The University of Texas MD Anderson Cancer Center (colloquially MD Anderson Cancer Center) is a comprehensive cancer center in Houston, Texas. It is the largest cancer center in the U.S. and one of the original three comprehensive cancer centers in the country. It is both a degree-granting academic institution and a cancer treatment and research center located at the Texas Medical Center in Houston. It is affiliated with The University of Texas Health Science Center at Houston. According to Newsweek, MD Anderson Cancer Center is considered the best hospital in the world for oncology and related cancer treatment.S.
Alterations in chromatin remodeling genes have been increasingly implicated in human oncogenesis. Specifically, the biallelic inactivation of the SWI/SNF subunit SMARCB1 results in the emergence of extremely aggressive pediatric malignancies. Here, we developed embryonic mosaic mouse models of malignant rhabdoid tumors (MRTs) that faithfully recapitulate the clinical-pathological features of the human disease. We demonstrated that SMARCB1-deficient malignancies exhibit dramatic activation of the unfolded protein response (UPR) and ER stress response via a genetically intact MYC-p19ARF-p53 axis. As a consequence, these tumors display an exquisite sensitivity to agents inducing proteotoxic stress and inhibition of the autophagic machinery. In conclusion, our findings provide a rationale for drug repositioning trials investigating combinations of agents targeting the UPR and autophagy in SMARCB1-deficient MRTs.
Measurable residual disease (MRD) monitoring has become a critical component in the management of acute myeloid leukemia (AML), to inform prognosis, guide therapy, and serve as a key endpoint in clinical trials. The 2025 update of the MRD guideline provides a comprehensive and refined framework for MRD assessment, aligned with the ELN 2022 genetic risk classification. Developed by members of the ELN-DAVID consortium, the guidelines incorporate expert consensus determined through a two-stage Delphi round. They address the clinical implementation of MRD methodologies, technical considerations, integration into clinical trials, and future directions. Importantly, MRD recommendations are tailored to individual prognostic and genetic subgroups. A new qualitative MRD response category, designated as optimal, warning, or high risk of treatment failure, has been introduced to facilitate contextual interpretation of the MRD burden and its clinical relevance. Notably, ultrahigh-sensitivity (UHS) NGS-based MRD assessment is now recommended for FLT3-ITD-mutated AML following intensive chemotherapy and prior to allogeneic hematopoietic cell transplantation. A total of 56 recommendations were formulated, with 53 achieving a high level of consensus (≥90%). These updated guidelines represent a major step forward toward harmonizing MRD assessments in AML and enhancing its clinical utility across diverse treatment settings.
BACKGROUND:Triple-negative breast cancer is an aggressive breast cancer subtype, and there remains an unmet need to improve outcomes in patients with previously untreated, programmed death ligand 1 (PD-L1)-positive, locally advanced unresectable or metastatic triple-negative breast cancer. METHODS:In this phase 3, open-label, international trial, we randomly assigned patients in a 1:1 ratio to receive sacituzumab govitecan plus pembrolizumab or chemotherapy plus pembrolizumab. The primary end point was progression-free survival as assessed by blinded independent central review. Secondary end points included overall survival, objective response (complete or partial response) and duration of response as assessed by blinded independent central review, and safety. RESULTS:A total of 443 patients were randomly assigned to receive sacituzumab govitecan plus pembrolizumab (221 patients) or chemotherapy plus pembrolizumab (222 patients). The median progression-free survival was 11.2 months (95% confidence interval [CI], 9.3 to 16.7) with sacituzumab govitecan plus pembrolizumab and 7.8 months (95% CI, 7.3 to 9.3) with chemotherapy plus pembrolizumab (hazard ratio for disease progression or death, 0.65; 95% CI, 0.51 to 0.84; two-sided P<0.001). Data for overall survival were immature. The percentage of patients with an objective response was 60% (95% CI, 53 to 66) with sacituzumab govitecan plus pembrolizumab and 53% (95% CI, 46 to 60) with chemotherapy plus pembrolizumab; among patients with a response, the median duration of response was 16.5 months (95% CI, 12.7 to 19.5) and 9.2 months (95% CI, 7.6 to 11.3), respectively. Adverse events of grade 3 or higher occurred in 71% of the patients receiving sacituzumab govitecan plus pembrolizumab and in 70% of those receiving chemotherapy plus pembrolizumab; the incidence of treatment discontinuation due to adverse events was 12% and 31%, respectively. Adverse events leading to death occurred in 3% of the patients in each group. CONCLUSIONS:Sacituzumab govitecan plus pembrolizumab led to significantly longer progression-free survival than chemotherapy plus pembrolizumab among patients with previously untreated, PD-L1-positive, advanced triple-negative breast cancer. (Funded by Gilead Sciences; ASCENT-04/KEYNOTE-D19 ClinicalTrials.gov number, NCT05382286.).
ABSTRACT:Pirtobrutinib, a noncovalent, reversible Bruton tyrosine kinase inhibitor (BTKi), demonstrated efficacy in patients with chronic lymphocytic leukemia (CLL), resistant to covalent BTKi (cBTKi). We analyzed genomic correlations with response and resistance to pirtobrutinib in relapsed/refractory (R/R) patients with CLL pretreated with cBTKi enrolled in the phase 1/2 BRUIN trial. DNA sequencing was performed on peripheral blood mononuclear cells at baseline, on treatment, and at progressive disease (PD). Common alterations at baseline included mutations in BTK (43%), TP53 (38%), SF3B1 (25%), NOTCH1 (23%), ATM (19%), XPO1 (11%), PLCG2 (9%), BCL2 (8%), and 17p deletion (28%). Common baseline BTK mutations included C481S (85%), C481R (10%), C481F (6%), and C481Y (4%). At PD, 60 of 88 patients (68%) acquired ≥1 mutation, including 44% with acquired BTK mutations and 24% with other acquired mutations. A total of 55 acquired BTK mutations were detected in 39 patients, including gatekeeper mutations (T474I/F/S/Y/L, 26%), kinase-impaired L528W (16%), C481S/R/Y (5%), V416L (2%), and A428D (1%) and others proximal to the adenosine triphosphate-binding pocket, D539A/G/H (1%) and Y545N (1%). Decrease or complete clearance of BTK C481x was observed at PD in 36 of 43 patients (84%). Using a more sensitive assay, 37% (18/49) of acquired BTK mutations were detected at baseline at low allele frequency. Using a highly sensitive assay at progression, a similar frequency of acquired BTK mutations (39%) was detected, and all patients had detectable acquired mutations. This study highlights the complex clonal dynamics of BTK mutations in patients with R/R CLL undergoing pirtobrutinib treatment, and the extent of resistance without an obvious genomic driver. Trial registration: #NCT03740529 at www.ClinicalTrials.gov.
Cancer interception is a preventative approach aiming to reduce cancer incidence by targeting precancers and early-stage cancers. Lynch syndrome (LS) is a prevalent hereditary cancer syndrome affecting 1 in 300 individuals, with an overall lifetime cancer risk as high as 80 NCT05078866 ). In a phase 1b/2 trial, an off-the-shelf vaccine using gorilla adenoviral and modified vaccinia Ankara vectors with over 200 mutated peptides known to be present in persons with mismatch-repair-deficient tumors is safe and elicits neoantigen-specific T cells in individuals with Lynch syndrome.
