KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab

Roock, Wendy De; Schutter, Jef De; Hertogh, Gert De; Janssens, M.; Biesmans, Bart; Personeni, Nicola; Geboes, Karel; Verslype, Chris; Cutsem, Éric Van; Tejpar, Sabine

doi:10.1200/jco.2007.25.18_suppl.4132

Cited by 16 publications

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“…This observation was further confirmed by several studies presented at 2007 American Society of Clinical Oncology (ASCO) annual meeting 54, 55. In a recently published report, De Roock et al found that K‐ ras mutations precluded tumor response to cetuximab 55, 56. However, all of these studies suffered from small patient cohorts.…”

Section: K‐ras Gene Mutation and Epidermal Growth Factor Receptor Tarmentioning

confidence: 75%

Assessment of K‐ras mutation

Jiang

Kimchi

Staveley-O’Carroll

et al. 2009

Cancer

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Some of the most significant therapeutic advances in the treatment of cancer have occurred in the management of colorectal metastases. The introduction of new cytotoxic chemotherapeutic and biologic agents has changed the approach to these patients from both an oncologic and a surgical perspective. In addition, an understanding of the molecular mechanisms by which these agents affect tumors is developing. This molecular information will be critical in the future in designing therapeutic regimens based on an individual tumor's genetic profile rather than treatment for a specific tumor type. The rapidly evolving treatment of colon cancer has provided several interesting genetic biomarkers/pathways/genes‐/kinases that have been targeted or seem to play an important role. Of particular interest is the blockade of epidermal growth factor receptor (EGFR) with monoclonal antibodies. This treatment is efficacious when used alone or combined with chemotherapy. However, recent data revealed that patients with tumors positive for the K‐ras mutation do not benefit from EGFR blockade. Compelling evidence has indicated that mutated K‐ras is an important oncogene involved at the early stage of the development of colorectal cancer. Furthermore, mutations in the K‐ras gene have been associated with aggressive tumor biology. K‐ras mutational analysis is an important step in the overarching goal of developing personalized medicine. New treatment strategies are needed to more effectively treat patients with the K‐ras mutation. Cancer 2009. © 2009 American Cancer Society.

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Section: K‐ras Gene Mutation and Epidermal Growth Factor Receptor Tarmentioning

confidence: 75%

Assessment of K‐ras mutation

Jiang

Kimchi

Staveley-O’Carroll

et al. 2009

Cancer

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Controversial evaluation of EGFR protein and gene status in predicting response to anti-EGFR monoclonal antibodies in metastatic colorectal cancer: a case report and review of the literature

et al. 2008

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Clinical studies showed that only 10% of patients with metastatic colorectal cancer (mCRC) respond to treatment with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies panitumumab or cetuximab, regardless of the line of treatment. The current tool used to select patients, i.e. immunohistochemistry (IHC) evaluation of EGFR expression by EGFR pharmDx™ Kit, is not reliable in predicting response. Retrospective analyses of factors such as increased EGFR gene copy number and KRAS and/or BRAF mutations showed that such molecular changes could affect clinical benefit from anti-EGFR monoclonal antibodies. We report here the case of a 66-year-old man with chemorefractory mCRC, considered not eligible to salvage treatment with the anti-EGFR monoclonal antibody cetuximab and irinotecan because the primary adenocarcinoma of the rectum was found not expressing EGFR protein by IHC. However, FISH analysis of EGFR gene copy number and evaluation of KRAS and/or BRAF specific mutations by gene sequencing showed characteristics associated with favourable clinical outcome to anti-EGFR therapy. Based on the EGFR protein expression by IHC in a liver metastasis, the patient was then treated with cetuximab plus irinotecan, obtaining symptoms improvement and a dramatic objective tumor response in all sites of disease, lasting 4.2 months. We also discuss literature findings about the role of different biological characteristics in predicting clinical benefit from anti-EGFR therapy in patients with mCRC. Keywords Colorectal cancer . EGFR . FISH . KRAS . Monoclonal antibodies Case reportA 66-year-old man with metastatic colorectal cancer (mCRC) in progressive disease after fluoropyrimidine-, irinotecan-, oxaliplatin-, and mytomiycin-containing regimens was initially considered not eligible for salvage treatment with the anti-epidermal growth factor receptor (EGFR) monoclonal antibody (moAb) cetuximab and irinotecan because the primary adenocarcinoma of the rectum was found not to express EGFR protein by immunohistochemistry (IHC; Fig. 1a) [1]. Given that discrepancies between EGFR expression in primary versus metastatic sites can occur in the same patient [2], subsequent evaluation of specimens from liver and abdominal metastases were performed, showing 5% EGFRpositive cells by IHC exclusively in liver metastases (Fig. 1c). Intriguingly, fluorescence-in situ-hybridization (FISH) analysis detected an EGFR gene increased copy number, consisting in a chromosome 7 polysomy in >90% of cells, both in primary and in metastatic sites, with a mean EGFR gene/cell of 3.88 in the primary tumor, 3.64 in liver metastasis and 3.43 in soft tissue metastasis (Fig. 1b,d, and f).

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The Biology of K-Ras and B-Raf Mutations in Colorectal Cancer

Jiang

Mackley

Cheng

et al. 2010

Curr Colorectal Cancer Rep

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Ras and Raf proteins are two major players in the MAP kinase pathway. They are crucial downstream regulators of multiple receptor tyrosine kinase-mediated cell growth, transformation, and maintenance of the malignant phenotype in human cancers. Mutations have been identified in K-Ras and B-Raf in patients with colorectal cancer. Clinical studies in colorectal cancers demonstrate that the therapeutic efficacy of cetuximab, a chimeric monoclonal antibody against epidermal growth factor receptor, depends on the presence of wild-type KRas. However, mutations in B-Raf do not predict cetuximab resistance. These observations have led to the use of K-Ras as a predictive biomarker, allowing clinicians to direct the therapy of cancer patients based on their K-Ras mutational status.

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KRAS mutations preclude tumor shrinkage of colorectal cancers treated with cetuximab

Cited by 16 publications

References 0 publications

Assessment of K‐ras mutation

Assessment of K‐ras mutation

Controversial evaluation of EGFR protein and gene status in predicting response to anti-EGFR monoclonal antibodies in metastatic colorectal cancer: a case report and review of the literature

The Biology of K-Ras and B-Raf Mutations in Colorectal Cancer

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