2022
Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers
Batalini F, Gulhan DC, Mao V, Tran A, Polak M, Xiong N, Tayob N, Tung NM, Winer EP, Mayer EL, Knappskog S, Lønning PE, Matulonis UA, Konstantinopoulos PA, Solit DB, Won H, Eikesdal HP, Park PJ, Wulf GM. Mutational Signature 3 Detected from Clinical Panel Sequencing is Associated with Responses to Olaparib in Breast and Ovarian Cancers. Clinical Cancer Research 2022, 28: of1-of10. PMID: 36048535, PMCID: PMC9623231, DOI: 10.1158/1078-0432.ccr-22-0749.Peer-Reviewed Original ResearchConceptsHomologous recombination deficiencyTriple-negative breast cancerMutational signature 3Ovarian cancerImproved progression-free survivalPARP inhibitorsPanel sequencingHigh-grade serous ovarian cancerPI3K inhibitor buparlisibPhase Ib trialProgression-free survivalIdentification of patientsRoutine clinical careSignature 3Serous ovarian cancerPARP inhibitor olaparibSame patient sampleIb trialObjective responseTNBC patientsBreast cancerBRCA1/2 mutationsClinical careInstability scoreGenomic instability scoreSTING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer
Wang Q, Bergholz JS, Ding L, Lin Z, Kabraji SK, Hughes ME, He X, Xie S, Jiang T, Wang W, Zoeller JJ, Kim HJ, Roberts TM, Konstantinopoulos PA, Matulonis UA, Dillon DA, Winer EP, Lin NU, Zhao JJ. STING agonism reprograms tumor-associated macrophages and overcomes resistance to PARP inhibition in BRCA1-deficient models of breast cancer. Nature Communications 2022, 13: 3022. PMID: 35641483, PMCID: PMC9156717, DOI: 10.1038/s41467-022-30568-1.Peer-Reviewed Original ResearchConceptsAnti-tumor immunityBreast cancerPARP inhibitorsSTING agonistsBRCA-mutant breast cancerTumor cellsAnti-tumor stateAdvanced ovarian tumorsCell-mediated suppressionType I IFN responseTumor-associated macrophagesInnate immune suppressionI IFN responseBreast tumor cellsTreatment landscapePro-tumor macrophagesImmune suppressionOvarian tumorsImmune cellsBRCA mutationsSystemic administrationT cellsMouse modelTherapeutic benefitBreast tumors
2020
TBCRC 048: A phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded).
Tung N, Robson M, Ventz S, Santa-Maria C, Marcom P, Nanda R, Shah P, Ballinger T, Yang E, Melisko M, Brufsky A, Vinayak S, Demeo M, Jenkins C, Domchek S, Wulf G, Krop I, Wolff A, Winer E, Garber J. TBCRC 048: A phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded). Journal Of Clinical Oncology 2020, 38: 1002-1002. DOI: 10.1200/jco.2020.38.15_suppl.1002.Peer-Reviewed Original Research
2019
Reversion and non-reversion mechanisms of resistance (MoR) to PARP inhibitor (PARPi) or platinum chemotherapy (chemotx) in patients (pts) with BRCA1/2 -mutant metastatic breast cancer (MBC).
Waks A, Cohen O, Kochupurakkal B, Kim D, Wander S, Buendia-Buendia J, Helvie K, Matulonis U, Krop I, Tolaney S, Winer E, D'Andrea A, Shapiro G, Lin N, Wagle N. Reversion and non-reversion mechanisms of resistance (MoR) to PARP inhibitor (PARPi) or platinum chemotherapy (chemotx) in patients (pts) with BRCA1/2 -mutant metastatic breast cancer (MBC). Journal Of Clinical Oncology 2019, 37: 1085-1085. DOI: 10.1200/jco.2019.37.15_suppl.1085.Peer-Reviewed Original ResearchFork protectionRAD51 fociHomologous recombinationWhole-exome sequencingReplication fork protectionDNA end resectionPARP inhibitorsReversion mutationsIntact homologous recombinationEnd resectionGenomic dataBRCA1/2 proteinsMetastatic tumor biopsiesExome sequencingMutationsGenesResponse/resistanceGermline DNAWES analysisIntrinsic resistanceReversionSequencingProteinDNAAlterations
2017
Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer
Matulonis U, Wulf G, Barry W, Birrer M, Westin S, Farooq S, Bell-McGuinn K, Obermayer E, Whalen C, Spagnoletti T, Luo W, Liu H, Hok R, Aghajanian C, Solit D, Mills G, Taylor B, Won H, Berger M, Palakurthi S, Liu J, Cantley L, Winer E. Phase I dose escalation study of the PI3kinase pathway inhibitor BKM120 and the oral poly (ADP ribose) polymerase (PARP) inhibitor olaparib for the treatment of high-grade serous ovarian and breast cancer. Annals Of Oncology 2017, 28: 512-518. PMID: 27993796, PMCID: PMC5834157, DOI: 10.1093/annonc/mdw672.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAminopyridinesBRCA1 ProteinBRCA2 ProteinBreast NeoplasmsDose-Response Relationship, DrugFemaleGerm-Line MutationHumansMiddle AgedMorpholinesNeoplasm GradingNeoplasm Recurrence, LocalOvarian NeoplasmsPhosphoinositide-3 Kinase InhibitorsPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsPoly(ADP-ribose) PolymerasesConceptsGermline BRCA mutationsOvarian cancerStudy treatmentPARP inhibitorsRandomized phase II studyDose-expansion cohortsPhase II studyPhase I trialDose-escalation designWild-type patientsBiomarkers of responsePARP inhibitor combinationsCombination of BKM120Polymerase inhibitor olaparibPoly (ADP-ribose) polymerase (PARP) inhibitor olaparibPI3K inhibitorsAdditional DLTsOlaparib 300Preclinical synergyRecurrent breastEscalation studyII studyI trialClinical benefitBRCA mutations
2014
A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer.
