Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit From Cetuximab Therapy in Wild-Type KRAS Metastatic Colon Cancer

Laurent‐Puig, Pierre; Cayre, Anne; Manceau, Gilles; Buc, Emmanuel; Bachet, Jean‐Baptiste; Lecomte, Thierry; Rougier, Philippe; Lièvre, Astrid; Landi, Bruno; Boige, Valérie; Ducreux, Michel; Ychou, Marc; Bibeau, Frédéric; Bouché, Olivier; Reid, Julia; Stone, Steven; Penault‐Llorca, Frédérique

doi:10.1200/jco.2008.21.6796

Cited by 624 publications

(509 citation statements)

References 38 publications

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“…Recent experience has demonstrated the benefit of epidermal growth factor receptor inhibitors in metastatic colorectal cancers, but these agents are not useful in tumors with KRAS or BRAF mutations. 51,52 In view of the presence of these mutations in a vast majority of signet ring cell carcinoma, it is unlikely that anti-epidermal growth factor receptor therapy will be beneficial.…”

Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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The relationship of molecular abnormalities with clinicopathologic features and survival in colorectal signet ring cell carcinoma, and its comparison with mucinous and conventional adenocarcinomas, has not been well studied. High-level microsatellite instability, loss of heterozygosity (LOH) at four loci, CpG island methylation phenotype based on seven loci, BRAF V600E mutation and KRAS mutation in signet ring cell carcinoma were compared with mucinous and conventional adenocarcinomas. The relationship of these molecular features in signet ring cell carcinoma with clinicopathologic features and survival was examined. LOH was observed in 93% of signet ring cell carcinomas compared with 62 and 70% of mucinous and conventional adenocarcinomas. Also, 80% of signet ring cell carcinomas with high-level microsatellite instability showed LOH compared with 14% each of mucinous and conventional adenocarcinomas. High-level microsatellite instability, CpG island methylation phenotype-positive status and BRAF V600E mutation were more often seen in signet ring cell carcinoma and mucinous adenocarcinoma compared with conventional adenocarcinoma. BRAF V600E mutation was significantly associated with CpG island methylation phenotype-positive status. Stage and BRAF V600E mutation in microsatellite-stable cases were the only variables with an affect on survival. In conclusion, chromosomal instability manifested by LOH is nearly a universal finding in signet ring cell carcinoma, including cases with highlevel microsatellite instability. This may explain the aggressive behavior of signet ring cell carcinoma irrespective of high-level microsatellite-instability status. BRAF V600E mutation and CpG island methylation phenotypepositive status are similar in signet ring cell carcinoma and mucinous adenocarcinoma but more frequent when compared with conventional adenocarcinoma. In signet ring cell carcinoma, BRAF V600E mutation adversely affects survival in microsatellite-stable tumors, but not in high-level microsatellite-unstable tumors. The high frequency of methylation and BRAF V600E mutation suggests that many signet ring cell carcinomas may be related to the serrated pathway of carcinogenesis.

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Section: Discussionmentioning

confidence: 99%

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

et al. 2012

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“…Treatment with sorafenib, a BRAF inhibitor, restored the sensitivity to cetuximab or panitumumab of these three BRAF-mutated colorectal cancer cell lines. Since then, three independent retrospective studies have also shown lack of response to cetuximab and a shorter survival of patients with BRAF-mutated tumour among the subgroup of KRAS wild-type patients (Laurent-Puig et al, 2009;Souglakos et al, 2009;Loupakis et al, 2009b) (Table 2). These findings clearly show that BRAF mutations are an additional tool for the selection of patients who might be resistant to anti-EGFR antibodies and that they should be considered before considering anti-EGFR therapies for mCRC.…”

Section: Kras Somatic Mutationsmentioning

confidence: 99%

Oncogenic mutations as predictive factors in colorectal cancer

2010

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“…45 PTEN is a tumor suppressor that acts as a negative regulator of PI3K signaling by converting PIP3 to PIP2, and truncating mutations which result in loss of PTEN expression, reported in~20% of MSI colon cancers. [46][47][48][49][50][51] The molecular alteration of PTEN is often caused by epigenetic mechanisms, 45 supporting the detection of the intact protein by IHC as a better diagnostic tool than gene sequencing, as it potentially covers more mechanisms of alteration. PIK3CA mutation and PTEN expression status predicts response of colon cancer cells to the EGFR inhibitor cetuximab distinguishing drug sensitive and resistant cell lines.…”

Section: Pten-pi3k-akt-mtor Pathway Alterationsmentioning

confidence: 99%

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

Rizzo

Bronte

Fanale

et al. 2010

Cancer Treatment Reviews

102

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s u m m a r yAn important molecular target for metastatic CRC treatment is the epidermal growth factor receptor (EGFR). Many potential biomarkers predictive of response to anti-EGFR monoclonal antibodies (cetuximab and panitumumab) have been retrospectively evaluated, including EGFR activation markers and EGFR ligands activation markers. With regard to the "negative predictive factors" responsible for primary or intrinsic resistance to anti-EGFR antibodies a lot of data are now available. Among these, KRAS mutations have emerged as a major predictor of resistance to panitumumab or cetuximab in the clinical setting and several studies of patients receiving first and subsequent lines of treatment have shown that those with tumors carrying KRAS mutations do not respond to EGFR-targeted monoclonal antibodies or show any survival benefit from such treatments. The role of B-RAF mutations, mutually exclusive with KRAS mutations, in predicting resistance to anti-EGFR mAbs is not yet consolidated. It therefore appears that BRAF mutations may play a strong negative prognostic role and only a slight role in resistance to anti-EGFR Abs.

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Analysis of PTEN, BRAF, and EGFR Status in Determining Benefit From Cetuximab Therapy in Wild-Type KRAS Metastatic Colon Cancer

Abstract: BRAF status, EGFR amplification, and cytoplasmic expression of PTEN were associated with outcome measures in KRAS wild-type patients treated with a cetuximab-based regimen. Subsequent studies in clinical trial cohorts will be required to confirm the clinical utility of these markers.

Cited by 624 publications

References 38 publications

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Loss of heterozygosity, aberrant methylation, BRAF mutation and KRAS mutation in colorectal signet ring cell carcinoma

Oncogenic mutations as predictive factors in colorectal cancer

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

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