2023
Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers
Hutchinson K, Chen J, Savage H, Stout T, Schimmoller F, Cortés J, Dent S, Harbeck N, Jacot W, Krop I, Trabucco S, Sivakumar S, Sokol E, Wilson T. Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers. Genome Medicine 2023, 15: 28. PMID: 37101291, PMCID: PMC10131374, DOI: 10.1186/s13073-023-01181-8.Peer-Reviewed Original ResearchMeSH KeywordsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesFemaleFulvestrantHumansMutationPhosphatidylinositol 3-KinasesReceptor, ErbB-2ConceptsPI3K pathwayBreast cancerK pathwayP110α inhibitionLonger progression-free survivalReceptor tyrosine kinasesProgression-free survivalMetastatic breast cancerComprehensive genomic profilingPI3K pathway genesFurther clinical investigationP110α inhibitorsHigh response rateSolid tumor typesBreast cancer tumorsP110α catalytic subunitClinical trialsClinical investigationIndependent cohortImportant molecular determinantResponse rateTumor typesPIK3CA geneConclusionsOur studyTumor DNAER+, HER2− advanced breast cancer treated with taselisib and fulvestrant: genomic landscape and associated clinical outcomes
Chen J, Jacot W, Cortés J, Krop I, Dent S, Harbeck N, De Laurentiis M, Diéras V, Im Y, Stout T, Schimmoller F, Savage H, Hutchinson K, Wilson T. ER+, HER2− advanced breast cancer treated with taselisib and fulvestrant: genomic landscape and associated clinical outcomes. Molecular Oncology 2023, 17: 2000-2016. PMID: 36892268, PMCID: PMC10552898, DOI: 10.1002/1878-0261.13416.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesFemaleFulvestrantGenomicsHumansPhosphatidylinositol 3-KinasesReceptor, ErbB-2Receptors, EstrogenTumor Suppressor Protein p53ConceptsProgression-free survivalBreast cancerShorter progression-free survivalNeurofibromin 1Advanced breast cancerBreast cancer patientsP53 pathway genesPI3K inhibitorsPI3K inhibitionBaseline ctDNAEndocrine therapyClinical outcomesCancer patientsEstrogen receptorCatalytic subunit alphaTumor DNATaselisibK inhibitorsK inhibitionPI3KOutcomesCancerAlterationsGenomic landscapeProtein p53
2022
Phase II Study of Taselisib in PIK3CA-Mutated Solid Tumors Other Than Breast and Squamous Lung Cancer: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol I
Krop IE, Jegede OA, Grilley-Olson JE, Lauring JD, Mitchell EP, Zwiebel JA, Gray RJ, Wang V, McShane LM, Rubinstein LV, Patton D, Williams PM, Hamilton SR, Kono SA, Ford JM, Garcia AA, Sui XD, Siegel RD, Slomovitz BM, Conley BA, Arteaga CL, Harris LN, O'Dwyer PJ, Chen AP, Flaherty KT. Phase II Study of Taselisib in PIK3CA-Mutated Solid Tumors Other Than Breast and Squamous Lung Cancer: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol I. JCO Precision Oncology 2022, 6: e2100424. PMID: 35138919, PMCID: PMC8865530, DOI: 10.1200/po.21.00424.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Squamous CellClass I Phosphatidylinositol 3-KinasesHumansImidazolesLung NeoplasmsNational Cancer Institute (U.S.)OxazepinesPhosphatidylinositol 3-KinasesUnited StatesConceptsProgression-free survivalOverall survivalSix-month progression-free survivalSolid tumorsMedian progression-free survivalSix-month overall survivalEnd pointSquamous cell lung carcinomaNational Cancer Institute-Molecular AnalysisMedian overall survivalObjective response ratePhase II studyPrimary end pointSecondary end pointsCell lung carcinomaSquamous lung cancerMutant breast cancerCommon toxicitiesEligible patientsProtocol therapyUnacceptable toxicityII studyPartial responseAdvanced cancerClinical outcomes
2021
The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2-positive breast cancer
