showed a greater degree of interpatient variability, with no
significant difference observed in the presence or absence of concomitant
V. Conclusions: Combining S with V at full doses is feasible, but not devoid
of toxicity. A PK interaction may contribute to the frequent dose reductions.
A reasonable option in clinical practice is to start therapy at lower doses of
both agents, with a gradual dose increase if well tolerated. Promising
efficacy of this combination is documented, with a very high rate of disease
control.
Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
73s
1098 General Poster Session (Board #30B), Sat, 8:00 AM-12:00 PM
A study of sperm-associated antigen 5 (SPAG5) in predicting response to
anthracycline (ATC)/platinum chemotherapies (CT) in breast (BC) and
ovarian cancers (OVC). Presenting Author: Tarek M. A. Abdel-Fatah,
Nottingham University City Hospital NHS Trust, Nottingham, United
Kingdom
Background: Recently TOP2A alteration was found to be a predictor for
ATC-CT and our neural network analysis of BC gene expression array (GEA)
data has revealed SPAG5 gene as a major hubs in both TOP2A and
proliferation pathways. In this study the molecular and clinicopathological
functions of SPAG5 was investigated in BC and OVC. Methods: (1) A series
of 171 BC was evaluated for SPAG5 gene copy number (using aCGH) and
mRNA expression (using GEA) which were validated in 5 independent
databases. (2) The expression of SPAG5 protein was evaluated preclinically
in BC and OVC cell lines and in both 40 normal breast tissues and
a series of 1650 primary BC and was correlated to clinicopathological and
other biomarkers. (3) The association between SPAG5 and response to CT
was investigated in a) 350 ER negative BC treated with adjuvant ATC-CT, b)
250 BC treated with neoadjuvant (NEO-A)-ATC-CT, and c) 200 primary
OVC treated with cisplatinum based adjuvant CT. Results: (1) 5% and 15%
of the 171 BC showed amplification and gain of SPAG5 locus, respectively,
at 17q11.2. SPAG5 mRNA expression displayed a significant correlation
with its copy number (p� 0.0001). (2) 30% and 20% of ovarian and BC
respectively, showed overexpression of SPAG5 protein (�). In BC, SPAG5�
at both mRNA and protein levels showed a significant association with
aggressive phenotypes, high mitosis, ER-, high grade, p53 mutation and
epithelial mesenchymal transition phenotypes (ps �0.0001). SPAG5
mRNA (�) was statistically associated with poor survivals (p�0.0001). (3)
In ER- BC treated with adjuvant ATC-CT, SPAG5 negative (-)had 7-times
higher risk of progression compared with SPRAG� BC (p�0.0001).
SPAG5� BC received NEO-A-ATC based CT achieved 38% pathological
complete response (pCR) vs. 6% of SPAG5- (p�0.0001). After controlling
to other predictors for pCR, SPAG5 was an independent predictor (HR; 2.4;
p�0.001). Similarly, SPAG5- OVCs were resistant to platinum (p�0.001)
and independently associated with poor survival (p�0.001). Conclusions:
SPAG5 is an important novel gene implicated in the survival of BC and OVC
cells and its protein expression is an independent predictor for anthracycline/
cisplatinum CT.
1100 General Poster Session (Board #31A), Sat, 8:00 AM-12:00 PM
Receipt of locoregional therapy among young women with breast cancer.
Presenting Author: Rachel A. Freedman, Dana-Farber Cancer Institute,
Boston, MA
Background: Although younger women with breast cancer have the most to
gain from receipt of optimal care, few data are available regarding their
receipt of locoregional breast cancer treatments. Methods: We identified
318,083 women aged 18-64 who were diagnosed with invasive breast
cancer at hospitals reporting to the National Cancer Data Base, a large
national cancer registry, during 2004-2008. We used multivariable logistic
regression to assess the association of patient age with mastectomy vs.
breast-conserving surgery (BCS), radiation with BCS, and post-mastectomy
radiation (PMRT) with varying indications, adjusting for patient and tumor
characteristics, area-level socioeconomic status, and insurance. Results:
Overall, 4% of women were aged �35 and 7% were aged 36-40. Women
aged �35 were significantly more likely to have mastectomy than BCS
compared with women aged 56-60 (57% vs. 35%, adjusted odds ratio [OR]
1.97; 95% Confidence Interval [CI] 1.87-2.07) but were less likely to
receive radiation if BCS was performed (69% vs. 80%, OR 0.77; 95% CI
0.73-0.82). For those who underwent mastectomy, although overall rates
of PMRT receipt were low, women aged �35 were more likely to receive
postmastectomy radiation (PMRT) despite the presence or absence of
clinical indications for PMRT (OR 1.11; 95% CI 1.01-1.22 for strong
indications, OR 1.71; 95% CI 1.53-1.91 for borderline indications, and
OR 1.49; 95% CI 1.28-1.73 for no indications [all vs. ages 56-60]).
Conclusions: Young women with breast cancer may not be receiving optimal
locoregional therapy. We observed lower odds of radiation after BCS but
higher odds of PMRT for young women regardless of indications for PMRT.
Efforts are needed to further understand and improve the receipt of
appropriate adjuvant radiation therapy among young women to improve
their disease-free and overall survival.
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