Mutational analysis of primary and metastatic colorectal cancer
samples underlying the resistance to cetuximab-based therapy

J 2016

Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy

NĚMEČEK, Radim; Jitka BERKOVCOVÁ; Lenka RADOVÁ; Tomáš KAZDA; Jitka MLČOCHOVÁ et. al.

Základní údaje

Originální název

Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy

Autoři

NĚMEČEK, Radim (203 Česká republika, domácí); Jitka BERKOVCOVÁ (203 Česká republika); Lenka RADOVÁ (203 Česká republika, domácí); Tomáš KAZDA (203 Česká republika, domácí); Jitka MLČOCHOVÁ (203 Česká republika, domácí); Petra VYCHYTILOVÁ (203 Česká republika, domácí); Ondřej SLABÝ (203 Česká republika, garant, domácí) a Marek SVOBODA (203 Česká republika, domácí)

Vydání

ONCOTARGETS AND THERAPY, Auckland, DOVE MEDICAL PRESS LTD, 2016, 1178-6930

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30200 3.2 Clinical medicine

Stát vydavatele

Nový Zéland

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 2.612

Kód RIV

RIV/00216224:14740/16:00090994

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.2147/OTT.S102891

UT WoS

000380519700001

EID Scopus

2-s2.0-84982701952

Klíčová slova anglicky

colorectal cancer; cetuximab; resistance to anti-EGFR therapy; next-generation sequencing; FBXW7; KRAS

Štítky

podil, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 22. 3. 2018 09:19, Mgr. Pavla Foltynová, Ph.D.

Anotace

V originále

Purpose: Although several molecular markers predicting resistance to cetuximab-or panitumumab-based therapy of metastatic colorectal cancer were described, mutations in RAS proto-oncogenes remain the only predictors being used in daily clinical practice. However, 35%-45% of wild-type RAS patients still do not respond to this anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody-based therapy, and therefore the definition of other predictors forms an important clinical need. The aim of the present retrospective single-institutional study was to evaluate potential genes responsible for resistance to anti-EGFR therapy in relation to mutational analysis of primary versus metastatic lesions. Patients and methods: Twenty-four paired primary and corresponding metastatic tissue samples from eight nonresponding and four responding metastatic colorectal cancer patients treated with cetuximab-based therapy were sequenced using a next-generation sequencing panel of 26 genes involved in EGFR signaling pathway and colorectal carcinogenesis. Results: Mutational status of primary tumors and metastatic lesions was highly concordant in TP53, APC, CTNNB1, KRAS, PIK3CA, PTEN, and FBXW7 genes. Metastatic samples harbor significantly more mutations than primary tumors. Potentially negative predictive value of FBXW7 mutations in relationship to anti-EGFR treatment outcomes was confirmed. Finally, new occurrences of activating KRAS mutations were identified in a group of patients initially determined as wild-type RAS by routinely used qPCR-based RAS mutational tests. All newly detected activating KRAS mutations most likely led to cetuximab treatment failure. Conclusion: The results of the present study suggest a need of careful consideration of previously published results of anti-EGFR-targeted therapy with regard to potentially inaccurate diagnostic tools used in the past. Based on our findings, we recommend more extensive use of next-generation sequencing testing in daily clinical practice, as it brings a significant added value in terms of validity of the diagnostic procedure.

Návaznosti

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

Citovat

NĚMEČEK, Radim; Jitka BERKOVCOVÁ; Lenka RADOVÁ; Tomáš KAZDA; Jitka MLČOCHOVÁ; Petra VYCHYTILOVÁ; Ondřej SLABÝ a Marek SVOBODA. Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy. ONCOTARGETS AND THERAPY. Auckland: DOVE MEDICAL PRESS LTD, 2016, roč. 9, July, s. 4695-4703. ISSN 1178-6930. Dostupné z: https://dx.doi.org/10.2147/OTT.S102891.

