2024
CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors
Skoulidis F, Araujo H, Do M, Qian Y, Sun X, Cobo A, Le J, Montesion M, Palmer R, Jahchan N, Juan J, Min C, Yu Y, Pan X, Arbour K, Vokes N, Schmidt S, Molkentine D, Owen D, Memmott R, Patil P, Marmarelis M, Awad M, Murray J, Hellyer J, Gainor J, Dimou A, Bestvina C, Shu C, Riess J, Blakely C, Pecot C, Mezquita L, Tabbó F, Scheffler M, Digumarthy S, Mooradian M, Sacher A, Lau S, Saltos A, Rotow J, Johnson R, Liu C, Stewart T, Goldberg S, Killam J, Walther Z, Schalper K, Davies K, Woodcock M, Anagnostou V, Marrone K, Forde P, Ricciuti B, Venkatraman D, Van Allen E, Cummings A, Goldman J, Shaish H, Kier M, Katz S, Aggarwal C, Ni Y, Azok J, Segal J, Ritterhouse L, Neal J, Lacroix L, Elamin Y, Negrao M, Le X, Lam V, Lewis W, Kemp H, Carter B, Roth J, Swisher S, Lee R, Zhou T, Poteete A, Kong Y, Takehara T, Paula A, Parra Cuentas E, Behrens C, Wistuba I, Zhang J, Blumenschein G, Gay C, Byers L, Gibbons D, Tsao A, Lee J, Bivona T, Camidge D, Gray J, Lieghl N, Levy B, Brahmer J, Garassino M, Gandara D, Garon E, Rizvi N, Scagliotti G, Wolf J, Planchard D, Besse B, Herbst R, Wakelee H, Pennell N, Shaw A, Jänne P, Carbone D, Hellmann M, Rudin C, Albacker L, Mann H, Zhu Z, Lai Z, Stewart R, Peters S, Johnson M, Wong K, Huang A, Winslow M, Rosen M, Winters I, Papadimitrakopoulou V, Cascone T, Jewsbury P, Heymach J. CTLA4 blockade abrogates KEAP1/STK11-related resistance to PD-(L)1 inhibitors. Nature 2024, 1-10. PMID: 39385035, DOI: 10.1038/s41586-024-07943-7.Peer-Reviewed Original ResearchNon-small-cell lung cancerImmune checkpoint blockadeTumor suppressor genePD-L1Advanced non-small-cell lung cancerCD8+ cytotoxic T cellsSuppressor geneCD4+ effector cellsDual immune checkpoint blockadeMouse modelPD-L1 inhibitor durvalumabSuppressive myeloid cellsPD-L1 inhibitorsImmune-related toxicitiesPD-(L)1 inhibitorsAnti-tumor efficacyCytotoxic T cellsMyeloid cell compartmentAdverse tumor microenvironmentAssociated with higher ratesAnti-tumor activityLoss of Keap1CTLA4 inhibitorsSTK11 alterationsCheckpoint blockadeASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts.
Hu B, Wiesehöfer M, de Miguel F, Liu Z, Chan L, Choi J, Melnick M, Arnal Estape A, Walther Z, Zhao D, Lopez-Giraldez F, Wurtz A, Cai G, Fan R, Gettinger S, Xiao A, Yan Q, Homer R, Nguyen D, Politi K. ASCL1 Drives Tolerance to Osimertinib in EGFR Mutant Lung Cancer in Permissive Cellular Contexts. Cancer Research 2024, 84: 1303-1319. PMID: 38359163, PMCID: PMC11142404, DOI: 10.1158/0008-5472.can-23-0438.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsPatient-derived xenograftsEGFR mutant lung cancerMutant lung cancerPre-treatment tumorsResidual diseaseDrug toleranceLung cancerResidual tumor cells in vivoEGFR mutant lung adenocarcinomaTyrosine kinase inhibitor osimertinibEGFR tyrosine kinase inhibitorsTyrosine kinase inhibitor treatmentTumor cells in vivoMutant lung adenocarcinomaMaximal tumor regressionTranscription factor Ascl1Drug-tolerant cellsTime of maximal responseEvidence of cellsCells in vivoOsimertinib treatmentTumor regressionSingle cell transcriptional profilingTumor cellsA destabilizing Y891D mutation in activated EGFR impairs sensitivity to kinase inhibition
Lenchner D, Petrova Z, Hunihan L, Ashtekar K, Walther Z, Wilson F. A destabilizing Y891D mutation in activated EGFR impairs sensitivity to kinase inhibition. Npj Precision Oncology 2024, 8: 3. PMID: 38182677, PMCID: PMC10770066, DOI: 10.1038/s41698-023-00490-w.Peer-Reviewed Original Research
2023
Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer
