2023
Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium
El Zarif T, Nassar A, Adib E, Fitzgerald B, Huang J, Mouhieddine T, Rubinstein P, Nonato T, McKay R, Li M, Mittra A, Owen D, Baiocchi R, Lorentsen M, Dittus C, Dizman N, Falohun A, Abdel-Wahab N, Diab A, Bankapur A, Reed A, Kim C, Arora A, Shah N, El-Am E, Kozaily E, Abdallah W, Al-Hader A, Abu Ghazal B, Saeed A, Drolen C, Lechner M, Drakaki A, Baena J, Nebhan C, Haykal T, Morse M, Cortellini A, Pinato D, Dalla Pria A, Hall E, Bakalov V, Bahary N, Rajkumar A, Mangla A, Shah V, Singh P, Aboubakar Nana F, Lopetegui-Lia N, Dima D, Dobbs R, Funchain P, Saleem R, Woodford R, Long G, Menzies A, Genova C, Barletta G, Puri S, Florou V, Idossa D, Saponara M, Queirolo P, Lamberti G, Addeo A, Bersanelli M, Freeman D, Xie W, Reid E, Chiao E, Sharon E, Johnson D, Ramaswami R, Bower M, Emu B, Marron T, Choueiri T, Baden L, Lurain K, Sonpavde G, Naqash A. Safety and Activity of Immune Checkpoint Inhibitors in People Living With HIV and Cancer: A Real-World Report From the Cancer Therapy Using Checkpoint Inhibitors in People Living With HIV-International (CATCH-IT) Consortium. Journal Of Clinical Oncology 2023, 41: 3712-3723. PMID: 37192435, PMCID: PMC10351941, DOI: 10.1200/jco.22.02459.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsProgression-free survivalObjective response rateOverall survivalMetastatic NSCLCCheckpoint inhibitorsGrade immune-related adverse eventsImmune checkpoint inhibitor trialsNeck squamous cell carcinomaActivity of ICICheckpoint inhibitor trialsCohort of PWHImmune checkpoint inhibitorsHIV viral loadKaplan-Meier methodSquamous cell carcinomaUse of ICIMean survival timeMost common cancersL1 monotherapyRECIST 1.1Adverse eventsInhibitor trialsMedian ageAdvanced cancerEpigenomic charting and functional annotation of risk loci in renal cell carcinoma
Nassar A, Abou Alaiwi S, Baca S, Adib E, Corona R, Seo J, Fonseca M, Spisak S, El Zarif T, Tisza V, Braun D, Du H, He M, Flaifel A, Alchoueiry M, Denize T, Matar S, Acosta A, Shukla S, Hou Y, Steinharter J, Bouchard G, Berchuck J, O’Connor E, Bell C, Nuzzo P, Mary Lee G, Signoretti S, Hirsch M, Pomerantz M, Henske E, Gusev A, Lawrenson K, Choueiri T, Kwiatkowski D, Freedman M. Epigenomic charting and functional annotation of risk loci in renal cell carcinoma. Nature Communications 2023, 14: 346. PMID: 36681680, PMCID: PMC9867739, DOI: 10.1038/s41467-023-35833-5.Peer-Reviewed Original ResearchConceptsMaster transcription factorChIP-seqATAC-seq dataH3K27ac ChIP-seqCcRCC cell linesEpigenomic atlasATAC-seqFunctional annotationTranscriptional landscapePrimary human samplesTranscription factorsRNA-seqRisk lociTranscriptional upregulationSNP arrayRisk SNPsETS-1EpigenomeCell linesFOXI1Renal cell carcinomaEPAS1RCC histologic subtypesHuman samplesBHLHE41
2022
Germline variants associated with toxicity to immune checkpoint blockade
Groha S, Alaiwi S, Xu W, Naranbhai V, Nassar A, Bakouny Z, El Zarif T, Saliby R, Wan G, Rajeh A, Adib E, Nuzzo P, Schmidt A, Labaki C, Ricciuti B, Alessi J, Braun D, Shukla S, Keenan T, Van Allen E, Awad M, Manos M, Rahma O, Zubiri L, Villani A, Fairfax B, Hammer C, Khan Z, Reynolds K, Semenov Y, Schrag D, Kehl K, Freedman M, Choueiri T, Gusev A. Germline variants associated with toxicity to immune checkpoint blockade. Nature Medicine 2022, 28: 2584-2591. PMID: 36526723, PMCID: PMC10958775, DOI: 10.1038/s41591-022-02094-6.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsImmune checkpoint inhibitorsGrade immune-related adverse eventsGermline variantsICI initiationCheckpoint inhibitorsAdverse eventsCheckpoint blockadeImproved survivalDiscovery cohortLymphocyte homeostasisSignificant associationCancer typesIL7Remarkable responsePatientsCritical regulatorGenome-wide significant associationAssociationWide association studyIndependent studiesAssociation studiesBlockadeCohortVariantsImpact of renin-angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors.
