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Clinical Advances in Hematology &... Sep 2023Multiple myeloma (MM) is a clonal plasma cell dyscrasia and the most common form of primary bone marrow cancer. Nearly 35,000 new cases of MM are diagnosed in the United... (Review)
Review
Multiple myeloma (MM) is a clonal plasma cell dyscrasia and the most common form of primary bone marrow cancer. Nearly 35,000 new cases of MM are diagnosed in the United States each year. MM is a slowly progressive illness that remains incurable. The median survival for patients with MM is approximately 7 years, during which these patients suffer substantial morbidity. Despite the introduction of new drugs and immune-based therapies, many patients unfortunately relapse and require further therapies. Therefore, it is becoming increasingly important to be able to accurately and quickly determine changes in a patient's clinical status. Assessments of monoclonal protein and serum free light chain levels are the most common tests now available for monitoring patients with MM; however, these assays have several drawbacks. Modern radiologic techniques such as positron emission tomography and computed tomography are better than standard radiographs but are costly and cumbersome. Serum B-cell maturation antigen is a new biomarker for both the diagnosis and prognosis of MM. Assessment of measurable residual disease is becoming an important endpoint. The creation of better ways to predict outcomes and promptly and accurately monitor changes for patients with MM should lead to improved quality of life and longer survival.
Topics: Humans; Multiple Myeloma; Quality of Life; Antibodies, Monoclonal; B-Cell Maturation Antigen; Neoplasm, Residual
PubMed: 37647495
DOI: No ID Found -
Nature Communications May 2024Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies...
Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant persister cells (DTPs) which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.
Topics: Humans; Lung Neoplasms; Signal Transduction; Transcription Factors; Carcinoma, Non-Small-Cell Lung; YAP-Signaling Proteins; Cell Line, Tumor; Animals; Drug Resistance, Neoplasm; Adaptor Proteins, Signal Transducing; Neoplasm, Residual; Mice; Focal Adhesion Kinase 1; ErbB Receptors; Anaplastic Lymphoma Kinase; Proto-Oncogene Proteins p21(ras); Focal Adhesion Protein-Tyrosine Kinases; Antineoplastic Agents; Xenograft Model Antitumor Assays
PubMed: 38702301
DOI: 10.1038/s41467-024-47423-0 -
Med (New York, N.Y.) Nov 2023Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a...
Frontline treatment and resultant cure rates in patients with advanced ovarian cancer have changed little over the past several decades. Here, we outline a multidisciplinary approach aimed at gaining novel therapeutic insights by focusing on the poorly understood minimal residual disease phase of ovarian cancer that leads to eventual incurable recurrences.
Topics: Humans; Female; Neoplasm, Residual; Ovarian Neoplasms; Carcinoma, Ovarian Epithelial
PubMed: 37951209
DOI: 10.1016/j.medj.2023.08.004 -
Cancers Nov 2023Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular... (Review)
Review
Analyzing blood as a so-called liquid biopsy in breast cancer (BC) patients has the potential to adapt therapy management. Circulating tumor cells (CTCs), extracellular vesicles (EVs), cell-free DNA (cfDNA) and other blood components mirror the tumoral heterogeneity and could support a range of clinical decisions. Multi-cancer early detection tests utilizing blood are advancing but are not part of any clinical routine yet. Liquid biopsy analysis in the course of neoadjuvant therapy has potential for therapy (de)escalation.Minimal residual disease detection via serial cfDNA analysis is currently on its way. The prognostic value of blood analytes in early and metastatic BC is undisputable, but the value of these prognostic biomarkers for clinical management is controversial. An interventional trial confirmed a significant outcome benefit when therapy was changed in case of newly emerging cfDNA mutations under treatment and thus showed the clinical utility of cfDNA analysis for therapy monitoring. The analysis of PIK3CA or ESR1 variants in plasma of metastatic BC patients to prescribe targeted therapy with alpesilib or elacestrant has already arrived in clinical practice with FDA-approved tests available and is recommended by ASCO. The translation of more liquid biopsy applications into clinical practice is still pending due to a lack of knowledge of the analytes' biology, lack of standards and difficulties in proving clinical utility.
PubMed: 38001722
DOI: 10.3390/cancers15225463 -
The Journal of Clinical Endocrinology... May 2024There is a lack of reliable biomarkers capable of predicting postoperative tumor progression of nonfunctioning pituitary adenomas (NFPAs).
