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

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10602 General Poster Session (Board #50C), Mon, 1:15 PM-5:15 PM<br />

The components <strong>of</strong> progression as explanatory variables for overall survival<br />

in the RECIST database. Presenting Author: Saskia Litière, European<br />

Organisation for Research and Treatment <strong>of</strong> Cancer, Brussels, Belgium<br />

Background: Progressive disease (PD) according to RECIST 1.1 (Eisenhauer<br />

et al, 2009) is defined as one or more <strong>of</strong> (1) PD <strong>of</strong> measurable target<br />

lesions, (2) the presence <strong>of</strong> a new lesion (NL) or (3) the unequivocal PD <strong>of</strong><br />

non-target disease (NT-PD). We explored the impact <strong>of</strong> these components,<br />

varying over time, on predicting overall survival (OS) in the RECIST<br />

database residing at EORTC (Bogaerts et al, 2009). Methods: Data was<br />

selected from 12 randomized clinical trials (3530 patients with breast,<br />

lung or colorectal cancer). A maximum <strong>of</strong> 5 target lesions was used to<br />

determine the sum <strong>of</strong> diameters. The following were calculated or assigned<br />

at each measurement time t: best response (BR) was best % improvement<br />

from baseline up to t (0% if no improvement - 100% if complete response<br />

(CR)); tumor growth (TG) was the weekly rate <strong>of</strong> increase from nadir to t (0 if<br />

no increase; irrespective <strong>of</strong> prior shrinkage), presence <strong>of</strong> NL (yes/no), and<br />

occurrence <strong>of</strong> NT-PD (yes/no); categories were not mutually exclusive. OS<br />

was analyzed by tumor type using a Cox regression model, adjusting for<br />

baseline sum, and including BR, TG, presence <strong>of</strong> NL and NT-PD as time<br />

dependent covariates. Results: Thirty-six percent <strong>of</strong> patients had NL, 26%<br />

had NT-PD, 11% achieved CR and 14% did not have shrinkage <strong>of</strong> target<br />

lesions, while 46% experienced TG (median strongest growth per patient <strong>of</strong><br />

0.5 mm/week). Regardless <strong>of</strong> tumor type, the presence <strong>of</strong> NL (Hazard Ratio<br />

(HR) ranging 1.4-2.5), NT-PD (HR 1.2-2.5) and TG (per 1mm/week<br />

increase; HR 1.1-1.4) were associated with worse OS, while achieving CR<br />

was associated with a longer OS (HR 0.2-0.8). Further analyses exploring<br />

the functional shape <strong>of</strong> the association between BR and TG, and OS are<br />

ongoing. This includes putting TG in contrast with the more usual % cut<strong>of</strong>f<br />

defining target PD. Conclusions: All three components <strong>of</strong> PD according to<br />

RECIST are independently strongly associated with OS. Quantification<br />

such as this will enable a better understanding <strong>of</strong> the role <strong>of</strong> each<br />

component (e.g. clinical aspect <strong>of</strong> NT-PD assessment) in PD evaluation.<br />

Work is ongoing to incorporate this information into an updated RECIST<br />

with enhanced prediction <strong>of</strong> subsequent survival.<br />

10604 General Poster Session (Board #50E), Mon, 1:15 PM-5:15 PM<br />

Monitoring <strong>of</strong> plasma pro-GRP level during EGFR-TKI treatment. Presenting<br />

Author: Yuko Kawano, Cancer Institute Hospital <strong>of</strong> the Japanese<br />

