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

668s Tumor Biology
10548 General Poster Session (Board #43E), Mon, 1:15 PM-5:15 PM
Different EGFR/KRAS mutation spectrums in lung cancer between never
smokers and heavy smokers. Presenting Author: Kazuya Takamochi,
Juntendo University School of Medicine, Tokyo, Japan
Background: EGFR mutations are more commonly found in lung adenocarcinomas
in never smokers, while KRAS mutations are more frequently
present in those in heavy smokers. Although the incidence is low, EGFR
mutations are also found in tumors in heavy smokers and KRAS mutations
also occur in tumors in never smokers. Therefore, there may be different
biological characteristics in EGFR/ KRAS mutated lung cancers according
to the smoking status. Methods: This was a retrospective review of 382
patients with surgically resected lung cancers between February 2009 and
March 2011. The clinicopathological factors (age, gender, histology, serum
CEA level, pathological nodal status, lymphatic permeation, and blood
vessel invasion) and EGFR/KRAS mutation spectrums were compared
between never smokers (pack-year � 0, n � 161) and heavy smokers
(pack-year � 20, n � 167). Results: EGFR mutations were detected in 88
(55%) never smokers and in 33 (20%) heavy smokers. In contrast, K-ras
mutations were detected in 7 (4%) never smokers and in 31 (19%) heavy
smokers. Both EGFR and KRAS mutations were more frequently observed
in female never smokers and in male heavy smokers. The spectrum of both
EGFR and KRAS mutation differed according to the smoking status. Minor
EGFR mutations other than exon 21 L858R and exon 19 deletions that are
activating mutations indicating the efficacy of EGFR tyrosine kinase
inhibitors (TKIs) were more frequently found in heavy smokers than in never
smokers. G¡A transitions were more common KRAS mutations in never
smokers and G¡T transversions that are thought to be related to exposure
to the polycyclic aromatic hydrocarbons found in cigarette smoke were
more common KRAS mutations in heavy smokers. Conclusions: The
EGFR/KRAS mutation spectrums in lung cancer were quite different in
never smokers and heavy smokers. Further study is needed to evaluate the
relationship between the efficacy of such molecular targeting agents as
EGFR TKIs and the EGFR/KRAS mutation spectrums.
10551 General Poster Session (Board #43H), Mon, 1:15 PM-5:15 PM
Prediction of late metastasis in node-negative breast cancer. Presenting
Author: Marcus Schmidt, Department of Obstetrics and Gynecology,
Johannes Gutenberg University, Mainz, Germany
Background: Prediction of late metastasis is of clinical relevance in breast
cancer. However, systematic genome-wide studies to identify genes associated
with increased risk of metastasis 5 or more years after surgery are
scarce. Methods: We examined the natural course of disease in three
previously published cohorts (Mainz, Rotterdam, Transbig) including 766
node-negative breast cancer patients with gene array data who did not
receive systemic chemotherapy in the adjuvant setting. We established a
Cox regression based method adjusted for multiple testing that identified
genes predicting late metastasis (5 or more years after surgery). Only those
genes were accepted that showed similar results in all three cohorts.
Metastasis-free survival (MFS) was analyzed with univariate and multivariate
Cox regression. Results: We identified 9 genes [ABCC5 (Hazard Ratio
(HR) 2.19, p�0.003), EDDM3B (HR 3.58, p�0.044), RAD23B (HR
0.37, p�0.001), XYLT2 (HR 2.19, p�0.027), DDX18 (HR 0.35,
p�0.006), GPBP1L1 (HR 0.20, p�0.018), UBB (HR 9.73, p�0.025),
RPS24 (HR 0.20, p�0.050), GPC1 (HR 2.36, p�0.013)] predicting late
metastasis. These genes retained their independent prognostic significance
after adjustment for established clinical factors (age, tumor size,
grade, hormone receptor status, HER2) and biological motives like estrogen
receptor, proliferation, B or T cells. These late-type genes are largely
associated with resistance to hypoxia, apoptosis and DNA damage, suggesting
that they might contribute to persistence of disseminated tumor cells.
Conclusions: Genes associated with late metastasis offer a perspective to
identify breast cancer patients suitable for additional and prolonged
therapies.
10549 General Poster Session (Board #43F), Mon, 1:15 PM-5:15 PM
Combined targeting of LSD1 (KDM1A) and histone deacetylases exerts
superior efficacy against human AML. Presenting Author: Warren Fiskus,
University of Kansas Medical Center, Kansas City, KS
Background: LSD1 (KDM1A) is FAD-dependent histone H3K4Me2 demethylase.
