Prediction of response to anti-EGFR antibody-based therapies by
multigene sequencing in colorectal cancer patients.

J 2015

Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients.

LUPINI, Laura, Cristian BASSI, Jitka MLČOCHOVÁ, Gentian MUSA, Marta RUSSO et. al.

Basic information

Original name

Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients.

Authors

LUPINI, Laura (380 Italy), Cristian BASSI (380 Italy), Jitka MLČOCHOVÁ (203 Czech Republic, belonging to the institution), Gentian MUSA (380 Italy), Marta RUSSO (380 Italy), Petra VYCHYTILOVÁ (203 Czech Republic, belonging to the institution), Marek SVOBODA (203 Czech Republic, belonging to the institution), Silvia SABBIONI (380 Italy), Radim NĚMEČEK (203 Czech Republic), Ondřej SLABÝ (203 Czech Republic, guarantor, belonging to the institution) and Massimo NEGRINI (380 Italy)

Edition

BMC Cancer, LONDON, BIOMED CENTRAL LTD, 2015, 1471-2407

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30200 3.2 Clinical medicine

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 3.265

RIV identification code

RIV/00216224:14740/15:00084505

Organization unit

Central European Institute of Technology

DOI

http://dx.doi.org/10.1186/s12885-015-1752-5

UT WoS

000363502400001

Keywords (in Czech)

kolorektální karcinom; resistence k anti-EGFR protilátkám; mutace genů; sekvenování nové generace

Keywords in English

colorectal cancer; resistance to anti-EGFR antibodies; gene mutations; next-generation sequencing

Abstract

V originále

Background: The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (moAbs) cetuximab or panitumumab are administered to colorectal cancer (CRC) patients who harbor wild-type RAS proto-oncogenes. However, a percentage of patients do not respond to this treatment. In addition to mutations in the RAS genes,mutations in other genes, such as BRAF, PI3KCA,or PTEN, could be involved in the resistance to anti-EGFR moAb therapy. Methods: In order to develop a comprehensive approach for the detection of mutations and to eventually identify other genes responsible for resistance to anti-EGFR moAbs, we investigated a panel of 21 genes by parallel sequencing on the Ion Torrent Personal Genome Machine platform. We sequenced 65 CRCs that were treated with cetuximab or panitumumab. Among these, 37 samples were responsive and 28 were resistant. Results: We confirmed that mutations in EGFR-pathway genes (KRAS, NRAS , BRAF, PI3KCA) were relevant for conferring resistance to therapy and could predict response (p = 0.001). After exclusion of KRAS, NRAS, BRAF and PI3KCA combined mutations could still significantly associate to resistant phenotype ( p = 0.045, by Fisher exact test). In addition, mutations in FBXW7 and SMAD4 were prevalent in cases that were non-responsive to anti-EGFR moAb. After we combined the mutations of all genes (excluding KRAS), the ability to predict response to therapy improved significantly (p = 0.002, by Fisher exact test). Conclusions: The combination of mutations at KRAS and at the five gene panel demonstrates the usefulness and feasibility of multigene sequencing to assess response to anti-EGFR moAbs. The application of parallel sequencing technology in clinical practice, in addition to its innate ability to simultaneously examine the genetic status of several cancer genes, proved to be more accurate and sensitive than the presently in use traditional approaches.

Links

ED1.1.00/02.0068, research and development project

Name: CEITEC - central european institute of technology

Citovat

LUPINI, Laura, Cristian BASSI, Jitka MLČOCHOVÁ, Gentian MUSA, Marta RUSSO, Petra VYCHYTILOVÁ, Marek SVOBODA, Silvia SABBIONI, Radim NĚMEČEK, Ondřej SLABÝ and Massimo NEGRINI. Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients. BMC Cancer. LONDON: BIOMED CENTRAL LTD, 2015, vol. 15, October, p. nestránkováno, 11 pp. ISSN 1471-2407. Available from: https://dx.doi.org/10.1186/s12885-015-1752-5.

