<i>KRAS</i> Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab

Lièvre, Astrid; Bachet, Jean‐Baptiste; Boige, Valérie; Cayre, Anne; Corre, Delphine Le; Buc, Emmanuel; Ychou, Marc; Bouché, Olivier; Landi, Bruno; Louvet, Christophe; André, Thierry; Bibeau, Frédéric; Diébold, Marie-Danièle; Rougier, Philippe; Ducreux, Michel; Tomasic, Gorana; Émile, Jean-François; Penault‐Llorca, Frédérique; Laurent‐Puig, Pierre

doi:10.1200/jco.2007.12.5906

Cited by 1,332 publications

(816 citation statements)

References 22 publications

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“…Considering the molecular basis of EGFR-targeting agents, blocking EGFR at the receptor level will not ablate downstream signaling activities in tumors with KRAS mutations and hence constitutively active RAS proteins. Indeed, several studies have reported that KRAS mutations confer resistance to anti-EGFR monoclonal antibodies [24,48,[61][62][63][64][65]. KRAS mutations are associated with poor responses to therapy, reduced PFS and shorter OS in colorectal cancer patients treated with cetuximab alone or in combination with chemotherapy [48,[62][63][64][65].…”

Section: Kras: a Downstream Target Of Egfr Signalingmentioning

confidence: 99%

“…Indeed, several studies have reported that KRAS mutations confer resistance to anti-EGFR monoclonal antibodies [24,48,[61][62][63][64][65]. KRAS mutations are associated with poor responses to therapy, reduced PFS and shorter OS in colorectal cancer patients treated with cetuximab alone or in combination with chemotherapy [48,[62][63][64][65]. Similarly, an analysis of KRAS mutations in tumor samples from 92% of patients in a registrational clinical trial of panitumumab for the treatment of metastatic colorectal cancer predicted a lack of efficacy of panitumumab on PFS and OS in patients with KRAS mutant tumors [24].…”

Section: Kras: a Downstream Target Of Egfr Signalingmentioning

confidence: 99%

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KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

et al. 2008

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Novel therapeutic agents targeting the epidermal growth factor receptor (EGFR) have improved outcomes for patients with colorectal carcinoma. However, these therapies are effective only in a subset of patients. Activating mutations in the KRAS gene are found in 30-40% of colorectal tumors and are associated with poor response to anti-EGFR therapies. Thus, KRAS mutation status can predict which patient may or may not benefit from anti-EGFR therapy. Although many diagnostic tools have been developed for KRAS mutation analysis, validated methods and standardized testing procedures are lacking. This poses a challenge for the optimal use of anti-EGFR therapies in the management of colorectal carcinoma. Here we review the molecular basis of EGFR-targeted therapies and the resistance to treatment conferred by KRAS mutations. We also present guideline recommendations and a proposal for a European quality assurance program to help ensure accuracy and proficiency in KRAS mutation testing across the European Union.

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Section: Kras: a Downstream Target Of Egfr Signalingmentioning

confidence: 99%

Section: Kras: a Downstream Target Of Egfr Signalingmentioning

confidence: 99%

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

et al. 2008

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“…[1][2][3][4][5][6][7] Indeed, KRAS mutations result in constitutively active KRAS proteins that lead to continuous activation of the RAS signaling pathway independently of the upstream stimulation by EGFR ligands. As only patients with wild-type KRAS tumors benefit from therapies with anti-EGFR antibodies, accurate determination of the KRAS mutation status is crucial for ethical and economic reasons.…”