Inhibition of LSD1 increases H3K4Me3-a permissive mark for gene
expression, and inhibits growth of pluripotent cancer cells. We have
previously noted that treatment with the histone deacetylase (HDAC)
inhibitor panobinostat (PS) depletes EZH2 (the catalytic subunit of the
polycomb repressive complex 2, PRC2) and disrupts its interaction with the
other PRC2 proteins, attenuates LSD1, and de-represses growth inhibitory
and pro-apoptosis genes. Methods: In the present studies, we determined
the chromatin effects and the pre-clinical in vitro and in vivo anti-AML
activity of the novel, non-monoamine oxidase, reversible inhibitor of LSD1,
HCI2509 (100 to 500 nM), alone and in combination with PS, utilizing
cultured (OCI-AML3 and HL-60) and primary human AML blast progenitor
cells. Results: Treatment with HCI2509 dose-dependently increased the
levels of H3K4Me3, p16, p27, and CEBP� in cultured AML cells. This
correlated with inhibition of cell growth and induction of morphologic
differentiation in AML cells. Exposure to HCI2509 disrupted the binding of
LSD1 with the co-repressor CoREST and HDAC1. Treatment with PS (10 to
50 nM) dose-dependently depleted not only LSD1 but also EZH2, SUZ12
and BMI1 in AML cells. Co-treatment with PS enhanced the chromatin
modifying effects of HCI2509. The combination also synergistically induced
loss of viability of cultured and primary AML cells (combination
indices, CI �1.0). Following tail vein infusion and establishment of AML by
OCI-AML3 cells in NOD-SCID mice, treatment with HCI2509 (25 mg/kg,
b.i.w, IP, for 3 weeks) improved survival, as compared to the control mice
(p �0.001). HCI2509 treatment (15 mg/kg IP) also dramatically improved
survival of NSG mice with established human AML following tail-vein
injection of primary AML blasts expressing FLT3-ITD. Survival was further
improved upon co-treatment with HCI2509 and PS (5 mg/kg IP, MWF).
Mice did not experience any toxicity or weight loss. Conclusions: Combined
epigenetic therapy with HCI2509 and PS exerts superior pre-clinical
activity, warranting further in vivo development and testing of HCI2509
against human AML.
10552 General Poster Session (Board #44A), Mon, 1:15 PM-5:15 PM
Prognostic role of microRNA polymorphisms in advanced gastric cancer
patients. Presenting Author: Linnea Stenholm, University Hospital Aachen,
Aachen, Germany
Background: As little is known about the impact of microRNA (mir)
polymorphisms on prognosis of advanced gastric cancer (AGC) we sought to
determine their impact on overall survival (OS) in these patients (pts).
Methods: Pts were treated with either 5-fluorouracil, leucovorin and
oxaliplatin (FLO) or with additional docetaxel (FLOT) in frame of a phase III
or 3 phase II trials of the Arbeitsgemeinschaft Internistische Onkologie. All
pts consented genetic analyses. DNA was extracted from whole blood
samples (n�515) and polymorphisms of mir26a1 (rs7372209), mir27a
(rs895819), mir100 (rs1834306), mir125a (rs12975333), mir146a
(rs2910164), mir196a2 (rs11614913), mir219-1 (rs107822) and mir423
(rs6505162) were genotyped using PCR-based methods. Hetero- and
homozygous variant genotypes were grouped versus homozygous wild type
genotypes. Selection of clinical and genetic parameters for the final
multivariate model was based on univariate and multivariate Cox-regression
analyses with a cut-off value of p � 0.25 and included 498 pts. Results:
Median age was 67 (range 23 to 86) years. 42% were treated with FLO and
58% with FLOT with a median OS of 14 months. Multivariate analyses
revealed following associations: Genetic factors significantly associated
with OS were mir26a1 variant genotypes (HR 1.3 [95%CI (1.01;1.6),
p�.025]), mir27a variant genotypes (HR 1.3 [95%CI (1.01;1.6), p�.036])
and mir196a2 variant genotypes (HR 0.8 [95%CI (0.6;0.99), p�.046]).
Clinical factors with significant impact on OS were ECOG 2 performance
status (HR 1.9 [95%CI (1.3;2.8), p�.002]), curative surgery of advanced
disease (HR 0.3 [95%CI (0.1;0.5), p�.001]) and locally advanced disease
(HR 0.5 [95%CI (0.3;0.7), p�.001]). Combined analyses of the identified
adverse genotypes of mir26a1, mir27a and mir196a2 resulted in a median
OS of 9, 13, 14 and 17 months for pts with 0 (n�72), 1 (n�193), 2
(n�171) and 3 (n�54) adverse genotypes (p�.029), respectively.
Conclusions: In addition to established clinical factors, mir26a1, mir27a
and mir196a2 polymorphisms were significantly associated with OS. Our
data suggest a strong impact of these mir polymorphisms on prognosis in
AGC and might be of help for a better guidance of treatment decisions.
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