{"id":"https://openalex.org/W4361959080","doi":"https://doi.org/10.1158/1078-0432.c.6532460","title":"Data from Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases","display_name":"Data from Mechanistic Modeling of Central Nervous System Pharmacokinetics and Target Engagement of HER2 Tyrosine Kinase Inhibitors to Inform Treatment of Breast Cancer Brain Metastases","publication_year":2023,"publication_date":"2023-03-31","ids":{"openalex":"https://openalex.org/W4361959080","doi":"https://doi.org/10.1158/1078-0432.c.6532460"},"language":"en","primary_location":{"id":"doi:10.1158/1078-0432.c.6532460","doi":"https://doi.org/10.1158/1078-0432.c.6532460","is_oa":true,"landing_page_url":"https://doi.org/10.1158/1078-0432.c.6532460","pdf_url":null,"source":null,"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"American Association for Cancer Research","raw_type":"posted-content"},"volume":null,"type":"other","indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"gold","oa_url":"https://doi.org/10.1158/1078-0432.c.6532460","any_repository_has_fulltext":null},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5018071939","display_name":"Jing Li","orcid":"https://orcid.org/0000-0002-9924-1386","observed_orcids":["https://orcid.org/0000-0002-9924-1386"]},"institutions":[{"id":"https://openalex.org/I4210090317","display_name":"The Barbara Ann Karmanos Cancer Institute","ror":"https://ror.org/00ee40h97","country_code":"US","type":"facility","lineage":["https://openalex.org/I2800590384","https://openalex.org/I4210090317"]},{"id":"https://openalex.org/I99319750","display_name":"Seagen (United States)","ror":"https://ror.org/01vwesc15","country_code":"US","type":"company","lineage":["https://openalex.org/I99319750"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Jing Li","raw_affiliation_strings":["HWCRC, Room 523, Detroit, MI 48201","Karmanos Cancer Institute, 4100 John R Street,","Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA"],"raw_orcid":"https://orcid.org/0000-0002-9924-1386","affiliations":[{"raw_affiliation_string":"HWCRC, Room 523, Detroit, MI 48201","institution_ids":[]},{"raw_affiliation_string":"Karmanos Cancer Institute, 4100 John R Street,","institution_ids":["https://openalex.org/I4210090317"]},{"raw_affiliation_string":"Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA","institution_ids":["https://openalex.org/I99319750"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5071975498","display_name":"Jun Jiang","orcid":"https://orcid.org/0000-0002-8931-9872","observed_orcids":["https://orcid.org/0000-0002-8931-9872","https://orcid.org/0000-0001-8690-397X"]},"institutions":[{"id":"https://openalex.org/I4210090317","display_name":"The Barbara Ann Karmanos Cancer Institute","ror":"https://ror.org/00ee40h97","country_code":"US","type":"facility","lineage":["https://openalex.org/I2800590384","https://openalex.org/I4210090317"]},{"id":"https://openalex.org/I99319750","display_name":"Seagen (United States)","ror":"https://ror.org/01vwesc15","country_code":"US","type":"company","lineage":["https://openalex.org/I99319750"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Jun Jiang","raw_affiliation_strings":["HWCRC, Room 523, Detroit, MI 48201","Karmanos Cancer Institute, 4100 John R Street,","Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"HWCRC, Room 523, Detroit, MI 48201","institution_ids":[]},{"raw_affiliation_string":"Karmanos Cancer Institute, 4100 John R Street,","institution_ids":["https://openalex.org/I4210090317"]},{"raw_affiliation_string":"Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA","institution_ids":["https://openalex.org/I99319750"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5102220426","display_name":"Xun Bao","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I4210090317","display_name":"The Barbara Ann Karmanos Cancer Institute","ror":"https://ror.org/00ee40h97","country_code":"US","type":"facility","lineage":["https://openalex.org/I2800590384","https://openalex.org/I4210090317"]},{"id":"https://openalex.org/I99319750","display_name":"Seagen (United