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

3597 General Poster Session (Board #34B), Mon, 8:00 AM-12:00 PM
Genetic variants of kinases suppressors of ras in KRAS-BRAF wild-type
metastatic colorectal cancer patients treated with cetuximab and irinotecan.
Presenting Author: Leonor Benhaim, University of Southern California
Norris Comprehensive Cancer Center, Los Angeles, CA
Background: Scaffold proteins kinase suppressor of ras (KSRs) have
emerged as critical modulators of the EGFR pathway that binds to RAS
promoting ERK activation. KSR1 and KSR2 have been shown to be over
expressed in various solid tumours including colon cancer. In-vitro, the
down-regulation of KSR results in reduction of cells proliferation and
tumour growth independently to KRAS status. Moving from this biological
rational we investigated the correlation between functional polymorphisms
in the KSR genes and clinical outcomes in patients with KRAS and BRAF
wild-type mCRC treated with cetuximab and irinotecan. Methods: Germline
DNA was obtained from peripheral blood of patients with mCRC KRAS and
BRAF wild- type resistant to irinotecan treated with a combination of
cetuximab and irinotecan. Seven functionally relevant SNP were selected
on the basis of public literature resources and databases, 4 in the KSR1
and 3 in the KSR2 genes and analyzed by PCR followed by direct
sequencing. All candidate SNPs were evaluated for association with
response rate, PFS and OS. Results: A total of 66 patients were included.After
a median follow-up of 13.3 months, median PFS and OS were
4.7 and 11.3 months respectively. Seventeen out of 66 patients (26%)
achieved a RECIST response. In univariate analysis, KSR2 rs11068551
any G(AG/GG) genotype was significantly associated with shorter PFS
compared to that of A/A carriers (median 3.5 vs. 7.4 months, HR�1.74
[95%CI: 1-3.04] p�0.049, log-rank test). This result remained significant
in a multivariate model (HR�2.13 [95%CI: 1.15-3.95], p�0.017, logrank
test). None of the other tested SNPs were significantly associated with
outcomes. Conclusions: Beyond KRAS and BRAF, some proteins including
KSR are involved in modulating the level of activation of the EGFR pathway.
Our results show that the functionally relevant KSR2 rs11068551 could
affect PFS in advanced mCRC patients treated with cetuximab and
irinotecan. Preclinical studies to confirm and further explain these preliminary
findings are ongoing.
3599 General Poster Session (Board #34D), Mon, 8:00 AM-12:00 PM
The effect of deprivation on uptake and outcomes in a population-based
FOBt colorectal cancer screening program. Presenting Author: David
Mansouri, Department of Surgery, University of Glasgow, Glasgow, United
Kingdom
Background: Population-based FOBt colorectal cancer screening has been
shown to reduce cancer specific mortality and is used across the UK.
Despite evidence that socioeconomic deprivation is associated with increased
incidence of colorectal cancer, uptake of screening may be lower in
those who are more deprived. The aim of this study was to assess the impact
of deprivation on the screening process. Methods: A prospectively maintained
database, encompassing the first screening round in a single
geographical area, was analysed with deprivation categories calculated
from the Scottish Index of Multiple Deprivation 2009. Results: Overall,
395,698 individuals were invited to screening, 204,812(52%) participated
and 6,094(3%) tested positive. 32% of screened individuals were in
the most deprived quintile. Of the positive tests, 5,457(95%) agreed to be
pre-assessed for colonoscopy. 839(16%) did not proceed to colonoscopy
following pre-assessment. Of the 4,618 that attended for colonoscopy,
cancer was detected in 7%. Colonoscopy results were not recorded in
1,035(22%) cases. Lower uptake of screening was seen in males, those
that were younger and those who were more deprived (p�0.001). Higher
levels of deprivation were also associated with not proceeding to colonoscopy
following pre-assessment (p�0.001). Higher positivity rates were
seen in males, those that were older and more deprived (p�0.001). Despite
higher positivity rates in the more deprived individuals (4% most deprived
vs 2% least deprived, p�0.001), the positive predictive value of detecting
cancer in those attending for colonoscopy was lower in those who were more
deprived (6% most deprived vs 8% least deprived, p�0.040). Conclusions:
Socioeconomic deprivation has a significant effect throughout the FOBt
screening process. Individuals who are more deprived are less likely to
participate in screening, less likely to complete the screening process and
less likely to have cancer identified as a result of a positive test. This study
adds further weight to existing evidence that individuals who are more
deprived are less likely to engage in population-based FOBt colorectal
cancer screening. Novel strategies to improve this are required.