Nuzzo PV, Adib E, Weise N, Curran C, Stewart T, Freeman D, Nassar AH, Abou Alaiwi S, Bakouny Z, McGregor BA, Choueiri TK, Jain RK, McKay RR, Sonpavde G. Impact of renin-angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma treated with immune-checkpoint inhibitors. Clinical Genitourinary Cancer 2022, 20: 301-306. PMID: 35614012, DOI: 10.1016/j.clgc.2022.04.012.Peer-Reviewed Original ResearchVariation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology.
Adib E, Nassar AH, Abou Alaiwi S, Groha S, Akl EW, Sholl LM, Michael KS, Awad MM, Jӓnne PA, Gusev A, Kwiatkowski DJ. Variation in targetable genomic alterations in non-small cell lung cancer by genetic ancestry, sex, smoking history, and histology. Genome Medicine 2022, 14: 39. PMID: 35428358, PMCID: PMC9013075, DOI: 10.1186/s13073-022-01041-x.Peer-Reviewed Original ResearchClonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenström macroglobulinemia.
Tahri S, Mouhieddine TH, Redd R, Lampe L, Nilsson KI, El-Khoury H, Su NK, Nassar AH, Adib E, Bindra G, Abou Alaiwi S, Trippa L, Steensma DP, Castillo JJ, Treon SP, Ghobrial IM, Sperling AS. Clonal hematopoiesis is associated with increased risk of progression of asymptomatic Waldenström macroglobulinemia. Blood Advances 2022, 6: 2230-2235. PMID: 34847227, PMCID: PMC9006277, DOI: 10.1182/bloodadvances.2021004926.Peer-Reviewed Original ResearchCDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer.
Adib E, El Zarif T, Nassar AH, Akl EW, Abou Alaiwi S, Mouhieddine TH, Esplin ED, Hatchell K, Nielsen SM, Rana HQ, Choueiri TK, Kwiatkowski DJ, Sonpavde G. CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer. British Journal Of Cancer 2022, 126: 797-803. PMID: 34949788, PMCID: PMC8888603, DOI: 10.1038/s41416-021-01673-7.Peer-Reviewed Original ResearchPrevalence of pathogenic germline cancer risk variants in testicular cancer patients: Identifying high risk groups.
Ramamurthy C, Nassar AH, Abou Alaiwi S, Adib E, Akl EW, Yang S, Esplin ED, Liss MA, Tomlinson GE, Sonpavde GP. Prevalence of pathogenic germline cancer risk variants in testicular cancer patients: Identifying high risk groups. Urologic Oncology 2022, 40: 113.e9-113.e15. PMID: 35022142, DOI: 10.1016/j.urolonc.2021.12.014.Peer-Reviewed Original ResearchFGFR2/3 genomic alterations and response to Enfortumab Vedotin in metastatic urothelial carcinoma.
