Biomedical Engineering Reference
In-Depth Information
biomarker for the selection of mCRC patients responsive to anti-
EGFR moAbs until larger prospective studies suggest otherwise (see
Table 7.5).
7.4.3.7
PIK3CA mutations
PIK3CA
gene encodes the p110 alpha kinase domain of PI3K. The
encoded lipid kinase regulates signaling pathways downstream of
the EGFR [25]. The PIK3CA gene is mutated in 20% of CRCs with
mutations frequently occurring in exon 9 and 20 [24]. In preclinical
models, these mutations result in activation of the EGFR pathway
and are oncogenic in cellular models. In various colon cancers cell
lines, activating
PIK3CA
mutations appear to confer resistance to
cetuximab [118].
7.4.3.8
Measuring PIK3CA mutations
To detect these mutations, studies have typically employed direct
sequencing of exons 9 and 20 or mass spectrometry [90, 119-121].
The latter involves PCR amplification of the region containing the
mutation of interest, an extension reaction to generate allele-specific
DNA products, and chip-based mass spectrometry for separation and
analysis of the DNA. A single base extension reaction was performed
using extension primers that hybridize immediately adjacent to the
mutation. The extension reaction generates diagnostic products that,
based on their unique mass values, allow discrimination between
two alleles. This method is very sensitive, but only known mutations
can be tested and it sometimes requires direct sequencing for
verification.
7.4.3.9
Specimen selection for PIK3CA mutation testing
Currently, only one study has addressed the potential heterogeneity
of the PIK3CA mutation status among primary tumors and
metastatic tissue from the same patient [90]. In this study, there
was no significant discordance between primary tumor and distant
metastasis with only 1 case of 20 showing a PIK3CA mutation in
the primary tumor but not in the distant metastasis. Hence, this
suggests that PIK3CA mutation testing of primary tumors as well as
distant metastases is appropriate to determine the PIK3CA mutation
status.
