Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer

Adams, Rachel; Maughan, Tim

doi:10.1586/14737140.7.4.503

Cited by 32 publications

(17 citation statements)

References 92 publications

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“…2, [7][8][9] KRAS, the human homolog of the Kirsten rat sarcoma-2 virus oncogene, encodes a small GTPbinding protein that acts as a self-inactivating signal transducer by cycling from GDP-to GTP-bound states in response to stimulation of a cell surface receptor, including EGFR. 10,11 KRAS can harbor oncogenic mutations that yield a constitutively active protein.…”

Section: Introductionmentioning

confidence: 99%

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Amado

Wolf

Peeters

et al. 2008

JCO

2,942

1,952

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A B S T R A C T PurposePanitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and MethodsKRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. ResultsKRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P Ͻ .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. ConclusionPanitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

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Section: Introductionmentioning

confidence: 99%

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Amado

Wolf

Peeters

et al. 2008

JCO

2,942

1,952

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“…The rationale for this combination is that these targeted drugs capable of specific blockade of activated endothelial cell survival mechanisms, will selectively enhance the damaging or cytotoxic effects of LDM chemotherapy on newly formed blood vessels [11]. The epidermal growth factor receptor (EGFR) and its ligands EGF and tumor growth factor-a play important roles in the growth and survival of colorectal tumors [12]. The expression of EGFR in CRC correlates with more aggressive diseases and poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts

et al. 2009

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Low-dose metronomic (LDM) chemotherapy represents a new strategy to treat solid tumors by stronger antiangiogenic activity and lower side effects, especially in combination with other antiangiogenic agents. This study aims to investigate whether LDM chemotherapy of paclitaxel could synergize with cetuximab, an antiangiogenic agent to suppress HT-29 human colon tumors in BALB/c nude mice. To explore its possible mechanism, the tumor vascular status was detected by staining with anti-CD31 Ab and the tumoral expression of thrombospondin-1 was examined by immunohistochemistry, western blot analysis, and real-time PCR. Our results showed that empirical metronomic paclitaxel regimens in combination with cetuximab induces significant and durable antitumor responses without overt toxicity. Paclitaxel LDM chemotherapy displayed stronger antiangiogenic activity than maximum tolerable dose (MTD) chemotherapy, whereas MTD chemotherapy induced more apoptotic cells. The combinational therapy with LDM and cetuximab showed the strongest antiangiogenic activity among all the groups. Paclitaxel LDM chemotherapy also dramatically upregulated the expression of thrombospondin-1, but MTD chemotherapy did not. These results suggest that the combination of paclitaxel LDM chemotherapy and cetuximab represents a potent strategy to combat colon cancers.

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“…Of particular interest is a KRAS gene mutation occurring in codon 12 (G12D) which is a hot spot mutation commonly identified in colorectal cancer [20]. Approximately 90% of the activating mutations are found in this particular codon, which represents a highly specific mutation for colorectal carcinoma [21]. Several groups have recently validated that KRAS mutations are a negative predictor of colorectal carcinoma response to monoclonal antibodies (e.g.…”

Section: Resultsmentioning

confidence: 99%

A Flexible Approach for Highly Multiplexed Candidate Gene Targeted Resequencing

Natsoulis

Bell

et al. 2011

PLoS ONE

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We have developed an integrated strategy for targeted resequencing and analysis of gene subsets from the human exome for variants. Our capture technology is geared towards resequencing gene subsets substantially larger than can be done efficiently with simplex or multiplex PCR but smaller in scale than exome sequencing. We describe all the steps from the initial capture assay to single nucleotide variant (SNV) discovery. The capture methodology uses in-solution 80-mer oligonucleotides. To provide optimal flexibility in choosing human gene targets, we designed an in silico set of oligonucleotides, the Human OligoExome, that covers the gene exons annotated by the Consensus Coding Sequencing Project (CCDS). This resource is openly available as an Internet accessible database where one can download capture oligonucleotides sequences for any CCDS gene and design custom capture assays. Using this resource, we demonstrated the flexibility of this assay by custom designing capture assays ranging from 10 to over 100 gene targets with total capture sizes from over 100 Kilobases to nearly one Megabase. We established a method to reduce capture variability and incorporated indexing schemes to increase sample throughput. Our approach has multiple applications that include but are not limited to population targeted resequencing studies of specific gene subsets, validation of variants discovered in whole genome sequencing surveys and possible diagnostic analysis of disease gene subsets. We also present a cost analysis demonstrating its cost-effectiveness for large population studies.

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Predicting response to epidermal growth factor receptor-targeted therapy in colorectal cancer

Cited by 32 publications

References 92 publications

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Wild-Type KRAS Is Required for Panitumumab Efficacy in Patients With Metastatic Colorectal Cancer

Low-dose metronomic chemotherapy of paclitaxel synergizes with cetuximab to suppress human colon cancer xenografts

A Flexible Approach for Highly Multiplexed Candidate Gene Targeted Resequencing

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