States)","ror":"https://ror.org/01vwesc15","country_code":"US","type":"company","lineage":["https://openalex.org/I99319750"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Xun Bao","raw_affiliation_strings":["HWCRC, Room 523, Detroit, MI 48201","Karmanos Cancer Institute, 4100 John R Street,","Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"HWCRC, Room 523, Detroit, MI 48201","institution_ids":[]},{"raw_affiliation_string":"Karmanos Cancer Institute, 4100 John R Street,","institution_ids":["https://openalex.org/I4210090317"]},{"raw_affiliation_string":"Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA","institution_ids":["https://openalex.org/I99319750"]}]},{"author_position":"middle","author":{"id":null,"display_name":"Vineet Kumar","orcid":"https://orcid.org/0000-0001-7193-9646","observed_orcids":["https://orcid.org/0000-0001-7193-9646"]},"institutions":[{"id":"https://openalex.org/I4210090317","display_name":"The Barbara Ann Karmanos Cancer Institute","ror":"https://ror.org/00ee40h97","country_code":"US","type":"facility","lineage":["https://openalex.org/I2800590384","https://openalex.org/I4210090317"]},{"id":"https://openalex.org/I99319750","display_name":"Seagen (United States)","ror":"https://ror.org/01vwesc15","country_code":"US","type":"company","lineage":["https://openalex.org/I99319750"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Vineet Kumar","raw_affiliation_strings":["HWCRC, Room 523, Detroit, MI 48201","Karmanos Cancer Institute, 4100 John R Street,","Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA"],"raw_orcid":"https://orcid.org/0000-0001-7193-9646","affiliations":[{"raw_affiliation_string":"HWCRC, Room 523, Detroit, MI 48201","institution_ids":[]},{"raw_affiliation_string":"Karmanos Cancer Institute, 4100 John R Street,","institution_ids":["https://openalex.org/I4210090317"]},{"raw_affiliation_string":"Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA","institution_ids":["https://openalex.org/I99319750"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5072073795","display_name":"Stephen C. Alley","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I4210090317","display_name":"The Barbara Ann Karmanos Cancer Institute","ror":"https://ror.org/00ee40h97","country_code":"US","type":"facility","lineage":["https://openalex.org/I2800590384","https://openalex.org/I4210090317"]},{"id":"https://openalex.org/I99319750","display_name":"Seagen (United States)","ror":"https://ror.org/01vwesc15","country_code":"US","type":"company","lineage":["https://openalex.org/I99319750"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Stephen C. Alley","raw_affiliation_strings":["HWCRC, Room 523, Detroit, MI 48201","Karmanos Cancer Institute, 4100 John R Street,","Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"HWCRC, Room 523, Detroit, MI 48201","institution_ids":[]},{"raw_affiliation_string":"Karmanos Cancer Institute, 4100 John R Street,","institution_ids":["https://openalex.org/I4210090317"]},{"raw_affiliation_string":"Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA","institution_ids":["https://openalex.org/I99319750"]}]},{"author_position":"middle","author":{"id":null,"display_name":"Scott Peterson","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I4210090317","display_name":"The Barbara Ann Karmanos Cancer Institute","ror":"https://ror.org/00ee40h97","country_code":"US","type":"facility","lineage":["https://openalex.org/I2800590384","https://openalex.org/I4210090317"]},{"id":"https://openalex.org/I99319750","display_name":"Seagen (United States)","ror":"https://ror.org/01vwesc15","country_code":"US","type":"company","lineage":["https://openalex.org/I99319750"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Scott Peterson","raw_affiliation_strings":["HWCRC, Room 523, Detroit, MI 48201","Karmanos Cancer Institute, 4100 John R Street,","Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"HWCRC, Room 523, Detroit, MI 48201","institution_ids":[]},{"raw_affiliation_string":"Karmanos Cancer Institute, 4100 John R Street,","institution_ids":["https://openalex.org/I4210090317"]},{"raw_affiliation_string":"Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA","institution_ids":["https://openalex.org/I99319750"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5102984039","display_name":"Anthony