@article{1315757,
   author = {Lupini, Laura and Bassi, Cristian and Mlčochová, Jitka and Musa, Gentian and Russo, Marta and Vychytilová, Petra and Svoboda, Marek and Sabbioni, Silvia and Němeček, Radim and Slabý, Ondřej and Negrini, Massimo},
   article_location = {LONDON},
   article_number = {October},
   doi = {http://dx.doi.org/10.1186/s12885-015-1752-5},
   keywords = {colorectal cancer; resistance to anti-EGFR antibodies; gene mutations; next-generation sequencing},
   language = {eng},
   issn = {1471-2407},
   journal = {BMC Cancer},
   title = {Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients.},
   url = {http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1752-5},
   volume = {15},
   year = {2015}
}

TY  - JOUR
ID  - 1315757
AU  - Lupini, Laura - Bassi, Cristian - Mlčochová, Jitka - Musa, Gentian - Russo, Marta - Vychytilová, Petra - Svoboda, Marek - Sabbioni, Silvia - Němeček, Radim - Slabý, Ondřej - Negrini, Massimo
PY  - 2015
TI  - Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients.
JF  - BMC Cancer
VL  - 15
IS  - October
SP  - nestránkováno
EP  - nestránkováno
PB  - BIOMED CENTRAL LTD
SN  - 14712407
KW  - colorectal cancer
KW  - resistance to anti-EGFR antibodies
KW  - gene mutations
KW  - next-generation sequencing
UR  - http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1752-5
L2  - http://bmccancer.biomedcentral.com/articles/10.1186/s12885-015-1752-5
N2  - Background: The anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (moAbs) cetuximab or panitumumab are administered to colorectal cancer (CRC) patients who harbor wild-type RAS proto-oncogenes. However, a percentage of patients do not respond to this treatment. In addition to mutations in the RAS genes,mutations in other genes, such as BRAF, PI3KCA,or PTEN, could be involved in the resistance to anti-EGFR moAb therapy. Methods: In order to develop a comprehensive approach for the detection of mutations and to eventually identify other genes responsible for resistance to anti-EGFR moAbs, we investigated a panel of 21 genes by parallel sequencing on the Ion Torrent Personal Genome Machine platform. We sequenced 65 CRCs that were treated with cetuximab or panitumumab. Among these, 37 samples were responsive and 28 were resistant. Results: We confirmed that mutations in EGFR-pathway genes (KRAS, NRAS , BRAF, PI3KCA) were relevant for conferring resistance to therapy and could predict response (p = 0.001). After exclusion of KRAS, NRAS, BRAF and PI3KCA combined mutations could still significantly associate to resistant phenotype ( p = 0.045, by Fisher exact test). In addition, mutations in FBXW7 and SMAD4 were prevalent in cases that were non-responsive to anti-EGFR moAb. After we combined the mutations of all genes (excluding KRAS), the ability to predict response to therapy improved significantly (p = 0.002, by Fisher exact test). Conclusions: The combination of mutations at KRAS and at the five gene panel demonstrates the usefulness and feasibility of multigene sequencing to assess response to anti-EGFR moAbs. The application of parallel sequencing technology in clinical practice, in addition to its innate ability to simultaneously examine the genetic status of several cancer genes, proved to be more accurate and sensitive than the presently in use traditional approaches.
ER  -

LUPINI, Laura, Cristian BASSI, Jitka MLČOCHOVÁ, Gentian MUSA, Marta RUSSO, Petra VYCHYTILOVÁ, Marek SVOBODA, Silvia SABBIONI, Radim NĚMEČEK, Ondřej SLABÝ and Massimo NEGRINI. Prediction of response to anti-EGFR antibody-based therapies by multigene sequencing in colorectal cancer patients. \textit{BMC Cancer}. LONDON: BIOMED CENTRAL LTD, 2015, vol.~15, October, p.~nestránkováno, 11 pp. ISSN~1471-2407. Available from: https://dx.doi.org/10.1186/s12885-015-1752-5.

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