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confidence: 99%

KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

Boissière‐Michot¹,

Lopez-Crapez²,

Frugier³

et al. 2012

Modern Pathology

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KRAS status assessment is mandatory in patients with metastatic colorectal cancer before therapy with antiepidermal growth factor receptor monoclonal antibodies, as KRAS mutations are associated with resistance to this treatment. However, KRAS genotyping may be very challenging in case of poor tumor cellularity, particularly when major tumor regression is achieved in locally advanced rectal adenocarcinomas after radiochemotherapy. We aimed at identifying the most reliable strategy to detect KRAS mutations in such samples. DNA was extracted from 31 surgical specimens with major tumor regression, following manual dissection, and from paired pre-treatment biopsies and analyzed by high-resolution melting. DNA samples displaying altered melting curve shapes were then sequenced. Samples with unmodified melting curves or wild-type sequence were further investigated by using an allele-specific PCR assay (TheraScreen) and laser microdissection (followed by high-resolution melting and sequencing analyses). In the 31 post-radiochemotherapy surgical specimens, seven KRAS mutations were identified by high-resolution melting analysis/sequencing. One additional mutation was detected by the TheraScreen assay and two mutations, including the one identified by the TheraScreen assay, were detected following laser microdissection. Altogether, 9/31 surgical specimens (29%) presented KRAS mutations. In the manually dissected pre-treatment biopsies, 12 mutations (39%) were identified by high-resolution melting analysis and sequencing. No additional mutations were found by using the TheraScreen assay or laser microdissection. These results indicate that, in the case of post-radiochemotherapy surgical specimens of colorectal cancer with low tumor cellularity, pre-treatment biopsies might represent the most cost-effective option for reliable KRAS genotyping. The use of more sensitive assays, such as allelespecific PCR or laser microdissection, can be envisaged but with higher costs and longer delays.

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“…Cetuximab (CTX), an anti‐EGFR monoclonal antibody, has been widely used particularly for treatment of colorectal and lung cancers 14, 15. However, some patients with colorectal cancer (CRC) are resistant to EGFR inhibitors because of the continuous activation of the RAS/mitogen‐activated protein kinase (MAPK) pathway by a mutation in codon 12 of the wild‐type v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) gene 14, 15, 16, 17. Therefore, the use of CTX is currently restricted to patients with wild‐type KRAS .…”

mentioning

confidence: 99%

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

Kato

Futamura

Kanematsu

et al. 2015

Intl Journal of Cancer

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Targeted molecular therapy is an effective anticancer strategy. Anti‐EGFR monoclonal antibodies such as cetuximab (CTX) have been approved for the treatment of various malignancies, including colorectal cancer (CRC) with wild‐type KRAS. However, their efficacy in patients with KRAS mutations has not been established. Therefore, we investigated whether CTX treatment was effective as a single agent or in combination with zoledronic acid (ZOL) in human CRC cell lines with different KRAS status. CRC cell lines SW48 (wild‐type KRAS) and LS174T (mutant KRAS) were treated with ZOL, CTX and a combination of both drugs. Cytotoxicity was measured using the MTT assay. Changes in the levels of intracellular signaling proteins were evaluated using western blot analysis. Finally, we evaluated the efficacy of the combination treatment in an in vivo xenograft model. We observed that ZOL apparently inhibited growth in both cell lines, whereas CTX showed little effect. ZOL also increased the levels of unprenylated RAS. Combined ZOL and CTX treatment was synergistic in both cell lines and was associated with inhibition of the RAS‐MAPK and AKT‐mTOR signaling pathways. Furthermore, the combination treatment was more effective in suppressing the growth of xenografts derived from both SW48 and LS174T cells; this effect was associated with increased apoptosis. These results demonstrate that ZOL inhibits the growth of colon cancer cells regardless of KRAS status, and combination therapy using ZOL and CTX enhances this growth suppression. These findings suggest a novel strategy for the treatment of CRC independent of KRAS mutational status.

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KRAS Mutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab

Abstract: These results confirm the high prognostic value of KRAS mutations on response to cetuximab and survival in metastatic CRC patients treated with cetuximab.

Cited by 1,332 publications

References 22 publications

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

KRAS mutation testing for predicting response to anti-EGFR therapy for colorectal carcinoma: proposal for an European quality assurance program

KRAS genotyping in rectal adenocarcinoma specimens with low tumor cellularity after neoadjuvant treatment

Combination therapy with zoledronic acid and cetuximab effectively suppresses growth of colorectal cancer cells regardless of KRAS status

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