Janiszewska M, Stein S, Filho O, Eng J, Kingston NL, Harper NW, Rye IH, Alečković M, Trinh A, Murphy KC, Marangoni E, Cristea S, Oakes B, Winer EP, Krop I, Russnes HG, Spellman PT, Bucher E, Hu Z, Chin K, Gray JW, Michor F, Polyak K. The impact of tumor epithelial and microenvironmental heterogeneity on treatment responses in HER2-positive breast cancer. JCI Insight 2021, 6: e147617. PMID: 33886505, PMCID: PMC8262355, DOI: 10.1172/jci.insight.147617.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDNA Copy Number VariationsDrug Resistance, NeoplasmEpithelial CellsFemaleFibroblastsHumansMacrophagesMiddle AgedMutationNeoplasm TransplantationReceptor, ErbB-2TrastuzumabTumor MicroenvironmentVesicular Transport ProteinsConceptsBreast cancerTherapeutic resistanceHuman epidermal growth factor receptor 2HER2-positive breast cancerEpidermal growth factor receptor 2Patient-derived xenograft modelsLymphatic vessel endothelial hyaluronan receptorHER2-targeted therapiesGrowth factor receptor 2Impact of tumorFibroblastic reticular cellsFactor receptor 2Tumor epithelial cellsIntratumor heterogeneityDivergent cellular phenotypesResistance-conferring mutationsClinical outcomesPIK3CA mutationsTreatment responseClinical challengeDifferent therapiesFrequency of cellsXenograft modelReceptor 2Stromal determinants
2020
Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial ☆
Dent S, Cortés J, Im Y, Diéras V, Harbeck N, Krop IE, Wilson TR, Cui N, Schimmoller F, Hsu JY, He J, De Laurentiis M, Sousa S, Drullinsky P, Jacot W. Phase III randomized study of taselisib or placebo with fulvestrant in estrogen receptor-positive, PIK3CA-mutant, HER2-negative, advanced breast cancer: the SANDPIPER trial ☆. Annals Of Oncology 2020, 32: 197-207. PMID: 33186740, PMCID: PMC8457522, DOI: 10.1016/j.annonc.2020.10.596.Peer-Reviewed Original ResearchConceptsInvestigator-assessed progression-free survivalClinical benefit ratePIK3CA-mutant tumorsObjective response rateSecondary endpointsPrimary endpointObjective responseBenefit rateBreast cancerResponse ratePhase III Randomized StudyDisease recurrence/progressionBlinded independent central reviewPIK3CA mutation statusSerious adverse eventsAdvanced breast cancerProgression-free survivalHealth-related qualityMetastatic breast cancerRecurrence/progressionModest clinical benefitIndependent central reviewSelective PI3K inhibitorPI3K inhibitorsMore discontinuationsPhase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer
Garrido-Castro AC, Saura C, Barroso-Sousa R, Guo H, Ciruelos E, Bermejo B, Gavilá J, Serra V, Prat A, Paré L, Céliz P, Villagrasa P, Li Y, Savoie J, Xu Z, Arteaga CL, Krop IE, Solit DB, Mills GB, Cantley LC, Winer EP, Lin NU, Rodon J. Phase 2 study of buparlisib (BKM120), a pan-class I PI3K inhibitor, in patients with metastatic triple-negative breast cancer. Breast Cancer Research 2020, 22: 120. PMID: 33138866, PMCID: PMC7607628, DOI: 10.1186/s13058-020-01354-y.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAminopyridinesAntineoplastic Combined Chemotherapy ProtocolsClass I Phosphatidylinositol 3-KinasesDisease ProgressionFemaleHigh-Throughput Nucleotide SequencingHumansMiddle AgedMorpholinesNeoplasm MetastasisPatient SafetyProtein Kinase InhibitorsProteomicsResponse Evaluation Criteria in Solid TumorsSurvival RateTreatment OutcomeTriple Negative Breast NeoplasmsConceptsTriple-negative breast cancerProgression-free survivalPan-class I PI3K inhibitorMetastatic triple-negative breast cancerStable diseasePhase 2 studyBreast cancerOverall survivalPI3K inhibitorsPI3K pathwayPartial responseComplete responseClinical benefitSingle-arm phase 2 studyTriple-negative metastatic breast cancerMedian progression-free survivalK inhibitorsClinical benefit rateEfficacy of buparlisibK pathwayFrequent adverse eventsMedian overall survivalPercent of patientsMetastatic breast cancerSubset of patients
