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

10602 General Poster Session (Board #50C), Mon, 1:15 PM-5:15 PM
The components of progression as explanatory variables for overall survival
in the RECIST database. Presenting Author: Saskia Litière, European
Organisation for Research and Treatment of Cancer, Brussels, Belgium
Background: Progressive disease (PD) according to RECIST 1.1 (Eisenhauer
et al, 2009) is defined as one or more of (1) PD of measurable target
lesions, (2) the presence of a new lesion (NL) or (3) the unequivocal PD of
non-target disease (NT-PD). We explored the impact of these components,
varying over time, on predicting overall survival (OS) in the RECIST
database residing at EORTC (Bogaerts et al, 2009). Methods: Data was
selected from 12 randomized clinical trials (3530 patients with breast,
lung or colorectal cancer). A maximum of 5 target lesions was used to
determine the sum of diameters. The following were calculated or assigned
at each measurement time t: best response (BR) was best % improvement
from baseline up to t (0% if no improvement - 100% if complete response
(CR)); tumor growth (TG) was the weekly rate of increase from nadir to t (0 if
no increase; irrespective of prior shrinkage), presence of NL (yes/no), and
occurrence of NT-PD (yes/no); categories were not mutually exclusive. OS
was analyzed by tumor type using a Cox regression model, adjusting for
baseline sum, and including BR, TG, presence of NL and NT-PD as time
dependent covariates. Results: Thirty-six percent of patients had NL, 26%
had NT-PD, 11% achieved CR and 14% did not have shrinkage of target
lesions, while 46% experienced TG (median strongest growth per patient of
0.5 mm/week). Regardless of tumor type, the presence of NL (Hazard Ratio
(HR) ranging 1.4-2.5), NT-PD (HR 1.2-2.5) and TG (per 1mm/week
increase; HR 1.1-1.4) were associated with worse OS, while achieving CR
was associated with a longer OS (HR 0.2-0.8). Further analyses exploring
the functional shape of the association between BR and TG, and OS are
ongoing. This includes putting TG in contrast with the more usual % cutoff
defining target PD. Conclusions: All three components of PD according to
RECIST are independently strongly associated with OS. Quantification
such as this will enable a better understanding of the role of each
component (e.g. clinical aspect of NT-PD assessment) in PD evaluation.
Work is ongoing to incorporate this information into an updated RECIST
with enhanced prediction of subsequent survival.
10604 General Poster Session (Board #50E), Mon, 1:15 PM-5:15 PM
Monitoring of plasma pro-GRP level during EGFR-TKI treatment. Presenting
Author: Yuko Kawano, Cancer Institute Hospital of the Japanese
Foundation for Cancer Research, Tokyo, Japan
Background: Lung cancers harboring mutations in the epidermal growth
factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors
(EGFR-TKI), but drug resistance invariably emerges. The major acquired
mechanisms of resistance are the EGFR T790M mutation or MET gene
amplification. Transformation from NSCLC into small-cell lung cancer
(SCLC) has been recently identified in acquired resistance to EGFR-TKI.
However, it is difficult to predict the transformation during EGFR-TKI
treatment because obtaining serial and sufficient specimens for biopsy is
difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive
tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in
EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels
could predict SCLC transformation in resistance to EGFR-TKI. Methods:
From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC
who received EGFR-TKI treatment were enrolled. Plasma was obtained
from these patients before EGFR-TKI treatment and when EGFR-TKI
treatment failed. Pro-GRP and CEA levels were measured and compared
before and after treatment. Results: Patient characteristics for 49 patients
(15 men, 34 women) were as follows: median age, 62 years (41–81 years);
histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR
mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49
patients had received EGFR-TKI treatment (45 with gefitinib and 4 with
erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD
in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at
pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI
treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the
Pro-GRP levels had increased after treatment, but the CEA level did not
increase. Objective responses to cytotoxic chemotherapy were noted in all 3
patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma
Pro-GRP during EGFR-TKI treatment may be useful for early detection of
SCLC transformation in resistance to EGFR-TKI.
Tumor Biology
681s
10603 General Poster Session (Board #50D), Mon, 1:15 PM-5:15 PM
pAKT expression in paraffin-embedded xenograft tumors after fixation
delays and human breast cancer by optimized immunohistochemistry.
