TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

Oden-Gangloff, A.; Fiore, Frédéric Di; Bibeau, Frédéric; Lamy, Aude; Bougeard, Gaëlle; Charbonnier, Françoise; Blanchard, F.; Tougeron, David; Ychou, Marc; Boissière, Florence; Pessot, Florence Le; Sabourin, Jean Christophe; Tuech, Jean Jacques; Michel, Pierre; Frébourg, Thierry

doi:10.1038/sj.bjc.6605008

Cited by 77 publications

(53 citation statements)

References 34 publications

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“…Nevertheless, the observed trend for metastatic disease (if validated) could be clinically useful, facilitating the selection of cases for chemotherapy and/or anti-EGFR therapy, based on combined EGFR/p53 status and tumor location. Notably, as recently reported, p53 mutation may predict response to cetuximab treatment (26), suggesting that p53 inactivation is likely one of the mechanisms leading to EGFR activation, as indicated by the 90% concordance between p53 mutations and the EGFR copy number increase (26). Given that, at present, sufficient evidence of prognostic and predictive significance for any single marker is lacking, including EGFR and p53 (3,27), the potential usefulness of marker combinations appears to be a more promising approach (28,29).…”

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confidence: 83%

The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

et al. 2012

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Abstract. The role of epidermal growth factor receptor (EGFR) in colorectal cancer (CRC) prognosis remains unclear despite the recent development of anti-EGFR treatments for metastatic disease. The heterogeneity of CRC may account for this discrepancy; proximal and distal CRC has been found to be genetically and clinicopathologically different. The aim of this study was to investigate the effect of tumor location on the association of EGFR with the conventional prognostic indicators (stage and grade) in CRC. Immunohistochemical assessment of EGFR was retrospectively performed in 119 primary CRC specimens and data were correlated with tumor stage and grade in the proximal and distal tumor subset. The molecular combination of EGFR with p53 (previously assessed in this sample) was similarly analyzed. EGFR positivity was detected in 34, 30 and 35% of the entire cohort, proximal and distal tumors, respectively. The pattern of EGFR clinicopathological correlation was found to differ by site. A reduction in the frequency of EGFR(+) with progression of stage and/or worsening of grade was observed proximally, whereas an opposite trend was recorded distally. Proximal tumors with stage I or with indolent features (stage I, welldifferentiated) exhibited a significantly higher proportion of EGFR positivity than other tumors of this location (p=0.023 and p=0.022, respectively) or corresponding distal tumors (p=0.018 and p=0.035, respectively). Moreover, the co-existence of EGFR and high p53 staining (accounting for 11% of cases) was found in a significantly higher proportion of stage IV tumors compared to other stages (p=0.004), although only for the distal subset. Proximal and distal tumors showed various patterns of EGFR variation with disease progression and aggressiveness. This disparity provides further support to the hypothesis that these particular subsets of CRC are distinct tumor entities. It may also be suggestive of a potentially different therapeutic approach according to tumor site, particularly regarding anti-EGFR targeted treatment. IntroductionColorectal cancer (CRC) is one of the most common malignancies and remains a major cause of cancer mortality in the West (1). It is also a multi-pathway disease with disparate subgroups exhibiting distinct genetic and clinicopathological features, and probably different outcomes (2). This may be the main reason for the variability in treatment response observed among patients of the same disease stage. Therefore, a combination of the conventional TNM staging classification (at present, the major prognostic indicator) with certain molecular markers involved in CRC tumorigenesis, with verified prognostic and predictive impact, is one of the main objectives of research worldwide (3).Epidermal growth factor receptor (EGFR) is a transmembrane glycoprotein member of the tyrosine-kinase receptor family, encoded by the c-erB1 proto-oncogene and is considered as a major regulator of several distinct cellular pathways. Activation of EGFR promotes carcinogenesis, by increasing prol...

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confidence: 83%

The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

et al. 2012

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“…22 For example, mutant TP53 is a predictor of better clinical outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. 81 These observations suggest that molecular genotyping of tumors may yield molecular profiles that are useful for stratification and selection of patients who will benefit from targeted therapies, and may ultimately prove useful for selection of patients that receive BiTE Ò antibody therapies.…”

