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We discuss a recent manuscript providing recommendations to improve use and access for liquid biopsy in oncology. [ABSTRACT FROM AUTHOR]

We discuss a recent manuscript providing recommendations to improve use and access for liquid biopsy in oncology. [ABSTRACT FROM AUTHOR]

Secretory carcinoma is a rare breast tumor driven by ETV6::NTRK3 fusion. It has characteristic morphologic features and identification of these tumors is critical as these patients may benefit from TRK inhibitors. Morphologic shift upon treatment has not been reported in secretory carcinoma or other NTRK-driven tumors. Herein we describe a patient with secretory carcinoma showing transdifferentiation into metaplastic carcinoma (spindle cell and squamous cell carcinoma) at the metastatic site following treatment. Identification of these morphologic shifts is crucial for accurate classification and identification of potential resistant mechanisms. [ABSTRACT FROM AUTHOR]

A case study of a 76-Year-Old Woman with Nausea, Diarrhea, and Acute Kidney Failure is presented. Topics include the patient was admitted to this hospital with respiratory failure due to an exacerbation of heart failure and pneumonia; and treated with intravenous ceftriaxone and oral doxycycline for 5 days, and diuretic agents were adjusted during a 3-week hospitalization.

Triple-negative breast cancer (TNBC) is a heterogeneous disease that is historically difficult to treat, but advances in molecular targeted therapies, including the use of antibodies, are changing the standard of care. Translational research over the years has revealed various actionable targets allowing TNBC to be subtyped in novel ways. In this article, we review the molecular targets that guide current management of patients with metastatic TNBC (mTNBC), including programmed death-ligand 1, germline BRCA1 and BRCA2 mutations, and the transmembrane glycoprotein Trop-2. These targets allow for the treatment of mTNBC with immunotherapy, poly(ADP-ribose)polymerase inhibitors, and antibody-drug conjugates (ADC), such as sacituzumab govitecan, the first ADC approved for the treatment of breast cancer. We also review upcoming therapies, such as datopotamab deruxtecan and trastuzumab deruxtecan. Although mTNBC is complex in nature, molecular studies are making treatments more personalized by identifying actionable targets in what was once thought to be a nontargetable disease. [ABSTRACT FROM AUTHOR]

PURPOSE: As the continuation beyond progression (BP) of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) is becoming increasingly attractive for the treatment of patients with hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative metastatic breast cancer (MBC), the definition of resistance factors is crucial. The aim of the study was to investigate the impact of CDK 4/6i BP and to explore potential genomic stratification factors. MATERIALS AND METHODS: We retrospectively analyzed a multi-institutional cohort of patients with HR-positive HER2-negative MBC characterized for circulating tumor DNA through next-generation sequencing before treatment start. Differences across subgroups were analyzed by chi-square test, and survival was tested by univariable and multivariable Cox regression. Further correction was applied by propensity score matching. RESULTS: Among the 214 patients previously exposed to CDK4/6i, 172 were treated with non–CDK4/6i-based treatment (non-CDK) and 42 with CDK4/6i BP. Multivariable analysis showed a significant impact of CDK4/6i BP, TP53 single-nucleotide variants, liver involvement, and treatment line on both progression-free survival (PFS) and overall survival (OS). Propensity score matching confirmed the prognostic role of CDK4/6i BP both for PFS and OS. The favorable impact of CDK4/6i BP was consistent across all subgroups, and a differential benefit was suggested for ESR1 -mutated patients. ESR1 and RB1 mutations were more represented in the CDK4/6i BP subgroup with respect to CDK4/6i upfront. CONCLUSION: The study highlighted a significant prognostic impact of the CDK4/6i BP strategy with a potential added benefit in patients with ESR1 mutations suggesting the need for an extensive biomarker characterization. A significant impact for CDK4/6i BP was highlighted, especially in patients with ESR1 mutations. [ABSTRACT FROM AUTHOR]

The study explored endocrine resistance by leveraging machine learning to establish the prognostic stratification of predicted Circulating tumor cells (CTCs), assessing its integration with circulating tumor DNA (ctDNA) features and contextually evaluate the potential of CTCs-based transcriptomics. 1118 patients with a diagnosis of luminal-like Metastatic Breast Cancer (MBC) were characterized for ctDNA through NGS before treatment start, predicted CTCs were computed through a K nearest neighbor algorithm. Differences across subgroups were analyzed through chi square or Fisher's exact test according to sample size and corrected for False Discovery Rate. Differences in survival were tested by log-rank test and uni- and multivariable Cox regression. CTCs transcriptomics was performed through RNAseq after sorting with DEPArray NxT. Univariable and multivariable analysis adjusted for ctDNA alterations revealed a significant impact of CTCs predictive stratification on both progression-free survival (PFS) and overall survival (OS). Alterations in RTK and ER pathways were significantly correlated with predicted-Stage IV aggressive. The combined impact of CTCs stratification and RTK/ER pathway alterations influenced patient outcomes, with predicted-Stage IV aggressive having a negative impact on PFS regardless of the mutational status. The pilot exploratory CTCs transcriptomics analysis showed transcriptional changes linked to cell proliferation such as under expression of MALAT1 and overexpression of GREM1 , GPR85 and OCM. Our data underline the potential of an integration between ctDNA and CTCs, both through quantification and transcriptomic analysis, for a deeper understanding of tumor biology and treatment response in HR-positive, HER2-negative MBC. • Machine learning-based CTCs prediction (pCTCs) significantly impacted on PFS and OS. • Combined pCTCs and ctDNA RTK/ER alterations impacted on endocrine therapy PFS. • CTCs transcriptomics was feasible and showed alterations in MALAT1, GREM1, GPR85. • Integration of ctDNA and CTCs enhances understanding of endocrine resistance in MBC. [ABSTRACT FROM AUTHOR]

Bone marrow transplantation (BMT) represents a cure for nonmalignant hematological disorders. However, compared with the stringent conditioning regimens used when performing BMT to treat hematological malignancies, the reduced intensity conditioning regimen used in the context of nonmalignant hematological disorders leads to substantially higher rates of BMT rejection, presumably due to an intact immune system. The relevant patient population typically receives transfusion support, often including platelets, and the frequency of BMT rejection correlates with the frequency of transfusion. Here, we demonstrate that immunity to transfused platelets contributes to subsequent BMT rejection in mice, even when the BMT donor and recipient are MHC matched. We used MHC-matched bone marrow because, although immunity to transfused platelets is best characterized in relation to HLA-specific antibodies, such antibodies are unlikely to play a role in clinical BMT rejection that is HLA matched. However, bone marrow is not matched in the clinic for minor histocompatibility antigens, such as those carried by platelets, and we report that transfusion of minor histocompatibility antigen-mismatched platelets induced subsequent BMT rejection. These findings indicate previously unappreciated sequelae of immunity to platelets in the context of transplantation and suggest that strategies to account for minor histocompatibility mismatching may help to reduce the chance of BMT rejection in human patients. [ABSTRACT FROM AUTHOR]

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers. [ABSTRACT FROM AUTHOR]