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

1024 Poster Discussion Session (Board #16), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A gene expression signature of MEK pathway activation to predict survival
in triple-negative breast cancer. Presenting Author: Justin M. Balko,
Vanderbilt University, Nashville, TN
Background: Tumor cell proliferation measured by Ki67 in the surgically
removed tumor after neoadjuvant chemotherapy (NAC) has been shown to
predict patient outcome in breast cancer. It is unclear from these studies if
breast cancer subtype may account in part for the predictive ability of Ki67.
Thus, we tested whether Ki67 score in the surgically-resected residual
tumor (RT) after NAC predicted outcome in a cohort of triple negative
breast cancer (TNBC). Gene expression profiling was performed to identify
molecular subtype and test the association with gene modules indicative of
signaling pathway activation. Methods: Ki67 was scored in the RT of 89
patients with stage II-III TNBC (ER/PR/HER2 negative by IHC at diagnosis)
that had been treated with NAC. Expression levels for 450 genes were
quantified by Nanostring. Ki67, node and menopause status, age, therapy
type (� taxanes), molecular subtype, and gene expression scores were
tested for association to RFS and OS using univariate and multivariate
CoxPH models. Results: Ki67 score in the post-NAC RT demonstrated a
wide range (1.5-77.7%; median: 36.2%). Twenty seven % of RTs were 3�
HER2 by IHC. Molecular subtype in the RT was as follows: 64% Basal-like;
20% HER2-enriched; 6% LumA; 6% LumB; 4% Normal-like. In univariate
analyses to respectively predict RFS and OS, node status (p�0.005 and
p�0.02), number of nodes (p�0.003 and p�0.001), and the score of a
gene expression module of MEK pathway activation (p�0.04 and p�0.01,)
were significant. Basal-like subtype approached significance for RFS
(p�0.1) and OS (p�0.05). In multivariate analyses, node status (p�0.002
for RFS and p�0.001 for OS) and MEK pathway activation score (p�0.04
and p�0.01) were significant predictors. Conclusions: Ki67 in the RT after
NAC was not predictive of outcome in a cohort of TNBC. However, a gene
expression signature of activated MEK was negatively associated with
outcome. These data are consistent with the reported preclinical activity of
MEK inhibitors against basal-like breast cancer cells and a possible role of
this signaling pathway in chemotherapy resistance. They also support deep
sequencing studies to identify genetic alterations in the RAS/MEK/MAPK
pathway in TNBC.
1026 Poster Discussion Session (Board #18), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
A phase II study of preoperative (preop) bevacizumab (bev) followed by
dose-dense (dd) doxorubicin (A)/cyclophosphamide (C)/paclitaxel (T) in
combination with bev in HER2-negative operable breast cancer (BC).
Presenting Author: Sara M. Tolaney, Dana-Farber Cancer Institute, Boston,
MA
Background: Two recent preop studies evaluating bev showed conflicting
results, particularly in hormone receptor (HR)� BC. Identification of
predictive markers and their relationship to the pharmacodynamic effects
of bev would facilitate the identification of BCs most likely to benefit from
bev. To accomplish these goals, we conducted a unique preop trial with a
run-in of single agent bev followed by ddACT with bev in two cohorts, one
with HR�HER2– BC, and a smaller triple negative (TN) cohort. Methods:
Pts with HR�, HER2– or TN BC were eligible if their tumor (T) was �1.5
cm and high grade, or had axillary LN involvement; or if T�2.5cm and was
low/intermediate grade. Treatment consisted of a single dose of bev 10
mg/kg, followed two wks later by A 60 mg/m2 and C 600 mg/m2 with bev 10
mg/kg q2 wks x 4, followed by T 175 mg/m2 with bev 10 mg/kg q2 wks x 3,
followed by T 175 mg/m2 x1. Research core biopsies and interstitial fluid
pressure (IFP) were assessed pre- and post- bev alone. Pathologic response
was confirmed centrally and Miller-Payne (MP) was assessed. Results: 84
pts with HR� and 20 pts with TN breast cancer were enrolled. Amongst
HR� pts, 74 had surgical tissue centrally reviewed, and 6 (8%) had a pCR.
Amongst TN pts, 18 pts had tissue centrally reviewed and 8 (44%) had a
pCR. Grade was found to predict MP response in both HR� and TN pts
(p�0.001). Several biomarkers were evaluated as predictors of response to
bev. Baseline sVEGFR1 correlated with MP response to treatment among
TN pts (p�0.015). Single-agent bev reduced the mean vascular density by
18.5% (p�0.049) in HR� patients and the mean IFP in the overall cohort
and HR� patients by 20 (p�0.020) and 24.5% (p�0.001), respectively.
The reductions in IFP correlated with higher levels of sVEGFR2 (p�0.003).
The IFP decreased � 50% in 24/65 pts and did not change in others. Gene
expression profiling by PAM50 is underway. Conclusions: The addition of
bev to preop chemotherapy is well tolerated. Tumor grade appears to
predict MP response in HR� and TN tumors, and sVEGFR1 may be a
predictor of MP response to bev in TN tumors. Further work for biomarker
predictors of response to bev is ongoing.
