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

3508 Oral Abstract Session, Sun, 9:45 AM-12:45 PM
EORTC liver metastases intergroup randomized phase III study 40983:
Long-term survival results. Presenting Author: Bernard Nordlinger, Hopital
Ambroise Paré, Boulogne, France
Background: This study evaluates the benefit of combining peri-operative
chemotherapy and surgery for patients with liver only metastases from
colorectal cancer (LM) deemed resectable on pre-operative imaging. The
PFS results, the primary endpoint, were reported (ASCO 2007). We now
report on the secondary endpoint overall survival (OS) results, after a
median follow-up of 8.5 years. Methods: Between September 2000 and
July 2004, 364 patients (pts) with up to 4 LM were randomized between
peri-operative FOLFOX4 (oxaliplatin 85mg/m² and LV5FU2), 6 cycles
before and 6 cycles after surgery, (CT arm), and surgery alone (S arm). OS
was compared between arms using a 2-sided non-stratified log-rank test at
the 0.05 level of significance (intent-to-treat analysis). Results: 182 pts
were randomized in each arm (CT arm and S arm) of which 171 were
eligible (CT and S) and 152 underwent resection (CT and S). In the CT arm,
171 received preop CT and 115 received postop CT. At a median follow-up
of 8.5 years, 221 deaths were reported (61 % of all randomized pts).
Causes of death in CT arm were cancer relapse (85 pts), complication of
surgery (2 pts), other causes (16 pts) and unknown cause (4 pts), and in S
arm, cancer relapse (99 pts), complication of surgery (2 pts), other causes
(11 pts) and unknown cause (2 pts). Observed median OS was higher in CT
arm: 61 months (CT) vs. 54 months (S) in all randomized pts and 64
months (CT) vs. 55 months (S) in eligible pts. The 5 year OS rate was
51.2% (CT) vs. 47.8% (S) (all randomized) and 52.4% (CT) vs. 48.3% (S)
(eligible pts). There was no significant difference in OS between arms
(HR�0.88, 95% CI 0.68-1.14, p�0.34) (all randomized). After progression,
second line treatment with chemotherapy was given in 59 % (CT) and
77% (S) of the pts with cancer progression and repeat surgery in 46% (CT)
and 40% (S), respectively. Conclusions: Peri-operative chemotherapy with
FOLFOX4 improves PFS but does not significantly improve OS over surgery
alone. A potential benefit may have been diluted by second treatment lines
and by more deaths unrelated to cancer in the CT arm.
3510 Poster Discussion Session (Board #2), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Validation of a genomic classifier (ColoPrint) for predicting outcome in the
T3-MSS subgroup of stage II colon cancer patients. Presenting Author:
Ramon Salazar, Institut Catala d’Oncologia, Barcelona, Spain
Background: Adjuvant therapy for stage II patients is recommended for
patients with high risk features, especially with T4 tumors. Adjuvant
therapy is not indicated for patients with MSI-H status who are considered
of being at low risk of disease relapse. However, this leaves the majority of
patients with an undetermined risk. ColoPrint is an 18-gene expression
classifier that identifies early-stage colon cancer patients at higher risk of
disease relapse. Methods: ColoPrint was developed using whole genome
expression data and was validated in public datasets (n�322) and
independent patient cohorts from 5 European hospitals. Tissue specimen,
clinical parameters, MSI-status and follow-up data (median follow-up 70
months) for patients were available and the ColoPrint index was determined
using validated diagnostic arrays. Uni-and multivariate analysis was performed
on the pooled stage II patient set (n�320) and the subset of
patients who were T3/ MSS (n�227). Results: In the analysis of all stage II
patients, ColoPrint classified two-third of stage II patients as being at lower
risk. The 3-year Relapse-Free-Survial (RFS) RFS was 91% for Low Risk and
74% for patients at higher risk with a HR of 2.9 (p�0.001). Clinicopathological
parameters from the ASCO recommendations (T4, perforation, �12
LN assessed, and/ or high grade) or NCCN guidelines (ASCO factors plus
angio-lymphatic invasion) did not predict a differential outcome for high
risk patients (p� 0.20). In the subgroup of patients with T3 and MSS
phenotype, ColoPrint classified 61% of patients at lower risk with a 3-year
RFS of 91% (86-96%) and 39% of patients at higher risk with a 3-year RFS
of 73% (63-83%) (p�0.002). No clinical parameter was significantly
prognostic in this subgroup. Conclusions: ColoPrint combined with established
clinicopathological factors and MSI, significantly improves prognostic
accuracy, thereby facilitating the identification of patients at higher risk
who might be considered for additional treatment.
