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

1064 General Poster Session (Board #22G), Sat, 8:00 AM-12:00 PM
Low-dose, short-course sunitinib may normalize tumor vasculature and
improve tumor blood flow to enhance chemotherapy efficacy in breast
cancers. Presenting Author: Soo-Chin Lee, National University Cancer
Institute, Singapore, Singapore, Singapore
Background: Small molecule VEGFR inhibitors (VEGFR-I) have failed to
improve outcome with chemotherapy in most solid tumors. Continuous
administration of a potent VEGFR-I may destroy vasculature and impede
drug delivery; in contrast, low-dose, short-course VEGFR-I before chemotherapy
may normalize tumor vasculature and enhance drug delivery.
Methods: We conducted a phase Ib followed by phase II randomized study
in patients with measurable primary breast tumors using low-dose sunitinib
(Su) for 1 week prior to doxorubicin/cyclophosphamide (AC) and measured
tumor blood flow with DCE-MRI and microvessel density and pericyte
recoverage with CD31 and �-smooth muscle actin (SMA) staining on tumor
biopsies, at baseline, after 1 week of Su, and 2 weeks after cycle 1 AC.
Patients in phase Ib received 12.5-25mg Su prior to AC; in phase II,
patients were randomized to AC�/-12.5mg Su. Results: 21 patients have
been enrolled, including 3 patients on 25mg Su�AC, 11 on 12.5mg
Su�AC, and 7 on AC alone. After 1 week of 25mg Su, 2/3 patients had
reduced tumor blood flow on DCE-MRI indicating anti-angiogenic effects.
After 1 week of 12.5mg Su, significant increase in tumor fractional plasma
volume (Vp) occurred (�28%�28%, p�0.025) suggesting increased
perfusion, followed by decrease 2 weeks after AC (-33%�26%,p�0.035)
corresponding to mean tumor size change of -17�15%, while no significant
Vp changes occurred with AC alone (p�0.823); CD31 expression
reduced (20.7 vs 15.7, p�0.173) while SMA/CD31 double staining
increased (2.45 vs 7.34, p�0.046) indicating lower microvessel density
and normalization of residual vasculature, which was not seen with AC
alone (CD31, p�0.434; CD31/SMA, p�0.605). The main toxicity of
Su�AC and AC alone was febrile neutropenia (29% vs 43%). 14 patients
had surgery with pathological complete response in 1/6 patients who
received 12.5mg Su�AC. Conclusions: 25mg Su for 1 week can reduce
tumor blood flow, suggesting that concomitant standard dose Su may
compromise drug delivery. Low dose 12.5mg Su for 1 week is sufficient to
normalize tumor vasculature and increase tumor fractional plasma volume,
and may potentially improve drug delivery and treatment outcome.
1066 General Poster Session (Board #23A), Sat, 8:00 AM-12:00 PM
Early changes in angiogenesis and hypoxia following bevacizumab therapy
in primary breast cancer. Presenting Author: Shaveta Mehta, University
Department of Oncology, Oxford, United Kingdom
Background: Bevacizumab (BV), a monoclonal antibody directed against
vascular endothelial growth factor (VEGF), is an approved anti-angiogenic
agent, but despite its widespread use, little is known about how tumours
develop resistance to BV. We have conducted a window-of-opportunity
study in which BV is administered as a short-term first-line treatment for
primary breast cancer (PBC) patients, and assessed histological markers of
tumour angiogenesis and hypoxia before and after therapy. Methods: 47
patients with locally advanced breast cancer were prospectively enrolled.
Informed consent was obtained from all patients. A single infusion of BV
(15 mg/kg) was given 2 weeks before starting neoadjuvant chemotherapy.
Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and
core biopsies for immunohistochemistry (IHC) analysis were performed
immediately prior to and 2 weeks after BV. 36 patients with invasive ductal
carcinoma and good quality MRI scans and core biopsies were included in
this analysis. Wilcoxon rank test and Spearman’s correlation test were used
for statistical analysis. Results: IHC revealed a significant upregulation of
carbonic anhydrase 9 (P � 0.04) and hypoxia inducible factor-1a (P �
0.001) following BV therapy along with a significant reduction in plasmalemma
vesicle associated protein (PLVAP) (p�0.01) and Ki67 (p� 0.006).
DCE-MRI analysis revealed a significant reduction in vessel permeability
and blood flow following BV, as measured by a decrease in the forward
transfer constant Ktrans (P � 0.0001) and the reverse rate constant kep (P �
0.0001). In addition, we found a significant negative correlation between
CA9 levels and median Ktrans at baseline (Spearman’s rho � -0.46; P �
0.01). Conclusions: Using combined DCE-MRI and IHC analysis, we found
that PBC patients treated with single-agent BV showed a decrease in
markers of tumour angiogenesis, together with a corresponding increase in
tumour hypoxia. Our results suggest that tumour hypoxia may be a key
mechanism governing the early onset of resistance to BV therapy, and argue
for the use of suitable combination therapies to overcome the resistance
and ultimately improve patient survival.
Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
65s
1065 General Poster Session (Board #22H), Sat, 8:00 AM-12:00 PM
Efficacy of low-dose capecitabine in metastatic breast cancer. Presenting
Author: Caitlin Bertelsen, Keck School of Medicine of the University of
Southern California, Los Angeles, CA
Background: The FDA-approved dose of capecitabine (cape) of 1250mg/m2 twice daily (BID) is associated with treatment-limiting toxicities. Published
reports suggest that lower starting doses of cape can be as effective as the
approved dose in treating metastatic breast cancer (MBC). We compared
the efficacy of lower than previously published doses of cape with results of
registrational Phase III trials using the approved dose. Methods: We
performed a retrospective analysis of patients treated at the University of
Southern California hospitals who received cape as the first, second, or
third line of chemotherapy for MBC to determine the progression-free
survival (PFS) associated with low starting doses. The primary endpoint was
PFS among patients with measurable disease, and secondary aims were to
analyze the relationships between PFS and various clinical characteristics
for all patients. Results: Patients (n�84) received a median cape dose of
565 mg/m2 BID, often administered as a flat dose (not adjusted for body
surface area) of 1000 mg BID. Median PFS among patients with measurable
disease (n�62) was 4.1 months (95% confidence interval or CI �
2.9-5.7), which was similar to the median PFS values of 4.4 months (95%
CI � 4.14-5.42, n�480) (Sparano et al. JCO 2010;28:3256) and 4.2
months (95% CI � 3.81-4.50, n�377) (Thomas et al. JCO 2008;25:
5210) for single-agent cape reported in the major trials with similar
eligibility criteria. Among all patients, PFS was shorter in measurable
disease, triple negative and HER2� subtypes, and was similar in all lines of
therapy. Only two patients (2.4%) discontinued cape due to toxicity.
Conclusions: These data support the efficacy of very low doses of cape for
MBC. Prospective randomized controlled trials testing lower starting doses
of cape are needed to optimize the benefit/risk ratio.
Variable Median PFS (mo) Multivariate PFS OR p value
Entire cohort 4.4
Non-measurable; measurable 19.7; 4.1 Ref; 1.6 0.13
ER or PR�/HER2-; triple negative; HER2� 8.5; 3.0; 6.0 Ref; 3.2; 2.5 0.011
DFI � 0; >0-5yr 3.0; 4.4; 8.5 Ref; 0.42; 0.36 0.031
No trastuzumab; trastuzumab in HER2� 4.1; 9.6 Ref; 0.31 0.079
OR � odds ratio; DFI � disease free interval; Ref � reference; yr � year.
1067 General Poster Session (Board #23B), Sat, 8:00 AM-12:00 PM
Accuracy of MRI, mammography (MG), and 2D and 3D ultrasound
(2DUS/3DUS) in determining the pathologic tumor response after neoadjuvant
chemotherapy (NACT) in breast cancer patients. Presenting Author:
Markus Hahn, University Hospital Tuebingen, Department of Gynecology
and Obstetrics, Tuebingen, Germany
Background: The pathological tumor response in patients with locally
advanced breast cancer to NACT is essential for survival and for surgical
strategies. Therapy monitoring based on German recommendations is
routinely performed by clinical examination, MG and 2DUS. The clinical
value of MRI and 3DUS has not been established yet. The aim of the study
was to determine the accuracy, sensitivity, specificity, positive predictive
value (PPV), negative predictive value (NPV) between the different imaging
techniques in predicting postoperative histological tumor response after
NACT. Methods: Patients with primary breast cancer (cT1-T4, cN0-1, M0)
undergoing neoadjuvant chemotherapy between 2005 and 2010 were
eligible for this prospective trial. The response was measured by MRI, MG,
2DUS and 3DUS for complete or partial remission versus stable disease
after the last cycle of treatment and compared with the final pathological
response. Patients with progressive disease were excluded from the study.
Statistical analysis was done by calculating the accuracy of each imaging
technique and the size difference between imaging and histological tumor
size. Sensitivity, specificity, PPV and NPV were calculated for complete or
partial pathological response. The study was approved by the local ethic
committee (BCD001 194/2004). Results: 103 patients with the mean age
of 47.7 (range 24.5 – 71.4) years were evaluated. The accuracy was 0.680
(95%CI: 0.580 -0.768) for MRI, 0.563 (95%CI: 0.453-0.669) for MG,
0.724 (95%CI: 0.618 -0.815) for 2DUS and 0.710 (95%CI: 0.588-
0.813) for 3DUS. Sensitivity, specificity, PPV and NPV were 78%, 47%,
75% and 52% for MRI, 61%, 45%, 69% and 36% for MG, 93%, 23%,
74% and 60% for 2DUS, 94%, 19%, 73% and 57% for 3DUS. The mean
(standard deviation) size difference was -1.8 mm (14.8) on MRI, 1.5 mm
(26.0) on MG, -9.1mm (19.1) on 2DUS and for the volume difference
-6916mm3 (15831) on 3DUS. Conclusions: The data suggest that 2DUS is
sufficient in predicting tumor response between NACT treatment. MRI and
MG are more accurate the 2DUS in predicting the tumor size for surgical
planning.
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