Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin

Lenz, Heinz‐Josef; Mayer, Ruth; Gold, Philip J.; Mirtsching, B.; Stella, Phillip J.; Cohn, Allen Lee; Pippas, Andrew W.; Azarnia, Nozar; Needle, Michael N.; Cutsem, Éric Van

doi:10.1200/jco.2004.22.14_suppl.3510

Cited by 50 publications

(53 citation statements)

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“…Moreover, in a retrospective series of 16 chemo-refractory patients not expressing EGFR, cetuximab was shown to produce an RR of 25% (Chung et al, 2005). In addition, two PR were seen in nine patients with EGFR-negative tumours enrolled in a phase II study of single agent cetuximab (Lenz et al, 2005). It has been shown that the choice of fixative and storage time of tumour tissue, (Atkins et al, 2004) the choice of primary antibody and scoring system (Kersting et al, 2006), and the lack of standardised criteria for evaluation (Langner et al, 2004) all represent potential pitfalls and have a substantial impact on determination of EGFR immunoreactivity.…”

Section: Discussionmentioning

confidence: 98%

PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients

et al. 2007

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To evaluate whether the epidermal growth factor receptor (EGFR), K-Ras and PTEN, all members of the EGFR signalling pathway, may affect the clinical response in cetuximab-treated metastatic colorectal cancer (mCRC) patients. Twenty-seven cetuximab-treated mCRC patients were evaluated for drug response and investigated for EGFR protein expression and gene status, K-Ras mutational status and PTEN protein expression. Ten patients achieved a partial response (PR) to cetuximab-based therapy. All 27 patients showed EGFR protein overexpression. Epidermal growth factor receptor gene amplification was observed in eight out of 27 (30%) and chromosome 7 marked polysomy in 16 (59%) patients. Partial response was observed in six out of eight patients with EGFR gene amplification, four out of 16 with marked polysomy and none out of three with eusomy ( P <0.05). The K-Ras wild-type sequence was observed in 17 patients, and nine of them experienced a PR. Conversely, K-Ras was mutated in 10 cases, of which one patient experienced a PR ( P <0.05). The PTEN protein was normally expressed in 16 patients, and 10 of them achieved a PR. In contrast, no benefit was documented in 11 patients with loss of PTEN activity ( P <0.001). Patients with EGFR gene amplification or chromosome 7 marked polysomy respond to cetuximab. In addition to K-Ras mutations, we demonstrate for the first time that the loss of PTEN protein expression is associated with nonresponsiveness to cetuximab.

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Section: Discussionmentioning

confidence: 98%

PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients

et al. 2007

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“…[8][9][10][11] Furthermore, response to cetuximab has recently been shown in patients with EGFR-negative colorectal carcinomas. 12,13 Thus, the value of immunohistochemical detection of EGFR in selecting patients for treatment with cetuximab has failed to be borne in our clinical trails. An alternative methodology that offers higher sensitivity and specificity in predicting treatment response would be highly desirable.…”

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confidence: 99%

Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study

et al. 2005

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Recent data suggest that detection of epidermal growth factor receptor protein by immunohistochemistry (IHC) does not predict response to the antiepidermal growth factor receptor drug, cetuximab, in patients with colorectal carcinoma. In searching for foundation for further investigation to optimize patient selection for cetuximab therapy, this study sought to exploit the tissue microarray and chromogenic in situ hybridization techniques to evaluate the status of epidermal growth factor receptor gene amplification in colorectal cancer and its relationship with protein expression by IHC. The study included 158 primary or metastatic colorectal adenocarcinomas. Immunohistochemical results were scored as 0-3 þ based on the intensity of membrane staining. The in situ hybridization signals were counted in 30 nuclei per tissue core. Overall, the rate of tissue loss was 7%, yielding 147 analyzable cases: 123 primary, 24 metastatic. Positive immunohistochemical staining of any intensity was detected in 85% (105/123) of primary and 79% (19/24) of metastatic tumors, whereas gene amplification (45 gene copies/nucleus) was only seen in 12% (15/123) of primary and 8% (2/24) of metastatic tumors. Only 2/15 primary and 1/2 metastatic tumors that showed gene amplification were amplified at a high level (410 gene copies/nucleus). Although a positive correlation was detected between the intensity of protein expression and the likelihood of gene amplification in both the primary (P ¼ 0.01) and the metastatic (P ¼ 0.05) tumors, IHC had a low specificity (17% in primary, 23% in metastatic) in predicting gene amplification. Conversely, all tumors that did not express the protein by IHC lacked gene amplification. Thus, this study shows that only a small fraction of epidermal growth factor receptor-positive colorectal carcinomas detected by IHC are associated with gene amplification. Additional studies are needed to determine whether epidermal growth factor receptor gene amplification bears any informative value in predicting response to cetuximabbased therapy. The epidermal growth factor receptor (EGFR) is a member of the HER tyrosine kinase growth factor receptor family, and is involved in signaling pathways affecting cell growth. [1][2][3][4] Recent studies have shown that EGFR expression is present in approximately 60-80% of colorectal carcinomas 5,6 and the receptor has emerged as a rational target for anticancer therapy in these tumors. 2,7 Cetuximab is a human-murine chimeric monoclonal antibody that specifically blocks the EGFR. Several clinical trials have demonstrated activity of cetuximab in patients with advanced colorectal carcinoma 3,4 and the drug is currently licensed in the US and Switzerland for use in such patients.

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“…However, response rates to cetuximab appear comparable irrespective of the EGFR status, including those tumors that are negative for EGFR by immunohistochemistry. 43,44 The EGFR immunoreactivity can vary significantly depending on fixation methodology and storage time of tissue samples. 45 Therefore, there is no rational basis to use EGFR status to select patients for cetuximab based on expression of EGFR in the tumor.…”

Section: Cetuximabmentioning

confidence: 99%

Role of novel targeted agents in the treatment of metastatic colorectal cancer

Damianovich¹,

Tebbutt²

2007

Asia-Pac J Clncl Oncology

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Modern chemotherapy regimens, combining bolus or infused schedules of 5-fluorouracil (5-FU) with irinotecan or oxaliplatin, have significantly improved the treatment outcomes of patients with metastatic colorectal cancer (CRC). The addition of novel targeted agents to chemotherapy has the potential to increase the median survival of patients with metastatic CRC beyond 2 years. Bevacizumab, a monoclonal antibody (mAb) to vascular endothelial growth factor, has an established role in first-line treatment in combination with either 5-FU/leucovorin or irinotecan/5-FU/leucovorin regimens, while cetuximab, a mAb to epidermal growth factor receptor, in combination with irinotecan is more suitable for the treatment of refractory metastatic CRC. The use of bevacizumab in later stages of the disease and cetuximab in chemotherapynaive patients as well as concurrent treatment with both agents is still under investigation. The landmark studies leading to the approval of these agents in the treatment of metastatic CRC as well as associated toxicity profiles and detailed treatment recommendations are discussed in this review.

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Activity of cetuximab in patients with colorectal cancer refractory to both irinotecan and oxaliplatin

Cited by 50 publications

References 0 publications

PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients

PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients

Epidermal growth factor receptor expression and gene amplification in colorectal carcinoma: an immunohistochemical and chromogenic in situ hybridization study

Role of novel targeted agents in the treatment of metastatic colorectal cancer

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