Issue 4 - August 2010 - Pacini Editore

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therapy alone, the addition of trastuzumab to chemotherapy
boosts response rate, progression-free survival and overall
survival in patients with metastatic disease 5 6 . In patients
with operable, HER2-positive breast cancer, the inclusion
of trastuzumab in adjuvant chemotherapy programs reduces
the risk of relapse and prolongs survival 7-9 . More recently,
several other HER2-targeting agents have shown clinical efficacy
both in trastuzumab-naïve and in trastuzumab-resistant
patients and several others are expected in the near future 10 .
This tremendous research effort has become necessary because
resistance to HER2-inhibition is a major challenge. In
fact, as a single agent or in combination with chemotherapy,
trastuzumab induces tumor regression in about 20-30% and
60-70% of HER2-positive metastatic breast cancer patients,
respectively 11 . Unfortunately, the vast majority of patients,
including those with impressive initial responses, will ultimately
show disease progression.
Overcoming primary and acquired resistance to trastuzumab
has been the focus of several preclinical and clinical investigations
to increase the efficiency of HER2-targeting.
These studies have clarified several aspects of the high level
of interaction between signal transduction pathways, which
account for the ability of cancer cells to circumvent inhibition.
For example, tyrosine-kinase receptors can be seen as one
layer of a complex, multilayered network 12 . Other layers are
represented by extracellular ligands and downstream signalling
pathways. By virtue of this architecture, a “core function”
like for example proliferation or survival may be sustained by
different effectors, in a bow-tie structure. This high level of
integration is the result of an evolutionary process that started
with a single ancestral tyrosine-kinase receptor, activated by
one ligand and transmitting signals through a single cascade
of intracellular mediators.
The four EGFR family members have probably originated
from a single receptor through gene duplication. Inactive
monomers form homo- and heterodimeric structures with
other members of the family, resulting in receptor activation
and phosphorilation of downstream signalling effectors.
HER2 has an “always-on” structure and lacks the capacity to
interact with growth-factors ligands. HER3 has no tyrosine
kinase activity. Despite this loss of functions, both HER and
HER3 form hetherodimers with other EGFR members that
are capable of generating potent cellular signals 3 . Apart from
this “family-specific” cooperation, HER receptors can engage
“external cooperation” with members of other families of
tyrosine-kinase receptors, like for example the Insulin-like
growth 1 receptor or with the estrogen receptor pathway 13 14 .
Multiple ligands and intracellular cross-talk between signal
transduction pathways complete this complex evolutionary
network. This architecture has properties that are critical for
both normal and cancer cells 12 . Robustness, which is the ability
of the system to function despite external (environmental)
and internal (genetic) perturbations, is ensured by modularity
and redundancy. Furthermore, the system is able to learn how
to circumvent common, single-hit perturbations (network
training). It appears more and more evident that simultaneous
targeting at several different levels in this multi-layered
biological network is required for maximum clinical efficacy.
Multiple targeting can be accomplished by using single agents
5 th triennial congress of the italian society of anatomic Pathology and diagnostic cytoPathology
with the ability to inhibit different substrates or by cocktails
of selective or non-selective inhibitors. Furthermore, it can
involve other members of the HER2 family or also connected
“external” pathways. Examples of multiple targeting are
already available in the clinic: pan-HER inhibitors, combinations
of HER inhibitors with endocrine agents, antiangiogenic
compounds and heat shock protein inhibitors 15 . HER2- negative
tumors can be targeted successfully with antiangiogenetic
agents 15 . Even “triple negative tumors” (hormone-receptors
and HER2 negative) are no-longer a “targetless” subgroup
since the therapeutic success achieved by PARP-inhibitors 16 .
Due to several unanswered questions on the optimal use of
these agents, this rapidly evolving scenario requires rigorously
conducted clinical studies to select patients who are
most likely to benefit from treatments.
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