Download Editorial The distinctive nature of HER2

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EJSO 41 (2015) 271e273
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Editorial
The distinctive nature of HER2-positive gastric
cancers
Keywords: Gastric cancer; HER2; Trastuzumab; Targeted therapy
Gastric cancer is not a single disease, but a conglomerate of histologically, biologically and genetically heterogenous diseases, conditioned by gradual accumulation
of various genetic and epigenetic alterations leading to
the activation of several molecular pathways resulting in
a markedly different responses to the same treatment. In
the wake of increased molecular pathways underlying
the breast cancer, more is actually known about the biological behavior of gastric cancer and its intrinsic subtypes,
particularly the identification of the human epidermal
growth factor receptor-2 (HER2) amplified gastric cancer
subtype.
The HER2 protein (p185, HER2/neu, ErbB-2) is a 185kDa transmembrane tyrosine kinase receptor encoded by a
HER2/neu gene located on chromosome 17q21. It is a
member of the epidermal growth factor receptors (EGFRs)
family that comprise four structurally same members
(HER1 or EGFR or erbB-1, HER2, HER3 or ErbB-3,
and HER4 or ErbB-4) with an extracellular ligandbinding domain, a short transmembrane domain, and an
intracellular domain with tyrosine kinase activity.1
HER2 is considered an orphan receptor which does not
require any known ligand, operating primarily as a coreceptor that modulate signals after ligand binding to other
EGFR family receptors. Homodimerization independently
of a ligand, as well as heterodimerization with other types
of HER proteins, initiate a signal transduction cascade
influencing many aspects of tumor cell biology, including
cell proliferation, apoptosis, adhesion, migration and differentiation. The HER2/neu oncogene amplification by
means of still unknown mechanism, with subsequent
HER2 protein overexpression on the gastric cancer cells’
surface enhances and prolongs signals that lead to an
acquisition of advantageous properties for a malignant
phenotype transformation, facilitating excessive/uncontrolled cell growth, tumorigenesis and metastasis.2,3
Furthermore, a discrepancy between protein expression
and gene amplification indicates that overexpression of
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HER2 in gastric cancer, differently from breast cancer,
may be regulated by several mechanisms, including
transcriptional activation by other genes or posttranscriptional events.
The importance of addressing HER2 as a distinguished
one intrinsic subtype of gastric cancer associated with specific phenotype is underscored by its impact on carcinogenesis processes as well as adverse and distinctive clinicopathological features.
HER2 overexpression is not an event acquired at a later
moment by malignant cells, but represents the initial
timing of this process probably occurring in early stages
of cancerogenesis with subsequent increase of expression
proportionally to disease progression, making possible
the HER2 test on either the primary tumor or a metastatic
tumor with similar results. About 10%e38% of gastric
cancers present HER2 overexpression, with a higher prevalence in tumors from the upper third of the stomach than
in those located in more distal areas. Furthermore, the
HER2 amplification has been observed mainly in Lauren’s
intestinal type gastric cancer, with low prevalence in
diffuse-type cancer.4
Previously, the HER2 overexpression was considered a
negative prognostic factor, associated with a worse effect
on overall survival. However, despite conflicting results of
more recent published studies addressing the prognostic
significance of HER2 overexpression, to date the relationship between HER2 status and prognosis of gastric cancer
patients remains controversial, differently from the negative prognostic effect of HER2 positivity assessed in
breast cancer.5e7 However, inhibition of the HER2
pathway in HER2-positive gastric cancer patients demonstrated clinical benefits. Trastuzumab, a monoclonal antibody that binds to the extracellular domain of the HER2
receptor blocking its downstream signaling as well as promoting an antibody-dependent cell-mediated cytotoxicity
with activation of apoptotic signals of the tumor cells,8
is approved by the United States Food and Drug Administration from 1998 for the treatment of breast cancer, representing the first approved monoclonal antibody for use
in solid tumor therapy. From a clinical perspective,
272
Editorial / EJSO 41 (2015) 271e273
published data from studies on breast cancer suggested
that trastuzumab administration might have benefits in
overall survival. The first randomized prospective phase
