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PURPOSE: NCI-MATCH assigned patients with advanced cancer and progression on prior treatment, based on genomic alterations in pretreatment tumor tissue. Arm J (EAY131-J) evaluated the combination of trastuzumab/pertuzumab (HP) across HER2-amplified tumors. PATIENTS AND METHODS: Eligible patients had high levels of HER2 amplification [copy number (CN) ≥7] detected by central next-generation sequencing (NGS) or through NCI-designated laboratories. Patients with breast/gastroesophageal adenocarcinoma and those who received prior HER2-directed therapy were excluded. Enrollment of patients with colorectal cancer was capped at 4 based on emerging data. Patients received HP IV Q3 weeks until progression or unacceptable toxicity. Primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty-five patients were enrolled, with 25 included in the primary efficacy analysis (CN ≥7 confirmed by a central lab, median CN = 28). Median age was 66 (range, 31-80), and half of all patients had ≥3 prior therapies (range, 1-11). The confirmed ORR was 12% [3/25 partial responses (colorectal, cholangiocarcinoma, urothelial cancers), 90% confidence interval (CI) 3.4%-28.2%]. There was one additional partial response (urothelial cancer) in a patient with an unconfirmed ERBB2 copy number. Median PFS was 3.3 months (90% CI 2.0-4.1), and median OS 9.4 months (90% CI 5.0-18.9). Treatment-emergent adverse events were consistent with prior studies. There was no association between HER2 CN and response. CONCLUSIONS: HP was active in a selection of HER2-amplified tumors (non-breast/gastroesophageal) but did not meet the predefined efficacy benchmark. Additional strategies targeting HER2 and potential resistance pathways are warranted, especially in rare tumors.
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Neoplasias da Mama , Receptor ErbB-2 , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Intervalo Livre de Progressão , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Laparoscopic pancreaticoduodenectomy has been found safe and associated with advantages over open pancreaticoduodenectomy in prior studies. We compared outcomes of laparoscopic pancreaticoduodenectomy versus open pancreaticoduodenectomy at a single institution after applying technical aspects and perioperative care learned from laparoscopic pancreaticoduodenectomy to the open pancreaticoduodenectomy practice. METHODS: From January 2010 to December 2020, all patients undergoing pancreaticoduodenectomy were identified, and information was collected in a prospective fashion. Open pancreaticoduodenectomy (n = 347) and laparoscopic pancreaticoduodenectomy (n = 242) were performed using the same selection criteria, operative technique, and recovery protocols at a single institution. Propensity score matching was performed, and then perioperative data and 90-day outcomes were compared, and statistical analysis was performed. RESULTS: A total of 589 patients underwent pancreaticoduodenectomy, including open pancreaticoduodenectomy (n = 347) and laparoscopic pancreaticoduodenectomy (n = 242). After excluding those undergoing total pancreatectomy or major vascular or concomitant organ resection, there were 497 patients (open pancreaticoduodenectomy = 301 and laparoscopic pancreaticoduodenectomy = 196). Propensity score matching was performed, and 187 open pancreaticoduodenectomy patients were matched to 187 laparoscopic pancreaticoduodenectomy patients. Operative time (475 vs 280 minutes) was longer, and estimated blood loss (150 vs 212 mL) was less for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy, respectively. Pancreatic fistula (18.8% vs 5.4%) and delayed gastric emptying (18.8% vs 9.7%) were higher for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy, respectively. Postpancreatectomy hemorrhage, major morbidity, mortality, hospital stay, and readmissions were nonsignificantly higher for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy. Intensive care use and overall costs were significantly higher for laparoscopic pancreaticoduodenectomy than open pancreaticoduodenectomy. CONCLUSION: In our experience, open pancreaticoduodenectomy offers similar to improved outcomes over laparoscopic pancreaticoduodenectomy, with less use of perioperative resources, thereby offering better value to patients requiring pancreaticoduodenectomy.
