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

3516 Poster Discussion Session (Board #8), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Epiregulin (EREG) and amphiregulin (AREG) gene expression to predict
response to cetuximab therapy in combination with oxaliplatin (Ox) and
5FU in first-line treatment of advanced colorectal cancer (aCRC). Presenting
Author: Richard A. Adams, School of Medicine, Cardiff University,
Cardiff, United Kingdom
Background: Previous data suggest the EGF ligands EREG/AREG may
predict outcome of KRAS wt patients (pts) in the chemo-refractory setting
but has not been previously reported from first line randomised trials.
Methods: FFPE samples from primary tumors of pts in Arms A&B of the
COIN trial of Ox fluoropyrimidine (Fp) �/- cet were analysed for EGFR IHC,
KRAS/NRAS/BRAF mutation and EREG/AREG expression by RT-PCR.
Ligand levels were assessed against baseline data, prognostic markers as
uni/multivariate analyses and as predictive markers in wild type (wt) and
mutant (mt) cohorts and separately by Fp backbone [capecitabine (CapOx)
or 5FU (FOLFOX)]. Tests for interaction were performed with EREG/AREG
continuous, using Flexible Parametric survival analysis. Optimal cutoffs for
predictive effects were defined using point at which 95% CI first excluded
zero. Results: 952/1630 (57%) of pts were evaluable for all parameters.
EREG/AREG were highly correlated Pearson’s rho (�) � 0.74; p�0.0001.
High EREG/AREG levels were associated with KRAS wt (p�0.005) and
with primary tumor in left colon/rectum, presence of liver metastases and
high CEA (p�0.05). In the control arm, high EREG/AREG conferred a
better prognosis among KRAS wt pts in multivariate. EREG superseded
AREG in a combined model. High EREG predicted for OS benefit in KRAS
wt pts treated with FOLFOX �cet, with optimal cut-off 80th centile. OS HR
for �cet �80th centile �0.33, 95% CI 0.14-0.78, p�0.011; �80%
centile HR�0.99, 95% CI 0.67-1.47, p�0.96; interaction p�0.059;
�50th centile HR�0.66, 95% CI 0.40-1.09, p�0.11; �50% centile
HR�1.09, 95% CI 0.66-1.81, p�0.73; interaction p�0.17. Similar
results were seen for PFS, with optimal cut-off 50th centile. There was no
predictive effect for pts treated with CapOx. Conclusions: The data suggest a
prognostic effect of EREG/AREG in aCRC. The original hypothesis, that
KRAS wt patients with high EREG expression have improved outcome with
cet, seems to be limited to patients treated with FOLFOX in the first-line
setting.
3518 Poster Discussion Session (Board #10), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in
metastatic colorectal cancer (mCRC) patients (pts) treated with first-line
FOLFIRI plus bevacizumab (BV). Presenting Author: Chiara Cremolini,
U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto
Toscano Tumori, Pisa, Italy
Background: Despite several attempts, no predictors of benefit from BV
have been so far identified. We reported the association of VEGF rs833061
T/T to a worse outcome in mCRC pts treated with first-line FOLFIRI�BV,
but not in a historical cohort treated with FOLFIRI. Recent post-hoc
analyses on randomized trials suggested the potential prognostic and/or
predictive role of other VEGF and VEGFR1/2 SNPs. Methods: Moving from
our retrospective finding, we designed a prospective validation trial in
mCRC pts treated with first-line FOLFIRI� BV to detect a HR for PFS of 1.7
for VEGF rs833061 T/T compared to C- variants. With two-sided a�0.05
and b�0.20, 199 events were required. Accrual was faster than expected
and in the meanwhile promising results about other SNPs were reported
and we therefore included a confirmatory analysis of VEGF rs699946 A/G,
VEGFR1 rs9582036 A/C and rs7993418 A/G, VEGFR2 rs11133360 C/T,
rs12505758 C/T and rs2305948 C/T and EPAS rs4145836 A/G SNPs.
Germ-line DNA was extracted from peripheral blood. SNPs were analyzed
by PCR and sequencing. Results: Four-hundred-twenty-four pts were
included. At a median follow up of 24 months, median PFS was 10.5
months. At the univariate analysis, no differences in PFS according to
VEGF rs833061 C/T variants were observed (p�0.38). Among analyzed
SNPs, only VEGFR2 rs12505758 C- variants (n�118) were associated to
shorter PFS compared to TT (n�306) (HR: 1.40 [95%CI: 1.07-1.84],
p�0.015). In the multivariate model, this association retained significance
(HR: 1.402 [95%CI:1.079-1.822], p�0.012), that was lost by applying
multiple testing correction. Conclusions: This prospective experience failed
to validate the hypothesized predictive impact of VEGF rs833061 variants.
Also other previous retrospective findings on different candidate SNPs were
not confirmed. Only VEGFR2 rs12505758 variants, whose prognostic
rather than predictive impact was previously reported, correlated with PFS.
We suggest that future studies on biomarkers of benefit from BV should
look at the complexity of tumoral angiogenesis at different levels and not
only from the genetic perspective.
Gastrointestinal (Colorectal) Cancer
207s
3517 Poster Discussion Session (Board #9), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
A novel interaction of genotype, gender, and adjuvant treatment in survival
after resection of stage III colon cancer: Results of CALGB 89803.
