349whereas cetuximab has little effect on the mutant signal, evidently because it strikes
at a different part of the EGFR molecule. Thus those with EGFR mutations benefi t
from gefi tinib or erlotinib, whereas those without EGFR mutations benefi t from
cetuximab. Cetuximab binds to a portion of the EGFR receptor that extends outside
the cell. This difference in action is the apparent explanation for why they perform
differently against the mutant EGFR cells. These fi ndings show that in order to
inhibit the mutant receptor, one should inhibit the domain of the EGFR molecule
that lies within the cell, as opposed to the extracellular domain.
Previously, tumor biopsies have been used in NSCLC for EGFR genotyping as it
has been diffi cult to detect the low levels of specifi c mutations shed from the tumor
into the blood against the high background of normal DNA. Testing DNA isolated
from blood, rather than tumor tissue, would be better for predicting responses to
gefi tinib, erlotinib (Tarceva) and other cancer therapies. If EGFR mutations can be
observed in serum DNA, this could serve as a noninvasive source of information on
the genotype of the original tumor cells as compared to direct sampling of the tumor
and could infl uence treatment and the ability to predict patient response to gefi tinib.
In one study, serum genomic DNA was obtained from Japanese patients with
NSCLC before fi rst-line gefi tinib monotherapy (Kimura et al. 2006 ). Scorpion
Amplifi ed Refractory Mutation System technology (QIAGEN) was used to detect
EGFR mutations. In pairs of tumor and serum samples obtained from patients, the
EGFR mutation status in the tumors was consistent with those in the serum of
72 % of the paired samples. The QIAGEN test kit detected mutations that were
missed by direct sequencing techniques. These results suggest that patients with
EGFR mutations seem to have better outcomes with gefi tinib treatment, in terms of
progression-free survival, overall survival, and response, than those patients without
EGFR mutations. TheraScreen EGFR 29 Mutation Test (QIAGEN) detects muta-
tions that correlate with responsiveness to EGFR tyrosine kinase inhibitors.
Therascreen EGFR RGQ Plasma PCR was CE-marked in Europe in January 2015
for marketing in >30 European countries, making it fi rst-ever regulated companion
diagnostic assay that has demonstrated clinical utility for guiding treatment deci-
sions in patients with solid tumors based on the analysis of molecular biomarkers
obtained from a body fl uid (liquid biopsy). This test may be used to help physicians
choose NSCLC patients who are most likely to respond to treatment with EGFR
tyrosine kinase inhibitors. European Medicines Agency has extended the drug label
of Iressa ® to include the detection of EGFR mutations in circulating tumor DNA
obtained from a blood sample when a tumor sample is not evaluable.
Dacomitinib (Pfi zer) is an oral, once-daily, pan-HER inhibitor. It is an irrevers-
ible inhibitor of HER-1 (EGFR), HER-2 and HER-4 tyrosine kinases. Dacomitinib
targets multiple receptors of the HER pathway, whereas currently marketed HER-1
(EGFR) inhibitors for NSCLC target only one receptor in this pathway. QIAGEN is
developing a companion diagnostic for dacomitinib be based on its proprietary
KRAS assay technology, which reliably detects mutations of the KRAS gene that
are frequently found in human cancers. Because EGFR inhibitors are generally
effective in patients without these KRAS mutations, the QIAGEN assay can be use-
ful in identifying patients most appropriate for EGFR-inhibitor therapies.
Personalized Management of Cancers of Various Organs