New insights to gene expression signatures from primary FFPE
tumors for the prediction of response to cetuximab in KRAS and
BRAF wild-type colorectal cancer (CRC).

a 2010

New insights to gene expression signatures from primary FFPE tumors for the prediction of response to cetuximab in KRAS and BRAF wild-type colorectal cancer (CRC).

BUDINSKA, Eva; Mauro DELORENZI; Wendy DE ROOCK; Bart JACOBS; Steven WALKER et al.

Základní údaje

Originální název

New insights to gene expression signatures from primary FFPE tumors for the prediction of response to cetuximab in KRAS and BRAF wild-type colorectal cancer (CRC).

Autoři

BUDINSKA, Eva; Mauro DELORENZI; Wendy DE ROOCK; Bart JACOBS; Steven WALKER; Claire WILSON; Timothy DAVISON; Richard D. KENNEDY a Sabine TEJPAR

Vydání

2010

Další údaje

Jazyk

angličtina

Typ výsledku

Konferenční abstrakt

Obor

30200 3.2 Clinical medicine

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Označené pro přenos do RIV

Organizační jednotka

Institut biostatistiky a analýz

Klíčová slova anglicky

colorectal cancer, cetuximab, stage IV, primary tumor, PFS, response to treatment

Příznaky

Mezinárodní význam

Změněno: 6. 12. 2010 16:09, Mgr. Eva Budinská, Ph.D.

Anotace

V originále

Background: Cetuximab - an anti-EGFR monoclonal antibody improves overall and progression-free survival (PFS) in a subset of advanced-CRC patients. It has been demonstrated that KRAS and BRAF mutations are negative predictors of response to cetuximab and it has become standard to reserve treatment for KRAS wild-type (wt) tumors. However, there is an important proportion of KRAS and BRAF wt patients that do not respond to cetuximab. Our study aimed at identifying markers for response prediction to cetuximab in KRAS and BRAF wt patients via gene expression profiling. Methods: A CRC specific DNA microarray platform (CRCDSA) designed to work with formalin-fixed paraffin-embedded (FFPE) tissue was used for expression profiling of 65 FFPE CRC primary tumor samples. 44 KRAS and BRAF wt patients were selected for the analysis. We fitted a Cox proportional hazards model on PFS (42 events) in order to identify genes related to increased risk of progression after cetuximab treatment. Results: In the top 100 genes significantly associated with progression, the FGFR2 receptor was identified suggesting the activation of a signaling pathway alternative to EGFR. Other interesting genes connected to increased risk of progression were CTSE, S100B, MUC2, APC. Genes negatively correlated with progression were TOE1, XIAP, NAIP (inhibitors of apoptosis). Some of the genes (VAV3, EREG, PLAGL2, DIDO1,YES1) were in agreement with results of the same analysis we have performed on a publicly available dataset derived from metastatic tissues (Khambata-Ford S et al, JCO 2007). Conclusions: By using a transcriptome-focused approach to analyze FFPE primary tumor samples, we have identified novel targets and pathways of potential relevance to response to cetuximab in BRAF and KRAS wt tumors. This could be of significance in the development of new therapeutics for KRAS and BRAF wt nonresponsive patients and demonstrates the usefulness of FFPE primary material for response prediction of metastatic disease.

Citovat

BUDINSKA, Eva; Mauro DELORENZI; Wendy DE ROOCK; Bart JACOBS; Steven WALKER; Claire WILSON; Timothy DAVISON; Richard D. KENNEDY a Sabine TEJPAR. New insights to gene expression signatures from primary FFPE tumors for the prediction of response to cetuximab in KRAS and BRAF wild-type colorectal cancer (CRC). 2010.

@proceedings{911182,
   author = {Budinska, Eva and Delorenzi, Mauro and De Roock, Wendy and Jacobs, Bart and Walker, Steven and Wilson, Claire and Davison, Timothy and Kennedy, Richard D. and Tejpar, Sabine},
   keywords = {colorectal cancer, cetuximab, stage IV, primary tumor, PFS, response to treatment},
   language = {eng},
   title = {New insights to gene expression signatures from primary FFPE tumors for the prediction of response to cetuximab in KRAS and BRAF wild-type colorectal cancer (CRC).},
   year = {2010}
}

TY  - CONF
ID  - 911182
AU  - Budinska, Eva - Delorenzi, Mauro - De Roock, Wendy - Jacobs, Bart - Walker, Steven - Wilson, Claire - Davison, Timothy - Kennedy, Richard D. - Tejpar, Sabine
PY  - 2010
TI  - New insights to gene expression signatures from primary FFPE tumors for the prediction of response to cetuximab in KRAS and BRAF wild-type colorectal cancer (CRC).
KW  - colorectal cancer, cetuximab, stage IV, primary tumor, PFS, response to treatment
N2  - Background: Cetuximab - an anti-EGFR monoclonal antibody improves overall and progression-free survival (PFS) in a subset of advanced-CRC patients. It has been demonstrated that KRAS and BRAF mutations are negative predictors of response to cetuximab and it has become standard to reserve treatment for KRAS wild-type (wt) tumors. However, there is an important proportion of KRAS and BRAF wt patients that do not respond to cetuximab. Our study aimed at identifying markers for response prediction to cetuximab in KRAS and BRAF wt patients via gene expression profiling. Methods: A CRC specific DNA microarray platform (CRCDSA) designed to work with formalin-fixed paraffin-embedded (FFPE) tissue was used for expression profiling of 65 FFPE CRC primary tumor samples. 44 KRAS and BRAF wt patients were selected for the analysis. We fitted a Cox proportional hazards model on PFS (42 events) in order to identify genes related to increased risk of progression after cetuximab treatment. Results: In the top 100 genes significantly associated with progression, the FGFR2 receptor was identified suggesting the activation of a signaling pathway alternative to EGFR. Other interesting genes connected to increased risk of progression were CTSE, S100B, MUC2, APC. Genes negatively correlated with progression were TOE1, XIAP, NAIP (inhibitors of apoptosis). Some of the genes (VAV3, EREG, PLAGL2, DIDO1,YES1) were in agreement with results of the same analysis we have performed on a publicly available dataset derived from metastatic tissues (Khambata-Ford S et al, JCO 2007). Conclusions: By using a transcriptome-focused approach to analyze FFPE primary tumor samples, we have identified novel targets and pathways of potential relevance to response to cetuximab in BRAF and KRAS wt tumors. This could be of significance in the development of new therapeutics for KRAS and BRAF wt nonresponsive patients and demonstrates the usefulness of FFPE primary material for response prediction of metastatic disease.
ER  -

BUDINSKA, Eva; Mauro DELORENZI; Wendy DE ROOCK; Bart JACOBS; Steven WALKER; Claire WILSON; Timothy DAVISON; Richard D. KENNEDY a Sabine TEJPAR. \textit{New insights to gene expression signatures from primary FFPE tumors for the prediction of response to cetuximab in KRAS and BRAF wild-type colorectal cancer (CRC).}. 2010.

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