Presenting Author: Robert S. Warren, University of California, San Francisco,
San Francisco, CA
Background: The p53 tumor suppressor is frequently mutated in colon
cancer, but the influence of such mutations on survival is remains
undefined. We investigated whether domain-specific mutations in p53 are
predictive of survival in stage III colon cancer. Methods: p53 was evaluated
in an intergroup trial (CALGB 89803) of patients with stage III colon cancer
who were randomized to receive adjuvant 5-fluorouracil/leucovorin (5FU/
LV) or 5FU/LV with irinotecan (IFL) Tissue was collected to allow correlation
of molecular markers with outcomes. p53 was genotyped in 607
patient tumors. Results: p53 mutations were identified in 274 tumors,
divided ~ equally between zinc binding and non-zinc binding regions of the
DNA binding domain. Overall, p53 status was not predictive of benefit from
either adjuvant regimen. Unexpectedly, the 5 year overall survival (OS) of
women with tumors harboring non-zinc binding mutations treated with
5FU/LV was 97% compared to OS of 72% for women with p53 wild-type
(wt) tumors (p �0.004). Adding irinotecan to 5FU/LV negated this survival
benefit (5 year OS of 81% vs. 72%). Conversely, 5 year OS of women
harboring tumors with zinc binding mutations who received 5FU/LV was
50% compared to 72% for women with p53 wt tumors (p�0.04). Adding
irinotecan to 5FU/LV reversed the poor survival of women with tumors
harboring zinc binding mutations and improved 5 year OS (50% vs. 73%;
p�0.1). No difference in OS was observed for men on either treatment arm
or when genotype was considered. Conclusions: CALGB 89803 demonstrated
a lack of survival benefit for stage III colon cancer patients when
irinotecan was added to 5FU/LV (IFL). We now show that in the setting of a
large clinical trial, refined stratification of women, based upon domainspecific
mutations of p53 identifies subsets of patients likely to benefit
from, or respond poorly to, adjuvant 5FU/LV. The interaction of p53
genotype, gender, and adjuvant therapy regimen has the potential to be
paradigm changing in the treatment of colon cancer, and possibly other
malignancies. These data, if validated, suggest that evaluation of p53
genotype and gender may guide clinicians to make rational choices of
adjuvant therapy.
3519^ Poster Discussion Session (Board #11), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Ligand expression of the EGFR ligands amphiregulin, epiregulin, and
amplification of the EGFR gene to predict for treatment efficacy in KRAS
wild-type mCRC patients treated with cetuximab plus CAPIRI and CAPOX:
Analysis of the randomized AIO CRC-0104 trial. Presenting Author:
Sebastian Stintzing, Department of Hematology and Oncology, Klinikum
Grosshadern and Comprehensive Cancer Center, LMU Munich, Munich,
Germany
Background: We investigated the expression of the EGFR ligands amphiregulin
(AREG) and epiregulin (EREG) as well as the amplification of the
EGFR-gene in tumor specimens of mCRC patients (pts) treated first-line
with anti-EGFR targeted cetuximab together with CAPOX or CAPIRI.
Expression levels were correlated with overall response rate (ORR), progression
free survival (PFS) and overall survival (OS) to determine their
relationship with effectiveness in this setting. Methods: A total of 185
mCRC pts were randomized to cetuximab (400mg/m² day 1, followed by
250mg/m² weekly) plus CAPIRI (irinotecan 200mg/m², day 1; capecitabine
800mg/m² twice daily days 1-14, every 3 weeks; 20% dose reduction of
both agents for pts older than 65 years) or plus CAPOX (oxaliplatin
130mg/m² day 1; capecitabine 1000mg/m² twice daily days 1-14, every
three weeks). The primary study endpoint was ORR. KRAS mutational
status did not correlate with treatment outcome. The cut-offs for EGFRamplification
using FISH, AREG and EREG levels determined by RT-qPCR
were calculated using ROC analysis for ORR. Results: Within the subgroup
of KRAS wildtype tumors, analysis of EREG- and AREG-expression was
possible in 99 pts and of EGFR-amplification in 63 pts. Higher AREG levels
correlated significantly with higher ORR (83% vs 46%, p�0.006, OR
0.31), longer PFS (9.6mo vs 4.9, p�0.001, HR 0.35) and longer OS
(39.9mo vs 17.2mo, p�0.001, HR 0.36). Higher EREG levels showed a
significant correlation with ORR (74% vs 47%, p�0.036, OR 0.54), longer
PFS (7.9mo vs 4.9mo, p�0.026, HR 0.57) and OS (33.0mo vs 20.2mo,
p�0.041, HR 0.57). EGFR-amplification correlated significantly with
higher ORR (71% vs 33%, p�0.004, OR 0.49), longer PFS (8.4mo vs
4.6mo, p�0.004, HR 0.50) and longer OS (30.5mo vs 15.2mo, p�0.001,
HR 0.44). Conclusions: In the treatment setting of cetuximab combined
with CAIPIRI or CAPOX, AREG, EREG and EGFR-amplification predicted
treatment efficacy. Within the subgroup of pts with KRAS wildtype tumors,
EGFR-FISH and AREG expression have the strongest relationship with
treatment efficacy.
Visit abstract.asco.org and search by abstract for the full list of abstract authors and their disclosure information.