J. Lee","orcid":"https://orcid.org/0009-0005-6112-2006","observed_orcids":["https://orcid.org/0009-0005-6112-2006"]},"institutions":[{"id":"https://openalex.org/I4210090317","display_name":"The Barbara Ann Karmanos Cancer Institute","ror":"https://ror.org/00ee40h97","country_code":"US","type":"facility","lineage":["https://openalex.org/I2800590384","https://openalex.org/I4210090317"]},{"id":"https://openalex.org/I99319750","display_name":"Seagen (United States)","ror":"https://ror.org/01vwesc15","country_code":"US","type":"company","lineage":["https://openalex.org/I99319750"]}],"countries":["US"],"is_corresponding":false,"raw_author_name":"Anthony J. Lee","raw_affiliation_strings":["HWCRC, Room 523, Detroit, MI 48201","Karmanos Cancer Institute, 4100 John R Street,","Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"HWCRC, Room 523, Detroit, MI 48201","institution_ids":[]},{"raw_affiliation_string":"Karmanos Cancer Institute, 4100 John R Street,","institution_ids":["https://openalex.org/I4210090317"]},{"raw_affiliation_string":"Translational Sciences, Seagen Inc., Bothell, WA, 98021, USA","institution_ids":["https://openalex.org/I99319750"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":2,"corresponding_author_ids":[],"corresponding_institution_ids":[],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11600","display_name":"Brain Metastases and Treatment","score":0.2727000117301941,"subfield":{"id":"https://openalex.org/subfields/2740","display_name":"Pulmonary and Respiratory Medicine"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T11600","display_name":"Brain Metastases and Treatment","score":0.2727000117301941,"subfield":{"id":"https://openalex.org/subfields/2740","display_name":"Pulmonary and Respiratory Medicine"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10570","display_name":"Drug Transport and Resistance Mechanisms","score":0.24950000643730164,"subfield":{"id":"https://openalex.org/subfields/2730","display_name":"Oncology"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T11872","display_name":"Barrier Structure and Function Studies","score":0.10570000112056732,"subfield":{"id":"https://openalex.org/subfields/2808","display_name":"Neurology"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/her2-tyrosine-kinase-inhibitor","display_name":"HER2 tyrosine kinase inhibitor","score":0.8980000019073486},{"id":"https://openalex.org/keywords/breast-cancer-brain-metastases","display_name":"breast cancer brain metastasis","score":0.9580000042915344},{"id":"https://openalex.org/keywords/target-engagement","display_name":"target engagement","score":0.8709999918937683},{"id":"https://openalex.org/keywords/tucatinib","display_name":"tucatinib","score":0.8880000114440918},{"id":"https://openalex.org/keywords/lapatinib","display_name":"lapatinib","score":0.9300000071525574},{"id":"https://openalex.org/keywords/neratinib","display_name":"neratinib","score":1.0},{"id":"https://openalex.org/keywords/physiologically-based-pharmacokinetic-model","display_name":"physiologically based pharmacokinetic modeling","score":0.9419999718666077},{"id":"https://openalex.org/keywords/brain-permeability","display_name":"brain permeability","score":0.6140000224113464},{"id":"https://openalex.org/keywords/blood-brain-barrier","display_name":"blood-brain barrier","score":0.8579999804496765},{"id":"https://openalex.org/keywords/efflux-pumps","display_name":"efflux pumps","score":0.8550000190734863},{"id":"https://openalex.org/keywords/micrometastasis","display_name":"micrometastases","score":0.8169999718666077},{"id":"https://openalex.org/keywords/brain-metastasis-prevention","display_name":"brain metastasis prevention","score":0.6480000019073486}],"concepts":[{"id":"https://openalex.org/C2777329042","wikidata":"https://www.wikidata.org/wiki/Q420323","display_name":"Lapatinib","level":5,"score":0.8600425720214844},{"id":"https://openalex.org/C112705442","wikidata":"https://www.wikidata.org/wiki/Q323936","display_name":"Pharmacokinetics","level":2,"score":0.7455235719680786},{"id":"https://openalex.org/C2779413316","wikidata":"https://www.wikidata.org/wiki/Q6995920","display_name":"Neratinib","level":5,"score":0.619377076625824},{"id":"https://openalex.org/C185867374","wikidata":"https://www.wikidata.org/wiki/Q2562769","display_name":"Physiologically