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

218s Gastrointestinal (Colorectal) Cancer
3561 General Poster Session (Board #27B), Mon, 8:00 AM-12:00 PM
Relationship of Src activity and prior oxaliplatin on outcomes after
hepatectomy for metastatic colorectal cancer. Presenting Author: Van
Karlyle Morris, University of Texas M. D. Anderson Cancer Center, Houston,
TX
Background: The nonreceptor tyrosine kinase Src regulates pathways
critical to tumor proliferation, chemoresistance, and epithelial-tomesenchymal
transition. In vitro, Src is activated after acute oxaliplatin
exposure and in acquired oxaliplatin resistance, but not after 5-FU alone.
Activation of Src and its substrate FAK in metastatic colorectal cancer
treated with oxaliplatin has not been studied in human specimens.
Methods: Samples from 170 hepatic resections from two cohorts of patients
with metastatic colorectal cancer were examined by IHC for expression of
activated Src (pSrc) and FAK (total and pFAK). In the first cohort (n�50),
tissue was collected at consecutive hepatic resections before and after
oxaliplatin. Patients in the second cohort (n�120) were compared based
on whether or not oxaliplatin was administered after resection. IHC was
graded semi-quantitatively, 0 to 4 based on intensity (first cohort), and by
automated image analysis (second cohort). Results: In the first cohort,
pFAK expression increased after oxaliplatin exposure (mean IHC score
2.04 vs. 1.18, p�0.01). In the second cohort, Src activation was
correlated with pFAK expression (p�0.01). Patients pretreated with
oxaliplatin demonstrated increased expression of activated FAK (p�0.02)
compared to 5-FU alone or irinotecan regimens. There was a weak
association between total Src expression and the number of oxaliplatin
cycles (p�0.06). Among patients in the second cohort, five-year relapsefree
survival was inversely related to levels of pFAK (21.1%, 16.5%, and
7.4% for low, medium, and high levels of pFAK, respectively; p�0.02) and
of pSrc (19.6%, 13.6%, and 8.2% for low, medium, and high levels of
pSrc, respectively; p� 0.01). Conclusions: Patients treated with neoadjuvant
oxaliplatin demonstrated increased Src signaling in liver metastases, a
finding associated with worse relapse-free survival. These results are
consistent with prior in vitro studies correlating oxaliplatin exposure with
Src pathway activation and support the idea that inhibition of Src, when
used in combination with platinum chemotherapy, warrants further investigation
in patients with metastatic colorectal cancer.
3563 General Poster Session (Board #28A), Mon, 8:00 AM-12:00 PM
Evaluation of FDG-PET in pretreatment staging in locally advanced rectal
cancer: A prospective study. Presenting Author: Jose G. Guillem, Memorial
Sloan-Kettering Cancer Center, New York, NY
Background: The utility of adding 18F-Fluorodeoxyglucose-Positron Emission
Tomography (PET) to the pre-treatment staging of patients with locally
advanced rectal cancer has not been well evaluated. Methods: Following
completion of standard work-up, including physical examination, endorectal
ultrasound, CT of the abdomen and pelvis, and chest CT or chest x-ray,
150 patients with primary, resectable, biopsy-proven rectal adenocarcinoma
requiring neoadjuvant chemoradiation were enrolled in a prospective,
single-stage, phase II study evaluating the role of PET. All patients
underwent a dedicated whole-body PET prior to initiation of neoadjuvant
chemoradiation. The primary endpoint of this analysis was to determine the
accuracy of PET in detecting extrapelvic metastatic disease in primary
rectal cancer patients considered operable on the basis of currentlystandard
work-up. Results: Among the 117 eligible patients found to be
stage II or III by standard staging techniques, none (0%) were found by PET
to have extrapelvic metastatic disease. PET yielded a false positive result in
3 patients (2.6%). PET yielded a false-negative result in 3 patients who
were subsequently diagnosed with metastatic disease: 2 pre-operatively
(liver, lung) and 1 intra-operatively (obturator lymph node). In 1 patient,
PET did identify a previously unappreciated obturator lymph node metastasis;
left pelvic sidewall dissection at the time of rectal resection confirmed
metastatic adenocarcinoma in one obturator lymph node. Conclusions: Of
the 117 rectal cancer patients evaluated and found to have locoregional
disease by standard examination and imaging techniques, none had
extrapelvic metastatic disease accurately identified by PET. PET did not
improve the accuracy of pre-treatment staging. As such, consistent with
current NCCN guidelines, PET does not have a role in pre-treatment staging
of locally advanced rectal cancer.