Breast Cancer—Triple-Negative/Cytotoxics/Local Therapy
55s
1025 Poster Discussion Session (Board #17), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
NSABP FB-6: Phase II trial of weekly paclitaxel (WP) and pazopanib
following doxorubicin and cyclophosphamide (AC) as neoadjuvant therapy
for HER2-negative locally advanced breast cancer (LABC). Presenting
Author: Antoinette R. Tan, National Surgical Adjuvant Breast and Bowel
Project and The Cancer Institute of New Jersey, New Brunswick, NJ
Background: Pazopanib is an oral, small molecule inhibitor of VEGFR-1, -2,
and-3, PDGFR-�, and -�, and c-kit tyrosine kinases. The purpose of this
trial was to determine the activity and safety profile of pazopanib when
added to neoadjuvant WP following AC in LABC. The primary endpoint was
pathologic complete response in the breast and nodes (pCR-BN). Methods:
Women with HER2-negative stage IIIA-IIIC breast cancer were treated with
AC (60 mg/m2 /600 mg/m2 ) for 4 cycles every 3 weeks followed by WP 80
mg/m2 on days 1, 8, and 15 every 28 days for 4 cycles concurrently with
pazopanib 800 mg orally daily prior to surgery. Postoperatively, pazopanib
was given for 6 months. The regimen would be considered active if �14
responses (16% pCR rate in breast and nodes) were observed in 87
evaluable patients. Patients were considered evaluable if they received at
least 1 dose of pazopanib. Results: Between July 2009 and March 2011,
101 pts (median age 51 yrs, range 30-71) were enrolled; 56% had stage
IIIA, 34% stage IIIB, and 10% stage IIIC disease. 74 pts (73%) had
ER-and/or PR-positive tumors and 27 pts (27%) were triple negative. 8
patients did not begin pazopanib. The pCR-BN rate in evaluable patients
for whom surgical information was known was 18% (16/89). The pCR-BN
rate in ER positive disease was 9% (6/65) and was 42% (10/24) in TNBC.
Toxicities observed with WP and pazopanib included diarrhea (gr 2/3,
10%/5%), hand-foot syndrome (gr 2/3, 11%/1%), hypertension (gr 2/3,
12%/3%), neuropathy (gr 2/3, 14%/1%), and neutropenia (gr 3/4, 25%/
1%). Liver toxicity during WP and pazopanib included ALT (gr 2/3/4,
13%/7%/1%), AST (gr 2/3, 7%/7%), and total bilirubin (gr 2, 2%).
Conclusions: A regimen of WP and pazopanib following AC was active as
neoadjuvant therapy in women with LABC and met the pre-specified criteria
of interest. The activity in TNBC was notable. The toxicity profile of WP and
pazopanib was consistent with previous experience. Support: GlaxoSmith-
Kline.
1027 Poster Discussion Session (Board #19), Mon, 1:15 PM-5:15 PM and
4:45 PM-5:45 PM
Association of a compact 13-gene VEGF signature with OS in E2100.
Presenting Author: Scooter Willis, Scripps Research Institute, Jupiter, FL
Background: E2100, an open-label, randomized, phase III trial, demonstrated
a significant improvement in progression free survival and overall
response rate with paclitaxel plus bevacizumab compared with paclitaxel
alone as initial chemotherapy for patients with HER2-negative metastatic
breast cancer. Genentech completed additional clinical trials and submitted
these data to the FDA. On 18 Nov, 2011, the FDA Commissioner
revoked the agency’s approval of bevacizumab for the breast cancer
indication because of the lack of evidence of an improvement in overall
survival or a clinical benefit to patients sufficient to outweigh the risks.
However, the Commissioner “encouraged Genentech to consider additional
studies to identify if there are select subgroups of women who might benefit
from this drug”. Hu et al. (BMC Medicine 2009) published a compact 13
gene VEGF-signature associated with distant metastases and poor outcomes.
Supervised analyses comparing patients with distant metastases
versus primary tumors or regional metastases showed that the distant
metastases were distinct and distinguished by the lack of expression of
fibroblast/mesenchymal genes, and by the high expression of a 13 gene
profile that included VEGF, ANGPTL4, ADM and the monocarboxylic acid
transporter SLC16A3. Methods: We have investigated the VEGF signature in
silico on Illumina DASL analysis of 122 FFPE samples remaining from
E2100. Results: PFS benefit is seen for pacli � bev vs pacli in both
treatment arms with the low VEGF signature (HR 0.45 95% CI .27-.77 p
.009 n 67) and with the high VEGF signature (HR 0.57 95% CI .32-1.0 p
.015 n 55). However, OS benefit is only seen for pacli � bev vs pacli in the
high VEGF group (HR 0.56 95% CI .30-1.05 p .02 n 52) and not in
patients with the low VEGF signature (HR 1.12 95% CI .66-1.90 p .81 n
67). Conclusions: Hence, this signature, which suggests that the response
to hypoxia includes the ability to promote new blood and lymphatic vessel
formation, shows great potential as a predictive biomarker of those patients
to whom bevacizumab would convey an OS advantage benefit. We note with
great caution that this exploratory analysis of trial subset is underpowered,
hence, this compact VEGF signature is being pursued in other bevacizumab
trial sets.
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