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

208s Gastrointestinal (Colorectal) Cancer
3520 Poster Discussion Session (Board #12), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Effect of low-frequency KRAS mutations on the response to anti-EGFR
therapy in metastatic colorectal cancer. Presenting Author: David Tougeron,
Department of Gastroenterology, Poitiers University Hospital, Poitiers,
France
Background: Monoclonal antibodies against the epidermal growth factor
receptor (EGFR) are standard components of treatment algorithms in
metastatic colorectal cancer (mCRC). It is already well established that
only patients with wild-type KRAS tumors benefit from treatment with an
anti-EGFR agent. Pyrosequencing is now used for a precise determination
of KRAS mutation burden and a conservative cutoff of 10% was defined as
the lower limit of quantification for the assignment of mutation status. Up
to now, the impact of low-signal KRAS mutations below 10% on the
response to anti-EGFR therapy in mCRC has not been evaluated. Methods:
All consecutive patients treated by anti-EGFR for a mCRC between January
2006 and June 2011 have been retrospectively analyzed by pyrosequencing
using the therascreen KRAS Pyro Kit (Qiagen). All patients were defined
wild-type (WT) for KRAS status using direct sequencing. The PFS data were
plotted as Kaplan–Meier curve and compared by the log-rank test. Results:
A total of 141 patients treated by anti-EGFR for a mCRC were included in
the study. Mean age was 64.1 � 14.8 years and a majority of patients had
synchronous metastases (68.6%). Patients benefited from anti-EGFR in
first-line chemotherapy (30.7%), second-line (22.9%), third-line (35%) or
later (11.4%). Majority of patients benefited from anti-EGFR combined
with cytotoxic chemotherapy (91.4%), mostly irinotecan (78.6%). Using
pyrosequencing, 117 tumors had a KRAS WT status and 24 tumors had
low-signal mutation, between 2 and 10% (KRAS lowMT). Response rate
according RECIST criteria were 13.6% versus 35.4% partial response,
13.6% versus 37.2% stabilization and 72.7% versus 27.1% progression
(p�0.01), for KRAS lowMT versus KRAS WT respectively. The PFS was
respectively 2.6 � 0.2 months for KRAS lowMT versus 6.0 � 0.5 months
for KRAS WT (p�0.024). Overall survival was not different between the two
groups (27.4 months versus 33.0 months, p�0.4). Conclusions: Patients
with tumors harboring KRAS lowMT benefit less of anti-EGFR therapy than
patients with tumor harboring KRAS WT. While these results invite to
consider low-signal tumors as positives, generalization awaits a large
prospective trial.
3522 Poster Discussion Session (Board #14), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Impact of age and medical comorbidity (MC) on adjuvant treatment
outcomes for stage III colon cancer (CC): A pooled analysis of individual
patient data from four randomized controlled trials. Presenting Author:
Daniel G. Haller, Abramson Cancer Center at the University of Pennsylvania,
Philadelphia, PA
Background: Studies show significantly improved disease-free and overall
survival (DFS, OS) for oxaliplatin (Ox)-based vs. leucovorin/5-fluorouracil
(LV/5-FU) adjuvant therapy in CC, with conflicting reports of Ox benefit in
patients � 70 years old. The impact of MC on Ox benefit has not been
assessed. We assessed the impact of age and MC on adjuvant treatment
outcomes for stage III CC. Methods: N � 4,819 patients from NSABP C-08,
XELOXA, X-ACT, and AVANT were analyzed by Ox therapy (XELOX/FOLFOX)
vs. LV/5-FU, MC, and age; patients treated with bevacizumab were
excluded. Endpoints were DFS (primary), OS, and safety. MC was assessed
(except NSABP C-08) by adapted Charlson Comorbidity and NCI Combined
Indices (CCI, NCI): Low (� 1) vs. high (� 1). Hazardratios (HR) were
estimated by Cox regression analyses. Multivariate Cox regression analyses
(MVA) tested for independent effects of age and MC on Ox benefit,
controlling for gender, T, and N stage. Results: Patient demographics, MC,
and disease characteristics (except lymph nodes examined) were well
balanced across groups. Median follow-up was shorter in NSABP C-08 and
AVANT (36 and 50 months) vs. XELOXA and X-ACT (83 and 74 months).
MVA-confirmed DFS/OS benefit was consistently shown for XELOX/FOLFOX
vs. LV/5-FU, regardless of age or MC. Grade 3/4 serious adverse event (AE)
rates were comparable across cohorts and CCI scores, and higher in
patients aged � 70. Grade 3/4 AEs of interest, including peripheral sensory
neuropathy, were comparable across ages and CCI scores, and higher with
XELOX/FOLFOX. Conclusions: Ox benefit is modestly attenuated in patients
aged � 70; however, significant benefit is observed regardless of age or MC
in this analysis. Our results further support XELOX or FOLFOX as standard
options for the adjuvant management of stage III CC in all age groups.
