RESUMO
Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias Encefálicas , Neoplasias da Mama , Glioblastoma , Imunoconjugados , Recidiva Local de Neoplasia , Humanos , Feminino , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Adulto , Idoso , Imunoconjugados/uso terapêutico , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Estudos Prospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Antígenos de Neoplasias/metabolismo , Moléculas de Adesão Celular/metabolismoRESUMO
Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1,383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32 - 1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70 - 6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83 - 12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63 - 3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20 - 2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66 - 3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89 - 22.6]). Hispanic ethnicity, timing and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to Non-Hispanic White patients.
RESUMO
Background: Limited information is available for patients with breast cancer (BC) and coronavirus disease 2019 (COVID-19), especially among underrepresented racial/ethnic populations. Methods: This is a COVID-19 and Cancer Consortium (CCC19) registry-based retrospective cohort study of females with active or history of BC and laboratory-confirmed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection diagnosed between March 2020 and June 2021 in the US. Primary outcome was COVID-19 severity measured on a five-level ordinal scale, including none of the following complications, hospitalization, intensive care unit admission, mechanical ventilation, and all-cause mortality. Multivariable ordinal logistic regression model identified characteristics associated with COVID-19 severity. Results: 1383 female patient records with BC and COVID-19 were included in the analysis, the median age was 61 years, and median follow-up was 90 days. Multivariable analysis revealed higher odds of COVID-19 severity for older age (aOR per decade, 1.48 [95% CI, 1.32-1.67]); Black patients (aOR 1.74; 95 CI 1.24-2.45), Asian Americans and Pacific Islander patients (aOR 3.40; 95 CI 1.70-6.79) and Other (aOR 2.97; 95 CI 1.71-5.17) racial/ethnic groups; worse ECOG performance status (ECOG PS ≥2: aOR, 7.78 [95% CI, 4.83-12.5]); pre-existing cardiovascular (aOR, 2.26 [95% CI, 1.63-3.15])/pulmonary comorbidities (aOR, 1.65 [95% CI, 1.20-2.29]); diabetes mellitus (aOR, 2.25 [95% CI, 1.66-3.04]); and active and progressing cancer (aOR, 12.5 [95% CI, 6.89-22.6]). Hispanic ethnicity, timing, and type of anti-cancer therapy modalities were not significantly associated with worse COVID-19 outcomes. The total all-cause mortality and hospitalization rate for the entire cohort was 9% and 37%, respectively however, it varied according to the BC disease status. Conclusions: Using one of the largest registries on cancer and COVID-19, we identified patient and BC-related factors associated with worse COVID-19 outcomes. After adjusting for baseline characteristics, underrepresented racial/ethnic patients experienced worse outcomes compared to non-Hispanic White patients. Funding: This study was partly supported by National Cancer Institute grant number P30 CA068485 to Tianyi Sun, Sanjay Mishra, Benjamin French, Jeremy L Warner; P30-CA046592 to Christopher R Friese; P30 CA023100 for Rana R McKay; P30-CA054174 for Pankil K Shah and Dimpy P Shah; KL2 TR002646 for Pankil Shah and the American Cancer Society and Hope Foundation for Cancer Research (MRSG-16-152-01-CCE) and P30-CA054174 for Dimpy P Shah. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH). The funding sources had no role in the writing of the manuscript or the decision to submit it for publication. Clinical trial number: CCC19 registry is registered on ClinicalTrials.gov, NCT04354701.
Assuntos
Neoplasias da Mama , COVID-19 , Estados Unidos/epidemiologia , Humanos , Feminino , Pessoa de Meia-Idade , SARS-CoV-2 , Estudos de Coortes , Neoplasias da Mama/epidemiologia , Estudos RetrospectivosRESUMO
BACKGROUND: Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Frequent long-range chromatin interactions between transcription factors (TFs) and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Although studies have proposed models to explain the initiation of chromothripsis, few discussed how TFs influence this process for tumor progression. METHODS: This study focused on genomic alterations in amplification associated regions within chromosome 17. Inter-/intra-chromosomal rearrangements were analyzed using whole genome sequencing data of breast tumors in the Cancer Genome Atlas (TCGA) cohort. Common ERα binding sites were defined based on MCF-7, T47D, and MDA-MB-134 breast cancer cell lines using univariate K-means clustering methods. Nanopore sequencing technology was applied to validate frequent rearrangements detected between ATC loci on 17q23 and an ERα hub on 20q13. The efficacy of pharmacological inhibition of a potentially druggable target gene on 17q23 was evaluated using breast cancer cell lines and patient-derived circulating breast tumor cells. RESULTS: There are five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the locations of the rearrangements were often mapped within or close to dense ERα binding sites localized on these five 17q regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ERα hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. CONCLUSION: This study demonstrates a new approach for identifying tumorigenic drivers from genomic regions highly susceptible to ERα-related chromothripsis. We found a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.
Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Cromossomos Humanos Par 17/genética , Cromotripsia , Receptor alfa de Estrogênio/metabolismo , Regulação Neoplásica da Expressão Gênica , Biomarcadores Tumorais/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Proliferação de Células , Receptor alfa de Estrogênio/genética , Feminino , Humanos , Prognóstico , Taxa de Sobrevida , Transcrição Gênica , Células Tumorais Cultivadas , Sequenciamento do Exoma , Sequenciamento Completo do GenomaRESUMO
BACKGROUND: The Next Accreditation System (NAS) increases the focus on educational outcomes and meaningful evaluation of learners. This requires that key clinical faculty develop new assessment formats such as entrustable professional activities (EPAs). OBJECTIVES: To build and develop milestone-based assessment tools supporting 5 EPAs for a hematology/oncology fellow continuity clinic, and to educate key clinical faculty regarding the Clinical Competency Committee (CCC) and the NAS. METHODS: Program directors from 2 hematology/oncology fellowship programs developed 5 EPAs for continuity clinic evaluation supported by milestone-based assessment. The program directors met to create a unified CCC charter. Key clinical faculty helped to develop a milestone-based evaluation of fellow continuity clinic through creation of 5 hematology/oncology-specific EPAs. Formal entrustment regarding EPAs was deliberated by the CCC. RESULTS: A total of 18 fellows were evaluated. Clinical Competency Committee deliberation at each institution took approximately 10 minutes per fellow for discussion and decision regarding entrustment for all 5 EPAs supporting continuity clinic. One-third of postgraduate year (PGY)-4s, 50% of PGY-5s, and 100% of PGY-6s were deemed competent in all 5 EPAs by the CCC. CONCLUSIONS: All hematology/oncology trainees in San Antonio were evaluated using milestone-based assessment for continuity clinic, and entrustment decisions regarding 5 EPAs were made by the CCC. This project may provide other programs with a sound basis for adoption and further development of the next generation of evaluation tools at their institutions. Entrustable professional activities that are rotation specific should be used as a starting point for linking to the competencies, subcompetencies, and the reporting milestones.
Assuntos
Competência Clínica/normas , Educação Baseada em Competências/métodos , Educação de Pós-Graduação em Medicina/normas , Avaliação Educacional/métodos , Hematologia/educação , Oncologia/educação , Acreditação/normas , Humanos , Internato e Residência , Desenvolvimento de Programas , Avaliação de Programas e Projetos de Saúde , Texas , Estados UnidosRESUMO
PURPOSE: Recent studies from large nationwide cancer databases have consistently shown that Hispanic women with breast cancer have delays in treatment initiation compared with non-Hispanic white women. However, time to treatment initiation has not been studied in a community where Hispanics are the majority. PATIENTS AND METHODS: We conducted a retrospective, observational study of 362 female patients with breast cancer treated at a large National Cancer Institute (NCI) -designated cancer center with a largely Hispanic population. We examined the relationship between race/ethnicity and time from mammogram to biopsy as well as time from biopsy to treatment initiation using Kaplan-Meier analyses and multivariable Cox proportional hazards regression. RESULTS: Half of the female patients with breast cancer were of Hispanic descent (50.0%; n = 181). Hispanic patients were more likely to be obese, have an Eastern Cooperative Oncology Group functional status ≥ 1, and have higher histologic grade disease (all P ≤ .05); no differences in American Joint Committee on Cancer stage at diagnosis were observed. After comprehensive adjustment for demographic and clinical characteristics, we found no significant differences between Hispanic versus non-Hispanic white patients in time from mammogram to biopsy (hazard ratio [HR], 0.91; 95% CI, 0.68 to 1.21) or time from biopsy to treatment (HR, 1.13; 95% CI, 0.69 to 1.88). CONCLUSION: Hispanic women and Non-Hispanic white women with breast cancer treated at an NCI-designated cancer center had similar times to biopsy and treatment initiation. These findings suggest that in majority minority communities with large cancer centers, racial disparities can be reduced. With a growing Hispanic population throughout the United States, future studies should examine the long-term impact on improved breast cancer survival in this population.