2019
A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer
Abramson VG, Oliveira M, Cervantes A, Wildiers H, Patel MR, Bauer TM, Bedard PL, Becerra C, Richey S, Wei MC, Reyner E, Bond J, Cui N, Wilson TR, Moore HM, Saura C, Krop IE. A phase Ib, open-label, dose-escalation study of the safety and pharmacology of taselisib (GDC-0032) in combination with either docetaxel or paclitaxel in patients with HER2-negative, locally advanced, or metastatic breast cancer. Breast Cancer Research And Treatment 2019, 178: 121-133. PMID: 31368034, DOI: 10.1007/s10549-019-05360-3.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCarcinoma, Non-Small-Cell LungClass I Phosphatidylinositol 3-KinasesDocetaxelFemaleHumansImidazolesLung NeoplasmsMaleMaximum Tolerated DoseMiddle AgedMutationNeoplasm MetastasisOxazepinesPaclitaxelReceptor, ErbB-2Survival AnalysisTreatment OutcomeConceptsNon-small cell lung cancerDose-limiting toxicityMetastatic breast cancerAdverse eventsBreast cancerPhase IbClinical benefit rateDose-expansion studyObjective response ratePhase II doseSerious adverse eventsDose-escalation studyCell lung cancerBenefit-risk profileDays on/2ResultsEighty patientsPrimary endpointSecondary endpointsSafety profileLung cancerBenefit ratePatientsSingle agentResponse rateDocetaxelA combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer
Veeraraghavan J, De Angelis C, Mao R, Wang T, Herrera S, Pavlick AC, Contreras A, Nuciforo P, Mayer IA, Forero A, Nanda R, Goetz MP, Chang JC, Wolff AC, Krop IE, Fuqua SAW, Prat A, Hilsenbeck SG, Weigelt B, Reis-Filho JS, Gutierrez C, Osborne CK, Rimawi MF, Schiff R. A combinatorial biomarker predicts pathologic complete response to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2+ breast cancer. Annals Of Oncology 2019, 30: 927-933. PMID: 30903140, PMCID: PMC6594453, DOI: 10.1093/annonc/mdz076.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesFemaleFollow-Up StudiesGene AmplificationHumansIn Situ Hybridization, FluorescenceLapatinibNeoadjuvant TherapyPhosphatidylinositol 3-KinasesPrognosisReceptor, ErbB-2Remission InductionTrastuzumabConceptsPathologic complete responsePI3K pathway statusBreast cancerHER2 ratioPI3K pathwayNeoadjuvant lapatinibComplete responseHER2 amplificationPathway statusHER2-positive breast cancerPI3K pathway alterationsHER2 amplification levelHER2 FISH ratioK pathwayAnti-HER2 therapyWild-type PIK3CAPI3K pathway activationPIK3CA mutationsClinical subtypesHER2 overexpressionFISH ratioPatientsChemotherapyHER2High PTENGenomic alterations in breast cancer: level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)
Condorelli R, Mosele F, Verret B, Bachelot T, Bedard P, Cortes J, Hyman D, Juric D, Krop I, Bieche I, Saura C, Sotiriou C, Cardoso F, Loibl S, Andre F, Turner N. Genomic alterations in breast cancer: level of evidence for actionability according to ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Annals Of Oncology 2019, 30: 365-373. PMID: 30715161, DOI: 10.1093/annonc/mdz036.Peer-Reviewed Original ResearchConceptsLevel of evidenceBreast cancerESMO ScaleClinical actionabilityGenomic alterationsMicrosatellite instabilityLarge randomized trialsMolecular targetsBRCA 1/2 mutationsGermline BRCA1/2 mutationsESR1 mutationsPreclinical evidenceNTRK fusionsRandomized trialsPIK3CA mutationsERBB2 mutationsBRCA1/2 mutationsRecurrent genomic alterationsMDM2 amplificationERBB2 amplificationClinical practiceDriver alterationsPTEN lossTumor genomic landscapeAntitumor activity
2018
