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

3613 General Poster Session (Board #36B), Mon, 8:00 AM-12:00 PM
Neoadjuvant treatment of colorectal liver metastases (CRLM) with drug
eluting beads trans-arterial chemoembolization (DEBIRI-TACE): A multiinstitute
phase II study in resectable metastases. Presenting Author:
Robert Peter Jones, University of Liverpool, Liverpool, United Kingdom
Background: Perioperative chemotherapy confers 3-year progression free
survival advantage following resection of CRLM and good pathologic
response is associated with improved overall survival. However, systemic
neoadjuvant chemotherapy can increase postoperative morbidity and
mortality. TACE using preloaded Irinotecan eluting beads gives sustained
delivery of drug directly to tumor, thereby maximising response and
reducing systemic exposure. This study examined the feasibility and safety
of neoadjuvant DEBIRI-TACE before CRLM resection. Methods: Patients
with resectable CRLM received single DEBIRI-TACE (up to 200mg) 1
month pre-hepatectomy. Primary end-point: tumor resectability, secondary
end-points: safety, radiologic response (RECIST) and pathologic tumor
response. Results: TACE attempted in 49 patients, successful in 40.
Reasons for failed TACE included consent withdrawal (n�2), bilobar
disease (n�2), tumour involving gallbladder wall (n�1), suspected hepatoma
(n�1), arterial access difficulty (n�2), contrast medium allergy
(n�1). Post-TACE complications: 1 acute pancreatitis (3%); 4 postembolization
syndromes (10%). Imaging at 4 weeks post-TACE (30
patients): complete response 0/40 (0%); partial response 1/40 (3%);
stable disease 19/40 (48%); ‘progressive’ disease 10/40 (25%). 40
patients proceeded to surgery, 38 underwent hepatectomy (2 peritoneal
disease, resectability rate 95%). 30-day post-operative mortality 5%
(n�2), neither death TACE related (1 intraoperative pneumomediastinum,
1 aspiration pneumonia). 63 lesions (median 2 per patient) targeted with
TACE. Histology: no residual disease 17%; 1-49% residual disease 59%;
�50% residual disease 22%; no response 2%. Conclusions: Resection
after neoadjuvant DEBIRI-TACE for CRLM is feasible and safe. Single
treatment with DEBIRI-TACE resulted in tumor pathologic response similar
to that seen after protracted systemic chemotherapy.
3615 General Poster Session (Board #36D), Mon, 8:00 AM-12:00 PM
Association of HER2 and IGF1 germline polymorphisms with outcome in
metastatic colorectal cancer (mCRC) patients (pts) treated with secondline
irinotecan (IR) with or without cetuximab (CB): The EPIC experience.
Presenting Author: Dongyun Yang, University of Southern California Norris
Comprehensive Cancer Center, Los Angeles, CA
Background: EPIC, a multinational phase III clinical trial with IR � CB vs IR
alone in mCRC pts in the second-line setting after failure of FOLFOX
demonstrated a benefit for IR�CB in progression-free survival (PFS) and
response rate (RR). We evaluated 6 functional germline polymorphisms
involved in the IGF1 and HER2 for their potential role as molecular
predictors of clinical outcome in pts treated in the EPIC study. Methods:
DNA was extracted from all available formalin-fixed paraffin-embedded
tumor samples from the EPIC trial. Genotyping was performed using
PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols.
Univariate analysis (Fisher’s exact test for RR; log-rank test for PFS and OS)
was performed to examine associations between polymorphisms and
clinical outcome. Multivariate analysis (Logistic regression or Cox regression
model) was conducted to control baseline patient characteristics and
treatment. Results: 186 pts with available samples were treated either with
IR/CB (arm A, 84 pts) or IR alone (arm B, 102 pts). Median age was 59 yrs
(range 34-85yrs) for arm A and 61 yrs (range 25-90 yrs) for arm B. In arm
A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or
PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts
(94%) had SD or PD. Median PFS for arm A was 3.0 months (95%CI 2.4-
4.1 months) vs 2.7 months (95%CI 2.2-2.9 months) for arm B; median OS
was 9.3 months (95%CI 7.1-21.1 months) for arm A vs 12.3 months
(95%CI 10.4- 17.9 months) for arm B. KRAS mutation status was not
significantly associated with outcome in our patient cohort. We found that
HER2 rs 1136201 was significantly associated with response (RR: AA
6.5%, AG 12.5%, and GG 27.3%, Fisher’s exact test p�0.045). IGF1 rs
2946834 was significantly associated with PFS in both univariate and
multivariate analyses (median PFS was 2.8 months in patients with CC or
CT vs 1.8 months in patients with TT; log-rank p�0.009; Wald test
p�0.008). Conclusions: Our study suggests the prognostic value of polymorphisms
in the IGF1 and HER2-pathway in mCRC pts treated with IR� CB.
Prospective validation of these findings in clinical trials is warranted.
