Download università politecnica delle marche facoltà di medicina e chirurgia

UNIVERSITÀ POLITECNICA DELLE MARCHE FACOLTÀ DI MEDICINA E CHIRURGIA
Dipartimento di Neuroscienze-Sezione di Anatomia Patologica
Dottorato di Ricerca in Patologie Immunometaboliche Degenerative ed Infettive
Coordinatore: Chiar.mo Prof. Pietro E. Varaldo
Anno Accademico 2008-2009 – VIII ciclo – nuova serie
DETECTION OF K-RAS ONCOGENE MUTATION AND ITS CLINICAL IMPLICATION IN
COLON-RECTAL CANCER
ABSTRACT
Recent retrospective evidence from several randomized studies has established that advanced
colorectal cancer patients with tumors harboring a mutation in the KRAS gene do not derive benefit from the
administration of epidermal growth factor receptor–directed monoclonal antibodies, such as cetuximab or
panitumumab. This represents a paradigm-changing event and will have substantial impact on current and
future anticancer drug development.
To review the literature on the role of KRAS mutation testing for management of 350 patients with primary
and metastatic colorectal cancer and to discuss testing strategies.
Recent data suggested that in presence of IGF-1 system altered activation colorectal cancer cells may escape
anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis
was tested in order to verify the ability of IGF-1 to identify a sub-group of patients more likely to benefit
from EGFR-targeted antibodies treatment.
Methods
K-RAS gene mutations analysis (codon 12 and 13) was tumor tissue of 350 colon cancer patients
(primary/metastatic): determined by PCR/sequencing in 234 primary tumor and 55 metastatic tumor were
analyzed by PCR/direct sequencing. And 9 cases the evaluation was by Real-Time PCR. These cases were
subjected to immunohistochemical analysis of EGFR.
We compared the mutation status of gene KRAS between the primary tumors and the corresponding
metastases of 50 patients by PCR/sequencing.
IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients
receiving irinotecan/cetuximab.
Results
All cases evaluated the immunohistochemical expression of EGFR, which is positive in more than 1% of
neoplastic cells.
KRAS mutations were identified in 98 (42,3%)cases of 234 CRCs primary tumors and 23 (41,8%) in
metastatic tumor.
Among the K-RAS mutations detected in 50 primary end metastatic tumors, 42 cases were concordance: 14
(33,3%) cases were the same mutation pattern; in 8 (16%) cases we found a discrepancy of result.
IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients
receiving irinotecan/cetuximab.
One hundred and twelve patients were analyzed. IGF-1 was negative in 30 patients (27%). and
overexpressed in the remaining 82 cases (73%). In IGF-1 negative and IGF-1 positive tumors we observed
progressive disease in 9 (30%) and 55 (67%) patients respectively (p = 0.001). Median time to progression
was 7.5 months in patients showing IGF-1 negative tumors and 3 months for IGF-1 expressing tumors (p =
0.002).
Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to
cetuximab-irinotecan in 13 (65%) and 11 (22%) cases respectively (p = 0.002). Median time to progression
in IGF-1 negative tumors was 10 months and 3.2 months in IGF-1 positive colorectal cancers (p = 0.02).
Conclusions
The data obtained by PCR / direct sequencing and Real-Time PCR showed an overall mutation rate of 39%,
in line with data reported in literature.
Our study showed a correlation of results between primary tumor and metastatic (91.4% of cases) in most
patients, similar to those reported in literature.
IGF-1 proved to be a possible predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS
wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a
better selection of responding colorectal cancer patients.