based pharmacokinetic modelling","level":3,"score":0.6156471967697144},{"id":"https://openalex.org/C98274493","wikidata":"https://www.wikidata.org/wiki/Q128406","display_name":"Pharmacology","level":1,"score":0.6031402349472046},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.5996566414833069},{"id":"https://openalex.org/C2778820342","wikidata":"https://www.wikidata.org/wiki/Q906415","display_name":"Tyrosine-kinase inhibitor","level":3,"score":0.5872888565063477},{"id":"https://openalex.org/C530470458","wikidata":"https://www.wikidata.org/wiki/Q128581","display_name":"Breast cancer","level":3,"score":0.35678935050964355},{"id":"https://openalex.org/C126322002","wikidata":"https://www.wikidata.org/wiki/Q11180","display_name":"Internal medicine","level":1,"score":0.3123476505279541},{"id":"https://openalex.org/C121608353","wikidata":"https://www.wikidata.org/wiki/Q12078","display_name":"Cancer","level":2,"score":0.2878788709640503},{"id":"https://openalex.org/C71924100","wikidata":"https://www.wikidata.org/wiki/Q11190","display_name":"Medicine","level":0,"score":0.25892025232315063},{"id":"https://openalex.org/C2779786085","wikidata":"https://www.wikidata.org/wiki/Q412616","display_name":"Trastuzumab","level":4,"score":0.20824387669563293}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.1158/1078-0432.c.6532460","doi":"https://doi.org/10.1158/1078-0432.c.6532460","is_oa":true,"landing_page_url":"https://doi.org/10.1158/1078-0432.c.6532460","pdf_url":null,"source":null,"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"American Association for Cancer Research","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.1158/1078-0432.c.6532460","doi":"https://doi.org/10.1158/1078-0432.c.6532460","is_oa":true,"landing_page_url":"https://doi.org/10.1158/1078-0432.c.6532460","pdf_url":null,"source":null,"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"American Association for Cancer Research","raw_type":"posted-content"},"sustainable_development_goals":[{"score":1.0,"display_name":"Good health and well-being","id":"https://metadata.un.org/sdg/3"}],"study_designs":[],"awards":[{"id":"https://openalex.org/G9000145461","display_name":null,"funder_award_id":"CA022453","funder_id":"https://openalex.org/F4320332161","funder_display_name":"National Institutes of Health"},{"id":"https://openalex.org/G9000905662","display_name":"CANCER CENTER SUPPORT GRANT","funder_award_id":"P30CA022453","funder_id":"https://openalex.org/F4320337351","funder_display_name":"National Cancer Institute"}],"funders":[{"id":"https://openalex.org/F4320319515","display_name":"Seagen","ror":null},{"id":"https://openalex.org/F4320332161","display_name":"National Institutes of Health","ror":"https://ror.org/01cwqze88"},{"id":"https://openalex.org/F4320337351","display_name":"National Cancer Institute","ror":"https://ror.org/040gcmg81"}],"has_content":{"pdf":false,"grobid_xml":false},"content_urls":null,"referenced_works_count":47,"referenced_works":["https://openalex.org/W1922104457","https://openalex.org/W1966720603","https://openalex.org/W1996719014","https://openalex.org/W1998765747","https://openalex.org/W2003861703","https://openalex.org/W2005496979","https://openalex.org/W2015574368","https://openalex.org/W2031426306","https://openalex.org/W2040233060","https://openalex.org/W2051708290","https://openalex.org/W2052474126","https://openalex.org/W2056412577","https://openalex.org/W2062352315","https://openalex.org/W2066349153","https://openalex.org/W2089580511","https://openalex.org/W2095265260","https://openalex.org/W2104290477","https://openalex.org/W2109924789","https://openalex.org/W2120572090","https://openalex.org/W2125129553","https://openalex.org/W2127714076","https://openalex.org/W2130735457","https://openalex.org/W2131585462","https://openalex.org/W2141712412","https://openalex.org/W2151201474","https://openalex.org/W2161888863","https