CONTEXT
There is a lack of reliable biomarkers capable of predicting postoperative tumor progression of nonfunctioning pituitary adenomas (NFPAs).
OBJECTIVE
To discover proteomic profiles associated with postoperative tumor progression in patients with NFPAs. This was a case-controlled exploratory study at a tertiary university hospital. Tissue samples were obtained from 46 patients with residual tumor following surgery for NFPAs of gonadotroph lineage. Two patient groups were compared: patients requiring reintervention due to residual tumor progression (cases; reintervention group, n = 29) and patients with a residual tumor showing no progression for a minimum of 5 years (controls; radiologically stable group, n = 17). Differentially expressed proteins (DEPs) between patient groups were measured.
RESULTS
Global quantitative proteomic analysis identified 4074 proteins, of which 550 were differentially expressed between the 2 groups (fold change >80%, false discovery rate-adjusted P ≤ .05). Principal component analysis showed good separation between the 2 groups. Functional enrichment analysis of the DEPs indicated processes involving translation, ROBO-receptor signaling, energy metabolism, mRNA metabolism, and RNA splicing. Several upregulated proteins in the reintervention group, including SNRPD1, SRSF10, SWAP-70, and PSMB1, are associated with tumor progression in other cancer types.
CONCLUSION
This is the first exploratory study analyzing proteomic profiles as markers of postoperative tumor progression in NFPAs. The findings clearly showed different profiles between tumors with indolent postoperative behavior and those with postoperative tumor progression. Both enriched pathways involving DEPs and specific upregulated proteins have previously been associated with tumor aggressiveness. These results suggest the value of proteomic profiling for predicting tumor progression in patients with NFPAs.
Topics: Humans; Pituitary Neoplasms; Female; Male; Disease Progression; Proteomics; Middle Aged; Adenoma; Adult; Case-Control Studies; Biomarkers, Tumor; Neoplasm, Residual; Aged; Proteome
PubMed: 38157275
DOI: 10.1210/clinem/dgad767 -
International Journal of Molecular... Jul 2023Triple-negative breast cancer (TNBC) is particularly challenging due to the weak or absent response to therapeutics and its poor prognosis. The effectiveness of...
Triple-negative breast cancer (TNBC) is particularly challenging due to the weak or absent response to therapeutics and its poor prognosis. The effectiveness of neoadjuvant chemotherapy (NAC) response is strongly influenced by changes in elements of the tumor microenvironment (TME). This work aimed to characterize the residual TME composition in 96 TNBC patients using immunohistochemistry and in situ hybridization techniques and evaluate its prognostic implications for partial responders vs. non-responders. Compared with non-responders, partial responders containing higher levels of CD83+ mature dendritic cells, FOXP3+ regulatory T cells, and IL-15 expression but lower CD138+ cell concentration exhibited better OS and RFS. However, along with tumor diameter and positive nodal status at diagnosis, matrix metalloproteinase-9 (MMP-9) expression in the residual TME was identified as an independent factor associated with the impaired response to NAC. This study yields new insights into the key components of the residual tumor bed, such as MMP-9, which is strictly associated with the lack of a pathological response to NAC. This knowledge might help early identification of TNBC patients less likely to respond to NAC and allow the establishment of new therapeutic targets.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Matrix Metalloproteinase 9; Neoadjuvant Therapy; Neoplasm, Residual; Triple Negative Breast Neoplasms; Tumor Microenvironment
PubMed: 37511057
DOI: 10.3390/ijms241411297 -
Blood Cancer Discovery Sep 2023The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics...
UNLABELLED
The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus
SIGNIFICANCE
This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337.
Topics: Humans; Receptors, Chimeric Antigen; Prognosis; Multiple Myeloma; Immunotherapy, Adoptive; Neoplasm, Residual; Neoplasms, Plasma Cell
PubMed: 37486974
DOI: 10.1158/2643-3230.BCD-23-0044 -
Nature Communications Nov 2023While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL)...