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Laparoscopia , Neoplasias Pancreáticas , Humanos , Pancreaticoduodenectomia/efeitos adversos , Pancreaticoduodenectomia/métodos , Neoplasias Pancreáticas/cirurgia , Pontuação de Propensão , Pancreatectomia , Laparoscopia/efeitos adversos , Laparoscopia/métodos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Tempo de InternaçãoRESUMO
BACKGROUND: Neurocysticercosis (NCC) is a parasitic infection of the brain caused by ingesting water or food contaminated with tapeworm eggs. When it presents as a solitary mass, differentiation from a primary brain tumor on imaging can be difficult. Magnetic resonance imaging (MRI)-derived relative cerebral blood volume (rCBV) is a newer imaging technique used to identify areas of neovascularization in tumors, which may advance the differential diagnosis. OBSERVATIONS: A 25-year-old male presented after a seizure. Computed tomography (CT) and MRI demonstrated a partially enhancing lesion with microcalcifications and vasogenic edema. Follow-up rCBV assessment demonstrated mild hyperperfusion and/or small vessels at the lesional margins consistent with either an intermediate grade glioma or infection. Given the radiological equipoise, surgical accessibility, and differential diagnosis including primary neoplasm, metastatic disease, NCC, and abscess, resection was pursued. The calcified mass was excised en bloc and was confirmed as larval-stage NCC. LESSONS: CT or MRI may not always provide sufficient information to distinguish NCC from brain tumors. Although reports have suggested that rCBV may aid in identifying NCC, here the authors describe a case of pathologically confirmed NCC in which preoperative, qualitative, standardized rCBV findings raised concern for a primary neoplasm. This case documents the first standardized rCBV values reported in a pathologically confirmed case of NCC in the United States.
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BACKGROUND: The aim of this study is to report the feasibility and short-term outcomes of pancreaticoduodenectomy (PD) in patients who have undergone orthotopic liver transplantation (OLT). METHODS: We performed a retrospective review of a prospectively maintained pancreatic surgical database for all patients undergoing pancreaticoduodenectomy (PD) after liver transplant from January 1995 until June 2022. Demographics, indications for pancreatic resection, liver transplant and time from liver transplant to PD were reported. Operative mortality and morbidity were recorded within 90 days of surgery. Continuous variables were recorded as mean and range, while categorical variables were summarized using frequency and percentage. Postoperative complications within 90 days from PD were graded based on Clavien-Dindo classification with major complication recorded as grade IIIa or higher. Additionally, a comprehensive literature review was performed. RESULTS: A total of 916 patients who underwent PD at our institution between January 1995 and June 2022 were identified, and 9 patients had previous OLT. Five patients were females and 4 males with a mean age of 65 years (range 51-78). Average body mass index (BMI) was 30.8. Two patients had major complications, and three patients had minor complications. No clinically relevant POPF, PPH or DGE were observed. One patient died within 90 days from PD due to ischemic biliary pancreatic limb causing intrabdominal sepsis. CONCLUSION: Although uncommon, PD after OLT is feasible with acceptable outcomes at high volume institutions and if performed by experienced surgeons.
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Transplante de Fígado , Pancreaticoduodenectomia , Masculino , Feminino , Humanos , Pessoa de Meia-Idade , Idoso , Pancreaticoduodenectomia/efeitos adversos , Transplante de Fígado/efeitos adversos , Pancreatectomia/efeitos adversos , Pâncreas/cirurgia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/cirurgia , Estudos Retrospectivos , Fístula Pancreática/etiologiaRESUMO
BACKGROUND: Venous thromboembolism (VTE) is the most common cause of preventable mortality following colorectal surgery (CRS), occurring in about 2% of patients. As a result, prophylaxis including discharge chemoprophylaxis is recommended. While VTE risk assessment tools are available, the consistent adoption and utilization of these tools remains elusive. Our study objectives were to determine the utilization and impact of risk adjusted VTE prophylaxis in CRS patients. STUDY DESIGN: CRS cases performed between 1/1/2016 and 5/31/2021 were retrospectively analyzed. Caprini score and implemented VTE prophylaxis measures were determined. The primary outcome measure was receiving Caprini guideline indicated VTE prophylaxis. Secondary outcomes included VTE and bleeding. Categorical variables were compared by chi-square and Fisher's exact tests, and continuous variables by Kruskal-Wallis test. Logistic regression models were used to determine predictors of receiving appropriate VTE prophylaxis or experiencing postoperative VTE and bleeding. RESULTS: 10,422 CRS cases were analyzed and 90.6% were high risk for VTE. In-hospital appropriate prophylaxis rates in low, moderate, high, and very high-risk category patients were 91.2%, 56.1%, 61.0%, and 63.1%, respectively. Inpatient VTE was reduced by 75% in those receiving appropriate VTE prophylaxis. At discharge, 5.8% of patients received appropriate prophylaxis, in whom there were no VTE events at 30- and 90 days from discharge. Increasing Caprini score positively correlated with VTE risk in both the inpatient and discharge cohorts, but inversely correlated with the likelihood of receiving appropriate prophylaxis at discharge (OR .31, P <.0001). CONCLUSION: Caprini guideline indicated VTE prophylaxis in CRS patients reduced VTE events without increasing bleeding complications.
