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

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3573 General Poster Session (Board #31B), Mon, 8:00 AM-12:00 PM<br />

The relationship between microRNA-126 and maintenance therapy with<br />

bevacizumab after bevacizumab plus chemotherapy as first-line treatment<br />

for patients with metastatic colorectal cancer: Results <strong>of</strong> the phase III<br />

Nordic ACT trial NCT00598156 translational study. Presenting Author:<br />

Torben Hansen, Danish Colorectal Cancer Group South, Vejle Hospital and<br />

University <strong>of</strong> Southern Denmark, Vejle, Denmark<br />

Background: Maintenance therapy during chemotherapy free intervals is a<br />

debatable topic in metastatic colorectal cancer (mCRC). In the Nordic ACT<br />

trial patients benefitting from induction chemotherapy plus bevacizumab<br />

were randomized to bevacizumab with or without erlotinib. MicroRNA-126<br />

(miRNA-126) is believed to influence angiogenesis in several ways, and we<br />

investigated the relationship between miRNA-126 and progression free<br />

survival (PFS) under maintenance therapy. Methods: The miRNA-126 was<br />

analysed by polymerase chain reaction on both genomic DNA (by the<br />

pri-miRNA-126 (A24G) single nucleotide polymorphism (SNP)) and paraffin<br />

embedded primary tumors, (which were classified as low or high<br />

miRNA-126 expressing tumours using the median value as cut-<strong>of</strong>f).<br />

Diagnostic biopsies were not processed due to limited tumour tissue. Of the<br />

159 randomized patients blood samples were available from 151 and<br />

primary tumours from 91. The PFS (from time <strong>of</strong> randomization) was<br />

compared using the Kaplan-Meier method and the log rank test. The Cox<br />

Regression analyses were used to test for independent contributions.<br />

Results: The A24G SNP was not related to PFS, but a significant association<br />

was seen between genotypes and miRNA-126 expression levels.Furthermore,<br />

the PFS was increased in patients with high tumor miRNA-126<br />

expression compared to patients with low expression, hazard ratio (HR)<br />

0.58 (95% confidence interval (CI) 0.38-0.90), p � 0.015. The median<br />

PFS was 6.2 months (95% CI 4.3-6.6 months) and 4.0 months (95% CI<br />

2.6-4.5 months), respectively. Results did not differ between treatment<br />

arms, but the Cox Regression analysis confirmed an independent prognostic<br />

value <strong>of</strong> the tumor miRNA-126 expression, HR 0.61 (95% CI 0.39-<br />

0.95), p � 0.030. Conclusions: The miRNA-126 may be a potential marker<br />

for bevacizumab containing maintenance therapy. A similar relationship<br />

with PFS has recently been demonstrated in patients with mCRC treated<br />

with chemotherapy only. The results call for validation.<br />

3575 General Poster Session (Board #31D), Mon, 8:00 AM-12:00 PM<br />

Molecular and clinicopathologic evidence <strong>of</strong> heterogeneity in KRASmutant<br />

colon cancers. Presenting Author: Vlad Calin Popovici, Swiss<br />

Institute <strong>of</strong> Bioinformatics, Lausanne, Switzerland<br />

Background: The activation <strong>of</strong> the MEK/ERK signaling cascade by KRAS or<br />

BRAF mutations has a high incidence in colorectal cancer (CRC). While<br />

these mutations are mutually exclusive, we have identified a highly<br />

conserved gene expression pattern, characteristic to BRAF mutants, that<br />

can also be observed in KRAS mutants (AACR 2011, JCO 2012), and<br />

which defines a distinct subpopulation. Its characterization is important as<br />

it may shed a light on the observed survival and treatment response<br />

variability <strong>of</strong> this group <strong>of</strong> CRCs. Methods: A set <strong>of</strong> 257 stage II and III<br />

KRAS mutant CRCs from the PETACC3 clinical trial and a subset <strong>of</strong> 150<br />

CRCs from TCGA project were used for this study. Gene expression data was<br />

available for all samples and, additionally, CNV and methylation data was<br />

available for some <strong>of</strong> the samples. Due to the limited number <strong>of</strong> MSI<br />

samples, the analyses were focused on MSS subpopulation. Results: The<br />

cluster analysis on the genes from the BRAF signature clearly indicated a<br />

major split <strong>of</strong> the KRAS mutants into two subgroups, that were further<br />

compared in terms <strong>of</strong> clinico-pathological and survival parameters. The<br />

