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

3548 General Poster Session (Board #24C), Mon, 8:00 AM-12:00 PM
Plasma concentrations of YKL-40 in chemo-naive patients with metastatic
colorectal cancer treated with FLOX with or without cetuximab: Results
from the NORDIC VII study. Presenting Author: Line Schmidt Tarpgaard,
Department of Oncology, Odense University Hospital, Odense, Denmark
Background: KRAS status is presently the best biomarker to select patients
with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition
even though not confirmed in all phase III studies. In the NORDIC VII study
a survival benefit of adding cetuximab to the Nordic FLOX regimen could
not be confirmed. Identification of new predictive and prognostic biomarkers
is essential. Plasma concentration of YKL-40 is emerging as a new
biomarker in patients with cancer and inflammatory diseases. We tested
the hypothesis that high plasma YKL-40 associates with short progression
free survival (PFS) and short overall survival (OS) in patients included in the
NORDIC VII Study. Methods: 566 patients with mCRC were randomized to:
A) Nordic FLOX; B) FLOX � cetuximab; and C) FLOX for 16 weeks �
cetuximab continuously. Plasma samples were available from 510 patients
(90%). Pretreatment plasma YKL-40 was determined by ELISA (Quidel),
and the plasma YKL-40 concentration was dichotomized according to the
age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Plasma
YKL-40 was elevated in 204 patients (40%) and the median plasma
YKL-40 was higher in the study group compared to healthy subjects (120
mg/l vs. 40 mg/l, p�0.001). Elevated plasma YKL-40 was associated with
short PFS (HR�1.25, 95% CI 1.04-1.51, p�0.02). This relationship was
demonstrated only in patients treated with FLOX chemotherapy alone
(HR�1.42, 1.02-1.98, p�0.04). High plasma YKL-40 was associated
with short OS in all patients (HR�1.55, 1.25-1.92, p�0.001) and in the
different treatment groups (A: HR�1.54, 1.05-2.26, p�0.03; B:
HR�1.40, 0.97-2.01, p�0.07; C: 1.79, 1.23-2.60, p�0.002). Multivariate
analysis (YKL-40, performance status, number of metastatic sites)
demonstrated that elevated plasma YKL-40 was an independent biomarker
of short OS (HR�1.46, 1.17-1.81, p�0.001). Conclusions: Plasma
YKL-40 may be a new prognostic biomarker in patients with mCRC treated
with 1st line FLOX chemotherapy, with or without cetuximab. The predictive
value of plasma YKL-40 is not yet clarified.
3550 General Poster Session (Board #24E), Mon, 8:00 AM-12:00 PM
Adjuvant chemotherapy (ACT) in stage II colon cancer (CC) in patients with
Lynch syndrome. Presenting Author: Karsten Schulmann, Ruhr University
Bochum, Knappschaftskrankenhaus Med. Dpt., Bochum, Germany
Background: Previous studies showed conflicting results regarding the value
of ACT in MSI-H CC. A recent study reported differential benefits from
5-FU-based ACT comparing suspected sporadic vs suspected hereditary
MSI-H CC. We sought to evaluate the prognostic impact of ACT in a large
cohort of Lynch syndrome (LS) patients (pts) with stage II CC. Methods: To
minimize selection bias diagnoses �2 years prior to registration in the
database of the German HNPCC consortium were excluded. 278 patients
(61% male, mean age 42.9y, 13% stage IIB, 51% with MMR gene
mutation) were eligible. Overall Survival (OS), CC-specific Survival (CSS),
and Disease Free Survival (DFS) were analyzed using Kaplan-Meier and Cox
Regression analyses. Results: 5y OS, CSS and DFS were 95%, 95% and
93% respectively. Right-sided CC was independently associated with lower
DFS in stage II and IIA. Increasing age was associated with lower OS, CSS
and DFS in stage IIA, however we observed only trends in the multivariate
analysis. Surgery alone (without ACT) was associated with a slightly lower
OS in stage IIA (univariate HR 3,659; 95% CI 0,81-16,5; P�0.092); but
not with lower DFS and CSS. Prognosis was not different comparing
FOLFOX vs. 5-FU-based ACT. Conclusions: Our data suggest that LS pts
with stage II CC do not benefit from ACT. FOLFOX was not superior to
5-FU-based ACT. If our results are confirmed, LS pts with stage IIA CC
should not receive ACT. The group of stage IIB CC was too small to make
definite conclusions.
OS
Univariate
CSS DFS
HR 95% CI HR 95% CI HR 95% CI
Stage II
(n�278)
Age Per 10y 1,034 0,993-1,08 1,034 0,993-1,08 1,039 0,997-1,08 &
Localization Right
Left 1,58 0,64-3,90 1,58 0,64-3,890 2,78 1,10-6,98 *
T-stage T3
T4 2,12 0,69-6,51 2,12 0,69-6,51 2,66 0,85-8,37 &&
ACT No
Yes 1,37 0,50-3,70 1,37 0,50-3,70 0,99 0,35-2,78
ACT 5-FU
FOLFOX
0,04 0-887 0,04 0-887 1,82 0,33-9,93
Stage IIA
(n�242)
Age Per 10y 1,049 1,000-1,100 ** 1,067 1,000-1,139 *** 1,052 1,003-1,104 §
Localization Right
Left 1,474 0,526-4,131 2,730 0,760-9,805 3,039 1,069-8,683 #
ACT No
Yes 3,659 0,808-16,562 ## 3,974 0,477-33,070 1,566 0,415-5,908
ACT 5-FU
FOLFOX 0,046 0.000-.... 0,045 0.000-.... 1,871 0,169-20,668
*p�0.03; ** p�0.051; *** p� 0.052; § p�0.039; # p� 0.037; ## p�0.092; & p�0.07; && p�0.081.