Phase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor–Positive Advanced Breast Cancer
Dickler MN, Saura C, Richards DA, Krop IE, Cervantes A, Bedard PL, Patel MR, Pusztai L, Oliveira M, Cardenas AK, Cui N, Wilson TR, Stout TJ, Wei MC, Hsu JY, Baselga J. Phase II Study of Taselisib (GDC-0032) in Combination with Fulvestrant in Patients with HER2-Negative, Hormone Receptor–Positive Advanced Breast Cancer. Clinical Cancer Research 2018, 24: 4380-4387. PMID: 29793946, PMCID: PMC6139036, DOI: 10.1158/1078-0432.ccr-18-0613.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDisease-Free SurvivalDrug-Related Side Effects and Adverse ReactionsFemaleFulvestrantHumansImidazolesMiddle AgedMutationOxazepinesReceptor, ErbB-2Receptors, EstrogenConceptsAdverse eventsClinical activityBreast cancerMutation statusOpen-label phase II studyHR-positive breast cancerHigher objective response rateConfirmatory phase III trialNCI CTCAE v4.0Median treatment durationObjective response ratePhase II studySerious adverse eventsNew safety signalsPhase III trialsPositive breast cancerClin Cancer ResIntramuscular fulvestrantMeasurable diseaseRECIST v1.1II studyIII trialsPostmenopausal womenUnacceptable toxicityTumor response
2017
Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer
Rimawi MF, De Angelis C, Contreras A, Pareja F, Geyer FC, Burke KA, Herrera S, Wang T, Mayer IA, Forero A, Nanda R, Goetz MP, Chang JC, Krop IE, Wolff AC, Pavlick AC, Fuqua SAW, Gutierrez C, Hilsenbeck SG, Li MM, Weigelt B, Reis-Filho JS, Kent Osborne C, Schiff R. Low PTEN levels and PIK3CA mutations predict resistance to neoadjuvant lapatinib and trastuzumab without chemotherapy in patients with HER2 over-expressing breast cancer. Breast Cancer Research And Treatment 2017, 167: 731-740. PMID: 29110152, PMCID: PMC5821069, DOI: 10.1007/s10549-017-4533-9.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesFemaleGene Expression Regulation, NeoplasticHumansLapatinibMiddle AgedMutationNeoadjuvant TherapyPTEN PhosphohydrolaseQuinazolinesReceptor, ErbB-2TrastuzumabConceptsPathologic complete responsePIK3CA mutationsBreast cancerPTEN expression levelsPTEN statusClinical trialsHER2-positive breast cancerNeoadjuvant clinical trialsPIK3CA mutation analysisLow PTEN expression levelsExpression levelsPI3K pathwayEvaluable patientsNeoadjuvant lapatinibComplete responsePatientsChemotherapyPTEN immunohistochemistryTumor samplesTrastuzumabCancerPathway activationK pathwayFurther studiesPTEN levelsPhase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors
Juric D, Krop I, Ramanathan RK, Wilson TR, Ware JA, Bohorquez S, Savage HM, Sampath D, Salphati L, Lin RS, Jin H, Parmar H, Hsu JY, Von Hoff DD, Baselga J. Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors. Cancer Discovery 2017, 7: 704-715. PMID: 28331003, PMCID: PMC5501742, DOI: 10.1158/2159-8290.cd-16-1080.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityAdverse eventsMutant tumorsHigh-grade adverse eventsTreatment-related adverse eventsConfirmed response rateMetastatic solid tumorsTumor xenograft modelPatient tumor samplesMeasurable diseasePharmacodynamic findingsPreclinical dataTumor patientsTumor growth inhibitorLow doseXenograft modelDose levelsResponse rateSolid tumorsPathway inhibitionPatientsPathway suppressionTumor samplesTumorsHotspot mutations
2016
Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T‐DM1) vs. treatment of physician's choice in previously treated HER2‐positive advanced breast cancer