Stockhammer P, Grant M, Wurtz A, Foggetti G, Expósito F, Gu J, Zhao H, Choi J, Chung S, Li F, Walther Z, Dietz J, Duffield E, Gettinger S, Politi K, Goldberg S. Co-Occurring Alterations in Multiple Tumor Suppressor Genes Are Associated With Worse Outcomes in Patients With EGFR-Mutant Lung Cancer. Journal Of Thoracic Oncology 2023, 19: 240-251. PMID: 37806385, PMCID: PMC11364167, DOI: 10.1016/j.jtho.2023.10.001.Peer-Reviewed Original ResearchProgression-free survivalEGFR-mutant NSCLCTP53 mutationsOverall survivalClinical outcomesEGFR-TKIInferior outcomesWorse outcomesYale cohortMetastatic EGFR-mutant NSCLCShorter progression-free survivalEGFR-mutant lung cancerTyrosine kinase inhibitor therapyFirst-line TKIYale Cancer CenterSecond-line therapyInferior clinical outcomesSubset of patientsKinase inhibitor therapyAdditional therapeutic interventionsAggressive disease phenotypeCo-occurring alterationsTumor suppressor gene alterationsTumor genomic profilingMultiple tumor suppressor genesPlatinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All “BRCAness” Is Created Equal
Doroshow D, Wei W, Mehrotra M, Sia D, Eder J, Bindra R, Houldsworth J, LoRusso P, Walther Z. Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All “BRCAness” Is Created Equal. Cancer Investigation 2023, 41: 646-655. PMID: 37505929, DOI: 10.1080/07357907.2023.2242957.Peer-Reviewed Original ResearchConceptsClinical benefit rateIntrahepatic cholangiocarcinomaPlatinum sensitivityUnresectable intrahepatic cholangiocarcinomaObjective response rateMulticenter retrospective studyHomologous recombination repairDefective homologous recombination (HR) repairPrimary endpointPlatinum chemotherapyRetrospective studyPreclinical dataBenefit rateWildtype tumorsResponse rateMT tumorsWT diseasePatientsGene defectsCholangiocarcinomaTumorsNCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors
Cecchini M, Walther Z, Wei W, Hafez N, Pilat M, Boerner S, Durecki D, Eder J, Schalper K, Chen A, LoRusso P. NCI 7977: A Phase I Dose-Escalation Study of Intermittent Oral ABT-888 (Veliparib) Plus Intravenous Irinotecan Administered in Patients with Advanced Solid Tumors. Cancer Research Communications 2023, 3: 1113-1117. PMID: 37377610, PMCID: PMC10292219, DOI: 10.1158/2767-9764.crc-22-0485.Peer-Reviewed Original ResearchConceptsDose-limiting toxicityHomologous recombination deficiencyPARP inhibitorsStable diseaseWeekly irinotecanObjective responseDay 1Day 3Solid tumorsPhase I dose-escalation studyTwice daily days 1I dose-escalation studyPhase I clinical trialDaily days 1Dose level 1Doses of veliparibGrade 3 neutropeniaMultiple-dose schedulesProgression-free survivalAdvanced solid tumorsDose-escalation studyEvaluable patientsNonoverlapping toxicitiesDose scheduleSystemic treatmentEfficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations
Grant M, Aredo J, Starrett J, Stockhammer P, van Rosenburgh I, Wurtz A, Piper-Valillo A, Piotrowska Z, Falcon C, Yu H, Aggarwal C, Scholes D, Patil T, Nguyen C, Phadke M, Li F, Neal J, Lemmon M, Walther Z, Politi K, Goldberg S. Efficacy of Osimertinib in Patients with Lung Cancer Positive for Uncommon EGFR Exon 19 Deletion Mutations. Clinical Cancer Research 2023, 29: of1-of8. PMID: 36913537, PMCID: PMC10493186, DOI: 10.1158/1078-0432.ccr-22-3497.Peer-Reviewed Original ResearchConceptsProgression-free survivalNon-small cell lung cancerInferior progression-free survivalMulticenter retrospective cohortEfficacy of osimertinibMulti-institutional cohortCell lung cancerExon 19 deletion mutationUncommon EGFRRetrospective cohortClinical outcomesClinical efficacyLung cancerOsimertinib efficacyEGFR mutationsPreclinical modelsEx19delPatientsAACR Genie databaseLater linesOsimertinibMutant cohortFirst lineCohortEfficacy
2022
Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations
van Alderwerelt van Rosenburgh I, Lu D, Grant M, Stayrook S, Phadke M, Walther Z, Goldberg S, Politi K, Lemmon M, Ashtekar K, Tsutsui Y. Biochemical and structural basis for differential inhibitor sensitivity of EGFR with distinct exon 19 mutations. Nature Communications 2022, 13: 6791. PMID: 36357385, PMCID: PMC9649653, DOI: 10.1038/s41467-022-34398-z.Peer-Reviewed Original ResearchCirculating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI–Treated Patients with EGFR-Mutant NSCLC (SWOG S1403)
