Title: PIK3CA mutations do not confer resistance to the EGFR-inhibitor cetuximab in chemorefractory metastatic colorectal cancer
Authors: De Roock, Wendy ×
De Schutter, Jef
Prenen, Hans
Jacobs, Bart
Biesmans, Bart
Claes, Bart
Lambrechts, Diether
Van Cutsem, Eric #
Issue Date: Apr-2009
Conference: AACR Annual Meeting edition:100 location:San Diego, CA date:18-22 April 2009
Abstract: Background
It has been reported that activating KRAS mutations negatively affect response to anti-
EGFR monoclonal antibodies in metastatic colorectal cancer. The mutation status of
signaling molecules downstream of the EGFR target is thus crucial to predict clinical
benefit to EGFR targeted therapies. Other mechanisms of resistance to EGFR-inhibitors
could involve activating mutations of the other main EGFR effector pathway, i.e. the
PI3K/PTEN/AKT pathway.

We analysed the PIK3CA and KRAS mutation status in a large group (n=200) of
chemorefractory metastatic colorectal cancers treated with cetuximab in monotherapy or
in combination with irinotecan, and correlated the mutation status with outcome. The
analysis was performed using formalin-fixed, paraffin-embedded tissue of the primary
colorectal cancer. Seven KRAS codon 12 and 13 mutations were detected by allele
specific PCR on a 7500HT Real Time PCR System. Activating mutations in PIK3CA
tend to cluster in hotspots with about 80% accounted for by oncogenic substitution in
exon 20 (H1047R) and exon 9 (E542K and E545K) that encode portions of the helical
and kinase domains. Known PIK3CA mutations in these exons were evaluated using the
Sequenom MALDI TOF MassArray system.

KRAS mutations were detected in 1/38 (2.6%) responders and 76/161 (47%) non-
responders. Twenty-three (12%) out of the 200 samples carried one of the PIK3CA
mutations included in our assay. These missense mutations were found in exon 1 (n=1),
exon 9 (n=18) and exon 20 (n=3). One sample carried a mutation in both exon 9
(p.E545K) and 20 (p.H1047R). Nine out of 77 (11.7%) KRAS mutants and 14/122
(11.5%) KRAS wild type tumors harboured a PIK3CA mutation (p=1.00).
PIK3CA mutations were detected in 5/39 (13%) of the responders and 18/160 (11%) of
the non-responders (p=0.781). Median progression-free survival and overall survival in
PIK3CA mutant and wild type patients were 24 weeks [95% CI 17.3–30.7] vs 18 weeks
[95% CI 16.6–19.4 ] and 45 weeks [95% CI 32.5–57.5] vs 39 weeks [95% CI 35.4–42.6]
(p = 0.760 and p = 0.698) respectively.

Our results indicate that PIK3CA mutations occur independently of the KRAS mutation
status. We cannot provide any evidence for a strong role of PIK3CA mutations as a single
marker in determining response to cetuximab in chemorefractory metastatic colorectal
Since PIK3CA mutations are infrequent and the effect on response is more subtle then in
the case of KRAS mutations, there is a real risk for a type II error when the sample size is
not large enough. We will therefore analyze the PIK3CA mutation status in a large
European consortium of chemorefractory metastatic colorectal cancers treated with
EGFR-inhibitors and will correlate the mutation status with outcome.
Publication status: accepted
KU Leuven publication type: IMa
Appears in Collections:Vesalius Research Centre (-)
Translational Research in GastroIntestinal Disorders
Molecular Digestive Oncology (+)
Clinical Digestive Oncology (+)
Laboratory of Translational Genetics (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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