BRAF-mutant-like (BML) subgroup was clearly enriched in MSI-H<br />

(p�0.001), right-sided (p�0.038) and mucinous histology (p�0.001)<br />

tumors. The enrichment in mucinous tumors remained significant also in<br />

stratified analysis by MSI status. In MSS, the BML subpopulation <strong>of</strong> KRAS<br />

mutants had the worst prognosis for overall survival (p�0.05, HR�1.6)<br />

and survival after relapse (p�0.004, HR�2.1). Analysis <strong>of</strong> differentially<br />

expressed genes between BML and the rest <strong>of</strong> KRAS mutants identified<br />

genes responsible for colon crypt differentiation, Wnt pathway activation<br />

and, more intriguingly, 50 other genes, all located on chromosome 20q,<br />

that had significantly different activation levels in BML tumors. Among<br />

these genes, there are a number <strong>of</strong> important tumor suppressors, like<br />

PLAGL2, TP53RK and POFUT1. No differences in type <strong>of</strong> KRAS mutation<br />

nor in PIK3CA mutations were found between BML and the rest <strong>of</strong> KRAS<br />

mutants. Conclusions: We identified a subgroup <strong>of</strong> KRAS mutants formed <strong>of</strong><br />

more aggressive, poorly differentiated tumors. All these results prove that<br />

KRAS mutant CRCs form a heterogeneous group tumors.<br />

Gastrointestinal (Colorectal) Cancer<br />

221s<br />

3574 General Poster Session (Board #31C), Mon, 8:00 AM-12:00 PM<br />

Cetuximab combined with infusional 5-fluorouracil/folinic acid (5-FU/FA)<br />

and oxaliplatin in metastatic colorectal cancer (mCRC): A pooled analysis<br />

<strong>of</strong> COIN and OPUS study data. Presenting Author: Julien Taïeb, Georges<br />

Pompidou European Hospital, Paris, France<br />

Background: Infusional 5-FU/FA � oxaliplatin is a widely used schedule in<br />

the first-line treatment <strong>of</strong> mCRC. In the randomized phase II OPUS study,<br />

the addition <strong>of</strong> cetuximab to one such regimen (FOLFOX4) significantly<br />

improved response and progression-free survival (PFS) in patients (pts)<br />

with KRAS wild-type (wt) mCRC. However, in the randomized phase III<br />

COIN study, a benefit for the addition <strong>of</strong> cetuximab to first-line fluoropyrimidine<br />

(administered as either infusional 5-FU or capecitabine) � oxaliplatin<br />

was not confirmed in pts with KRAS wt tumors. Methods: A pooled<br />

study-based analysis <strong>of</strong> treatment outcome in pts with KRAS wt tumors<br />

from the OPUS study and COIN subgroup who received infusional 5-FU/FA<br />

� oxaliplatin (as the OxMdG regimen) was carried out using a random<br />

effects model. Outcome in the pooled analysis was considered in the<br />

context <strong>of</strong> other randomized studies investigating first-line chemotherapy<br />

regimens �/- cetuximab in pts with mCRC. Results: The pooled KRAS wt<br />

population included 179 pts from the OPUS study and 244 from the<br />

OxMdG subgroup <strong>of</strong> the COIN study. A benefit for the addition <strong>of</strong> cetuximab<br />

to infusional 5-FU/FA was suggested for response (odds ratio 1.87, 95% CI<br />

1.07–3.28) and PFS (hazard ratio, HR 0.69, 95% CI 0.52–0.92) but<br />

overall survival (OS) did not show a statistically significant improvement<br />

(HR 0.90, 95% CI 0.73–1.11). These response and PFS data are similar to<br />

those <strong>of</strong> the KRAS wt population <strong>of</strong> the CRYSTAL study investigating<br />

infusional 5-FU/FA and irinotecan �/- cetuximab (response: odds ratio<br />

2.07, 95% CI 1.52–2.83; PFS: HR 0.70, 95% CI 0.56–0.87) whereas the<br />

improvement in OS was statistically significant in that study (HR 0.80,<br />

95% CI 0.67–0.95). Similar efficacy <strong>of</strong> FOLFOX � cetuximab and<br />