Gastrointestinal (Colorectal) Cancer
227s
3598 General Poster Session (Board #34C), Mon, 8:00 AM-12:00 PM
Correlation of specific cytokine profiles with high blood neutrophil-tolymphocyte
ratio and outcome in metastatic colorectal cancer. Presenting
Author: Zhi-Yu Chen, Fudan University Shanghai Cancer Center, Shanghai,
China
Background: High blood neutrophil-to-lymphocyte ratio (NLR) has been
previously identified as a poor prognostic marker in patients with metastatic
colorectal cancer (mCRC). However, the underlying pathophysiology associated
with this marker is not well defined. We validated this biomarker and
investigated the relationship between circulating cytokines and high NLR.
Methods: NLRs were calculated retrospectively from the ratio of peripheral
blood absolute neutrophil and lymphocyte counts, and segregated based on
previously determined cutoff of �5 and �5. Four cohorts with a total of
805 CRC pts were evaluated to confirm the prognostic clinical significance
of NLR. Plasma cytokine levels were evaluated in exploratory (n�39) and
validation cohorts (n�166) of previously untreated mCRC patients using
multiplex-bead assays, and correlated with NLR. Results: High NLR is
present in 20% of CRC patients and is associated with poor prognosis,
independent of known prognostic factors (Table). Expression of 6 cytokines
(IL-6, IL-8, IL-2Ra, HGF, M-CSF and VEGF) correlated with NLR�5 in both
the exploratory and validation cohort. In the validation cohort, an additional
14 cytokines correlated with NLR�5, including high EREG,AREG, and
TGF-�, and low TRAIL. By hierarchial clustering, these 20 cytokines fall
into 3 overlapping major clusters: angiogenic cytokines, inflammatory
cytokines, and epidermal growth factor ligands. In the validation cohort, pts
with a composite cytokine score below the median have longer survival than
patients with high scores (40.0 mo vs 20.0 mo, HR � 2.24; 95%
CI�1.47–3.41; P�0.001). Conclusions: High peripheral blood neutrophil/
lymphocyte ratio (NLR) is associated with poor outcomes independent of
other known prognostic features. NLR correlates with discrete sets of
cytokines which may reflect important biological features in poor prognosis
mCRC.
Median OS (months) 3-yr survival rate
Cohort (number of pts) HR 95% CI P value NLR5 NLR5
Untreated mCRC (166) 2.7 1.8-4.3 �0.001 34.2 15.3
Phase � mCRC (167) 2.2 1.5-3.1 �0.001 9.0 3.7
Hepatectomy mCRC (208) 1.8 1.1-2.9 0.01 13.3 (DFS) 9.5 (DFS) 38% 8%
Stage II/ III CRC (274) 2.4 1.1-5.1 0.02 90% 75%
3600 General Poster Session (Board #34E), Mon, 8:00 AM-12:00 PM
HER2 status in locally advanced rectal cancer and metachronous metastases:
Opportunity for a new therapeutic approach? Presenting Author:
Lena-Christin Conradi, Department of General and Visceral Surgery, University
Medical Center, Georg-August-University, Göttingen, Germany
Background: Even though the implementation of multimodal treatment
strategies including neoadjuvant radiochemotherapy (RCT) has led to
improved survival distant metastases are still limiting the prognosis of
rectal cancer patients. In this context, we investigated the HER-2 status in
rectal cancer patients, UICC stages II and III. Our aim was to assess the
HER-2 positivity rate in primary tumors and metachronous metastases.
Methods: In this study 264 rectal cancer patients (192 male, 72 female;
median age 64 years) from phase-II/-III-trials of the German Rectal Cancer
Study Group (CAO/ARO/AIO-94 and 04) were included. HER-2 status was
determined pretherapeutically in tumor biopsies as well as resection
specimens and metachronous metastases (n�27) using immunohistochemistry
(IHC0 to IHC3�) scoring and S-ISH-amplification detection. Tumors
with IHC3� or S-ISH ratio ?2.0 were classified as HER-2 positive; results
were correlated with clinicopathological parameters and long-term survival.
Results: A positive HER-2 status was found in 12.4% of pre-treatment
biopsies, in 29.3% of the resection specimens and 22.2% (n�6) of
metastases. With a median follow-up of 46.5 months patients with
HER-2-positivity showed better disease free survival (p�0.06) and cancerspecific
survival (CSS, p�0.05). The 5-years survival rate was 96.4%
(HER-2-positive) versus 79.5% (HER-2-negative). In multivariate analyses
HER-2 status was as an independent (p�0.0053) predictor for CSS along
with (y)pN-status (p�0.0001) and R-status (p�0.023). Conclusions:
HER-2 amplification is detectable in a significant proportion (about 30%)
of primary tumors of patients with advanced rectal cancer. Furthermore
HER-2 amplification was detectable in 22% of resected metachronous
metastases during follow-up. Therefore HER-2 represents a promising
target and should be further assessed within prospective clinical trials.
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