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anti-EGFR treatment. The present study is aimed to analyze the prevalence of
Iow-frequent KRAS and BRAF V600 mutations in caucasian mCRC population.
Methods: A two institution retrospective cohort of 1238 consecutive KRAS wild
type mCRC patients previously studied for frequent 7 mutations in codons 12/13
by the CE-IVD marked ARMS-scorpion real-time polymerase chain reaction PCR
(Therascreen, Qiagen) was assayed by the diagnostic TaqMelt PCR assay cobas
KRAS Mutation and cobas BRAF V600 Mutation Tests (Roche), which are
designed to detect 19 mutations in KRAS codons 12, 13 and 61 (including G12F,
G13C, G13R, G13S, G13A, G13V, G131, Q61H, Q61K, Q61R, Q61L, Q61E and
Q61P) and BRAF V600 (V600E, V600K and V600D) mutations. DNA was
obtained by cobas DNA preparation kit from one single 5um formalin-fixed
paraffin-embedded tissue section. Discrepances in data are planned to confirm by
next-generation sequencing.
Results: In all samples, sufficient DNA was obtained for KRAS and BRAF mutational
studies. Among 1238 KRAS codons 12/13 wild-type patients by ARMS-scorpion
PCR, 166 (13.4%) showed KRAS mutations, 117 (9.5%) in codons 12/13, and 49
(4%) in codon 61. BRAF V600 mutations were detected in 9% cases. In
ARMS-scorpion PCR KRAS mutated patients, mutations were confirmed by cobas in
all cases.
Conclusions: The cobas Mutation Tests are robust and reproducible assays that, 1)
requires a very small amount of tissue; 2) detects up to 13.4% mutations in codons
12, 13 and 61 of the KRAS gene in wild-type mCRC population; and, 3) 9% of
patients showed BRAF mutations in same population.
Disclosure: All authors have declared no conflicts of interest.
538P THE ROLE OF COX-2 AND KI-67 OVEREXPRESSION IN THE
PREDICTION OF PATHOLOGIC RESPONSE OF RECTAL
CANCER TO NEOADJUVANT CHEMORADIATION THERAPY
A. Taghizadeh Kermani 1 , A. Jafarian 2 , J. Esmaeili 2 , N. Mohammadian Roshan 2 ,
M. Seilanian Toosi 1 , A. Omidi Ashrafi 2 , M. Karimi Shahri 2
1 Oncology, MUMS, Mashhad, IRAN, 2 Pathology, MUMS, Mashhad, IRAN
Background: The response to neoadjuvant chemoradiotherapy (CRT) is not the
same among all cases with advanced rectal cancer. Aims: In this study, we
investigated the association between overexpression of two molecular markers
(COX-2 and Ki-67) and tumor response to neoadjuvant therapy. Design: A
retrospective cohort study.
Materials and methods: Forty five patients with stage II-III rectal carcinoma were
enrolled. All patients were treated with neoadjuvant therapy (45-50.4 Gy plus
Capecitabin) between 2002 and 2009 in our institute. The pretreatment specimens
were IHC stained for COX-2 and Ki-67 markers. The tumor response to neoadjuvant
treatment was evaluated using a 5 point tumor regression grade (TRG) system. The
induced inflammation and necrosis after chemoradiotherapy were also investigated.
Statistical analysis: Statistical analysis was performed using SPSS version 11.5 and
statistical significance was determined at P < 0.05.
Results: The pathologic response to neoadjuvant treatment from complete response
as (TRG = 1) through no response as (TRG = 5) was found in 10 (22.2%), 8 (17%), 6
(13.3%), 16 (35.6%), and 5 (11.1%) cases. In comparison with poor responders
(TRG: 4,5), patients with good response to neoadjuvant treatment (TRG: 1,2) were
associated with lower pretreatment mean COX-2 staining extent (72.9% vs. 22.8%,
P < 0.001) as well as lower mean Ki-67 staining extent ( 70.7% vs. 28.5%, p < 0.001).
High COX-2 staining and high Ki-67 index were significantly associated with more
inflammation. Patients with high COX-2 expression showed also significantly more
necrosis in their postsurgical specimens.
Conclusions: Overexpression of COX-2 and high Ki-67 index were associated with a
poorer response to neoadjuvant chemoradiotherapy. These markers might be helpful
to define those patients with rectal carcinoma who benefit more from neoadjuvant
treatments.
Disclosure: All authors have declared no conflicts of interest.
539P PTK7 OVEREXPRESSION IS ASSOCIATED WITH REDUCED
METASTASIS-FREE SURVIVAL (MFS) IN COLORECTAL
CANCER
A. Gonçalves 1 , A. Lhoumeau 2 , G. Monges 3 , J. Delpero 4 , J.L. Raoul 2 , J. Borg 2
1 Medical Oncology, Institut Paoli-Calmettes, Marseille, FRANCE, 2 Molecular
Pharmacology, Institut Paoli-Calmettes, Marseille, FRANCE, 3 Biopathology,
Institut Paoli-Calmettes, Marseille, FRANCE, 4 Surgical Oncology, Institut
Paoli-Calmettes, Marseille, FRANCE
Background: Protein tyrosine kinase-7 (PTK7) is a receptor tyrosine kinase (TK),
with no identified natural ligand and a catalytically inactive intracellular TK domain.
PTK7 expression is up-regulated in many human cancers, including colorectal cancer
(CRC), but little is known about its role in cancer biology. Here, we have examined
PTK7 protein expression in tumor and matched normal tissues from CRC patients
by immunohistochemistry (IHC) and addressed the phenotypic impact of PTK7
down-regulation in CRC cell lines.