@article{1355438,
   author = {Němeček, Radim and Berkovcová, Jitka and Radová, Lenka and Kazda, Tomáš and Mlčochová, Jitka and Vychytilová, Petra and Slabý, Ondřej and Svoboda, Marek},
   article_location = {Auckland},
   article_number = {July},
   doi = {http://dx.doi.org/10.2147/OTT.S102891},
   keywords = {colorectal cancer; cetuximab; resistance to anti-EGFR therapy; next-generation sequencing; FBXW7; KRAS},
   language = {eng},
   issn = {1178-6930},
   journal = {ONCOTARGETS AND THERAPY},
   title = {Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy},
   url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968864/pdf/ott-9-4695.pdf},
   volume = {9},
   year = {2016}
}

TY  - JOUR
ID  - 1355438
AU  - Němeček, Radim - Berkovcová, Jitka - Radová, Lenka - Kazda, Tomáš - Mlčochová, Jitka - Vychytilová, Petra - Slabý, Ondřej - Svoboda, Marek
PY  - 2016
TI  - Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy
JF  - ONCOTARGETS AND THERAPY
VL  - 9
IS  - July
SP  - 4695-4703
EP  - 4695-4703
PB  - DOVE MEDICAL PRESS LTD
SN  - 11786930
KW  - colorectal cancer
KW  - cetuximab
KW  - resistance to anti-EGFR therapy
KW  - next-generation sequencing
KW  - FBXW7
KW  - KRAS
UR  - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968864/pdf/ott-9-4695.pdf
L2  - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968864/pdf/ott-9-4695.pdf
N2  - Purpose: Although several molecular markers predicting resistance to cetuximab-or panitumumab-based therapy of metastatic colorectal cancer were described, mutations in RAS proto-oncogenes remain the only predictors being used in daily clinical practice. However, 35%-45% of wild-type RAS patients still do not respond to this anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibody-based therapy, and therefore the definition of other predictors forms an important clinical need. The aim of the present retrospective single-institutional study was to evaluate potential genes responsible for resistance to anti-EGFR therapy in relation to mutational analysis of primary versus metastatic lesions. Patients and methods: Twenty-four paired primary and corresponding metastatic tissue samples from eight nonresponding and four responding metastatic colorectal cancer patients treated with cetuximab-based therapy were sequenced using a next-generation sequencing panel of 26 genes involved in EGFR signaling pathway and colorectal carcinogenesis. Results: Mutational status of primary tumors and metastatic lesions was highly concordant in TP53, APC, CTNNB1, KRAS, PIK3CA, PTEN, and FBXW7 genes. Metastatic samples harbor significantly more mutations than primary tumors. Potentially negative predictive value of FBXW7 mutations in relationship to anti-EGFR treatment outcomes was confirmed. Finally, new occurrences of activating KRAS mutations were identified in a group of patients initially determined as wild-type RAS by routinely used qPCR-based RAS mutational tests. All newly detected activating KRAS mutations most likely led to cetuximab treatment failure. Conclusion: The results of the present study suggest a need of careful consideration of previously published results of anti-EGFR-targeted therapy with regard to potentially inaccurate diagnostic tools used in the past. Based on our findings, we recommend more extensive use of next-generation sequencing testing in daily clinical practice, as it brings a significant added value in terms of validity of the diagnostic procedure.
ER  -

NĚMEČEK, Radim; Jitka BERKOVCOVÁ; Lenka RADOVÁ; Tomáš KAZDA; Jitka MLČOCHOVÁ; Petra VYCHYTILOVÁ; Ondřej SLABÝ a Marek SVOBODA. Mutational analysis of primary and metastatic colorectal cancer samples underlying the resistance to cetuximab-based therapy. \textit{ONCOTARGETS AND THERAPY}. Auckland: DOVE MEDICAL PRESS LTD, 2016, roč.~9, July, s.~4695-4703. ISSN~1178-6930. Dostupné z: https://dx.doi.org/10.2147/OTT.S102891.

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