Cox regression DFS HR OS HR 95% CI P
CCI � 1 0.59 0.59 0.46–0.760.44–0.78 � .0001 .0003
� 1 0.69 0.65 0.61–0.780.56–0.75 � .0001� .0001
NCI � 1 0.58 0.46–0.730.42–0.74 � .0001� .0001
0.56
� 1 0.70 0.66 0.62–0.790.57–0.76 � .0001� .0001
Age � 70 0.77 0.78 0.62–0.950.61–0.99 .014 .045
� 70 0.68 0.62 0.61–0.760.54–0.72 � .0001� .0001
3521 Poster Discussion Session (Board #13), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
MicroRNA signature to predict sensitivity to anti-EGFR monoclonal antibodies
in metastatic colorectal cancer (mCRC). Presenting Author: Federico
Cappuzzo, Istituto Toscano Tumori-Ospedale-Civile-Livorno, Livorno, Italy
Background: MicroRNAs (MiRNAs) are post-transcriptional regulators that
bind to complementary sequences on target messenger RNA transcripts,
usually resulting in gene silencing. Microarray technology is a powerful
high-throughput tool capable of monitoring the expression of thousands of
small noncoding RNAs at once. In the present study we aimed to
investigate whether MiRNA signature was predictive for sensitivity to
anti-EGFR monoclonal antibodies in mCRC. Methods: A total of 183 mCRC
from two independent cohorts (cohort 1: 74 cases; validation cohort: 109
cases) treated with cetuximab/panitumumab either alone (n�19) or in
combination with chemotherapy (n�164) were included onto the study.
MiRNA arrays were analysed using Agilent’s miRNA platform. Results:
MiRNA array analyses identified the cluster miR-99a/Let7c/miR-125b
located on 21p11.1 as associated with different outcome to anti-EGFR
therapies. In the first cohort, individuals with high signature (n�25,
33.8%) had a significantly longer progression free survival (PFS, 6.1 versus
2.3 months, p�0.01, HR�0.42) and overall survival (OS, 29.8 versus 7.0
months, p�0.04, HR�0.39) than patients with low signature (n�25,
33.8%). Similar results were observed in the validation cohort. Patients
with high signature (n�60, 32.8%) had a significantly longer PFS and
longer OS than individuals with low signature (PFS 8.2 versus 4.2 months,
p�0.04, HR�0.52; OS 12.8 versus 6.8 months, p�0.09, HR�0.65). To
further assess the potential confounding effect of KRAS and BRAF
mutations, we analyzed the outcome of patients with high and low signature
in the 75 cases with KRAS or BRAF mutation and in 90 cases KRAS and
BRAF wild-type. In the wild-type population, high signature patients
(n�29, 32.2%) had a significantly longer PFS (8.8 versus 4 months,
p�0.002, HR:0.46) and longer OS (17.7 versus 10 months, p�0.015,
HR�0.62) than low signature individuals, with no difference in the KRAS
or BRAF mutated patients. Conclusions: MiR-99a/Let7c/miR-125b signature
is useful for improving selection of KRAS/BRAF wild-type mCRC
patients candidate for anti-EGFR strategies.
3523 Poster Discussion Session (Board #15), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Effect of oxaliplatin-based adjuvant therapy on post-relapse survival (PRS)
in patients with stage III colon cancer: A pooled analysis of individual
patient data from four randomized controlled trials. Presenting Author:
Christopher Twelves, University of Leeds and St. James’s University
Hospital, Leeds, United Kingdom
Background: Oxaliplatin-based adjuvant therapy is the standard of care for
stage III colon cancer; however, its impact on PRS in these patients is
unclear. We therefore compared PRS in trials of patients with stage III
colon cancer treated with oxaliplatin plus capecitabine (XELOX) or 5-flourouracil
(5-FU; FOLFOX) vs. leucovorin/5-FU (LV/5-FU). Methods: Individual
patientdata (N � 4,819) from NSABP C-08, XELOXA, X-ACT, and AVANT
were pooled and analyzed by XELOX/FOLFOX vs. LV/5-FU; patients treated
with bevacizumab were excluded. Hazard ratios (HR) were estimated by
Cox regression analyses and multivariate Cox regression analyses controlled
for age, gender, T, and N stage. Post-relapse treatment data were collected
when available. Results: Patient demographics and disease characteristics
(except lymph nodes examined) were well balanced across analytic groups.
Median follow-up was shorter in NSABP C-08 and AVANT (36 and 50
months) than in XELOXA and X-ACT (83 and 74 months). PRS was very
similar for XELOX/FOLFOX and LV/5-FU (HR 0.94, 95% CI, 0.82–1.07; P
� .33). Multivariate analyses supported these findings, but showed that
PRS was associated with younger age and lower N stage at diagnosis after
controlling for gender and T stage. PRS was also comparable for capecitabine
or XELOX vs. LV/5-FU or FOLFOX (N � 5,819, HR 1.07, 95% CI,
0.95–1.20; P � .26). Post-relapse therapies were comparable across the
two cohorts. Conclusions: Adjuvant chemotherapy regimen did not impact
on PRS in patients with stage III colon cancer; however, both N stage and
age demonstrated independent effects on PRS. Studies have demonstrated
significantly improved disease-free and overall survival for oxaliplatinbased
therapy, and our data show that survival is not compromised by
worsened PRS at subsequent relapse.
Multivariate analysis PRS HR 95% CI P
Randomized treatment:
0.92 0.81–1.05 .23
XELOX/FOLFOX vs. LV/5-FU
Female vs. male 1.02 0.90–1.16 .71
< 70 vs. > 70 0.70 0.60–0.81 � .0001
T1–2 vs. T3–4 0.82 0.61–1.10 .19
N1 vs. N2 0.73 0.64–0.83 � .0001
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