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

206s Gastrointestinal (Colorectal) Cancer
3512 Poster Discussion Session (Board #4), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Validation of the 12-gene colon cancer recurrence score (RS) in NSABP
C07 as a predictor of recurrence in stage II and III colon cancer patients
treated with 5FU/LV (FU) and 5FU/LV�oxaliplatin (FU�Ox). Presenting
Author: Michael O’Connell, National Surgical Adjuvant Breast and Bowel
Project, Pittsburgh, PA
Background: Standardized clinical tools which accurately quantify recurrence
risk are needed for optimal adjuvant treatment of colon cancer. The
12-gene RS has been validated in stage II colon cancer pts from QUASAR
and CALGB 9581. We conducted a large prospectively-designed clinical
validation study of RS, w/ pre-specified endpoints, methods, and analysis
plan, in stage II and III colon cancer pts randomized to FU or FU�Ox in
NSABP C-07. Methods: 50% of C-07 pts w/ tissue were randomly selected,
stratified on stage (AJCC 6th ) and recurrence. Gene expression was
quantitated by RT-PCR on 25 �m manually microdissected fixed colon
tumor tissue. Data were analyzed by Cox regression controlling for stage and
treatment (TRT). Results: RT-PCR was successful in 892/921 pts (97%):
449 FU, 443 FU � Ox; 264 st II, 409 st IIIA/B, 219 st IIIC. The primary
endpoint was met: RS predicted recurrence (HR/25 units�1.96, 95% CI
1.50-2.55 p�.001). RS also predicted disease-free survival (p�.001) and
overall survival (p�.001). RS predicted recurrence (p�.001) independent
of T and N stage, MMR, nodes examined, grade, and TRT. Predefined high
RS group (26% of pts) had higher recurrence risk than low RS group (39%
of pts): HR�2.11, p�.001. Cox model 5 yr recurrence risk (95%CI) in FU
treated pts by RS group (low, int, high): st II 9% (6-13%), 13% (8-17%),
18% (12-25%); st IIIA/B 21% (16-26%), 29% (24-34%), 38% (30-
46%); st IIIC 40% (32-48%), 51% (43-59%), 64% (55-74%). RS did not
have significant interaction w/ stage (p�0.90) or age (p�0.76). Relative
benefit of Ox was similar across range of RS (interaction p�0.48);
accordingly, in Cox model and Kaplan-Meier analyses, absolute benefit of
Ox increased w/ higher RS. Conclusions: RS predicts recurrence risk in
stage II and III colon cancer, capturing underlying biology and providing
risk information beyond conventional factors. RS is not predictive of
relative benefit of Ox added to adjuvant FU but enables better discrimination
of absolute Ox benefit as a function of risk. Incorporating RS into the
clinical context may better inform adjuvant therapy decisions for pts w/
stage III as well as stage II colon cancer.
3514 Poster Discussion Session (Board #6), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
Prognostic impact of BRAF and KRAS mutations and their relationship to
DNA mismatch repair (MMR) status in 2,686 stage III colon cancer
patients (pts) treated in a phase III study of adjuvant FOLFOX with or
without cetuximab: NCCTG N0147. Presenting Author: Frank A. Sinicrope,
Mayo Clinic, Rochester, MN
Background: Activating mutations in the BRAF oncogene (mutBRAF) are
associated with deficient MMR (dMMR) in sporadic colon cancers and are
mutually exclusive with KRAS mutations (mutKRAS). We evaluated BRAF
and KRAS in relation to MMR and disease-free survival (DFS) in stage III
pts treated with adjuvant FOLFOX �/-cetuximab; study was amended
mid-way to require prospective KRAS testing (Alberts SR, ASCO 2010).
Methods: Extracted DNA from archival tumors was analyzed for BRAF exon
15 (V600E) and KRAS exon 2 mutations by allele specific RT-PCR. Tumors
with loss of any MMR protein (MLH1, MSH2, MSH6) were categorized as
dMMR vs proficient (pMMR). DFS was censored at 4 yrs; median follow-up
was 3.1 yrs. Results: Among 2,686 pts, 12% (314/2580) of tumors were
dMMR; 28% (716/2579) had mutKRAS, and 14% (346/2515) had
mutBRAF of which 43% (150/346) were dMMR. mutBRAF was associated
with high grade, proximal site, T3-4, �4 LNs, and dMMR (all p�0.002);
mutKRAS with low grade, proximal, �3 LNs, and pMMR (all p�0.02).
Among dMMR tumors, mutKRAS was more frequent in distal vs proximal
cancers (28% vs. 8%, p�0.0004). Both mutKRAS (HR�1.42, p�0.0001)
and mutBRAF (HR�1.34, p�0.02) were associated with worse DFS and
remained significant after adjustment for treatment, MMR, grade, site, T
stage and LNs. mutBRAF (p�0.003) and mutKRAS (p�0.003) were each
prognostic for DFS in pMMR, but not dMMR tumors (KRAS, p�0.79;
BRAF, p�0.60). While MMR was not significant univariately, proximal
dMMR tumors had favorable DFS [HR 0.8, 95% CI (0.6-1)] and distal
dMMR tumors had poor DFS [HR 2 (1.1-3.4)] after adjusting for KRAS,
BRAF, grade, T stage and LNs (pinteraction�0.02). pMMR/mutBRAF
(p�0.027) and pMMR/mutKRAS (p�0.001) had worse DFS vs pMMR/
bothWT. Conclusions: mutBRAF and mutKRAS were significantly associated
with worse DFS independent of treatment, covariates, and each other,
with the DFS impact restricted to pMMR tumors. Prognostic impact of
MMR was dependent upon tumor site after adjusting for covariates.