III trial testing trastuzumab efficacy and safety in combination with chemotherapy compared to standard chemotherapy alone for patients with HER2-positive advanced
gastric cancer showed an overall survival of 13.8 months
in the treatment group, compared with 11.1 months in the
control group. Although modest, the 2.7-month improvement was clinically meaningful despite the results of
many trials testing other chemotherapy regimens.9 ToGA
(Trastuzumab for Gastric Cancer) trial is considered a
milestone of a targeted therapy in gastric cancer that
may change the point of view of researchers about gastric
cancer. “I think this will have significant impact on how
we develop new drugs and new concepts for gastric cancer, going away from just mixing and matching cytotoxics,
taking advantage of a molecular characterization and
opening up targeted treatment options in addition to
chemotherapy, not instead of chemotherapy,” said HeinzJosef Lenz, M.D., University of Southern California. So
only twelve years later the United States Food and Drug
Administration and the European Medicines Agency
approved trastuzumab for HER2 overexpressing gastric
cancer patients, incorporating such a drug in clinical
guidelines as standard first-line treatment for HER2positive advanced gastric cancer. Furthermore, the greatest benefit has been demonstrated in patients with higher
levels of HER2 expression in which the overall survival
time reached 16 months, suggesting that a critical density
or threshold of HER2 expression or gene amplification is
necessary for trastuzumab to act, confined this treatment
to the defined subtypes of HER2-positive gastric cancer.
Although the clinical observations are undeniable, the
scientific basis for the effects of trastuzumab remains still
unknown, particularly as far as the mechanisms of resistance to trastuzumab. Thus, important information can
be retrieved from previous knowledge in the treatment
of breast cancer. Various are the mechanisms underlying
trastuzumab resistance and they can be synthesized as
follow: alterations of HER2 structure or surroundings
such as increased heterodimerization of HER2 with
EGFR or HER3, masked HER2 binding site by
membrane-associated glycoprotein MUC4 and HER2
cleavage producing a 95-kDa NH2 terminal-truncated
membrane-associated fragment (p95HER2) with increased
kinase activity; interaction of HER2 with other membrane
receptors such as insulin-like growth factor receptor 1
(IGF1R) and hepatocyte growth factor receptor MET; dysregulation of HER2 downstream signal effectors. Above
all the phosphatidylinositol-3-kinase (PI3K) pathway
alteration is recently found correlated with poor prognosis
also in HER2-positive gastric cancer patients. PIK3
pathway hyperactivation, involved in several malignancies
because it promotes cell proliferation, cell survival,
motility and cell growth, is positively regulated by
PIK3CA gene mutation as well as the inactivation of a tumor suppressor gene, phosphatase and tensin homolog
(PTEN), resulting in resistance to HER2-targeting
therapy.10
These results have potential clinical implications considering that the mutational status of several genes could
further stratify HER2-positive gastric cancer patients for
genotype-based molecular therapies. Thus, new diagnostic
biomarkers as well as others classes of targeted drugs,
including tyrosine kinase inhibitors, such as lapatinib, and
dacomitinib, mammalian target of rapamycin pathway inhibitors, such as everolimus, are ongoing and may prove
profitable.
In conclusion, the HER2 and its targeted therapy history represents a superb model of translational research
that epitomizes the often cited expression of “bedside to
bench to bedside” research, redefining deeply the natural
history of the gastric cancer and establishing a new standard for diagnostic, stadiative and therapeutic tools, with
the profound lesson that not all gastric cancers are the
same.
“The gastric cancer research community have realized
that it is possible to design and conduct molecularly targeted trials in gastric cancer, as well as to find a way to
show an effect in an enriched cohort where patients are
selected based on a genetic profile. We hope that what
this will do is spur some research.” (Jordan Berlin, M.D.,
Ingram Cancer Center, Nashville).
Conflict of interest
The authors have no conflict of interest or financial ties
to disclose.
References
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273
L. Marano*
F. Roviello
Unit of General and Minimally Invasive Surgery,
Department of Medicine, Surgery and Neurosciences,
University of Siena, Viale Mario Bracci, 16, 53100 Siena,
Italy
*Corresponding author. Tel./fax: þ39 0577585157.
E-mail address: [email protected] (L. Marano)
Accepted 21 December 2014