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

3581 General Poster Session (Board #32B), Mon, 8:00 AM-12:00 PM
Mutant (MT) KRAS codon 12 and 13 alleles in patients (pts) with
metastatic colorectal cancer (mCRC): Assessment as prognostic and
predictive biomarkers of response to panitumumab (pmab). Presenting
Author: Marc Peeters, Antwerp University Hospital, Edegem, Belgium
Background: Pmab is a fully human monoclonal antibody against the
epidermal growth factor receptor (EGFR). Significant improvement in
progression-free survival (PFS) was demonstrated in pts with wild-type
(WT) KRAS mCRC treated with pmab�FOLFOX4 (1st-line; study
20050203), pmab�FOLFIRI (2nd-line; study 20050181), and pmab
monotherapy (study 20020408). In mCRC, mutations in KRAS codons 12
and 13 are established biomarkers for lack of clinical benefit to anti-EGFR
therapies. We retrospectively examined individual MT KRAS codon 12 and
13 alleles as prognostic and predictive biomarkers of response in three
phase 3 studies. Methods: Pts were randomized to receive FOLFOX4,
FOLFIRI, or best supportive care �/- pmab 6.0 mg/kg Q2W in trials
20050203, 20050181, and 20020408, respectively. The MT KRAS
codon 12 and 13 alleles (G12A, G12C, G12D, G12R, G12S, G12V, G13D)
were detected using the Therascreen K-RAS Mutation Kit (Qiagen). Results:
MT KRAS codon 12 and 13 alleles were detected in 40% (440/1096),
45% (486/1083), and 43% (184/427) of pts in trials 20050203,
20050181, and 20020408, respectively. MT KRAS allele distribution was
conserved across studies and balanced between treatment arms. Baseline
demographic and clinical features were comparable between all MT KRAS
allele subgroups. There was no consistent evidence that any individual MT
KRAS allele, compared to the remaining MT KRAS alleles or the entire MT
KRAS group, differentially impacted PFS or overall survival (OS) in control
arm-treated or pmab-treated pts. Only in the pmab�FOLFOX4 arm of study
20050203 were G13D (unfavorably) and G12V (favorably) significantly
associated with OS. Response rates were similar between MT KRAS allele
groups in the 1st- and 2nd-line mCRC treatment setting. Finally, in analyses
of pts pooled from all 3 trials, only the G12A KRAS allele emerged as a
significant negative predictive factor for OS. Conclusions: The lack of
consistent results across three lines of therapy indicates pts whose tumors
harbor MT KRAS codon 12 or 13 alleles are unlikely to respond to pmab
therapy. Currently, only pts with WT KRAS mCRC should be treated with
EGFR antibodies.
3583 General Poster Session (Board #32D), Mon, 8:00 AM-12:00 PM
Is there any significant difference between tumor regression grade systems
of rectal cancer? Presenting Author: Atthaphorn Trakarnsanga,
Memorial Sloan-Kettering Cancer Center, New York, NY
Background: Tumor regression grade (TRG) is a measure of histopathologic
response of rectal cancer to preoperative chemoradiation (CRT) and
correlates with outcomes. Several TRG systems have been reported
including Mandard (5, 3 tier), Dowrak/Rodel (5, 3 tier), Memorial Sloan
Kettering Cancer Center (MSKCC), and American Joint Committee of
Cancer (AJCC). The purpose of this study is to compare the different TRG
systems and determine which one(s) best predict recurrence and survival.
Methods: Review of prospective maintained database from 1998 to 2007
identified 563 patients with locally advanced rectal cancer (T3/4 and/or
N1) and treated with long-course CRT followed by total mesorectal
excision. TRG was determined by measuring proportion of tumor mass
replaced by fibrosis. Patients were then classified into the various TRG
schemes which were compared by analyzing association with recurrence
and survival using concordance index (CI) and reclassification index. CI is a
measure that summarizes the predictive strength of a marker. Computing
and contrasting CI across several markers is a way of selecting the best
prognostic marker. Results: 75% of patients were noted to have clinical
stage III disease by endorectal ultrasound or rectal MRI. Following
resection with median follow-up of 39.3 months, 2% developed local
recurrence and 17% developed distant metastasis. The median interval
time between completion of CRT and surgery is 48 days. 20% demonstarted
complete pathological response. CI of the 3 tier Mandard, 3 tier
Dowrak/Rodel, MSKCC and AJCC are 0.665, 0.653, 0.683, and 0.694,
respectively (higher number indicates better prediction). The AJCC was
significantly more accurate in predicting recurrence than the 3- tier
Mandard (p�0.002), and Dowrak/Rodel (p�0.006). AJCC had a higher CI
than MSKCC although it did not reach significance (p�0.068). Comparing
the 3 tier systems, MSKCC was most accurate and correctly reclassified 17
% and 23 % of the patients Mandard and Dowrak/Rodel systems,
respectively. Conclusions: TRG predicts recurrence and survival following
combined modality therapy for rectal cancer. The TRG system that recently
was proposed in the 7thAJCC staging is currently the most accurate
predictor.
