1. Clinical Problem: WomenwithmetastaticHER2+ breast cancerrespondwell toHER2-directed
therapybuthave poor outcomeswith CNSrelapse,particularlywithCNS
carcinomatosisandleptomeningealdisease.
Context: There has beenincreasinginterestinusingradiotherapytopotentiate
immunotherapybyenhancedantigenpresentation.
 Trastuzumabmonoclonal antibodieshave beenusedintrathecallyforCNSrecurrence. (Figuraet
al,Bousquetetal)
 Data from neoadjuvant chemotherapy+Her2therapy trialssuggestimmune responseplaysan
importantrole - tumorinfiltratinglymphocytesare associatedwithpCRandevent-free survival
(Salgadoetal,Denkertetal)
 Some data suggestthatbetterHER2 expressionmayimprove response toHER2-directed
therapy inmetastaticbreastcancer (Scaltriti etal,Nishimuraetal,Montemurroetal)
 Patientswithbrainmetastasesmayhave higherexpressionbothof HER2 and p95 comparedto
womenwithnonmetastaticbreastcancer(Duchnowskaetal)
 Ionizingradiationcanupregulate HER-2antibodytargetsforbreastcancer,inHER2+ andtriple-
negative breastcancercell lines andcanenhance cell kill effectsof trastuzumab (Wattenberget
al).
 Most interesthasbeeninstereotacticradiation(Muranoetal) butfocal therapy maynot apply
well forbreastCNScarcinomatosis inpatientsoftenpreviouslytreated
 Low-dose radiationhasbeenusedtopotentiate systemicchemotherapyinheadandneck
cancer (Arnoldetal)
Hypothesis: Low-dose radiationpriortointrathecal trastuzumabmayinduce HER2expressionand
improve treatmentefficacyinwomenwithHER2+CNScarcinomatosis.
Proposal: Phase I/IIdose escalationtrial administeringMRI-directedradiationtherapy24-48hours
before weeklyITtrastuzumabat50 cGy x 10 weeks,100 cGy levelsx 10 weeks,
150 cGy x 5 (everyotherweek),200cGy x 5 (everyotherweek)
Endpoints:Response rates,CNSprogressionfreesurvival