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Cirurgia Colorretal , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle , Estudos Retrospectivos , Anticoagulantes/uso terapêutico , Medição de Risco , Hemorragia/complicações , Fatores de Risco , Complicações Pós-Operatórias/prevenção & controle , Complicações Pós-Operatórias/tratamento farmacológicoRESUMO
AKT- a key molecular regulator of PI-3K signaling pathway, is somatically mutated in diverse solid cancer types, and aberrant AKT activation promotes altered cancer cell growth, survival, and metabolism1-8. The most common of AKT mutations (AKT1 E17K) sensitizes affected solid tumors to AKT inhibitor therapy7,8. However, the pathway dependence and inhibitor sensitivity of the long tail of potentially activating mutations in AKT is poorly understood, limiting our ability to act clinically in prospectively characterized cancer patients. Here we show, through population-scale driver mutation discovery combined with functional, biological, and therapeutic studies that some but not all missense mutations activate downstream AKT effector pathways in a growth factor-independent manner and sensitize tumor cells to diverse AKT inhibitors. A distinct class of small in-frame duplications paralogous across AKT isoforms induce structural changes different than those of activating missense mutations, leading to a greater degree of membrane affinity, AKT activation, and cell proliferation as well as pathway dependence and hyper-sensitivity to ATP-competitive, but not allosteric AKT inhibitors. Assessing these mutations clinically, we conducted a phase II clinical trial testing the AKT inhibitor capivasertib (AZD5363) in patients with solid tumors harboring AKT alterations (NCT03310541). Twelve patients were enrolled, out of which six harbored AKT1-3 non-E17K mutations. The median progression free survival (PFS) of capivasertib therapy was 84 days (95% CI 50-not reached) with an objective response rate of 25% (n = 3 of 12) and clinical benefit rate of 42% (n = 5 of 12). Collectively, our data indicate that the degree and mechanism of activation of oncogenic AKT mutants vary, thereby dictating allele-specific pharmacological sensitivities to AKT inhibition.
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Neoplasias , Proteínas Proto-Oncogênicas c-akt , Alelos , Humanos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia , Oncogenes , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismoRESUMO
OBJECTIVES: Optimal use of surgery first (SF) vs neoadjuvant therapy (NAT) for localized pancreatic ductal adenocarcinoma (PDAC) is still unclear. There is concern that NAT may result in worsened post-operative outcomes. Our study objectives were to show the impact of NAT on post-operative morbidity and mortality. METHODS: All patients undergoing resection for PDAC between 1/1/2010 and 12/31/2020 were reviewed and those who underwent pancreaticoduodenectomy (PD) were included. Demographics, perioperative details, and pathology details were gathered. Data pertaining to 90-day complications were obtained and graded according to international consensus guidelines. Those undergoing SF were compared to those who had NAT. Categorical variables were compared by Fisher's exact test and continuous variables by Student's t-test. RESULTS: Two hundred and forty-one subjects who underwent PD for PDAC were included in this review. There was no significant difference in the rate of major morbidity between subjects who received NAT vs SF (19.4 vs 20.3%, P = 1.0). Similarly, there were no significant differences in the rates of mortality (3.1 vs 4.2%, P = .742), post-operative pancreatic fistula (8.2 vs 10.5%, P = .658), or post-pancreatectomy hemorrhage (7.1 vs 7.7%, P = 1.0), respectively. CONCLUSION: Post-operative outcomes are not worsened by the use of the NAT approach prior to PD for PDAC. Further investigation is needed to reveal which patient subgroups may benefit from the use of NAT, especially regarding survival.