Foundation for Cancer Research, Tokyo, Japan<br />

Background: Lung cancers harboring mutations in the epidermal growth<br />

factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors<br />

(EGFR-TKI), but drug resistance invariably emerges. The major acquired<br />

mechanisms <strong>of</strong> resistance are the EGFR T790M mutation or MET gene<br />

amplification. Transformation from NSCLC into small-cell lung cancer<br />

(SCLC) has been recently identified in acquired resistance to EGFR-TKI.<br />

However, it is difficult to predict the transformation during EGFR-TKI<br />

treatment because obtaining serial and sufficient specimens for biopsy is<br />

difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive<br />

tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in<br />

EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels<br />

could predict SCLC transformation in resistance to EGFR-TKI. Methods:<br />

From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC<br />

who received EGFR-TKI treatment were enrolled. Plasma was obtained<br />

from these patients before EGFR-TKI treatment and when EGFR-TKI<br />

treatment failed. Pro-GRP and CEA levels were measured and compared<br />

before and after treatment. Results: Patient characteristics for 49 patients<br />

(15 men, 34 women) were as follows: median age, 62 years (41–81 years);<br />

histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR<br />

mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49<br />

patients had received EGFR-TKI treatment (45 with gefitinib and 4 with<br />

erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD<br />

in 7, PD in 2, and NE in 1. Positive rate <strong>of</strong> ProGRP and CEA at<br />

pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI<br />

treatment was 6.1% and 69.4%, respectively. In 3 <strong>of</strong> 49 patients, the<br />

Pro-GRP levels had increased after treatment, but the CEA level did not<br />

increase. Objective responses to cytotoxic chemotherapy were noted in all 3<br />

patients after EGFR-TKI treatment. Conclusions: Monitoring <strong>of</strong> plasma<br />

Pro-GRP during EGFR-TKI treatment may be useful for early detection <strong>of</strong><br />

SCLC transformation in resistance to EGFR-TKI.<br />

Tumor Biology<br />

681s<br />

10603 General Poster Session (Board #50D), Mon, 1:15 PM-5:15 PM<br />

pAKT expression in paraffin-embedded xenograft tumors after fixation<br />

delays and human breast cancer by optimized immunohistochemistry.<br />

Presenting Author: Sherry X. Yang, Division <strong>of</strong> Cancer Treatment and<br />

Diagnosis, National Cancer Institute, Bethesda, MD<br />

Background: With progress in targeting PI3K/AKT pathway in the treatment<br />

<strong>of</strong> a wide range <strong>of</strong> cancers, it is getting more important than ever for<br />

optimization <strong>of</strong> detection method <strong>of</strong> AKT kinase, a central effector <strong>of</strong> the<br />

pathway, in archived tissues. Recently, we found that pAKT-S473 (pAKT)<br />

significantly predicts paclitaxel benefit in breast cancer (JCO 28: 2974,<br />

2010), in which a good analytical and clinical performance <strong>of</strong> quantitative<br />

pAKT immunohistochemistry (IHC) was demonstrated. The current study<br />

evaluates pAKT stability in human breast cancer xenograft tumors after<br />

delays in fixation, and assesses a detection window following fixation delays<br />

with an established cut<strong>of</strong>f [staining index (SI) � 2]. Methods: Xenograft<br />

tumors with high (MDA-MB-468) and intermediate levels (MDA-MB-231)<br />

<strong>of</strong> pAKT were fixed or snapped frozen in 10% neutral-buffered formalin or<br />

liquid nitrogen after delays post-excision. pAKT staining was performed in<br />

xenograft tumors and 96 cases <strong>of</strong> human surgical breast tumors by our<br />

optimized and traditional IHCs, and Western blot. Results: The mean SIs<br />

were 133, 121, 112, 94, 84, and 66 using optimized, and in contrast were<br />

51, 44, 29, 14, 12, and 6.4 on traditional method at 0, 15, 30, 60, 120<br />

and 180 min (2.6-fold by comparing the optimized with the traditional at<br />

baseline) in MDA-MB-468 xenograft tumors. pAKT level was ½ by the<br />

optimized, similar to the level detected by Western blot, relative to 1/8 <strong>of</strong><br />

the baseline by the traditional (10.6-fold) at 180 min. The logarithmic<br />

decline rate by the optimal was 3.1 times (95% CI, 2.4 - 3.7) less than that<br />

