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

682s Tumor Biology
10606 General Poster Session (Board #50G), Mon, 1:15 PM-5:15 PM
Evaluation of the clinical utility of kallikrein-related peptidase 6 gene
(KLK6) downregulation in breast cancer. Presenting Author: Kleita Michaelidou,
Department of Biochemistry and Molecular Biology, University of
Athens, Panepistimiopolis, Athens, Greece
Background: Breast cancer (BC), the most common malignancy among the
female population, remains a crucial public health problem. The identification
and exploitation of novel molecular biomarkers can contribute in the
multidimensional approach which is required for optimal management of
BC patients. The abnormal expression of several KLK members has been
documented for breast cancer. Interestingly, many of these genes are found
to be potential prognostic markers for this malignancy. KLK6 expression is
positively associated with tumor progression in various human malignancies;
however in breast cancer, it can restrain tumor progression. We
therefore sought to investigate the possible clinical value of KLK6 as a
breast cancer biomarker. Methods: Total RNA was isolated from 107 breast
tumors and their matched normal compartments. After testing the quality
of the extracted RNA, cDNA was prepared by reverse transcription.
Quantitative Real-time PCR was performed, for KLK6 mRNA quantification,
using the SYBR Green chemistry. Relative quantification analysis was
made using the comparative Ct (2-��C T) method. HPRT1 was used as an
endogenous control gene and BT-474 breast cancer cell line served as a
calibrator. Results: KLK6 mRNA levels were significantly downregulated in
the cancerous breast tissue specimens compared to their normal counterparts
(p�0.001). Additionally, a negative association was observed between
KLK6 expression status and tumor stage, given the fact that 54.2%
of less advanced breast tumors (TNM stage� T2a) were KLK6-positive
compared to the 34.6% of more advanced-stage tumors (TNM �T2a)
(p�0.034). Moreover, a statistically significant negative correlation was
documented between KLK6 mRNA levels and estrogen (p�0.001) and
progesterone receptor (p�0.003) statuses. Conclusions: The downregulation
of KLK6 in cancerous compared to normal sections of breast tissue
samples reflects the reported tumor suppressor properties of KLK6 gene in
breast malignancies. Furthermore, the negative association of KLK6 mRNA
expression with tumor stage, ER and PR statuses reveals the putative role of
KLK6 as a promising prognostic breast cancer biomarker.
10608 General Poster Session (Board #51A), Mon, 1:15 PM-5:15 PM
Study of the usefulness of angiotensin type 1 receptor (AGTR1) as a
possible response predictor in patients with metastatic breast cancer
(mBC) subjected to chemotherapy and treatment with bevacizumab
(AVALUZ Study). Presenting Author: Juan De la Haba- Rodriguez, Hospital
Universitario Reina Sofía, Cordoba, Spain
Background: Angiotensin type 1 receptor (AGTR1) is a membrane receptor
implicated in the regulation of arterial pressure. It has also been related to
carcinogenesis and tumor spread, and participates in neoangiogenesis.
AGTR1 is expressed in a number of neoplasms as BC. In a previous
neoadjuvant study, a significant relationship was observed between AGTR1
expression and CR to a regimen of chemo and bevacizumab (B). To study
and confirm the relationship between tumor expression of AGTR1 and
response to a regimen of chemo and B in pts with mBC. Methods: AGTR1
expression was subjected to immunofluorescence (monoclonal AGTR1
sc1173 antibody, Santa Cruz Biotechnology, CA, USA Dilution 1:50) in 50
samples of mBC pts from the AVALUZ study treated with first line
bevacizumab 10 mg/kg, paclitaxel 150 mg/m2 and gemcitabine 2000
mg/m2 d 1 and 15 c/28 d until PD, unacceptable toxicity or medical
decision. Immunoreactivity was reported as negative (0), low positive (1�)
and high positive (2�). RNA was extracted from paraffin blocks, using the
QIAamp DNA FFPE Tissue Kit and Deparaffinization Solution (QIAGEN)
and expression of AGTR1 candidate gene was quantified using reverse
transcription-PCR (RT-PCR). Results: 60% of the samples expressed
AGTR1 (26% weak and 34% intense) – expression being more frequent in
HR � tumors (65% vs 45%). Among the 50 samples analyzed, measurable
disease was present in 39 pts. Treatment activity was significantly greater
in the tumors AGTR1 expression 2� (p�0.009) (Table). With a median
follow-up of 19.30 months, the progression-free interval was longer in the
tumors with intense AGTR1 expression (17.7 vs 10.8 months, p�0.132).
More consolidated PFS and OS will be presented. Conclusions: AGTR1
expression may be useful as a predictor of response to chemo and
bevacizumab. Prospective studies are needed to confirm these findings.
