A set of defined oncogenic mutation alleles seems to better predict the response to cetuximab in CRC patient-derived xenograft than KRAS 12/13 mutations.
Oncotarget
; 6(38): 40815-21, 2015 Dec 01.
Article
em En
| MEDLINE
| ID: mdl-26512781
Cetuximab is a standard of care for treating EGFR-expressing metastatic colorectal carcinoma (mCRC) exclusive of those with KRAS mutations at codons 12/13. However, retrospective analysis has recently suggested that KRAS-G13D patients can still benefit, while only a fraction of KRAS wild-type patients can benefit, from the treatment. We set out to test this contradicting issue experimentally in an independent cohort of patient derived xenograft (PDX) diseases. We conducted a mouse clinical trial (MCT) enrolling a random cohort of 27 transcriptome sequenced CRC-PDXs to evaluate cetuximab activity. The treatment responses were analyzed against the KRAS 12/13 mutation alleles, as well as several other well-known oncogenic alleles. If the response is defined by >80% tumor growth inhibition, 8/27 PDXs (~30%) are responders versus 19/27 non-/partial responders (~70%). We found that indeed there are no significantly fewer KRAS-12/13-allele responders (4/8 or 50%) than non-/partial responders (7/19, or 37%). In particular, there are actually no fewer G13D responders (4/8, or 50%) than in non-/partial responders (2/19 or 10.5%) statistically. Furthermore, majority of the non-/partial responders tend to have certain activating oncogenic alleles (one or more of the following common ones: K/N-RAS-G12V/D, -A146T, -Q61H/R, BRAF-V600E, AKT1-L52R and PIK3CA-E545G/K). Our data on an independent cohort support the recent clinical observation, but against the current practiced patient stratification in the cetuximab CRC treatment. Meanwhile, our data seem to suggest that a set of the six-oncogenic alleles may be of better predictive value than the current practiced stratification, justifying a new prospective clinical investigation on an independent cohort for confirmation.
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01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
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Biomarcadores Tumorais
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Proteínas Proto-Oncogênicas p21(ras)
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Proteínas Proto-Oncogênicas
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Resistencia a Medicamentos Antineoplásicos
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Cetuximab
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Mutação
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Oncotarget
Ano de publicação:
2015
Tipo de documento:
Article