3562 General Poster Session (Board #27C), Mon, 8:00 AM-12:00 PM
Chemotherapy plus cetuximab in patients with liver-limited or non-liver-limited
KRAS wild-type colorectal metastases: A pooled analysis of the CRYSTAL and
OPUS studies. Presenting Author: Claus-Henning Kohne, Onkologie Klinikum
Oldenburg, Oldenburg, Germany
Background: In the CRYSTAL and OPUS studies, adding cetuximab (cet) to
first-line chemotherapy (CT) improved clinical benefit in patients (pts) with
KRAS wild-type (wt) metastatic colorectal cancer. In a pooled analysis of these
trials the benefit of treatment according to whether pts had liver-limited disease
(LLD) or non-LLD was analyzed. Methods: Cox‘s proportional hazards model for
overall survival (OS) and progression-free survival (PFS) or logistic regression
model for best overall response and R0 resection were used on individual pt data,
stratified by study. Likelihood ratio tests were used to explore interactions.
Results: Adding cet to CT significantly improved PFS and overall response rate
(ORR) in LLD pts, and OS, PFS and ORR in non-LLD pts and increased R0
resection rates (table). No treatment-by-study interactions were found. Treatment
effects did not vary significantly by LLD status (PFS p�0.60, OS p�0.68,
ORR p�0.0737, R0 resection p�0.71). However LLD vs non-LLD pts had
improved outcome in each treatment arm: PFS, CT hazard ratio, HR�0.74,
p�0.0910; CT � cet HR�0.66, p�0.0309; OS, CT HR�0.70, p�0.0091; CT
� cet HR�0.74, p�0.0388; ORR, CT odds ratio�1.20, p�0.47, CT � cet odds
ratio�2.32, p�0.0015; R0 resection, CT odds ratio�3.15, p�0.0496, CT �
cet odds ratio�3.82, p�0.0018. Kaplan Meier survival plots will be shown.
Conclusions: The OS benefit from adding cet to CT is more pronounced in
non-LLD pts, thus strengthening the value of cet in palliative treatment.LLD
status is associated with improved prognosis and may be predictive for response
in pts receiving CT � cet, facilitating potentially curative resection. More pts
(with R0 resection and longer follow-up) may be needed to confirm an OS benefit
from CT � cet in LLD pts.
CT
(n�95)
KRAS wt pts
LLD Non-LLD
CT� cet
(n�93)
CT
(n�352)
CT � cet
(n�305)
OS
Median, mo 27.0 27.0 17.3 22.0
HR 0.81 0.76
p
PFS
0.25 0.0023
Median, mo 9.2 11.9 7.4 9.4
HR 0.53 0.68
p
Response
0.0095 0.0004
ORR% 43.2 72.0 37.2 52.8
Odds ratio 3.51 1.88
p
R0 resection
�0.0001 �0.0001
Rate, % 5.3 11.8 1.7 3.3
Odds ratio 2.38 1.97
p 0.1121 0.1870
Data (except for R0 resection) are adjusted for differences in baseline characteristics
3564 General Poster Session (Board #28B), Mon, 8:00 AM-12:00 PM
Association study of the let-7 microRNA-binding site polymorphism in
3’-untranslated region (UTR) of the KRAS gene in stage III colon cancers
from adjuvant trial NCCTG N0147. Presenting Author: Dan Sha, Mayo
Clinic, Rochester, MN
Background: Lethal-7 (let-7) microRNA has been shown to inhibit colon
cancer cell proliferation by inducing KRAS downregulation after binding to
specific sites in the 3’- UTR. Recent studies identified a KRAS 3’-UTR
polymorphism in the let-7 complimentary site (LCS6) that has been shown
to weaken let-7 binding and alter KRAS expression. Carriers of the LCS6
G-allele showed worse survival in metastatic colorectal cancer from prior
studies of limited sample size. In the current study, we evaluated the LCS6
variant in 2,834 Stage III colon cancer patients and its association with
disease-free survival (DFS), KRAS mutation status, and other clinicopathological
features. Methods: In the NCCTG phase III trial (N0147), the LCS6
variant was assayed in germline DNA extracted from whole blood using
RT-PCR. Extracted tumor DNA was analyzed for KRAS exon 2 mutations.
Chi-squared and two-sample t test were used to compare baseline factors
and KRAS mutation status between patients defined by LCS6 variant
status. Log-rank tests and multivariate Cox models assessed the unadjusted
and adjusted associations between LCS6 status and DFS, respectively.
Results: We identified 432 (15.2%) patients heterozygous or
homozygous for the LCS6 G-allele and 2402 (84.8%) patients homozygous
for the LCS6 T-allele. G-allele carriers were significantly more frequent in
Caucasians than other races (Chi-Squared Test, p�0.0001). No associations
were found between the LCS6 genotype and T stage, positive lymph
node number, tumor differentiation, or primary tumor location (all p�0.2).
Moreover, the LCS6 genotype was not associated with DFS (hazard ratio �
0.93, p�0.49) even after combining LCS6 genotype with KRAS mutation
status. Conclusions: We report the largest association study investigating
the LCS6 polymorphism and colon cancer outcome. There is no significant
evidence that the germline LCS6 genotype was associated with DFS in
stage III colon cancer patients. Additional studies are needed to determine
if LCS6 genotype differs between tumor and germline DNA which may
further clarify its prognostic value.
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