52
The results revealed that ERBB2, VEGFA, GATA4, and GATA 6
were commonly amplified in adenocarcinoma. Esophageal adeno-
carcinoma is molecularly distinct from esophageal squamous cell
carcinoma and bears striking resemblance to the chromosomal
instability variant of gastric adenocarcinoma. DNA hypermethyl-
ation was detected disproportionally in esophageal adenocarci-
noma than gastric adenocarcinoma. The findings support including
adenocarcinoma of the esophagus and esophagogastric junction in
clinical studies of gastric adenocarcinoma and has laid the foun-
dation for systematic design of clinical trial of target therapy in
the future. This chapter shows the data that were mostly from
studies that enrolled both gastric and esophagogastric junction
adenocarcinoma.Epidermal growth factor receptor (EGFR) is a transmembrane gly-
coprotein that plays a major role in the cell proliferation, differen-
tiation, and metastasis [ 7 ]. The EGFR family includes HER1
(EGFR), HER2, HER3, and HER4. Binding of ligand to the
receptor leads to dimerization and eventually downstream signal-
ing. Among the four receptors, HER1 (EGFR) and HER2 are of
intense clinical study interest.The phase III (testing of drug on patients to assess efficacy, effec-
tiveness, and safety) ToGA trial was the landmark study that
defined the new standard of care for HER2-positive metastatic
gastric or esophagogastric junction adenocarcinoma. Trastuzumab,
a recombinant humanized IgG1 monoclonal antibody against
HER2, prolonged significantly the median overall survival by
2.7 months (13.8 months versus 11.1 months, hazard ratio = 0.74;
p = 0.0046) and progression-free survival by 1.2 months
(6.7 months versus 5.5 months, hazard ratio = 0.71; p = 0.002)
when added to the chemotherapy with cisplatin and fluorouracil.
In the pre-planned subgroup analysis, the clinical benefit was even
more pronounced in those carcinomas with high HER2 high
expression (Immunohistochemistry score = 2+ and florescent in
situ hybridization [FISH] positive or immunohistochemistry
score = 3+). Cardiac adverse events were 6% in both study arms
and less than 1% of patients experienced cardiac failure. Until now,
trastuzumab remains the only target therapy approved for use in
the first-line setting.
Lapatinib is an oral small molecule tyrosine kinase inhibitor
that targets both EGFR and HER2. Downstream signaling of
EGFR and HER2 is blocked by reducing phosphorylation of
receptors homodimers or heterodimers. In the phase III LOGiC
study, patients with advanced or metastatic gastric, esophageal, or
esophagogastric adenocarcinoma that are positive for HER-2 were
randomized to receive oxaliplatin and capecitabine with or without
lapatinib in the first-line setting [ 9 ]. The results of the trial was1.1 Epidermal
Growth Factor
Receptor (EGFR)
1.1.1 HER2
Ka-On Lam and Dora L. W. Kwong