AGTR1 expression/objective response CR PR SD PD
Intense AGTR1 expression (N:14 ) 35.7% (5) 64.3% (9) 0% 0%
Negative or weak AGTR1 expression (N:25) 4% (1) 56.0% (14) 28% (7) 12 (3%)
CR: complete response, PR: partial response, SD: stable disease, PD: progression disease
10607 General Poster Session (Board #50H), Mon, 1:15 PM-5:15 PM
p53 mutations in advanced cancers: Clinical characteristics and outcomes
in a phase I setting. Presenting Author: Rabih Said, Department of
Investigational Cancer Therapeutics (Phase I Program), University of Texas
M. D. Anderson Cancer Center, Houston, TX
Background: p53 mutation is one of the most common mutations in human
tumors and plays an important role in apoptosis, genomic stability and
inhibition of angiogenesis. Methods: We retrospectively reviewed 121
consecutive patients (pts) with solid tumors referred to the Clinical Center
for Targeted Therapy (Phase I program) who were tested for p53 mutation,
and compared clinical characteristics and outcomes in p53 positive vs.
wild-type (wt) pts. Results: Of the 121 tested pts, 65 (53.7%) were p53
mutation-positive. The presence of p53 mutation was not associated with
sex and race. Tumors with p53 mutation metastasized more often to the
liver (44 pts (67.7%) with mutated p53 vs. 26 pts (46.4%) with wt p53,
p�0.0264); there was no difference in metastasis to the bones, lungs,
brain, soft tissues and adrenals. p53 mutation also showed a trend toward
an association with PTEN-loss (13 out of 43 (30%) with p53 mutated vs. 4
out of 37 (11%) with wt p53, p�0.053). Among pts with the p53
mutation, the best median progression-free survival (PFS) prior to phase I
trial entry was 10.97 months (range 0.85–29.04 months) when the
treatment regimen included bevacizumab and 4.37 months (range 0.92–
14.98 months) when the treatment did not include bevacizumab
(P�0.0046). Among patients with wt p53, there was no significant
difference in PFS between bavacizumab-containing regimens and regimens
without bevacizumab. The median OS from diagnosis was 7.7 years
(95% CI 6.32–9.84 years) vs. 11.8 years (95% CI 10.37 years, not
attained) for p53 mutant vs. wild-type disease (p � 0.03). Univariate
analysis for OS from diagnosis showed that mutated p53, Hispanic race (vs.
Caucasians) and the shorter time from diagnosis to metastasis were
associated with a worse prognosis. Conclusions: Tumors with p53 mutation
have a more aggressive clinical behavior, metastasize more to the liver and
may have a higher rate of PTEN loss compared to tumors with wt p53; In
addition, anti-angiogenic agents may be of therapeutic value in p53mutated
pts.
10609 General Poster Session (Board #51B), Mon, 1:15 PM-5:15 PM
The lipid metabolome of clear cell renal cell carcinoma (CCRCC). Presenting
Author: Saby George, Roswell Park Cancer Institute, Buffalo, NY
Background: The commonest type of kidney cancer is CCRCC. Treatment
approaches mostly target aberrant vasculature. However, kidney cancer is
also known to accumulate lipids and a detailed knowledge of the lipid
species present in these tumors could lead to a better understanding of the
underlying aberrant metabolic pathways and suggest possible treatment
strategies. Lipidomics is an emerging field driven by rapid advances in
mass spectrometry (MS), and is widely used to discover biomarkers. We
attempt to identify the lipidomic profile of CCRCC using a liquid chromatography
MS-based approach (LC-MS). Methods: We utilized 6 fresh frozen
representative samples of CCRCC and matching non-tumor areas of kidney
from nephrectomy samples. Lipids and other non-polar cellular constituents
were extracted from both CCRCC and control tissues by methyl-t-butyl
ether /methanol. LC-MS based lipid profiling was performed on a Waters
Q-ToF Premier MS coupled with Ultra Performance LC. The peak detection
and alignment across all chromatograms were performed using the XCMS
software (v 1.14.1, Scripps Center for Metabolomics). Statistical comparisons
of the intensities of aligned peaks were performed using the XCMSbuilt-in
Welch’s t-test. Results: The outcome of XCMS was converted to a
table that contains fold change, p-value and mass to charge ratio (m/z) for
each peak, its corresponding retention time, and the integrated peak
intensities from all samples. 224 peaks out of 1419 differed between
CCRCC and the control group, with p �0.05, calculated by XCMS. About an
equal number of analytes increased or decreased in CCRCC compared with
control samples. Preliminary attempts to identify the analytes included use
of METLIN (Scripps Center for Metabolomics) and HMDB (Human metabolome
database, Genome Alberta & Genome Canada) databases. Many of the
hits identified phosphatidylcholines, phosphatidylethanolamines, triacylglycerols
and diacylglycerols, as well as other lipid species. Conclusions:
The lipid metabolomic profile varied significantly between CCRCC and
control. Further studies are required to confirm the identities of the lipid
species contributing to this variation by obtaining structural information
using tandem MS (LC-MS/MS).
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