Gastrointestinal (Colorectal) Cancer
231s
3614 General Poster Session (Board #36C), Mon, 8:00 AM-12:00 PM
Efficacy and safety of bevacizumab in metastatic colorectal cancer (mCRC):
Pooled analysis from randomized controlled trials (RCTs). Presenting
Author: Niall Christopher Tebbutt, Austin Hospital, Heidelberg, Australia
Background: Bevacizumab (BV) with chemotherapy (CT) is a standard
treatment for mCRC. This analysis pooled individual patient data from the
clinical databases of seven RCTs (phase II or III) of BV in 1st- or 2nd-line
treatment to further define clinical outcomes, including within subgroups.
Methods: Patient data were pooled from 1st-line (AVF2107, NO16966,
ARTIST, AVF2192, AVF0780, AGITG MAX) and 2nd-line (ECOG E3200)
trials. All analyses were based on the intent-to-treat population. Overall and
progression-free survival estimates (OS, PFS) were calculated by Kaplan-
Meier methods. To assess differences in time to response variables by
treatment arm (CT vs BV � CT), stratified random (overall) and fixed
(subgroup comparisons) models were used to estimate pooled hazard ratios
(HRs) and 95% confidence intervals (CIs), with each study included as a
stratum. Results: Of the 3,763 pooled patients (CT [n�1773]; BV � CT
[n�1990]), 58.8% were male, 39.6% were �65 years, and 45.7% had an
ECOG performance status �1. OS and PFS were statistically significantly
increased in BV-treated patients vs control patients. Safety data in this
pooled analysis were consistent with the profile of BV from the individual
studies. Conclusions: The addition of bevacizumab to CT resulted in
statistically significant improvements in survival outcomes for mCRC
patients in the overall analysis, with PFS benefit extending across subgroups
defined by CT intensity, CT regimen, and KRAS status.
Overall: BV � CT vs CT
HR (95% CI) P value
OS 0.80 (0.71�0.90) .0003
PFS 0.57 (0.46�0.71) �.0001
Subgroup comparisons: BV � CT vs CT
HR (95% CI) for OS HR (95% CI) for PFS
Monotherapy (n�751) 0.86 (0.72–1.02) 0.56 (0.48–0.67)
Doublets (n�3,012) 0.82 (0.76–0.89) 0.70 (0.64–0.76)
Irinotecan regimen (n�1,027) 0.71 (0.61–0.83) 0.55 (0.47–0.64)
Oxaliplatin regimen (n�1,985) 0.87 (0.79–0.96) 0.77 (0.70–0.85)
KRAS wild-type patients (n�364) 0.70 (0.54–0.91) 0.57 (0.45–0.72)
KRAS mutant patients (n�166) 0.85 (0.60–1.22) 0.54 (0.38–0.76)
3616 General Poster Session (Board #36E), Mon, 8:00 AM-12:00 PM
Incidence and prognostic impact of KRAS and BRAF mutations in patients
undergoing liver surgery for colorectal metastases. Presenting Author:
Georgios Karagkounis, The Johns Hopkins University School of Medicine,
Baltimore, MD
Background: Molecular biomarkers offer the potential for refining prognostic
determinants in patients undergoing cancer surgery. Among patients with
colorectal cancer metastases, KRAS and BRAF are important biomarkers,
but their role in patients undergoing surgical therapy for liver metastases is
unknown. In this study, the prevalence and prognostic significance of
KRAS and BRAF mutations were determined in patients undergoing
surgical therapy of colorectal liver metastases (CRLM). Methods: KRAS and
BRAF analysis was performed on 202 patients undergoing curative intent
surgical therapy of CRLM between 2003 and 2008. Tumor samples were
analyzed for somatic mutations using sequencing analysis (KRAS: codon
12/13, BRAF: V600E). The frequency of mutations was ascertained and
their impact on outcome determined relative to other clinicopathologic
factors. Results: KRAS gene mutations were detected in 58/202 patients
(29%) undergoing surgery for CRLM, comparable to that reported in
non-surgical patient series. In contrast, mutation in the BRAF gene was
identified in very low frequency in this surgical cohort, found in only 4/202
(2%) patients. KRAS mutations were associated with worse long-term
survival (HR�2.13, CI�1.25-3.65), as well as risk of recurrence (HR�1.89,
CI�1.12-3.19). ). In addition, KRAS mutation was also associated with
risk of recurrence following surgical therapy (HR�1.89, CI�1.12-
3.19).While other clinicopathologic features, including tumor number,
CEA and primary stage were also associated with survival, KRAS status
remained independently predictive of outcome. The low incidence of BRAF
mutation limited the ability to determine its prognostic impact. Conclusions:
While KRAS mutations were found in approximately one third of patients,
BRAF mutations were found in only 2% of patients undergoing surgery for
CRLM. KRAS status was an independent predictor of overall and diseasefree
survival. Molecular biomarkers such as KRAS may help to refine our
prognostic assessment of patients undergoing surgical therapy for CRLM.
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