While the prognostic role of immunoglobulin heavy chain locus (IGH) rearrangement in minimal residual disease (MRD) in pediatric B-acute lymphoblastic leukemia (B-ALL) has been reported, the contribution of light chain loci (IGK/IGL) remains elusive. This study is to evaluate the prognosis of IGH and IGK/IGL rearrangement-based MRD detected by next-generation sequencing in B-ALL at the end of induction (EOI) and end of consolidation (EOC). IGK/IGL rearrangements identify 5.5% of patients without trackable IGH clones. Concordance rates for IGH and IGK/IGL are 79.9% (cutoff 0.01%) at EOI and 81.0% (cutoff 0.0001%) at EOC, respectively. Patients with NGS-MRD < 0.01% at EOI or <0.0001% at EOC present excellent outcome, with 3-year event-free survival rates higher than 95%. IGH-MRD is prognostic at EOI/EOC, while IGK-MRD at EOI/EOC and IGL-MRD at EOI are not. At EOI, NGS identifies 26.2% of higher risk patients whose MRD < 0.01% by flow cytometry. However, analyzing IGK/IGL along with IGH fails to identify additional higher risk patients both at EOI and at EOC. In conclusion, IGH is crucial for MRD monitoring while IGK and IGL have relatively limited value.
Topics: Child; Humans; Genes, Immunoglobulin; Neoplasm, Residual; Immunoglobulin Heavy Chains; Precursor Cell Lymphoblastic Leukemia-Lymphoma; High-Throughput Nucleotide Sequencing
PubMed: 37978187
DOI: 10.1038/s41467-023-43171-9 -
Clinica Chimica Acta; International... Jan 2024Multiple myeloma (MM) is characterized by excessive production of monoclonal immunoglobulins (M proteins). Routine screening methods for M proteins to assess prognosis... (Review)
Review
Multiple myeloma (MM) is characterized by excessive production of monoclonal immunoglobulins (M proteins). Routine screening methods for M proteins to assess prognosis are unable to detect low levels of M proteins produced by residual tumor cells, ie, minimal residual disease (MRD). Assessment of MRD can be conducted by examining residual tumor cells in bone marrow or circulating M proteins. Advances in mass spectrometry have enabled reliable and highly sensitive detection of low abundance serum biomarkers making it a viable and significantly less invasive approach. Mass spectrometry can achieve dynamic monitoring of MRD and identify therapeutic monoclonal antibodies as well as oligoclonal proteins. In this review we summarize mass spectrometry methods in M protein detection and their applications of MRD detection in MM.
Topics: Humans; Multiple Myeloma; Neoplasm, Residual; Antibodies, Monoclonal; Mass Spectrometry
PubMed: 37924928
DOI: 10.1016/j.cca.2023.117623 -
Blood Advances Aug 2023Whether the LSC17 gene expression can improve risk stratification in the context of next generation sequencing-based risk stratification and measurable residual disease...
Whether the LSC17 gene expression can improve risk stratification in the context of next generation sequencing-based risk stratification and measurable residual disease (MRD) in patients with intensively treated AML has not been explored. We analyzed LSC17 in 504 adult patients prospectively treated in the ALFA-0702 trial. RUNX1 or TP53 mutations were associated with higher LSC1 scores while CEBPA and NPM1 mutations were associated with lower scores. Patients with high LSC17 scores had a lower rate of complete response (CR) in a multivariable analysis (odds ratio, 0.41; P = .0007), accounting for European LeukemiaNet 2022 (ELN22), age, and white blood cell count (WBC). LSC17-high status was associated with shorter overall survival (OS) (3-year OS: 70.0% vs 52.7% in patients with LSC17-low status; P < .0001). In a multivariable analysis considering ELN22, age, and WBC, patients with LSC17-high status had shorter disease-free survival (DFS) (hazard ratio [HR], 1.36; P = .048) than those with LSC17-low status. In 123 patients with NPM1-mutated AML in CR, LSC17-high status predicted poorer DFS (HR, 2.34; P = .01), independent of age, WBC, ELN22 risk, and NPM1-MRD. LSC-low status and negative NPM1-MRD identified a subset comprising 48% of patients with mutated NPM1 with a 3-year OS from CR of 93.1% compared with 60.7% in those with LSC17-high status and/or positive NPM1-MRD (P = .0001). Overall, LSC17 assessment refines genetic risk stratification in adult patients with AML treated intensively. Combined with MRD, LSC17 identifies a subset of patients with NPM1-mutated AML with excellent clinical outcome.
Topics: Adult; Humans; Nucleophosmin; Leukemia, Myeloid, Acute; Remission Induction; Disease-Free Survival; Risk Factors; Neoplasm, Residual
PubMed: 37205853
DOI: 10.1182/bloodadvances.2023010155