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

3573 General Poster Session (Board #31B), Mon, 8:00 AM-12:00 PM
The relationship between microRNA-126 and maintenance therapy with
bevacizumab after bevacizumab plus chemotherapy as first-line treatment
for patients with metastatic colorectal cancer: Results of the phase III
Nordic ACT trial NCT00598156 translational study. Presenting Author:
Torben Hansen, Danish Colorectal Cancer Group South, Vejle Hospital and
University of Southern Denmark, Vejle, Denmark
Background: Maintenance therapy during chemotherapy free intervals is a
debatable topic in metastatic colorectal cancer (mCRC). In the Nordic ACT
trial patients benefitting from induction chemotherapy plus bevacizumab
were randomized to bevacizumab with or without erlotinib. MicroRNA-126
(miRNA-126) is believed to influence angiogenesis in several ways, and we
investigated the relationship between miRNA-126 and progression free
survival (PFS) under maintenance therapy. Methods: The miRNA-126 was
analysed by polymerase chain reaction on both genomic DNA (by the
pri-miRNA-126 (A24G) single nucleotide polymorphism (SNP)) and paraffin
embedded primary tumors, (which were classified as low or high
miRNA-126 expressing tumours using the median value as cut-off).
Diagnostic biopsies were not processed due to limited tumour tissue. Of the
159 randomized patients blood samples were available from 151 and
primary tumours from 91. The PFS (from time of randomization) was
compared using the Kaplan-Meier method and the log rank test. The Cox
Regression analyses were used to test for independent contributions.
Results: The A24G SNP was not related to PFS, but a significant association
was seen between genotypes and miRNA-126 expression levels.Furthermore,
the PFS was increased in patients with high tumor miRNA-126
expression compared to patients with low expression, hazard ratio (HR)
0.58 (95% confidence interval (CI) 0.38-0.90), p � 0.015. The median
PFS was 6.2 months (95% CI 4.3-6.6 months) and 4.0 months (95% CI
2.6-4.5 months), respectively. Results did not differ between treatment
arms, but the Cox Regression analysis confirmed an independent prognostic
value of the tumor miRNA-126 expression, HR 0.61 (95% CI 0.39-
0.95), p � 0.030. Conclusions: The miRNA-126 may be a potential marker
for bevacizumab containing maintenance therapy. A similar relationship
with PFS has recently been demonstrated in patients with mCRC treated
with chemotherapy only. The results call for validation.
3575 General Poster Session (Board #31D), Mon, 8:00 AM-12:00 PM
Molecular and clinicopathologic evidence of heterogeneity in KRASmutant
colon cancers. Presenting Author: Vlad Calin Popovici, Swiss
Institute of Bioinformatics, Lausanne, Switzerland
Background: The activation of the MEK/ERK signaling cascade by KRAS or
BRAF mutations has a high incidence in colorectal cancer (CRC). While
these mutations are mutually exclusive, we have identified a highly
conserved gene expression pattern, characteristic to BRAF mutants, that
can also be observed in KRAS mutants (AACR 2011, JCO 2012), and
which defines a distinct subpopulation. Its characterization is important as
it may shed a light on the observed survival and treatment response
variability of this group of CRCs. Methods: A set of 257 stage II and III
KRAS mutant CRCs from the PETACC3 clinical trial and a subset of 150
CRCs from TCGA project were used for this study. Gene expression data was
available for all samples and, additionally, CNV and methylation data was
available for some of the samples. Due to the limited number of MSI
samples, the analyses were focused on MSS subpopulation. Results: The
cluster analysis on the genes from the BRAF signature clearly indicated a
major split of the KRAS mutants into two subgroups, that were further
compared in terms of clinico-pathological and survival parameters. The
BRAF-mutant-like (BML) subgroup was clearly enriched in MSI-H
(p�0.001), right-sided (p�0.038) and mucinous histology (p�0.001)
tumors. The enrichment in mucinous tumors remained significant also in
stratified analysis by MSI status. In MSS, the BML subpopulation of KRAS
mutants had the worst prognosis for overall survival (p�0.05, HR�1.6)
and survival after relapse (p�0.004, HR�2.1). Analysis of differentially
expressed genes between BML and the rest of KRAS mutants identified
genes responsible for colon crypt differentiation, Wnt pathway activation
and, more intriguingly, 50 other genes, all located on chromosome 20q,
that had significantly different activation levels in BML tumors. Among
these genes, there are a number of important tumor suppressors, like
PLAGL2, TP53RK and POFUT1. No differences in type of KRAS mutation
nor in PIK3CA mutations were found between BML and the rest of KRAS
mutants. Conclusions: We identified a subgroup of KRAS mutants formed of
more aggressive, poorly differentiated tumors. All these results prove that
KRAS mutant CRCs form a heterogeneous group tumors.