Gastrointestinal (Colorectal) Cancer
3509 Poster Discussion Session (Board #1), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Validation of two gene-expression risk scores in a large colon cancer cohort
and contribution to an improved prognostic method. Presenting Author:
Arnaud Roth, University Hospital Geneva, Geneva, Switzerland
Background: Prognosis prediction for resected primary colon cancer is
currently based on the tumor, nodes, metastasis (TNM) staging system.
Gene expression based risk scores have been proposed, but need to be
validated and integrated with clinical and TNM variables. We performed an
independent assessment of the individual recurrence signatures developed
for commercial use by Veridex and Genomic Health. Methods: The Veridex
(aVDS) and Genomic Health (aGHS) risk scores were applied to existing
gene expression data of 580 stage III and 108 stage II tumors from the
PETACC-3 trial. Association of the scores with relapse-free (RFS) and
overall survival (OS) of the patients was assessed singularly, and in a
combination with TNM and other clinico-pathological variables, by univariate
and multivariate Cox regression models and logrank methods. Results:
Both risk scores were significantly associated with RFS in univariate and
multivariate models (Table) for the stage III cohort. The scores contributed
different and additive prognostic information, and reached highest effect
sizes (approximate p-value 0.001 and HR per interquartile range 1.4 each)
in a combined model (Table) that includes both scores as well as T-stage,
N-stage and MSI status as significant factors. Analysis in the stage II cohort
gave similar effect estimates. Conclusions: This study confirms in an
independent colon cancer patient cohort that gene expression based risk
scores improve current prognostic models. The best prognostic model was
obtained by using clinico-pathological variables and both gene-expression
risk-scores.
aGHS aVDS
RFS OS RFS OS
Model HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value HR (95% CI) p value
Univariate 1.32(1.10 - 1.58) 0.0023 1.35(1.10 - 1.65) 0.0043 1.25(1.05 - 1.50) 0.0130 1.22(0.99 - 1.50) 0.0571
Multivariate 1.24(1.04 - 1.49) 0.0190 1.27(1.03 - 1.58) 0.0255 1.28(1.05 - 1.55) 0.0130 1.25(1.00 - 1.56) 0.0500
Combined
(aGHS
� aVDS)
1.36(1.13 - 1.65) 0.0014 1.40(1.11 - 1.75) 0.0037 1.41(1.15 - 1.73) 0.0011 1.38(1.09 - 1.75) 0.0074
Hazard ratios for 1 interquartile range variation.
205s
3511 Poster Discussion Session (Board #3), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Identification and validation of gene expression subtypes in a large set of
colorectal cancer samples. Presenting Author: Eva Budinska, Swiss Institute
of Bioinformatics, Lausanne, Switzerland
Background: From a clinical perspective colorectal cancer (CRC) is a
heterogeneous disease whose biological background is insufficiently understood.
In order to adapt targeted treatment to biologically different
categories of CRC patients, in depth understanding of the molecular
mechanisms involved in CRC heterogeneity is urgently needed. Methods:
Consensus cluster analysis of 1113 stage II-III CRC gene expression
profiles from PETACC3 and 4 public datasets defined a set of subtypes
which were confirmed in an independent set of 720 samples. The similarity
between tumors was based on a set of 54 meta-genes. This approach
improves the robustness to measurement noise and gives equal chances to
each biological process to be accounted for in the subtype definition. We
tested the association of the subtypes with clinical variables, molecular
markers and patient survival. Results: We identified and validated 5 major
subtypes A-E, with different levels of expression in 6 main molecular
processes: epithelial-mesenchymal transition (EMT), immune response,
colon crypt differentiation, proliferation, Wnt signaling and chromosome
20q. Significant differences in survival and an enrichment for markers such
as MSI, BRAF mutation, site or p53 status were found between the
subtypes. In addition, the new subtype classification uncovered heterogeneity
within groups defined by these commonly used markers. Survival
analysis showed significant prognostic value for meta-genes connected to
EMT, proliferation and differentiation. Identical data processing and
clustering applied to the validation set on the same meta-genes resulted in
subtypes with almost identical expression patterns. Conclusions: We
identified and validated robust molecular subtypes in the largest set of
stage II-III CRC samples as a combination of multiple molecular processes,
that complement current disease stratification based on clinico-pathological
variables and molecular markers. The biological relevance of these
subtypes was reflected in significant differences in survival. These insights
open new perspectives for improving prognostic models and rationalize the
prediction of tumor-specific drug sensitivity.
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