Gastrointestinal (Colorectal) Cancer
223s
3582 General Poster Session (Board #32C), Mon, 8:00 AM-12:00 PM
A phase II study of high-dose cetuximab plus irinotecan in colorectal
cancer patients with KRAS-wild type tumors who progressed on prior
standard dose cetuximab and irinotecan. Presenting Author: Ahmad Ali
Fora, Roswell Park Cancer Institute, Buffalo, NY
Background: Prior clinical data suggest a dose-related response to cetuximab
(cmab) when combined with irinotecan in patients (pts) with KRAS
WT tumors who do not develop grade � 2 rash with standard cmab dosing.
However, the investigation of higher doses of cmab in the setting of
acquired or innate resistance to standard dose cmab has not been
previously investigated. We conducted a phase II clinical trial of high-dose
cmab plus irinotecan in KRAS WT pts who progressed on standard-dose
cmab plus irinotecan. Methods: Pts who progressed within 4 weeks from
receiving a minimum of 6 weeks of standard dose cmab plus irinotecan
were included in this study. Cmab was administered at 500 mg/m2 /week
and irinotecan was administered at the same dose/schedule on which each
individual patient previously progressed. All pts received doxycyline 100
mg PO bid starting day 1 of treatment. 12-week PFS rate was the primary
endpoint. The regimen was considered interesting if 7/36 patients had
stable disease or response at 12 weeks. The study was closed early after
meeting its primary endpoint. Results: 20 pts were treated on study: median
age 65.5 yrs (44-84), 14 pts were males. 8 pts had grade � 2
hypomagnesaemia (3 grade 3 and 2 grade 4), 6 pts had grade � 2 skin rash
(1 grade 3, 0 grade 4), and 4 pts had grade � 2 diarrhea (1 grade 3, 0 grade
4). 1 pt had a confirmed PR and 12 pts had a SD (at 6 weeks). In 9 pts, SD
was confirmed at 12 weeks (3 pts� 24 weeks). Median PFS and OS were
2.8 and 6.6 months, respectively. The 1-year survival was 25%. Conclusions:
High-dose cmab plus irinotecan is well tolerated with an acceptable rate of
diarrhea and skin toxicities but with an increased rate of grade 3-4
hypomagnesemia. The prolonged disease stabilization and single response
suggest that resistance to standard dose cmab plus irinotecan can be
overcome by cmab dose escalation. The identification of predictive markers
of response from dose escalation will be necessary to implement this
strategy selectively in KRAS WT colorectal cancer patients.
3584 General Poster Session (Board #32E), Mon, 8:00 AM-12:00 PM
Association of genetic variants in obesity-related genes with tumor recurrence
in stage II/III colon cancer. Presenting Author: Robert D. Ladner,
University of Southern California Norris Comprehensive Cancer Center, Los
Angeles, CA
Background: High body mass index (BMI) is an established risk factor for
colorectal cancer incidence and death. Recent studies found obesity before
the diagnosis of colon cancer was associated with worse survival compared
with normal weight. Single nucleotide polymorphisms (SNPs) of obesityrelated
gene have been related with different cancer risk including
colorectal cancer. Here we tested the hypothesis whether SNPs in obesityrelated
genes (PPAR, LEP, NFKB, CD36, DRG1, NGAL, REGIA and
DSCR1) may predict tumor recurrence in adjuvant colon cancer. Methods:
Either blood or FFPE tissue specimens were obtained from 234 patients
(107 females and 127 males; median age 59 years (range 22–78 years))
with stage II (105 patients) or III (129 patients) colon cancer at the
University of Southern California/Norris Comprehensive Cancer Center. The
median follow-up was 4.4 years. SNPs in obesity-related genes were
determined by PCR-RFLP or PCR-based direct sequence. The primary
endpoint of the study was time to tumor recurrence (TTR). Results: in
univariable analysis, PPAR rs1801282 and DSCR1 rs6517239 were
independently associated with time to tumor recurrence (TTR). Patients
with PPAR CC genotype had longer median TTR 9.4 months (95% C.I: 5.6,
12.4�) compared to those with CG genotype, had median TTR 3.4 months
(95% C.I: 1.7, 16.8�)(p�0.04, log-rank test). Patients with DSCR1 AA
genotype had shorter median TTR 6.6 months (95% C.I: 4.0, 16.8�)
compared to those with AG and GG genotypes, which had longer median
TTR 9.4 months (95% C.I: 5.7, 10.7�)(p�0.027, log-rank test). The
multivariate analysis adjusting for stage and type of adjuvant therapy
showed a trend in the association between PPAR rs1801282 and DSCR1
rs6517239 and time to recurrence (Wald test p�0.08 and 0.058,
respectively). Conclusions: Our preliminary results demonstrated polymorphisms
in obesity-related gene might be potential molecular markers to
predict TTR in adjuvant colon cancer. Further large and biomarker
embedded trial needed to confirm our findings.
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