Gastrointestinal (Colorectal) Cancer
221s
3574 General Poster Session (Board #31C), Mon, 8:00 AM-12:00 PM
Cetuximab combined with infusional 5-fluorouracil/folinic acid (5-FU/FA)
and oxaliplatin in metastatic colorectal cancer (mCRC): A pooled analysis
of COIN and OPUS study data. Presenting Author: Julien Taïeb, Georges
Pompidou European Hospital, Paris, France
Background: Infusional 5-FU/FA � oxaliplatin is a widely used schedule in
the first-line treatment of mCRC. In the randomized phase II OPUS study,
the addition of cetuximab to one such regimen (FOLFOX4) significantly
improved response and progression-free survival (PFS) in patients (pts)
with KRAS wild-type (wt) mCRC. However, in the randomized phase III
COIN study, a benefit for the addition of cetuximab to first-line fluoropyrimidine
(administered as either infusional 5-FU or capecitabine) � oxaliplatin
was not confirmed in pts with KRAS wt tumors. Methods: A pooled
study-based analysis of treatment outcome in pts with KRAS wt tumors
from the OPUS study and COIN subgroup who received infusional 5-FU/FA
� oxaliplatin (as the OxMdG regimen) was carried out using a random
effects model. Outcome in the pooled analysis was considered in the
context of other randomized studies investigating first-line chemotherapy
regimens �/- cetuximab in pts with mCRC. Results: The pooled KRAS wt
population included 179 pts from the OPUS study and 244 from the
OxMdG subgroup of the COIN study. A benefit for the addition of cetuximab
to infusional 5-FU/FA was suggested for response (odds ratio 1.87, 95% CI
1.07–3.28) and PFS (hazard ratio, HR 0.69, 95% CI 0.52–0.92) but
overall survival (OS) did not show a statistically significant improvement
(HR 0.90, 95% CI 0.73–1.11). These response and PFS data are similar to
those of the KRAS wt population of the CRYSTAL study investigating
infusional 5-FU/FA and irinotecan �/- cetuximab (response: odds ratio
2.07, 95% CI 1.52–2.83; PFS: HR 0.70, 95% CI 0.56–0.87) whereas the
improvement in OS was statistically significant in that study (HR 0.80,
95% CI 0.67–0.95). Similar efficacy of FOLFOX � cetuximab and
FOLFIRI � cetuximab in the first-line treatment of mCRC was also
suggested by data from the randomized phase II CORE 1.2.001 and CELIM
studies. Overall, the safety profile of infusional 5-FU/FA and oxaliplatin �
cetuximab was found to be acceptable and manageable. Conclusions: The
pooled analysis supports the use of cetuximab combined with infusional
5-FU/FA and oxaliplatin in the first-line treatment of KRAS wt mCRC.
3576 General Poster Session (Board #31E), Mon, 8:00 AM-12:00 PM
Prognostic impact of preoperative plasma tissue inhibitor of metalloproteinase
1 (pTIMP-1) in colorectal cancer (CRC) patients (Pts): A pooled
analysis of 1,024 stage II/III pts. Presenting Author: Nils Brünner, Section
for Pathobiology, Department of Veterinary Disease Biology, Faculty of Life
Sciences, University of Copenhagen, Frederiksberg C, Denmark
Background: Identification of a marker with strong prognostic impact on
clinical outcomes would aid in the management of pts with primary,
curatively resected CRC. We conducted a pooled individual pt data analysis
to confirm the prognostic value of pTIMP-1 for overall survival (OS) in stage
II and III CRC. Methods: pTIMP-1 was determined in plasma using
immunoassays. Samples and clinical data were included from 5 studies
with a total of 1,042 stage II/III pts resected between 1991 – 2006
(Holten-Andersen (HA), 2000 [n�378], HA, 2004 [n�226], Waas, 2005
[52], Birgisson, 2010 [225], Nielsen, 2011[n�161]). To provide comparable
measures across studies, pTIMP-1 values were rescaled using
fractional ranks (FR, based on ranks and sample size). Pts were grouped by
the median of the pTIMP-1 FR score. Stratified log-rank tests and
multivariate Cox models assessed the association between OS and pT-
IMP-1 FR. Results: Overall, 59% were male; median age 69 years; 56% had
stage II disease and 50% had colon cancer. The median follow-up was 5.5
years with 457 deaths. Continuous pTIMP-1 FR as a linear effect was
significantly associated with OS (p � .0001, HR�1.38 for a 0.3 unit
increase in FR score, 95% CI 1.25 to 1.52).Pts with pTIMP-1 FR above vs
below the median had significantly shorter OS (HR, 1.72; 95% confidence
interval[CI], 1.42 to 2.08, p �0.0001), which remained significant after
adjusting for age, gender, stage, disease location, and serological CEA (HR,
1.31; 95%CI, 1.07 to 1.60; p � 0.009). Results by stage are shown in the
table. No evidence of an interaction between pTIMP-1 and stage or disease
location (colon vs. rectal) was observed (all p � 0.6). Conclusions: pTIMP-1
is a strong prognostic marker for predicting OS independent of age, gender,
CEA, stage and site of disease in curatively resected stage II and III CRC.
Stage II Stage III
pTIMP-1 FR < median pTIMP-1 FR > median pTIMP-1 FR < median pTIMP-1 FR > median
N (%) 281 (48%) 302 (52%) 240 (52%) 218 (48%)
# of events 71 125 116 145
5-yr OS rate
73.8%
62.6%
53.9%
34.4%
(95% CI) (68.2%-79.4%) (56.8%-68.4%) (47.1%-60.6%) (27.6%-41.2%)
HR (95% CI) ref 1.73 (1.29 – 2.31) ref 1.71 (1.34 – 2.19)
P 0.0002 �.0001
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