Adib E, El Zarif T, Jain RK, Skelton WP, Freeman D, Curran C, Akl E, Nassar AH, Ravi P, Mantia C, Kwiatkowski DJ, Choueiri TK, Sonpavde G. FGFR2/3 genomic alterations and response to Enfortumab Vedotin in metastatic urothelial carcinoma. BJUI Compass 2022, 3: 169-172. PMID: 35224552, PMCID: PMC8880907, DOI: 10.1002/bco2.125.Peer-Reviewed Original ResearchBiomarker-Based Phase II Study of Sapanisertib (TAK-228): An mTORC1/2 Inhibitor in Patients With Refractory Metastatic Renal Cell Carcinoma.
McGregor BA, Xie W, Adib E, Stadler WM, Zakharia Y, Alva A, Michaelson MD, Gupta S, Lam ET, Farah S, Nassar AH, Wei XX, Kilbridge KL, Harshman L, Signoretti S, Sholl L, Kwiatkowski DJ, McKay RR, Choueiri TK. Biomarker-Based Phase II Study of Sapanisertib (TAK-228): An mTORC1/2 Inhibitor in Patients With Refractory Metastatic Renal Cell Carcinoma. JCO Precision Oncology 2022, 6: e2100448. PMID: 35171658, PMCID: PMC8865529, DOI: 10.1200/PO.21.00448.Peer-Reviewed Original Research
2021
Angiotensin Blockade Modulates the Activity of PD1/L1 Inhibitors in Metastatic Urothelial Carcinoma.
Jain RK, Skelton Iv WP, Pond GR, Naqvi M, Kim Y, Curran C, Freeman D, Nuzzo PV, Alaiwi SA, Nassar AH, Jain RK, Sonpavde G. Angiotensin Blockade Modulates the Activity of PD1/L1 Inhibitors in Metastatic Urothelial Carcinoma. Clinical Genitourinary Cancer 2021, 19: 540-546. PMID: 34011489, PMCID: PMC8526625, DOI: 10.1016/j.clgc.2021.04.002.Peer-Reviewed Original ResearchClinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer
Nebhan CA, Cortellini A, Ma W, Ganta T, Song H, Ye F, Irlmeier R, Debnath N, Saeed A, Radford M, Alahmadi A, Diamond A, Hoimes C, Ramaiya N, Presley CJ, Owen DH, Alaiwi S, Nassar A, Ricciuti B, Lamberti G, Bersanelli M, Casartelli C, Buti S, Marchetti P, Giusti R, Filetti M, Vanella V, Mallardo D, Macherla S, Sussman TA, Botticelli A, Galetta D, Catino A, Pizzutilo P, Genova C, Dal Bello MG, Kalofonou F, Daniels E, Ascierto PA, Pinato DJ, Choueiri TK, Johnson DB, Marron TU, Wang Y, Naqash AR. Clinical Outcomes and Toxic Effects of Single-Agent Immune Checkpoint Inhibitors Among Patients Aged 80 Years or Older With Cancer. JAMA Oncology 2021, 7: 1856-1861. PMID: 34734989, PMCID: PMC8569601, DOI: 10.1001/jamaoncol.2021.4960.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsImmune checkpoint inhibitorsSingle-agent immune checkpoint inhibitorsGeriatric patientsClinical outcomesICI initiationCheckpoint inhibitorsAdverse eventsAnti-programmed cell death-1 therapySafety of ICIsNon-small cell lung cancerPatients Aged 80 YearsInternational retrospective studyCommon Terminology CriteriaInternational cohort studyObjective response rateDiscontinuation of treatmentCell lung cancerCancer clinical trialsGU tumorsICI discontinuationIrAE onsetMedian PFSTerminology CriteriaCohort studyRAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics
Bekele RT, Samant AS, Nassar AH, So J, Garcia EP, Curran CR, Hwang JH, Mayhew DL, Nag A, Thorner AR, Börcsök J, Sztupinszki Z, Pan CX, Bellmunt J, Kwiatkowski DJ, Sonpavde GP, Van Allen EM, Mouw KW. RAF1 amplification drives a subset of bladder tumors and confers sensitivity to MAPK-directed therapeutics. Journal Of Clinical Investigation 2021, 131 PMID: 34554931, PMCID: PMC8592548, DOI: 10.1172/jci147849.Peer-Reviewed Original ResearchConceptsBladder tumorsUrothelial tumorsTherapeutic strategiesNovel therapeutic strategiesRational therapeutic strategiesPatient-derived modelsRaf/MEK/ERKClinical outcomesMEK/ERKTreatment optionsBladder cancerHeterogeneous diseaseMEK inhibitionTumorsUnique subsetFocal amplificationRAF inhibitorsCell linesRAF1Gene expression patternsActivationExpression patternsSignalingSubsetRaf1 activityGene Expression Signature Correlates with Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Everolimus Alone or with a Vascular Disrupting Agent