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Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Adenocarcinoma/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Humanos , Terapia Neoadjuvante/efeitos adversos , Pancreatectomia/efeitos adversos , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia/efeitos adversos , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Neoplasias PancreáticasRESUMO
The efficacy of the highly selective RET inhibitor selpercatinib is now established in RET-driven cancers, and we sought to characterize the molecular determinants of response and resistance. We find that the pre-treatment genomic landscape does not shape the variability of treatment response except for rare instances of RAS-mediated primary resistance. By contrast, acquired selpercatinib resistance is driven by MAPK pathway reactivation by one of two distinct routes. In some patients, on- and off-target pathway reactivation via secondary RET solvent front mutations or MET amplifications are evident. In other patients, rare RET-wildtype tumor cell populations driven by an alternative mitogenic driver are selected for by treatment. Multiple distinct mechanisms are often observed in the same patient, suggesting polyclonal resistance may be common. Consequently, sequential RET-directed therapy may require combination treatment with inhibitors targeting alternative MAPK effectors, emphasizing the need for prospective characterization of selpercatinib-treated tumors at the time of monotherapy progression.
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Neoplasias Pulmonares , Neoplasias da Glândula Tireoide , Humanos , Pulmão , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-ret/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genéticaRESUMO
BACKGROUND: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).
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Tirosina Quinase da Agamaglobulinemia , Resistencia a Medicamentos Antineoplásicos , Leucemia Linfocítica Crônica de Células B , Mutação , Fosfolipase C gama , Inibidores de Proteínas Quinases , Humanos , Pessoa de Meia-Idade , Adenina/análogos & derivados , Adenina/farmacologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Tirosina Quinase da Agamaglobulinemia/genética , Tirosina Quinase da Agamaglobulinemia/ultraestrutura , Resistencia a Medicamentos Antineoplásicos/genética , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Fosfolipase C gama/genética , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptores de Antígenos de Linfócitos B/metabolismo , Análise de Sequência de RNA , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: We wanted to determine the prognosis and the phenotypic characteristics of hormone receptor-positive advanced breast cancer tumors harboring an ERBB2 mutation in the absence of a HER2 amplification. EXPERIMENTAL DESIGN: We retrospectively collected information from the American Association of Cancer Research-Genomics Evidence Neoplasia Information Exchange registry database from patients with hormone receptor-positive, HER2-negative, ERBB2-mutated advanced breast cancer. Phenotypic and co-mutational features, as well as response to treatment and outcome were compared with matched control cases ERBB2 wild type. RESULTS: A total of 45 ERBB2-mutant cases were identified for 90 matched controls. The presence of an ERBB2 mutation was not associated with worse outcome determined by overall survival (OS) from first metastatic relapse. No significant differences were observed in phenotypic characteristics apart from higher lobular infiltrating subtype in the ERBB2-mutated group. ERBB2 mutation did not seem to have an impact in response to treatment or time-to-progression (TTP) to endocrine therapy compared with ERBB2 wild type. In the co-mutational analyses, CDH1 mutation was more frequent in the ERBB2-mutated group (FDR < 1). Although not significant, fewer co-occurring ESR1 mutations and more KRAS mutations were identified in the ERBB2-mutated group. CONCLUSIONS: ERBB2-activating mutation was not associated with a worse OS from time of first metastatic relapse, or differences in TTP on treatment as compared with a series of matched controls. Although not significant, differences in coexisting mutations (CDH1, ESR1, and KRAS) were noted between the ERBB2-mutated and the control group.
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Neoplasias da Mama , Carcinoma Lobular , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Lobular/patologia , Estudos de Casos e Controles , Feminino , Humanos , Mutação , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Recidiva , Estudos RetrospectivosRESUMO
Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.