Presenting Author: Sherry X. Yang, Division of Cancer Treatment and
Diagnosis, National Cancer Institute, Bethesda, MD
Background: With progress in targeting PI3K/AKT pathway in the treatment
of a wide range of cancers, it is getting more important than ever for
optimization of detection method of AKT kinase, a central effector of the
pathway, in archived tissues. Recently, we found that pAKT-S473 (pAKT)
significantly predicts paclitaxel benefit in breast cancer (JCO 28: 2974,
2010), in which a good analytical and clinical performance of quantitative
pAKT immunohistochemistry (IHC) was demonstrated. The current study
evaluates pAKT stability in human breast cancer xenograft tumors after
delays in fixation, and assesses a detection window following fixation delays
with an established cutoff [staining index (SI) � 2]. Methods: Xenograft
tumors with high (MDA-MB-468) and intermediate levels (MDA-MB-231)
of pAKT were fixed or snapped frozen in 10% neutral-buffered formalin or
liquid nitrogen after delays post-excision. pAKT staining was performed in
xenograft tumors and 96 cases of human surgical breast tumors by our
optimized and traditional IHCs, and Western blot. Results: The mean SIs
were 133, 121, 112, 94, 84, and 66 using optimized, and in contrast were
51, 44, 29, 14, 12, and 6.4 on traditional method at 0, 15, 30, 60, 120
and 180 min (2.6-fold by comparing the optimized with the traditional at
baseline) in MDA-MB-468 xenograft tumors. pAKT level was ½ by the
optimized, similar to the level detected by Western blot, relative to 1/8 of
the baseline by the traditional (10.6-fold) at 180 min. The logarithmic
decline rate by the optimal was 3.1 times (95% CI, 2.4 - 3.7) less than that
of the traditional (normal approximation; 2-sided P � 0.0001). pAKT
expression was observed in 38.5% (37/96 ) of surgical breast tumors,
comparable to 38% (606/1581) in a large cohort derived from the NSABP
B-28 trial. There was little loss of pAKT in MDA-MB-231 xenograft tumors
up to 180 min by IHC and Western blot. Conclusions: The optimized pAKT
IHC significantly increases the sensitivity of detection with a large window
for positivity. It is suitable for use in archived human specimens although it
warrants further standardization and validation among research laboratories
and perhaps diagnostic laboratories in the future.
10605 General Poster Session (Board #50F), Mon, 1:15 PM-5:15 PM
Anti-AML activity of a novel beta-catenin antagonist BC2059. Presenting
Author: Kapil N. Bhalla, University of Kansas Medical Center, Kansas City,
KS
Background: The canonical WNT-�-catenin pathway is essential for selfrenewal,
growth and survivalof AML stem and progenitor cells. Deregulated
WNT signaling inhibits degradation of �-catenin, causing increased nuclear
translocation and interaction of �-catenin with the TCF/LEF transcription
factor, which up regulates cyclin D1, Myc and survivin expression in AML
progenitor cells. BC2059 (�-Cat Pharmaceuticals) is a potent, small
molecule, anthraquinone oxime-analog, which inhibits WNT-� catenin
pathway by promoting the degradation and attenuation of �-catenin levels.
Methods: We determined the in vitro anti-AML activity of BC2059 (BC)
(250 to 1000 nM) against cultured and primary human AML blast
progenitors, as well as evaluated the in vivo anti-AML efficacy of BC in
NOD-SCID and NOD-SCID-IL2� receptor deficient (NSG) mice. Results: BC
induced cell cycle G1 phase accumulation and apoptosis (40%) of the
cultured OCI-AML3, HL-60 and HEL92.1.7 (HEL) AML cells. BC dosedependently
also induced apoptosis of primary AML versus normal progenitors.
Treatment with BC resulted in proteasomal degradation and decline in
the nuclear levels of �-catenin, which led to decreased activity of the
LEF1/TCF4 transcription factor highlighted by reduced TOP-FLASH luciferase
activity in the AML cells. This was associated with reduced protein
levels of cyclin D1, MYC and survivin. Co-treatment with BC and the
histone deacetylase inhibitor panobinostat (PS) (10 to 20 nM) synergistically
induced apoptosis of cultured and primary AML blasts. Following tail
vein infusion and establishment of AML by OCI-AML3 or HEL cells in
NOD-SCID mice, treatment with BC (5, 10 or 15 mg/kg b.i.w, IV) for three
weeks demonstrated improved survival, as compared to the control mice (p
�0. 001). Survival was further improved upon co-treatment with BC and
PS (5 mg/kg IP, MWF). BC treatment (5 or 10 mg/kg IV) also dramatically
improved survival of NSG mice with established human AML following
tail-vein injection of primary AML blasts expressing FLT3 ITD. Mice did not
experience any toxicity or weight loss. Conclusions: These findings highlight
the notable pre-clinical in vitro and in vivo activity and warrant further
development and in vivo testing of BC against human AML.
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