Support: NIH Grant CA 25224, NCI K05CA 142885, Bristol-Myers
Squibb, ImClone, Sanofi-Aventis, and Pfizer.
3513 Poster Discussion Session (Board #5), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
The prognostic importance of miRNA-21 in stage II colon cancer: A
population-based study. Presenting Author: Sanne Kjaer-Frifeldt, Department
of Oncology, Vejle Hospital, and Danish Colorectal Cancer Group
South, Vejle, Denmark
Background: Adjuvant chemotherapy for stage II colon cancer patients is
still controversial and the debate on which patients should be considered as
high risk patients is still ongoing. The decision is based on clinical and
pathological markers of risk, which are inadequately informative in most of
the patients, and better methods are highly needed. The aim of the present
study was to investigate the possible prognostic importance of miRNA-21,
quantified by in situ hybridization (ISH), in a unique, large populationbased
cohort of patients treated for stage II colon cancer patients. Methods:
The study included all patients diagnosed with stage II colon cancer in
Denmark in the year 2003 (711 patients), representing a full population of
five million people. Patients receiving adjuvant chemotherapy were excluded
(N�15). One paraffin-embedded tissue block was obtained from
each patient. A 6�m-thick section was processed for formazan-based
chromogenic miR-21 ISH analysis and counter stained with nuclear red.
The blue miR-21 ISH signal was assessed by image analysis to obtain two
quantitative expression estimates: the total blue area (TB) and the ratio of
TB with the nuclear density (TBR). Results: The miRNA-21 signal was
predominantly observed in fibroblast-like cells located in the stromal
compartment of the tumors. Patients expressing high levels of miRNA-21
(high mean TBR) had significantly inferior cancer specific survival (CSS):
HR � 1.26 (95% CI; 1.15-1.60), p �0.001. In the COX regression
analysis (including; gender, T-category, malignancy grade, localization,
tumor perforation, tumor fixation, number of lymph nodes and MSI status),
mean TBR was found to be an independent predictive marker of poor CSS,
HR � 1.41 (95%CI; 1.19-1.67, p� 0.001). The same applied to TB.
Conclusions: The present study shows that increasing miRNA-21 expression
level is significantly correlated to decreasing CSS. Analyses of
miRNA-21 should be considered as a potential adjunct in the selection of
high risk stage II patients.
3515 Poster Discussion Session (Board #7), Fri, 1:00 PM-5:00 PM and
4:30 PM-5:30 PM
BRAF, PIK3CA, and PTEN status and benefit from cetuximab (CET) in the
treatment of advanced colorectal cancer (CRC): Results from NCIC CTG/AGITG
CO.17. Presenting Author: Derek J. Jonker, The Ottawa Hospital Research
Institute, Ottawa, ON, Canada
Background: CET, a monoclonal antibody targeting the epidermal growth factor
receptor, improves overall survival (OS) and progression free survival (PFS) in
patients (pts) with KRAS wild-type (WT) chemotherapy refractory CRC. BRAF
and PIK3CA mutation status, and PTEN expression levels may further predict
benefit from CET therapy. Methods: Available colorectal tumour samples were
analyzed from a phase III trial of CET plus best supportive care (BSC) vs BSC
alone (NEJM 2007; 357(20)). BRAF and PIK3CA mutations (MUT) identified in
tumour-derived DNA using a high resolution melting analysis to identify
amplicons with mutations were confirmed by sequencing. PTEN expression by
immunohistochemistry (IHC) was performed on tissue microarrays constructed
from available tumour blocks. For each biomarker, prognostic (treatment
independent) effects were assessed in patients on the BSC alone arm. Predictive
effects (benefit from CET) on OS and PFS among all patients and those in the
KRAS wild-type subset were examined using a Cox model with tests for
treatment-biomarker interaction, adjusting for covariates. Results: Of 401 pts
assessed for BRAF status (70% of CO17 population), 13(3%) had mutations. Of
407 pts assessed for PIK3CA status (71% of CO17 population), 61(15%) had
mutations. Of 205 pts assessed for PTEN (36% of CO17 population), 148(72%)
were negative for IHC expression. No biomarker was prognostic for OS or PFS,
and none were predictive of benefit from CET, either in the whole study
population or the KRAS WT subset. Conclusions: In chemotherapy-refractory
CRC, neither PIK3CA mutation status nor PTEN expression were predictive of
benefit from CET therapy. BRAF mutations are uncommon in this setting. Larger
sample sizes would be required to determine if BRAF status is predictive for CET
benefit.
Prognostic analysis in BSC patients
adj HR (MUT vs WT), [for PTEN, negative vs present]
Biomarker
OS PFS
BRAF 1.47, p�0.41 1.52, p�0.37
PI3KCA 1.11, p�0.65 1.10, p�0.66
PTEN 1.13, p�0.70 0.99, p�0.98
Predictive analysis in KRAS WT subset
adj HR (CET�BSC vs BSC), interaction p value
OS PFS
BRAF 1.39, p�0.69 1.18, p�0.84
PI3KCA 0.79, p�0.63 0.73, p�0.50
PTEN 0.75, p�0.61 2.47, p�0.08
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