Biomedical Engineering Reference
In-Depth Information
The.human.epidermal.growth.factor.receptor.2.(HER2).is.a.member.of.the.EGFR.family,.
which.is.a.receptor.tyrosine-speciic.protein.kinase.family.consisting.of.four.semihomolo-
gous.receptors:.EGFR.(ErbB1),.HER2/neu.(ErbB2),.HER3.(ErbB3),.and.HER4.(ErbB4)..These.
receptors.can.interact.with.several.ligands.and.generate.intracellular.signals.as.homodimer.
or.heterodimer.pairs.
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.HER2.is.a.cell.membrane.surface-bound.receptor.tyrosine.kinase.
and.is.normally.involved.in.the.signal.transduction.pathways.leading.to.cell.growth,.sur-
vival,. and. differentiation. in. a. complex. manner.. HER2. levels. correlate. strongly. with. the.
pathogenesis.and.prognosis.of.breast.cancer..The.level.of.HER2.in.human.cancer.cells.with.
gene. ampliication. is. much. higher. than. that. in. normal. adult. tissues,. which. potentially.
reduces.the.toxicity.of.HER2-targeting.drugs..It.is.well.known.that.HER2.is.overexpressed.
in.25%-30%.of.invasive.breast.cancers,.but.in.normal.tissues.its.expression.is.at.a.much.
lower. level.
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. HER2. overexpression. is. found. in. both. the. primary. tumor. and. metastatic.
sites,.indicating.that.anti-HER2.therapy.may.be.effective.in.all.disease.sites.
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.Thus,.HER2.
is.of.great.interest.as.an.important.therapeutic.target.in.breast.cancer.
8.3.2.2 Assessment of HER2 Status
The.HER2.status.of.a.tumor.is.the.critical.determinant.of.response.to.trastuzumab.as.it.
provides.prognostic.information..Thus,.accurate.assessment.of.HER2.expression.levels.is.
essential.for.identifying.breast.cancer.patients.who.will.beneit.from.trastuzumab.
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.There.
are.several.methods.to.test.the.HER2.levels,.and.testing.can.be.done.at.the.same.time.as.
initial.breast.cancer.surgery,.or.samples.of.cancer.cells.from.previous.biopsies.or.surgery.
may.be.used..Two.of.the.most.widely.used.methods.of.measuring.HER2.levels.in.the.clini-
cal.setting.are.immunohistochemistry.(IHC).and.luorescence.in.situ.hybridization.(FISH)..
Both. methods. have. been. approved. by. the. FDA. for. selecting. patients. for. trastuzumab-
based.therapy.
IHC.is.widely.used,.as.it.entails.staining.parafin-embedded.tissue.with.a.HER2-speciic.
antibody..When.using.commercially.available.kits.such.as.HercepTest.(Dako,.Carpinteria,.
California).and.Pathway.HER2.(Ventana,.Tucson,.Arizona),.staining.is.graded.semiquanti-
tatively.on.a.scale.from.0.(no.detectable.HER2).to.3+.(high.HER2.expression).on.the.basis.of.
comparison.with.cell.lines.of.known.HER2.receptor.density..Tumors.with.a.staining.score.
of.3+.are.the.most.responsive.to.trastuzumab.
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.The.disadvantages.of.IHC.include.the.sub-
jective.interpretation.and.semiquantitative.nature.of.the.results..Currently.available.IHC.
kits.provide.control.slides.against.which.samples.are.compared..Such.standardization.is.
essential.to.ensuring.accurate.assessment.of.HER2.status.
FISH. detects. HER2. gene. ampliication. and. is. more. speciic. and. sensitive. than. IHC.
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.
Importantly,. FISH. offers. quantitative. results,. possibly. eliminating. subjectivity. and. vari-
ability.among.different.laboratories..Furthermore,.FISH.predicts.prognosis.and.response.
to. trastuzumab. more. accurately. than. IHC. does,. as. the. subset. of. patients. whose. tumors.
overexpress.HER2.in.the.absence.of.gene.ampliication.is.less.likely.to.respond.to.trastu-
zumab-based.therapy..In.general,.a.concordance.rate.of.approximately.80%.can.be.achieved.
by.IHC.and.FISH.
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8.3.2.3 Trastuzumab (Herceptin)
Trastuzumab.(Herceptin).is.a.humanized.monoclonal.antibody.that.can.speciically.bind.
to.the.membrane.region.of.HER2/neu.with.a.high.afinity.and.inhibit.signal.transduction.
as.well.as.cell.proliferation,.which.offers.an.excellent.strategy.for.drug.targeting.due.to.the.
easy.accessibility.of.HER2..Trastuzumab.was.the.irst.HER2-targeted.therapy.approved.by.
