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KRAS mutation status is predictive of response to Cetuximab therapy in colorectal cancer


Colorectal cancer is one of the most common human malignancies with greater than 300,000 cases both in the United States and in the European Union each year.
In the past decade, survival of metastatic colorectal cancer patients has approximately doubled. This significant improvement is mainly due to the development of new combinations of standard chemotherapy, including 5-Fluorouracil, Irinotecan, and Oxaliplatin, and also to the introduction of new targeted therapies, such as monoclonal antibodies against epidermal growth factor receptor ( EGFR ) or monoclonal antibodies against vascular endothelial growth factor.

The addition of such targeted therapies to standard chemotherapy regimens results in an increase of toxicity and treatment costs and therefore requires the identification of decision-making tools to select patients who are likely to benefit from them.

The chimeric IgG1 monoclonal antibody Cetuximab ( Erbitux ) has been proven efficient in Irinotecan-resistant metastatic colorectal cancer expressing the EGFR by immunohistochemistry, with response rates ranging between 8.8% when used in monotherapy and 22.9% when combined with Irinotecan.
However, the molecular mechanisms underlying the clinical response or resistance to this drug remain unknown.
Recently, a 25% objective response rate ( ORR ) was obtained in a series of colorectal cancers that did not express EGFR by immunohistochemistry, highlighting the potential existence of other predictive markers of response to Cetuximab.

Recent progresses have been made in the understanding of the EGFR pathway involved in colorectal carcinogenesis. The binding of a ligand on the extracellular part of EGFR results in the phosphorylation of the tyrosine kinase domain located in its intracellular part. Then, the activation of the receptor leads to the activation of intracellular effectors involved in intracellular signaling pathways, such as the G protein K-ras, the protein kinase RAF [ Ras/mitogen-activated protein kinase ( MAPK ) pathway ], and phosphoinositide 3-kinase ( PI3K/Akt pathway ).

Cetuximab binds to EGFR with a high specificity and blocks ligand-induced phosphorylation of the receptor. Consequently, researchers have hypothesized that mutation in the KRAS, BRAF, and PI3KCA coding genes could affect the clinical response to this monoclonal antibody.

The study has assessed 30 metastatic colorectal cancer patients ( 19 males and 11 females; mean age, 62.3 years ) treated by antibodies against EGFR Cetuximab. All these patients had a metastatic colorectal adenocarcinoma histologically proved and underwent a surgical resection of their primary tumor.

Eleven of the 30 patients ( 37% ) responded to Cetuximab. The median duration of response to Cetuximab was 33.9 months ( range, 17.1-62.9 months ). In the six patients with stable disease under Cetuximab treatment, the median duration of stabilization was 18.3 months ( range, 14.7-20.0 months ).

A KRAS mutation was found in the tumor of 13 patients ( 43% ). No tumor had a BRAF mutation, which is consistent with the absence of microsatellite instability determined by the genotyping of five microsatellites in all the tumors included in the series. A PIK3CA mutation, located in the exon 9, was found in two tumors ( 7% ), which also had a KRAS mutation.

No KRAS mutation was found in the tumor from 11 patients with a clinical response to Cetuximab ( 0% ), whereas 13 tumors from the 19 nonresponder patients ( 68.4% ) were found mutated in this gene ( P=0.0003 ).
Therefore, the presence of KRAS mutation was significantly associated with the absence of response to Cetuximab.
This difference remained significant even if the three responder patients treated with the association of Cetuximab and FOLFIRI regimen as first-line treatment were removed from the analysis ( KRAS mutation: 0 of 8 responders versus 13 of 19 nonresponders; P = 0.002 ).

In this group of 27 patients, the overall survival of patients without KRAS mutation in their tumor was significantly higher compared with those patients with a mutated tumor ( P=0.016; median, 16.3 versus 6.9 months ).

No significant correlation was found between PIK3CA mutation and response to Cetuximab.

In the series, an increased EGFR copy number was found by CISH in 3 of 30 ( 10% ) patient tumors. Amplification was defined as six or more signals per nucleus in greater than 50% of cancer cells, or when a large gene copy cluster was seen. At least 30 nuclei were counted per slide. Slides were scored in a blinded manner by two pathologists.
All the patients with EGFR amplification were responders, leading to a significant association between EGFR amplification and response to Cetuximab ( EGFR amplification in responder vs nonresponder patients: 27% versus 0%; P = 0.04 ).

One study had previously assessed the mutation status of the EGFR catalytic domain and its downstream intracellular effectors PIK3CA, KRAS, and BRAF and found no significant correlation with response to Cetuximab. However, a potential trend toward higher response rates was seen in Cetuximab-treated colorectal cancer patients whose tumors were of KRAS wild-type status.

When the results were pooled with those of Moroni et al ( Lancet Oncology 2005 ), the predictive value of KRAS mutation remained significant with a KRAS mutation frequency of 52.5% in nonresponders compared with 9.5% in responders ( P=0.001 ).
When considering these pooled data, the probability to have no response to Cetuximab was 91.3% in the presence of KRAS mutation. Moreover, the probability to be responder was 50% when no KRAS mutation was identified.
The relative risk to obtain a response to Cetuximab was 10-fold higher for nonmutated patients compared with that of patients with KRAS mutation ( hazard ratio, 10.5 ). Thus, these data suggest that the wild-type KRAS status might identify patients with metastatic colorectal cancer who are likely to respond to Cetuximab and to have a longer overall survival.

The results suggest that Cetuximab should not be proposed to about 40% of all metastatic colorectal cancer patients having KRAS-mutated tumor cells.

The presence of a KRAS mutation in EGFR-positive colorectal cancers might partially explain why one part of these tumors does not respond to Cetuximab. K-ras is a G protein that plays a key role in the Ras/MAPK signaling pathway located downstream of many growth factor receptors, including EGFR, and involved in colorectal carcinogenesis. The recruitment of K-ras by the activated EGFR is responsible for the activation of a cascade of serine-threonine kinases from the cell surface to the nucleus. The Ras/MAPK pathway is one of the most important pathways for cell proliferation by inducing the synthesis of cyclin D1 and mutation of the KRAS proto-oncogene, which are found in 36% of colorectal cancers, leading to the activation of this pathway.
Consequently, researchers have hypothesize that whatever the expression level of EGFR is, the presence of a KRAS mutation is associated with a downstream activation of the Ras/MAPK pathway, leading to cell proliferation that cannot be significantly inhibited by Cetuximab that acts upstream of the K-ras protein.

In accordance with the results, KRAS mutations were found to be associated with resistance to EGFR kinase inhibitors Gefitinib ( Iressa ) and Erlotinib ( Tarceva ) in lung adenocarcinomas.
A similar trend was recently observed in a series of 30 colorectal cancers treated with Gefitinib, among which the response rate for tumors with and without KRAS mutation was 33% and 47%, respectively.

In conclusion, researchers have shown that KRAS mutation is associated with resistance to Cetuximab and a shorter survival in EGFR-positive metastatic colorectal cancer patients treated with this therapy. Thus, KRAS mutation status might allow the identification of patients who are likely to benefit from Cetuximab and avoid a costly and potentially toxic administration of this treatment in nonresponder patients. ( Xagena )

Lièvre A et al, Cancer Res 2006; 66: 3992-3995

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