Yang ES, Nassar AH, Adib E, Jegede OA, Alaiwi SA, Manna DLD, Braun DA, Zarei M, Du H, Pal SK, Naik G, Sonpavde GP. Gene Expression Signature Correlates with Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Everolimus Alone or with a Vascular Disrupting Agent. Molecular Cancer Therapeutics 2021, 20: 1454-1461. PMID: 34108261, DOI: 10.1158/1535-7163.mct-20-1091.Peer-Reviewed Original ResearchMeSH KeywordsAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBenzofuransBiomarkers, TumorCarcinoma, Renal CellClinical Trials, Phase III as TopicEverolimusFemaleFollow-Up StudiesGene Expression Regulation, NeoplasticHumansKidney NeoplasmsMaleMiddle AgedOrganophosphatesPrognosisSurvival RateTranscriptomeValidation Studies as TopicConceptsMetastatic renal cell carcinomaMedian PFSClinical benefitDiscovery cohortMetastatic renal cell carcinoma patientsPhase I/II trialRenal cell carcinoma patientsPhase III trialsCell carcinoma patientsLonger median PFSRenal cell carcinomaFour-gene signaturePropensity score covariate adjustmentVascular Disrupting AgentsCheckMate 025Monotherapy useStable diseaseII trialGene expression signaturesIII trialsAppropriate patientsCarcinoma patientsImmune checkpointsCell carcinomaVEGF inhibitorsCDKN2A Alterations and Response to Immunotherapy in Solid Tumors
Adib E, Nassar AH, Akl EW, Abou Alaiwi S, Nuzzo PV, Mouhieddine TH, Sonpavde G, Haddad RI, Mouw KW, Giannakis M, Hodi FS, Shukla SA, Gusev A, Braun DA, Choueiri TK, Kwiatkowski DJ. CDKN2A Alterations and Response to Immunotherapy in Solid Tumors. Clinical Cancer Research 2021, 27: 4025-4035. PMID: 34074656, PMCID: PMC8900067, DOI: 10.1158/1078-0432.ccr-21-0575.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsUrothelial carcinomaGenomic alterationsMemorial Sloan-Kettering Cancer CenterNon-small cell lungDana-Farber Cancer InstituteICI treatment outcomesPlatinum-based therapyTumor immune microenvironmentImmuno-inflammatory pathwaysRenal cell carcinomaDFCI cohortICI therapyCheckpoint inhibitorsCancer Genome AtlasClinical benefitCancer CenterCell carcinomaCell lungPredictive biomarkersDifferent cancer typesPoor responseWorse outcomesMSK-IMPACTMetastatic cancerReprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer.
Baca SC, Takeda DY, Seo JH, Hwang J, Ku SY, Arafeh R, Arnoff T, Agarwal S, Bell C, O'Connor E, Qiu X, Alaiwi SA, Corona RI, Fonseca MAS, Giambartolomei C, Cejas P, Lim K, He M, Sheahan A, Nassar A, Berchuck JE, Brown L, Nguyen HM, Coleman IM, Kaipainen A, De Sarkar N, Nelson PS, Morrissey C, Korthauer K, Pomerantz MM, Ellis L, Pasaniuc B, Lawrenson K, Kelly K, Zoubeidi A, Hahn WC, Beltran H, Long HW, Brown M, Corey E, Freedman ML. Reprogramming of the FOXA1 cistrome in treatment-emergent neuroendocrine prostate cancer. Nature Communications 2021, 12: 1979. PMID: 33785741, PMCID: PMC8010057, DOI: 10.1038/s41467-021-22139-7.Peer-Reviewed Original ResearchTrans-ethnic variation in germline variants of patients with renal cell carcinoma.
