Biomedical Engineering Reference
In-Depth Information
76-78
Currently, the only published study to evaluate the
prognostic and predictive significance of circulating ligands within
the context of a NSCLC clinical trial containing a placebo arm is a
retrospective analysis of the BR21 clinical trial of erlotinib. Baseline
plasma was collected from 565 patients of the randomized 731
patients, which was analyzed for TGF-α and amphiregulin levels. In
multivariate analysis, high amphiregulin levels (defined as ≥ 10pg/
mL) were prognostic for a poorer outcome compared with patients
with low amphiregulin, but did not predict for benefit from erlotinib.
Conversely, high TGF-α (defined as >12 pg/mL) was predictive of
lack of benefit from erlotinib but was not prognostic.
reported.
79
These results
are exploratory and require validation. Furthermore, the prognostic
and predictive significance of EGF ligands in patients defined by
other EGFR biomarkers is unclear. For example, in a small series of
patients with EGFR mutation positive NSCLC, Masago and colleagues
reported that five of the six patients who had primary resistance
to gefitinib had TGF-α and amphiregulin positive serum.
80
This
observation requires further evaluation, but as subsequent phase
III trials prospectively include ligand analyses, the role of ligand
expression may be better elucidated.
6.10
Polymorphism Studies and Anti-EGFR
Therapy
Functional germline polymorphisms within the
gene, pathway
or related genes including the multidrug transporter
EGFR
have
been evaluated for their association with outcome and toxicity from
EGFR active agents.
ABCG2
81
To date, the majority of published analyses
have utilized a candidate gene approach focusing on polymorphisms
for which there is evidence of functional change, primarily within
the
gene.
Intron 1 within the
EGFR
EGFR
gene contains a
CA
sequence repeat
1 varying from
dinucleotide repeats. Shorter repeats
are associated with higher transcription rates and increased
14 to 22
CA
EGFR
82,83
gene expression compared with the longer sequences.
However,
the reported association between sequence repeat length and
toxicity or outcome from EGFR TKIs has been inconsistent across
studies. In a study of 70 patients treated with EGFR TKIs, Nie
et
al.
reported an association between shorter
CA
repeats (defined