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Mutação em Linhagem Germinativa , Neoplasias/genética , Carcinogênese/genética , Variações do Número de Cópias de DNA , Reparo de Erro de Pareamento de DNA/genética , Predisposição Genética para Doença , Heterozigoto , Humanos , FenótipoAssuntos
Adenina/análogos & derivados , Antineoplásicos , Patentes como Assunto , Dano ao Paciente , Piperidinas , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Humanos , Leucemia/tratamento farmacológico , Linfoma/tratamento farmacológico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/uso terapêuticoRESUMO
PURPOSE: Cell-free DNA (cfDNA) analysis offers a noninvasive means to access the tumor genome. Despite limited sensitivity of broad-panel sequencing for detecting low-frequency mutations in cfDNA, it may enable more comprehensive genomic characterization in patients with sufficiently high disease burden. We investigated the utility of large-panel cfDNA sequencing in patients enrolled to a Phase I AKT1-mutant solid tumor basket study. METHODS: Patients had AKT1 E17K-mutant solid tumors and were treated on the multicenter basket study (ClinicalTrials.gov identifier: NCT01226316) of capivasertib, an AKT inhibitor. Serial plasma samples were prospectively collected and sequenced using exon-capture next-generation sequencing (NGS) analysis of 410 genes (Memorial Sloan Kettering [MSK]-Integrated Molecular Profiling of Actionable Cancer Target [IMPACT]) and allele-specific droplet digital polymerase chain reaction (ddPCR) for AKT1 E17K. Tumor DNA (tDNA) NGS (MSK-IMPACT) was also performed on available pretreatment tissue biopsy specimens. RESULTS: Among 25 patients, pretreatment plasma samples were sequenced to an average coverage of 504×. Somatic mutations were called in 20/25 (80%), with mutant allele fractions highly concordant with ddPCR of AKT1 E17K (r 2 = 0.976). Among 17 of 20 cfDNA-positive patients with available tDNA for comparison, mutational concordance was acceptable, with 82% of recurrent mutations shared between tissue and plasma. cfDNA NGS captured additional tumor heterogeneity, identifying mutations not observed in tDNA in 38% of patients, and revealed oncogenic mutations in patients without available baseline tDNA. Longitudinal cfDNA NGS (n = 98 samples) revealed distinct patterns of clonal dynamics in response to therapy. CONCLUSION: Large gene panel cfDNA NGS is feasible for patients with high disease burden and is concordant with single-analyte approaches, providing a robust alternative to ddPCR with greater breadth. cfDNA NGS can identify heterogeneity and potentially biologically informative and clinically relevant alterations.
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DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Mutação , Neoplasias/genética , Genoma , Humanos , Estudos ProspectivosRESUMO
Neurotrophic tyrosine receptor kinase (NTRK) gene fusions lead to chimeric tropomyosin receptor kinase (TRK) fusion proteins, which act as primary oncogenic drivers in diverse tumor types in adults and children. Larotrectinib, a highly selective and central nervous system-active TRK inhibitor, has shown high objective response rates, durable disease control, and a favorable safety profile in patients with TRK fusion cancer. The impact of larotrectinib on health-related quality of life (HRQoL) was evaluated in adult and pediatric patients in two phase I/II clinical trials (NAVIGATE; NCT02576431 and SCOUT; NCT02637687). Patients completed HRQoL questionnaires (EORTC QLQ-C30, EQ-5D-5L, and PedsQL) at baseline and at planned treatment cycle visits. Changes in questionnaire scores were evaluated over time, and by tumor type and treatment response. Questionnaires from 40 adult and 17 pediatric (2-19 years of age) patients receiving larotrectinib were completed at baseline and at least one post-baseline timepoint. Meaningful within-patient HRQoL improvements occurred at one or more timepoints in 60% of adults and 76% of pediatric patients. Sustained improvements in EORTC QLQ-C30 and PedsQL scores were rapid, occurring within 2 months of treatment initiation in 68% and 71% of patients, respectively. Improvements were observed regardless of tumor type and appeared to correlate with clinical efficacy. The rapid within-patient HRQoL improvements in adult and pediatric patients with TRK fusion cancer are consistent with the clinical profile of larotrectinib. Our results provide valuable information for use of this agent in this patient population. A plain language summary of this article is available in the supplementary appendix.
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Neoplasias/tratamento farmacológico , Neoplasias/psicologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Neoplasias/genética , Inibidores de Proteínas Quinases , Proteínas Quinases/genética , Receptor trkA/genética , Inquéritos e Questionários , Resultado do Tratamento , Tropomiosina/genética , Adulto JovemRESUMO
Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.