Annals of Oncology
Methods: A TMA containing both tumor and matched normal tissues was built
from a cohort of 192 patients with CRC collected between 1990 and 1998 at the
Institut Paoli-Calmettes, Marseille, France. PTK7 expression was analyzed by IHC
using polyclonal goat antibody anti-CC4 (R&D systems, USA). Percentage of stained
cells was measured and staining intensity was scored as 0 (absent), 1 (weak), 2
(moderate) and 3 (strong). PTK7-expressing CRC cell lines were transfected with
PTK7- or control- shRNA and evaluated for cell proliferation, cytotoxic-induced
apoptosis and cell migration.
Results: Patient population had the following characteristics: median age, 63 ys
(range 29-89); sex ratio = male (52%), female (48%); site = colon (90%), rectum
(10%); stage = I-III (64%), IV (36%); median follow-up = 104 months. Staining
intensity (0-1 = 65% of cases, 2 = 19% of cases, 3 =16% of cases, in tumor tissues
versus 0-1 = 86% of cases, 2 = 11% of cases, 3= 3% of cases, in normal tissues; p =
1,91.10-8) as well as average percentage of stained cells (30% in tumor tissues versus
2% in normal tissues; p = 5.74.10-14) were higher in tumor compared to normal
tissues. In stage I-III population (n = 122), 5-year MFS was lower in PTK7-positive
(>10% of cells stained with intensity > 2) compared to PTK7-negative CRC (54%
[95%CI: 38-75%] versus 75% [95%CI: 65-88%], p = 0.034, log-rank test). This impact
was maintained in multivariate analysis and similar trends were observed in overall
survival, while not reaching statistical significance. In vitro, PTK7 inhibition by
shRNA significantly reduced cell migration.
Conclusion: PTK7 protein is overexpressed in CRC and is associated with reduced
MFS, possibly due to an impact on cell migration.
Disclosure: All authors have declared no conflicts of interest.
540P THE INTRA-TUMOR STROMA MICROENVIRONMENT IN
THERAPY MANAGEMENT FOR COLON CANCER PATIENTS
W. Mesker 1 ,V.G.Pelt 1 , H. Gelderblom 2 , V. H. Krieken 3 , D.J. Kerr 4 , R. Tollenaar 1
1 Surgery, Leiden University Medical Center (LUMC), Leiden, NETHERLANDS,
2 Medical Oncology, Leiden University Medical Center (LUMC), Leiden,
NETHERLANDS, 3 Pathology, University Medical Center St. Radboud, Nijmegen,
NETHERLANDS, 4 Dept of Clinical Pharmacology, University of Oxford, Oxford,
UNITED KINGDOM
There is need to identify patients with colon cancer who benefit treatment. We
previously have found that the stroma-tissue surrounding cancer cells plays an
important role in tumor behavior and is reported as an independent prognostic
parameter. Patients with a high stroma percentage within the primary tumor have a
poor prognosis. Validation of the parameter was performed in the VICTOR trial.
Recently the stroma percentage in lymph nodes and metastases was found a
heterogenous process. Moreover the stroma groups respond differently to
chemotherapy regimens.
Methods: Tissue samples consisting of 5 µm Haematoxylin and Eosin (H&E) stained
sections from the most invasive part of the primary tumor were analyzed for their
tumor-stroma percentage. Stroma-high (>50% stroma) and stroma-low (≤50%
stroma) groups were evaluated with respect to survival time and response to therapy.
For patients with and without adjuvant therapy (CT) (n = 150) the primary tumor
(PT) lymph nodes (LN) and liver metastases were analyzed.
Findings: What is the profit of additional LN analysis? The CT treated stroma-low
patient group showed an improved survival (5-yr OS 75% vs 83%, DFS 76% vs 83%,
TTR 84% vs 100%). In the stroma-high patient group we did not notice any
improvement of survival (5-yr OS 77% vs. 72%, DFS 68% vs. 68%, TTR 81% vs.
77%). Which stroma group responds better to therapy? The stroma-high group
showed a better response to therapy compared to the stroma-low group (increase
5-yr OS 22% vs. 8%, DFS 18% vs. 8%, TTR 21% vs. 13%).
Interpretation: The intra-tumor stroma percentage has proven to be a prognostic
factor. It supports selective treatment for stroma-high and stroma-low patients.
Preliminary results show that adjuvant therapy is more efficient for patients with a
high stroma percentage.
Disclosure: All authors have declared no conflicts of interest.
541P THE HISTOLOGICAL IMPORTANCE OF SIGNET RING CELL
AND MUCINOUS ADENOCARCINOMA ON OUTCOMES IN
PATIENTS WITH COLORECTAL CANCER
S. Campos-Gomez 1 , V. Rosas Camargo 1 , R.A. Ramirez Fallas 1 , J.H.
Flores Arredondo 2 , L. Morales Juarez 1 , S.I. Perez Alvarez 1 ,D.
Valdez Bocanegra 1 , D. Huitzil Melendez 1
1 Medical Oncology, Instituto Nacional de Ciencias Medicas y Nutricion Salvador
Zubiran, Mexico DF, MEXICO, 2 Research Department, The Methodist Hospital
Research Institute, Houston, TX, UNITED STATES OF AMERICA
The diagnosis of signet ring cell carcinoma (SRC) and mucinous
adenocarcinoma (MC) represents approximately 1% and 15% of all colorectal
cancers (CRC) respectively. Both entities have an aggressive biological behavior,
but SRC tends to be the worst. A retrospective revision of cases was done in our
institution to evaluate the clinical relevance, including metastasic patterns and
ix184 | Abstracts Volume 23 | Supplement 9 | September 2012