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Trastuzumab + low dose radiation for HER2+ CNS progression in metastatic breast cancer

Breast cancer progression on effective drugs can be challenging to treat. Dr. Beverly Moy discussed how the central nervous system is a particularly challenge in HER2+ metastatic breast cancer. This is an idea for a novel clinical trial using radiation to make trastuzumab more effective based upon that discussion.

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Trastuzumab + low dose radiation for HER2+ CNS progression in metastatic breast cancer

  1. 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