Abou Alaiwi S, Nassar AH, Adib E, Groha SM, Akl EW, McGregor BA, Esplin ED, Yang S, Hatchell K, Fusaro V, Nielsen S, Kwiatkowski DJ, Sonpavde GP, Pomerantz M, Garber JE, Freedman ML, Rana HQ, Gusev A, Choueiri TK. Trans-ethnic variation in germline variants of patients with renal cell carcinoma. Cell Reports 2021, 34: 108926. PMID: 33789101, DOI: 10.1016/j.celrep.2021.108926.Peer-Reviewed Original ResearchIntegrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma
Bakouny Z, Braun DA, Shukla SA, Pan W, Gao X, Hou Y, Flaifel A, Tang S, Bosma-Moody A, He MX, Vokes N, Nyman J, Xie W, Nassar AH, Abou Alaiwi S, Flippot R, Bouchard G, Steinharter JA, Nuzzo PV, Ficial M, Sant’Angelo M, Forman J, Berchuck JE, Dudani S, Bi K, Park J, Camp S, Sticco-Ivins M, Hirsch L, Baca SC, Wind-Rotolo M, Ross-Macdonald P, Sun M, Lee GM, Chang SL, Wei XX, McGregor BA, Harshman LC, Genovese G, Ellis L, Pomerantz M, Hirsch MS, Freedman ML, Atkins MB, Wu CJ, Ho TH, Linehan WM, McDermott DF, Heng DYC, Viswanathan SR, Signoretti S, Van Allen EM, Choueiri TK. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma. Nature Communications 2021, 12: 808. PMID: 33547292, PMCID: PMC7865061, DOI: 10.1038/s41467-021-21068-9.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Agents, ImmunologicalB7-H1 AntigenCarcinoma, Renal CellCTLA-4 AntigenCyclin-Dependent Kinase Inhibitor p16Gene Expression ProfilingGene Expression Regulation, NeoplasticHigh-Throughput Nucleotide SequencingHumansImmune Checkpoint InhibitorsImmune Checkpoint ProteinsKidney NeoplasmsMutationProgrammed Cell Death 1 ReceptorProto-Oncogene Proteins c-mycRetrospective StudiesRhabdoid TumorSignal TransductionSurvival AnalysisTranscription, GeneticTumor Suppressor ProteinsUbiquitin ThiolesteraseConceptsRhabdoid renal cell carcinomaImmune checkpoint inhibitorsRenal cell carcinomaCell carcinomaImmune-inflamed phenotypeIntegrative molecular characterizationPD-L1 expressionReal-world cohortMultiple clinical trialsMYC transcriptional programsMolecular featuresCheckpoint inhibitorsClinical outcomesImmune activationImmunologic characteristicsAggressive tumorsImmune infiltrationClinical trialsClinical characterizationRCC tumorsBAP1 mutationsDistinctive molecular featuresTumorsCDKN2A deletionMolecular driversDistribution of KRAS G12C Somatic Mutations across Race, Sex, and Cancer Type.
Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRAS G12C Somatic Mutations across Race, Sex, and Cancer Type. The New England Journal Of Medicine 2021, 384: 185-187. PMID: 33497555, DOI: 10.1056/NEJMc2030638.Peer-Reviewed Original ResearchMITF is a driver oncogene and potential therapeutic target in kidney angiomyolipoma tumors through transcriptional regulation of CYR61.
Zarei M, Giannikou K, Du H, Liu HJ, Duarte M, Johnson S, Nassar AH, Widlund HR, Henske EP, Long HW, Kwiatkowski DJ. MITF is a driver oncogene and potential therapeutic target in kidney angiomyolipoma tumors through transcriptional regulation of CYR61. Oncogene 2021, 40: 112-126. PMID: 33082558, PMCID: PMC7796905, DOI: 10.1038/s41388-020-01504-8.Peer-Reviewed Original Research