Section: Discussionmentioning

confidence: 99%

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Oberst¹,

Fuhrmann²,

Mulgrew³

et al. 2014

mAbs

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A Hammond (2014) CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas, mAbs, 6:6, 1571-1584, DOI: 10.4161/19420862.2014 To link to this article: https://doi.org/10. 4161/19420862.2014 Individual or combinations of somatic mutations found in genes from colorectal cancers can redirect the effects of chemotherapy and targeted agents on cancer cell survival and, consequently, on clinical outcome. Novel therapeutics with mechanisms of action that are independent of mutational status would therefore fulfill a current unmet clinical need. Here the CEA and CD3 bispecific single-chain antibody MEDI-565 (also known as MT111 and AMG 211) was evaluated for its ability to activate T cells both in vitro and in vivo and to kill human tumor cell lines harboring various somatic mutations commonly found in colorectal cancers. MEDI-565 specifically bound to normal and malignant tissues in a CEA-specific manner, and only killed CEA positive cells. The BiTE Ò antibody construct mediated T cell-directed killing of CEA positive tumor cells within 6 hours, at low effector-to-target ratios which were independent of high concentrations of soluble CEA. The potency of in vitro lysis was dependent on CEA antigen density but independent of the mutational status in cancer cell lines. Importantly, individual or combinations of mutated KRAS and BRAF oncogenes, activating PI3KCA mutations, loss of PTEN expression, and loss-of-function mutations in TP53 did not reduce the activity in vitro. MEDI-565 also prevented growth of human xenograft tumors which harbored various mutations. These findings suggest that MEDI-565 represents a potential treatment option for patients with CEA positive tumors of diverse origin, including those with individual or combinations of somatic mutations that may be less responsive to chemotherapy and other targeted agents.

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“…A possible explanation is inhibition of JNK-mediated apoptosis by high MKP-1 levels, as has recently been reported by Takeuchi et al (2009). On the other hand, a recently published interesting hypothesis-generating study supports p53 mutations as a potential marker of response to cetuximab (Oden-Gangloff et al, 2009). MKP-1 has been shown to be transcriptionally regulated by p53, and mutations of p53 abrogate p53-dependent transcription of MKP-1 in vitro (Yang and Wu, 2004;Liu et al, 2008).…”

Section: Discussionmentioning

confidence: 80%

“…Tumour response was evaluated retrospectively according to the response evaluation criteria in solid tumours (Therasse et al, 2000). Patients with complete response, partial response or stable disease were considered to have controlled disease (CD) (Oden-Gangloff et al, 2009). This study was approved by the Ethics Board of the Hospital and was performed according to Institutional Guidelines.…”

Section: Patient Characteristics and Clinical Evaluationmentioning

confidence: 99%

Mitogen-activated protein kinase phosphatase-1 (MKP-1) impairs the response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab in metastatic colorectal cancer patients

et al. 2010

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BACKGROUND: The validation of KRAS mutations as a negative marker of response to anti-epidermal growth factor receptor (EGFR) antibodies has meant a seminal advance towards treatment individualisation of colorectal cancer (CRC) patients. However, as a KRAS wild-type status does not guarantee a response to anti-EGFR antibodies, a current challenge is the identification of other biomarkers of response. On the basis of pre-clinical evidence, we hypothesised that mitogen-activated protein kinase phosphatase-1 (MKP-1), a phosphatase that inactivates MAPKs, could be a mediator of resistance to anti-EGFR antibodies. METHODS: Tumour specimens from 48 metastatic CRC patients treated with cetuximab-based chemotherapy were evaluated for KRAS and BRAF mutational status and MKP-1 expression as assessed by immunohistochemistry. RESULTS: As expected, clinical benefit was confined to wild-type KRAS and BRAF patients. Mitogen-activated protein kinase phosphatase-1 was overexpressed in 16 patients (33%) and was not associated with patient baseline clinicopathological characteristics and KRAS mutational status. All patients with BRAF mutations (n ¼ 3) had MKP-1 overexpression. Among KRAS wildtype patients, MKP-1 overexpressors had a 7% response rate (RR), whereas patients not overexpressing MKP-1 had a 44% RR (P ¼ 0.03). Moreover, median time to progression was significantly longer in MKP-1 non-overexpressing patients (32 vs 13 weeks, P ¼ 0.009). CONCLUSION: These results support the concept of MKP-1 as a promising negative marker of response to cetuximab-based treatment in CRC patients with wild-type KRAS.

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TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy

Cited by 77 publications

References 34 publications

The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

The pattern of epidermal growth factor receptor variation with disease progression and aggressiveness in colorectal cancer depends on tumor location

CEA/CD3 bispecific antibody MEDI-565/AMG 211 activation of T cells and subsequent killing of human tumors is independent of mutations commonly found in colorectal adenocarcinomas

Mitogen-activated protein kinase phosphatase-1 (MKP-1) impairs the response to anti-epidermal growth factor receptor (EGFR) antibody cetuximab in metastatic colorectal cancer patients

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