Mack PC, Miao J, Redman MW, Moon J, Goldberg SB, Herbst RS, Melnick MA, Walther Z, Hirsch FR, Politi K, Kelly K, Gandara DR. Circulating Tumor DNA Kinetics Predict Progression-Free and Overall Survival in EGFR TKI–Treated Patients with EGFR-Mutant NSCLC (SWOG S1403). Clinical Cancer Research 2022, 28: 3752-3760. PMID: 35713632, PMCID: PMC9444942, DOI: 10.1158/1078-0432.ccr-22-0741.Peer-Reviewed Original ResearchConceptsProgression-free survivalOverall survivalEGFR mutationsNon-small cell lung cancerCycle 3 day 1Median progression-free survivalMedian overall survivalRisk of progressionCell lung cancerPresence of brainEGFR-mutant NSCLCBaseline ctDNAM1b stageProgression-FreeRECIST responseSerial plasmaLiver metastasesDecreased riskEGFR-TKILung cancerComplete clearanceLong-term benefitsClinical trialsTreatment outcomesPlasma clearanceComprehensive molecular profiling of pancreatic ductal adenocarcinoma in FNA, biopsy, and resection specimens
Razzano D, Bouza SJ, Hernandez PV, Wang M, Robert ME, Walther Z, Cai G. Comprehensive molecular profiling of pancreatic ductal adenocarcinoma in FNA, biopsy, and resection specimens. Cancer Cytopathology 2022, 130: 726-734. PMID: 35511415, DOI: 10.1002/cncy.22589.Peer-Reviewed Original ResearchConceptsFine-needle aspirationFine-needle biopsyPancreatic ductal adenocarcinomaOncomine Comprehensive AssayResection specimensMolecular alterationsMolecular testingFNB samplesDuctal adenocarcinomaTherapeutic implicationsSuccess rateComprehensive molecular analysisComprehensive molecular testingComprehensive molecular profilingPotential therapeutic implicationsSimilar success ratesResection casesKRAS mutationsFNB specimensFNA materialFNA specimensAmplification analysisMolecular profilingFusion assessmentGene mutationsAn Appraisal of Immunohistochemical Stain Use in Hepatic Metastasis Highlights the Effectiveness of the Individualized, Case-Based Approach: Analysis of Data From a Tertiary Care Medical Center.
Wang JD, Sebastian C, Walther Z, Suresh T, Lacy J, Zhang X, Jain D. An Appraisal of Immunohistochemical Stain Use in Hepatic Metastasis Highlights the Effectiveness of the Individualized, Case-Based Approach: Analysis of Data From a Tertiary Care Medical Center. Archives Of Pathology & Laboratory Medicine 2022, 147: 185-192. PMID: 35512224, DOI: 10.5858/arpa.2021-0457-oa.Peer-Reviewed Original ResearchConceptsLiver biopsyUnknown primaryIHC markersPrimary siteTrue carcinomaTertiary care medical centerAvailable clinicopathologic dataSquamous cell carcinomaClinicopathologic dataHepatic metastasesNonepithelial tumorsCell carcinomaInstitutional databaseClinical managementStain usePractice patternsNeuroendocrine neoplasmsImmunohistochemical markersMedical CenterMorphologic patternsIndividualized approachCarcinomaBiopsyMetastasisTumorsYale Precision Medicine Tumor Board: reawakening the guardian of the genome
Grant MJ, Finberg KE, Walther Z, Stein SM, Lacy J, Eder JP, Goldberg SB. Yale Precision Medicine Tumor Board: reawakening the guardian of the genome. The Lancet Oncology 2022, 23: 337-338. PMID: 35240081, DOI: 10.1016/s1470-2045(22)00037-7.Peer-Reviewed Case Reports and Technical Notes
2021
Pathogenic BRCA2 germline variants in combined hepatocellular‐cholangiocarcinoma
Li H, Zhang X, Finberg KE, Walther Z, Jain D, Gibson J. Pathogenic BRCA2 germline variants in combined hepatocellular‐cholangiocarcinoma. Pathology International 2021, 72: 138-140. PMID: 34808016, DOI: 10.1111/pin.13188.Peer-Reviewed Case Reports and Technical NotesEpidermotropic metastasis of squamous cell carcinoma of the tonsil: A case report with molecular confirmation