Kim S, Wildiers H, Krop IE, Smitt M, Yu R, de Haas S, Gonzalez‐Martin A. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T‐DM1) vs. treatment of physician's choice in previously treated HER2‐positive advanced breast cancer. International Journal Of Cancer 2016, 139: 2336-2342. PMID: 27428671, DOI: 10.1002/ijc.30276.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsCapecitabineClass I Phosphatidylinositol 3-KinasesFemaleHumansKaplan-Meier EstimateLapatinibMaytansinePhosphatidylinositol 3-KinasesQuinazolinesReceptor, ErbB-2TrastuzumabHeterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant
Spoerke JM, Gendreau S, Walter K, Qiu J, Wilson TR, Savage H, Aimi J, Derynck MK, Chen M, Chan IT, Amler LC, Hampton GM, Johnston S, Krop I, Schmid P, Lackner MR. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nature Communications 2016, 7: 11579. PMID: 27174596, PMCID: PMC4869259, DOI: 10.1038/ncomms11579.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBreastBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesDisease-Free SurvivalDNA Mutational AnalysisDNA, NeoplasmDrug Resistance, NeoplasmEstradiolEstrogen Receptor alphaEstrogen Receptor AntagonistsEstrogensFemaleFulvestrantHumansIndazolesMiddle AgedMutationProtein Kinase InhibitorsSulfonamidesConceptsMetastatic breast cancer patientsESR1 mutationsBreast cancer patientsCancer patientsPan-PI3K inhibitorPIK3CA-mutated tumorsProgression-free survivalMetastatic breast cancerWild-type patientsClinical trial samplesMutation allele frequencyInhibitor therapyFulvestrant treatmentBreast cancerClinical significanceClinical resistancePatientsBaseline samplesHotspot mutationsK inhibitorsTherapyLongitudinal analysisTrial samplesESR1Distinct clones
2015
PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling
Cheng H, Liu P, Ohlson C, Xu E, Symonds L, Isabella A, Muller WJ, Lin NU, Krop IE, Roberts TM, Winer EP, Arteaga CL, Zhao JJ. PIK3CAH1047R- and Her2-initiated mammary tumors escape PI3K dependency by compensatory activation of MEK-ERK signaling. Oncogene 2015, 35: 2961-2970. PMID: 26640141, PMCID: PMC4896860, DOI: 10.1038/onc.2015.377.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsClass I Phosphatidylinositol 3-KinasesCohort StudiesFemaleHumansMaleMAP Kinase Signaling SystemMiceMice, Inbred NODMice, TransgenicPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsReceptor, ErbB-2ConceptsBreast cancerPIK3CA mutationsMammary tumorsHER2 amplification/overexpressionHER2-positive breast cancerHER2-positive cancersPrimary mammary tumorsHER2/HER3PIK3CA-activating mutationsHER2/neuHuman breast cancerEffective treatment approachAmplification/overexpressionCompound mouse modelMEK-ERK signalingMouse mammary glandWorse prognosisCombination therapyMammary tumorigenesisMouse modelMutant PIK3CATreatment approachesHER2Combined inhibitionCompensatory activationPI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers
Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 2015, 35: 3607-3612. PMID: 26500061, PMCID: PMC4846581, DOI: 10.1038/onc.2015.406.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell SurvivalClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmFemaleHumansLapatinibMammary Neoplasms, ExperimentalMice, KnockoutMolecular Targeted TherapyPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseQuinazolinesReceptor, ErbB-2Signal TransductionThiazolesTumor BurdenXenograft Model Antitumor AssaysConceptsBreast tumorsP110β inhibitorsHuman epidermal growth factor receptor 2 (HER2) amplificationP110α inhibitionPTEN lossInhibition of HER2Treatment of HER2Human cancersPI3K pathway activationPTEN-deficient breast cancersGenetic mouse modelsPI3K/Akt signalingPTEN-deficient tumorsPI3K/AktDual HER2Therapeutic regimenHER2 inhibitionPIK3CA mutationsTumor regressionBreast cancerMouse modelXenograft modelHER2Null tumorsHER2 activation