<strong>of</strong> the traditional (normal approximation; 2-sided P � 0.0001). pAKT<br />

expression was observed in 38.5% (37/96 ) <strong>of</strong> surgical breast tumors,<br />

comparable to 38% (606/1581) in a large cohort derived from the NSABP<br />

B-28 trial. There was little loss <strong>of</strong> pAKT in MDA-MB-231 xenograft tumors<br />

up to 180 min by IHC and Western blot. Conclusions: The optimized pAKT<br />

IHC significantly increases the sensitivity <strong>of</strong> detection with a large window<br />

for positivity. It is suitable for use in archived human specimens although it<br />

warrants further standardization and validation among research laboratories<br />

and perhaps diagnostic laboratories in the future.<br />

10605 General Poster Session (Board #50F), Mon, 1:15 PM-5:15 PM<br />

Anti-AML activity <strong>of</strong> a novel beta-catenin antagonist BC2059. Presenting<br />

Author: Kapil N. Bhalla, University <strong>of</strong> Kansas Medical Center, Kansas City,<br />

KS<br />

Background: The canonical WNT-�-catenin pathway is essential for selfrenewal,<br />

growth and survival<strong>of</strong> AML stem and progenitor cells. Deregulated<br />

WNT signaling inhibits degradation <strong>of</strong> �-catenin, causing increased nuclear<br />

translocation and interaction <strong>of</strong> �-catenin with the TCF/LEF transcription<br />

factor, which up regulates cyclin D1, Myc and survivin expression in AML<br />

progenitor cells. BC2059 (�-Cat Pharmaceuticals) is a potent, small<br />

molecule, anthraquinone oxime-analog, which inhibits WNT-� catenin<br />

pathway by promoting the degradation and attenuation <strong>of</strong> �-catenin levels.<br />

Methods: We determined the in vitro anti-AML activity <strong>of</strong> BC2059 (BC)<br />

(250 to 1000 nM) against cultured and primary human AML blast<br />

progenitors, as well as evaluated the in vivo anti-AML efficacy <strong>of</strong> BC in<br />

NOD-SCID and NOD-SCID-IL2� receptor deficient (NSG) mice. Results: BC<br />

induced cell cycle G1 phase accumulation and apoptosis (40%) <strong>of</strong> the<br />

cultured OCI-AML3, HL-60 and HEL92.1.7 (HEL) AML cells. BC dosedependently<br />

also induced apoptosis <strong>of</strong> primary AML versus normal progenitors.<br />

Treatment with BC resulted in proteasomal degradation and decline in<br />

the nuclear levels <strong>of</strong> �-catenin, which led to decreased activity <strong>of</strong> the<br />

LEF1/TCF4 transcription factor highlighted by reduced TOP-FLASH luciferase<br />

activity in the AML cells. This was associated with reduced protein<br />

levels <strong>of</strong> cyclin D1, MYC and survivin. Co-treatment with BC and the<br />

histone deacetylase inhibitor panobinostat (PS) (10 to 20 nM) synergistically<br />

induced apoptosis <strong>of</strong> cultured and primary AML blasts. Following tail<br />

vein infusion and establishment <strong>of</strong> AML by OCI-AML3 or HEL cells in<br />

NOD-SCID mice, treatment with BC (5, 10 or 15 mg/kg b.i.w, IV) for three<br />

weeks demonstrated improved survival, as compared to the control mice (p<br />

�0. 001). Survival was further improved upon co-treatment with BC and<br />

PS (5 mg/kg IP, MWF). BC treatment (5 or 10 mg/kg IV) also dramatically<br />

improved survival <strong>of</strong> NSG mice with established human AML following<br />

tail-vein injection <strong>of</strong> primary AML blasts expressing FLT3 ITD. Mice did not<br />

experience any toxicity or weight loss. Conclusions: These findings highlight<br />

the notable pre-clinical in vitro and in vivo activity and warrant further<br />

development and in vivo testing <strong>of</strong> BC against human AML.<br />

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