Li P, Barbieri A, Walther Z, McNiff J, Panse G. Epidermotropic metastasis of squamous cell carcinoma of the tonsil: A case report with molecular confirmation. Journal Of Cutaneous Pathology 2021, 48: 1514-1519. PMID: 34302376, DOI: 10.1111/cup.14108.Peer-Reviewed Case Reports and Technical NotesConceptsSquamous cell carcinomaOropharyngeal squamous cell carcinomaCell carcinomaDe novo squamous cell carcinomaPrimary oropharyngeal squamous cell carcinomaTonsillar squamous cell carcinomaTargetable genetic aberrationsLesion biopsy specimensSkin biopsy specimenSkin lesion biopsy specimensMetastatic diseaseEpidermal involvementEpidermotropic metastasesMetastatic lesionsPoor prognosisBiopsy specimenCase reportClinical historyBiopsy specimensSecondary diseaseSkin lesionsTumor originMetastatic specimensMetastasisNeck skinYale Cancer Center Precision Medicine Tumor Board: molecular findings alter a diagnosis and treatment plan
Gibson JA, Finberg KE, Nalbantoglu I, Cecchini M, Ganzak A, Walther Z, Sklar JL, Eder JP, Goldberg SB. Yale Cancer Center Precision Medicine Tumor Board: molecular findings alter a diagnosis and treatment plan. The Lancet Oncology 2021, 22: 306-307. PMID: 33662283, DOI: 10.1016/s1470-2045(20)30683-5.Peer-Reviewed Case Reports and Technical Notes
2020
Yale Cancer Center Precision Medicine Tumor Board: new technology, new drugs, and the value of repeat testing
Hafez N, Walther Z, Eder JP, Sklar JL, Gettinger SN, Finberg KE, Goldberg SB. Yale Cancer Center Precision Medicine Tumor Board: new technology, new drugs, and the value of repeat testing. The Lancet Oncology 2020, 21: 343-344. PMID: 32950226, DOI: 10.1016/s1470-2045(20)30010-3.Peer-Reviewed Case Reports and Technical Notes
2019
The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma
Truini A, Starrett JH, Stewart T, Ashtekar K, Walther Z, Wurtz A, Lu D, Park JH, DeVeaux M, Song X, Gettinger S, Zelterman D, Lemmon MA, Goldberg SB, Politi K. The EGFR Exon 19 Mutant L747-A750>P Exhibits Distinct Sensitivity to Tyrosine Kinase Inhibitors in Lung Adenocarcinoma. Clinical Cancer Research 2019, 25: 6382-6391. PMID: 31182434, PMCID: PMC6825535, DOI: 10.1158/1078-0432.ccr-19-0780.Peer-Reviewed Original ResearchEndogenous development of Cystoisospora belli in intestinal and biliary epithelium of humans
Dubey JP, Evason KJ, Walther Z. Endogenous development of Cystoisospora belli in intestinal and biliary epithelium of humans. Parasitology 2019, 146: 865-872. PMID: 30859916, DOI: 10.1017/s003118201900012x.Peer-Reviewed Original ResearchConceptsBiliary epitheliumC. belliEpithelial cellsCystoisospora belliSingle parasitophorous vacuoleDuodenal biopsiesBiliary tractDepressed immunityPAS-positive granulesHistopathologic diagnosisHost epithelial cellsBiopsy samplesDigestive disordersSame PVParasitophorous vacuoleParasite multipliesCertain inclusionTransmission cycleEpitheliumCoccidian parasitesAsexual stagesBelliMerozoitesCellsOocystsUndifferentiated carcinoma with osteoclast-like giant cells of the pancreas arising from an intraductal papillary mucinous neoplasm
Charifa A, Walther Z, Salem R, Jain D. Undifferentiated carcinoma with osteoclast-like giant cells of the pancreas arising from an intraductal papillary mucinous neoplasm. Human Pathology Reports 2019, 15: 95-98. DOI: 10.1016/j.ehpc.2018.12.007.Peer-Reviewed Case Reports and Technical NotesOsteoclast-like giant cellsUndifferentiated carcinomaInvasive carcinomaGiant cellsMucinous neoplasmsEndoscopic ultrasoundIntraductal papillary mucinous neoplasmIntraductal mucinous neoplasmPapillary mucinous neoplasmRare pancreatic tumorPancreatic ductal carcinomaDuctal lesionsDuctal carcinomaPancreatic tumorsPancreatic adenocarcinomaCarcinoma subtypesHistological examinationPancreatic massCarcinomaEpithelial markersAmpullary massEpithelial originIPMNNeoplastic progressionNeoplasms
2018
Yale Cancer Center Precision Medicine Tumor Board: one tumour, multiple targets
Stewart T, Finberg K, Walther Z, Sklar JL, Hafez N, Eder JP, Anderson K, Wilson F, Goldberg SB. Yale Cancer Center Precision Medicine Tumor Board: one tumour, multiple targets. The Lancet Oncology 2018, 19: 1567-1568. PMID: 32956641, DOI: 10.1016/s1470-2045(18)30759-9.Peer-Reviewed Case Reports and Technical Notes