Liu J, Barry W, Birrer M, Lee J, Buckanovich R, Fleming G, Rimel B, Buss M, Nattam S, Hurteau J, Luo W, Quy P, Obermayer E, Whalen C, Lee H, Winer E, Kohn E, Ivy S, Matulonis U. A randomized phase 2 trial comparing efficacy of the combination of the PARP inhibitor olaparib and the antiangiogenic cediranib against olaparib alone in recurrent platinum-sensitive ovarian cancer. Journal Of Clinical Oncology 2014, 32: lba5500-lba5500. DOI: 10.1200/jco.2014.32.18_suppl.lba5500.Peer-Reviewed Original ResearchProgression-free survivalPartial responseComplete responseHazard ratioOvarian cancerRecurrent platinum-sensitive ovarian cancerMedian progression-free survivalPrior anti-angiogenic therapyPARP inhibitorsPlatinum-sensitive ovarian cancerRandomized phase 2 trialOpen-label studyRecurrent ovarian cancerPhase 2 trialPhase 1 studyExploratory subgroup analysisAnti-angiogenic therapyCombination of cediranibPARP inhibitor olaparibMeasurable diseaseRECIST 1.1Radiographic progressionPFS eventsPS 0Oral combination
2013
A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer
Liu JF, Tolaney SM, Birrer M, Fleming GF, Buss MK, Dahlberg SE, Lee H, Whalen C, Tyburski K, Winer E, Ivy P, Matulonis UA. A Phase 1 trial of the poly(ADP-ribose) polymerase inhibitor olaparib (AZD2281) in combination with the anti-angiogenic cediranib (AZD2171) in recurrent epithelial ovarian or triple-negative breast cancer. European Journal Of Cancer 2013, 49: 2972-2978. PMID: 23810467, PMCID: PMC3956307, DOI: 10.1016/j.ejca.2013.05.020.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAntineoplastic Combined Chemotherapy ProtocolsBreast NeoplasmsCapsulesCarcinoma, Ovarian EpithelialDiarrheaDose-Response Relationship, DrugDrug Administration ScheduleFatigueFemaleHumansMiddle AgedNauseaNeoplasm Recurrence, LocalNeoplasms, Glandular and EpithelialOvarian NeoplasmsPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsQuinazolinesReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneReceptors, Vascular Endothelial Growth FactorTabletsTreatment OutcomeConceptsTriple-negative breast cancerOvarian cancer patientsOverall response rateCombination of cediranibCancer patientsBreast cancerDose levelsMetastatic triple-negative breast cancerEvaluable breast cancer patientsPARP inhibitorsClinical benefit rateGrade 3 fatigueGrade 3 hypertensionPhase 2 dosingVascular endothelial growth factor receptorResponse Evaluation CriteriaSolid Tumors 1.1Endothelial growth factor receptorPhase 1 trialBreast cancer patientsDose-escalation designHighest dose levelPolymerase inhibitor olaparibCA125 criteriaGrowth factor receptor
2010
Poly(ADP-Ribose) Polymerase Inhibition: “Targeted” Therapy for Triple-Negative Breast Cancer
Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, Carey LA. Poly(ADP-Ribose) Polymerase Inhibition: “Targeted” Therapy for Triple-Negative Breast Cancer. Clinical Cancer Research 2010, 16: 4702-4710. PMID: 20858840, PMCID: PMC2948607, DOI: 10.1158/1078-0432.ccr-10-0939.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerBreast cancerPARP inhibitorsClinical trialsAdvanced triple-negative breast cancerHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2PARP inhibitionAdvanced breast cancerGrowth factor receptor 2Clinico-pathologic featuresPositive breast cancerNovel therapeutic classFactor receptor 2Mechanism of actionPreclinical rationalePreclinical modelsNovel agentsReceptor 2CancerTherapeutic classesPolymerase inhibitorsPolymerase inhibitionDNA repairInhibitors