Gastrointestinal (Colorectal) Cancer
215s
3549 General Poster Session (Board #24D), Mon, 8:00 AM-12:00 PM
Primary side of origin affects the outcome of mCRC patients treated with
first-line FOLFIRI plus bevacizumab independently of BRAF status and
mucinous histology. Presenting Author: Fotios Loupakis, University of
Southern California Norris Comprehensive Cancer Center, Los Angeles, CA
Background: Several studies tried to address the question of whether
primary site of CRC could affect the outcome. Those analyses were limited
by small sample size numbers and/or high degree of heterogeneity in stage
and received treatments and/or limited information regarding molecular
and pathologic features. Mucinous histology and BRAF mutations are more
frequent in right-sided tumors and are both associated with worse outcome
in the metastic setting. Methods: the analysis was conducted on a database
of 455 mCRC prospectively enrolled in a pharmacogenetic translational
study. Patients (pts) were treated with FOLFIRI/bevacizumab. Pts were
excluded if data regarding mucinous histology and/or BRAF mutational
status were lacking or if affected by synchronous right and left-sided
tumors. Results: 200 pts were identified and included in the study.
Mucinous histology, BRAF mutation and right-side primary were found in
35 (17.5%), 14 (7%) and 56 (28%) patients respectively. Right-side
tumors were more frequently BRAF mutated (p�0.001) and the association
was still significant when adjusting for mucinous histology (p�0.001).
There was a trend in the association between mucinous and side (p�0.082).
At a multivariate analysis, pts with right-side primary were at higher risk of
progression (HR�1.88 [95%CI: 1.25-2.84], p�0.0026) and death
(HR�2.07 [95%CI: 1.23-3.49], p�0.006). At a prespecified analysis in
the subgroup of non-mucinous and BRAF wild-type tumors, pts with
right-side primary achieved median PFS and OS of 10.0 and 28.9 mos
compared to 13.0 and 47.6 mos of left-side (PFS, right vs left: HR�1.87
[95%CI: 1.19-2.91], p�0.003; OS: HR�1.91 [95%CI: 1.07-3.39],
p�0.022). This was again confirmed in a multivariate model. Conclusions:
These data underline a possible strong impact of side on the outcome of
mCRC treated with first-line FOLFIRI plus bevacizumab. To give a biological
explanation for these results, a GWAS on germinal DNA and geneexpression
analyses on tumors are ongoing. In order to clarify the prognostic
vs predictive role to antiangiogenic treatments of this feature analyses from
2 phase III randomized trials have been planned.
3551 General Poster Session (Board #24F), Mon, 8:00 AM-12:00 PM
An 18-gene blood-based IVD test for colorectal cancer early detection with
high sensitivity and specificity. Presenting Author: Ye Xu, Fudan University
Cancer Hospital, Shanghai, China
Background: Colorectal cancer (CRC) is often curable particularly diagnosed
at early stages. Different screening strategies are in place in various
counties. However, the compliance rate with current CRC screening
recommendations remains poor. A simple blood-based IVD test would
represent an interesting alternative. We previously reported a 100-gene
signature for early detection of CRC using microarray technology. Based on
this result, we have developed a new blood test with real-time PCR
technology. Methods: 144 CRC cases and 153 Controls were enrolled. A
total of 52 genes were selected as candidate markers to be transferred from
microarray to real-time PCR. The gene expression profiles from 100 CRC
cases and 100 Controls were used as a training set for signature discovery.
Signature identification process was conducted by Minimum Redundancy
Maximum Relevance (mRMR) feature selection method and Support Vector
Machine (SVM) classification algorithm under the Leave-One-Out Cross
Validation (LOOCV) framework. The optimal size of signature was determined
by a stepwise inclusion selection procedure which started with one
gene and repeatedly added genes one by one until all genes were included.
The performance of each N-gene signature by the LOOCV was estimated
and used to determine the best size of signature. Results: The gene
expression profiles measured by microarray and real-time PCR technology
were highly comparable and resulted in a significant correlation in term of
fold change ratio between CRC cases and Controls (Pearson’s Correlation
Coefficient � 0.95). An 18-gene signature was identified and validated in
an independent validation set with 44 CRC cases and 53 Controls. The
performance of 18-gene signature in the validation set reached 88.7%
accuracy (95%CI: 0.80-0.94), 88.6% sensitivity (95%CI: 0.75-0.96),
and 88.7% specificity (95%CI: 0.76-0.95). Conclusions: Our new results
demonstrated the feasibility of technology transfer from microarray to
real-time PCR. The blood test could be offered to individuals who are
unwilling or unable to undergo colonoscopy to increase the CRC screening
compliance rate. Meanwhile, its high specificity could also help to avoid
unnecessary colonoscopies.
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