FOLFIRI � cetuximab in the first-line treatment <strong>of</strong> mCRC was also<br />

suggested by data from the randomized phase II CORE 1.2.001 and CELIM<br />

studies. Overall, the safety pr<strong>of</strong>ile <strong>of</strong> infusional 5-FU/FA and oxaliplatin �<br />

cetuximab was found to be acceptable and manageable. Conclusions: The<br />

pooled analysis supports the use <strong>of</strong> cetuximab combined with infusional<br />

5-FU/FA and oxaliplatin in the first-line treatment <strong>of</strong> KRAS wt mCRC.<br />

3576 General Poster Session (Board #31E), Mon, 8:00 AM-12:00 PM<br />

Prognostic impact <strong>of</strong> preoperative plasma tissue inhibitor <strong>of</strong> metalloproteinase<br />

1 (pTIMP-1) in colorectal cancer (CRC) patients (Pts): A pooled<br />

analysis <strong>of</strong> 1,024 stage II/III pts. Presenting Author: Nils Brünner, Section<br />

for Pathobiology, Department <strong>of</strong> Veterinary Disease Biology, Faculty <strong>of</strong> Life<br />

Sciences, University <strong>of</strong> Copenhagen, Frederiksberg C, Denmark<br />

Background: Identification <strong>of</strong> a marker with strong prognostic impact on<br />

clinical outcomes would aid in the management <strong>of</strong> pts with primary,<br />

curatively resected CRC. We conducted a pooled individual pt data analysis<br />

to confirm the prognostic value <strong>of</strong> pTIMP-1 for overall survival (OS) in stage<br />

II and III CRC. Methods: pTIMP-1 was determined in plasma using<br />

immunoassays. Samples and clinical data were included from 5 studies<br />

with a total <strong>of</strong> 1,042 stage II/III pts resected between 1991 – 2006<br />

(Holten-Andersen (HA), 2000 [n�378], HA, 2004 [n�226], Waas, 2005<br />

[52], Birgisson, 2010 [225], Nielsen, 2011[n�161]). To provide comparable<br />

measures across studies, pTIMP-1 values were rescaled using<br />

fractional ranks (FR, based on ranks and sample size). Pts were grouped by<br />

the median <strong>of</strong> the pTIMP-1 FR score. Stratified log-rank tests and<br />

multivariate Cox models assessed the association between OS and pT-<br />

IMP-1 FR. Results: Overall, 59% were male; median age 69 years; 56% had<br />

stage II disease and 50% had colon cancer. The median follow-up was 5.5<br />

years with 457 deaths. Continuous pTIMP-1 FR as a linear effect was<br />

significantly associated with OS (p � .0001, HR�1.38 for a 0.3 unit<br />

increase in FR score, 95% CI 1.25 to 1.52).Pts with pTIMP-1 FR above vs<br />

below the median had significantly shorter OS (HR, 1.72; 95% confidence<br />

interval[CI], 1.42 to 2.08, p �0.0001), which remained significant after<br />

adjusting for age, gender, stage, disease location, and serological CEA (HR,<br />

1.31; 95%CI, 1.07 to 1.60; p � 0.009). Results by stage are shown in the<br />

table. No evidence <strong>of</strong> an interaction between pTIMP-1 and stage or disease<br />

location (colon vs. rectal) was observed (all p � 0.6). Conclusions: pTIMP-1<br />

is a strong prognostic marker for predicting OS independent <strong>of</strong> age, gender,<br />

CEA, stage and site <strong>of</strong> disease in curatively resected stage II and III CRC.<br />

Stage II Stage III<br />

pTIMP-1 FR < median pTIMP-1 FR > median pTIMP-1 FR < median pTIMP-1 FR > median<br />

N (%) 281 (48%) 302 (52%) 240 (52%) 218 (48%)<br />

# <strong>of</strong> events 71 125 116 145<br />

5-yr OS rate<br />

73.8%<br />

62.6%<br />

53.9%<br />

34.4%<br />

(95% CI) (68.2%-79.4%) (56.8%-68.4%) (47.1%-60.6%) (27.6%-41.2%)<br />

HR (95% CI) ref 1.73 (1.29 – 2.31) ref 1.71 (1.34 – 2.19)<br />

P 0.0002 �.0001<br />

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