://openalex.org/W2168814163","https://openalex.org/W2263556989","https://openalex.org/W2329671310","https://openalex.org/W2754610420","https://openalex.org/W2768980003","https://openalex.org/W2897103850","https://openalex.org/W2910873703","https://openalex.org/W2921590809","https://openalex.org/W2969460503","https://openalex.org/W2979984433","https://openalex.org/W2982466751","https://openalex.org/W2995808512","https://openalex.org/W3015126839","https://openalex.org/W3030461309","https://openalex.org/W3037795108","https://openalex.org/W3043096450","https://openalex.org/W3049329286","https://openalex.org/W3129068140","https://openalex.org/W3170192455","https://openalex.org/W4298436768","https://openalex.org/W4300820219"],"related_works":["https://openalex.org/W4283260308","https://openalex.org/W3089012529","https://openalex.org/W4403936148","https://openalex.org/W4404237626","https://openalex.org/W1886326176","https://openalex.org/W3170192455","https://openalex.org/W2131558896","https://openalex.org/W4220724792","https://openalex.org/W2057097645","https://openalex.org/W2286030185"],"abstract_inverted_index":{"AbstractPurpose:":[0],"This":[1],"study":[2],"evaluated":[3],"the":[4,81,84,164,208,225,241],"central":[5],"nervous":[6],"system":[7],"(CNS)":[8],"pharmacokinetics":[9,220],"and":[10,16,42,48,67,72,119,137,177,221,235],"target":[11],"engagement":[12,76],"of":[13,83,104,115,228,232,243],"lapatinib,":[14],"neratinib,":[15],"tucatinib":[17,118,185,229],"in":[18,35,93,163,193,215,246],"patients":[19,247],"with":[20,50,59,198,217,248],"cancer,":[21],"using":[22],"a":[23,60,102,199],"physiologically":[24],"based":[25],"pharmacokinetic":[26],"(PBPK)":[27],"modeling":[28,182],"approach.":[29],"Experimental":[30],"Design:":[31],"Drug-specific":[32],"parameters":[33],"for":[34,69,96,142,170,175,230,240],"vitro":[36,94],"metabolism,":[37],"binding":[38],"to":[39,92],"plasma":[40,71],"proteins":[41],"brain":[43,63,89,167,196,233,244],"tissues,":[44],"transcellular":[45],"passive":[46],"permeability,":[47],"interactions":[49],"efflux":[51],"transporters":[52],"were":[53,139],"determined.":[54],"Whole-body":[55],"PBPK":[56,108,181],"models":[57,109],"integrated":[58],"4-compartment":[61],"permeability-limited":[62],"model":[64],"was":[65,99,133,152,168],"developed":[66],"verified":[68],"predicting":[70],"CNS":[73],"pharmacokinetics.":[74],"Target":[75],"ratio":[77,82],"(TER),":[78],"defined":[79],"as":[80,101],"average":[85],"steady-state":[86],"unbound":[87],"drug":[88],"concentration":[90],"(Css,ave,br)":[91],"IC50":[95],"HER2":[97,143,188],"inhibition,":[98],"used":[100],"predictor":[103],"intracranial":[105],"efficacy.":[106],"Results:":[107],"predicted":[110],"that":[111,184],"following":[112],"1":[113],"cycle":[114],"standard":[116],"dosing,":[117],"lapatinib":[120,151,176],"achieved":[121],"similar":[122],"Css,ave,br":[123,130],"(14.5":[124],"vs.":[125,147],"16.8":[126],"nmol/L),":[127,149],"while":[128,150],"neratinib":[129,138],"(0.68":[131],"nmol/L)":[132],"20-fold":[134],"lower.":[135],"Tucatinib":[136],"equally":[140],"potent":[141,154],"inhibition":[144,189],"(IC50,":[145,155],"6.9":[146],"5.6":[148],"less":[153],"109":[156],"nmol/L).":[157],"The":[158,180],"model-predicted":[159],"population":[160],"mean":[161],"TER":[162],"human":[165],"normal":[166],"2.1":[169],"tucatinib,":[171],"but":[172,204],"<":[173],"0.20":[174],"neratinib.":[178],"Conclusions:":[179],"suggests":[183],"induces":[186],"sufficient":[187],"(TER":[190],">":[191],"2.0)":[192],"not":[194],"only":[195],"metastases":[197,234,245],"disrupted":[200],"blood\u2013brain":[201],"barrier":[202],"(BBB),":[203],"also":[205],"micrometastases":[206],"where":[207],"BBB":[209],"largely":[210],"remains":[211],"intact.":[212],"These":[213],"findings,":[214],"line":[216],"available":[218],"clinical":[219,238],"efficacy":[222],"data,":[223],"support":[224],"therapeutic":[226],"value":[227],"treatment":[231],"warrant":[236],"further":[237],"investigation":[239],"prevention":[242],"HER2-positive":[249],"breast":[250],"cancer.":[251]},"counts_by_year":[],"updated_date":"2026-10-15T10:00:46.086208","created_date":"2023-04-05T00:00:00"}