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PURPOSE: This was a multicenter, histology-agnostic, single-arm prospective phase II trial of therapeutic activity of everolimus, an oral mTORC1 inhibitor, in patients with advanced solid tumors that harbored TSC1/TSC2 or MTOR mutations. PATIENTS AND METHODS: Patients with tumors with inactivating TSC1/TSC2 or activating MTOR mutations identified in any Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory were eligible. Patients were treated with everolimus 10 mg once daily until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). Whole-exome sequencing was performed to identify co-occurring genomic alterations. RESULTS: Between November 2015 and October 2018, 30 patients were enrolled at Dana-Farber Cancer Institute and Memorial Sloan Kettering Cancer Center. Tumors harbored TSC1 (13/30), TSC2 (15/30), concurrent TSC1 and TSC2 (1/30), or MTOR (1/30) mutations. The most common treatment-related adverse event of any grade was mucositis (8/30, 27%); 1 patient had fatal pneumonitis. Partial responses were seen in 2 patients [7%; 95% confidence interval (CI), 1%-22%]. Median progression-free survival was 2.3 months (95% CI, 1.8-3.7 months) and median overall survival (OS) was 7.3 months (95% CI, 4.5-12.7 months). There was no clear association between other genomic alterations and response. Of the 2 patients with objective response, 1 had upper tract urothelial carcinoma with biallelic inactivation of TSC1 and high tumor mutation burden, and the other had uterine carcinoma with biallelic TSC2-inactivating mutations and PEComa-like pathologic features. CONCLUSIONS: Everolimus therapy had a disappointing ORR (7%) in this pan-cancer, mutation-selected, basket study.See related commentary by Kato and Cohen, p. 3807.
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Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/genética , Serina-Treonina Quinases TOR/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
PURPOSE: Cancer classification is foundational for patient care and oncology research. Systems such as International Classification of Diseases for Oncology (ICD-O), Systematized Nomenclature of Medicine Clinical Terms (SNOMED-CT), and National Cancer Institute Thesaurus (NCIt) provide large sets of cancer classification terminologies but they lack a dynamic modernized cancer classification platform that addresses the fast-evolving needs in clinical reporting of genomic sequencing results and associated oncology research. METHODS: To meet these needs, we have developed OncoTree, an open-source cancer classification system. It is maintained by a cross-institutional committee of oncologists, pathologists, scientists, and engineers, accessible via an open-source Web user interface and an application programming interface. RESULTS: OncoTree currently includes 868 tumor types across 32 organ sites. OncoTree has been adopted as the tumor classification system for American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE), a large genomic and clinical data-sharing consortium, and for clinical molecular testing efforts at Memorial Sloan Kettering Cancer Center and Dana-Farber Cancer Institute. It is also used by precision oncology tools such as OncoKB and cBioPortal for Cancer Genomics. CONCLUSION: OncoTree is a dynamic and flexible community-driven cancer classification platform encompassing rare and common cancers that provides clinically relevant and appropriately granular cancer classification for clinical decision support systems and oncology research.
Assuntos
Neoplasias , Genômica , Humanos , Oncologia , National Cancer Institute (U.S.) , Neoplasias/diagnóstico , Neoplasias/genética , Neoplasias/terapia , Medicina de Precisão , Estados UnidosRESUMO
PURPOSE: Somatic mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), which encodes the p110α catalytic subunit of PI3K, are found in multiple human cancers. While recurrent mutations in PIK3CA helical, regulatory, and kinase domains lead to constitutive PI3K pathway activation, other mutations remain uncharacterized. To further evaluate their clinical actionability, we designed a basket study for patients with PIK3CA-mutant cancers with the isoform-specific PI3K inhibitor taselisib. PATIENTS AND METHODS: Patients were enrolled on the basis of local PIK3CA mutation testing into one of 11 histology-specific cohorts and treated with taselisib at 6 or 4 mg daily until progression. Tumor DNA from baseline and progression (when available) was sequenced using a next-generation sequencing panel. Exploratory analyses correlating genomic alterations with treatment outcomes were performed. RESULTS: A total of 166 patients with PIK3CA-mutant cancers were enrolled. The confirmed response rate was 9%. Activity varied by tumor type and mutant allele, with confirmed responses observed in head and neck squamous (15.4%), cervical (10%), and other cancers, plus in tumors containing helical domain mutations. Genomic analyses identified mutations potentially associated with resistance to PI3K inhibition upfront (TP53 and PTEN) and postprogression through reactivation of the PI3K pathway (PTEN, STK11, and PIK3R1). Higher rates of dose modification occurred at higher doses of taselisib, indicating a narrow therapeutic index. CONCLUSIONS: Taselisib had limited activity in the tumor types tested and is no longer in development. This genome-driven study improves understanding of the activity, limitations, and resistance mechanisms of using PI3K inhibitors as monotherapy to target PIK3CA-mutant tumors.