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Cancer Cell Oct 2023We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50...
We report a personalized tumor-informed technology, Patient-specific pROgnostic and Potential tHErapeutic marker Tracking (PROPHET) using deep sequencing of 50 patient-specific variants to detect molecular residual disease (MRD) with a limit of detection of 0.004%. PROPHET and state-of-the-art fixed-panel assays were applied to 760 plasma samples from 181 prospectively enrolled early stage non-small cell lung cancer patients. PROPHET shows higher sensitivity of 45% at baseline with circulating tumor DNA (ctDNA). It outperforms fixed-panel assays in prognostic analysis and demonstrates a median lead-time of 299 days to radiologically confirmed recurrence. Personalized non-canonical variants account for 98.2% with prognostic effects similar to canonical variants. The proposed tumor-node-metastasis-blood (TNMB) classification surpasses TNM staging for prognostic prediction at the decision point of adjuvant treatment. PROPHET shows potential to evaluate the effect of adjuvant therapy and serve as an arbiter of the equivocal radiological diagnosis. These findings highlight the potential advantages of personalized cancer techniques in MRD detection.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Lung Neoplasms; Cell-Free Nucleic Acids; DNA, Neoplasm; Small Cell Lung Carcinoma; Neoplasm, Residual; Biomarkers, Tumor; Neoplasm Recurrence, Local
PubMed: 37683638
DOI: 10.1016/j.ccell.2023.08.010 -
Blood Nov 2023Multiple myeloma remains an incurable disease plagued by high relapse rates. Deeper and more sustainable responses, however, have been consistently shown to improve... (Review)
Review
Multiple myeloma remains an incurable disease plagued by high relapse rates. Deeper and more sustainable responses, however, have been consistently shown to improve outcomes and could eventually pave the way to achieving a cure. Our understanding of disease response has surpassed complete response (CR), because the current definitions are suboptimal, and the treatment goal should aim even beyond stringent CR, toward molecular and flow CR, that is, measurable residual disease (MRD) negativity. It has been more than 20 years since the discrepancy in the outcome between patients in CR with and without MRD has been demonstrated, and the field has come a long way from multiparameter flow cytometry to next-generation flow and next-generation sequencing, able to detect up to a limit of detection of a single myeloma cell from 1 million healthy counterparts. This review aims to summarize the current available data regarding MRD but also its potential future use as a coprimary outcome both in clinical and trial settings as a survival surrogate as well as its use to evaluate treatment efficacy and for adaptive response-based and early-rescue therapy. Furthermore, we discuss whether these concepts are applicable in different settings (eg, newly diagnosed and relapsed/refractory myeloma, patients who are eligible and ineligible for tansplant, and standard- and high-risk disease).
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Treatment Outcome; Neoplasm, Residual; Flow Cytometry
PubMed: 37471603
DOI: 10.1182/blood.2023020284 -
Cancer Cell Jan 2024Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms...
Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence.
Topics: Humans; Female; Breast Neoplasms; Cell Survival; Neoplasm Recurrence, Local; Heparitin Sulfate; Glycosaminoglycans; Galactosyltransferases
PubMed: 38065100
DOI: 10.1016/j.ccell.2023.11.008 -
Journal of Clinical Oncology : Official... Oct 2023Although allogeneic hematopoietic cell transplantation (allo-HCT) remains the backbone of curative treatment for the majority of fit adults diagnosed with AML, there is... (Review)
Review
Although allogeneic hematopoietic cell transplantation (allo-HCT) remains the backbone of curative treatment for the majority of fit adults diagnosed with AML, there is indeed a subset of patients for whom long-term remission may be achieved without transplantation. Remarkable changes in our knowledge of AML biology in recent years has transformed the landscape of diagnosis, management, and treatment of AML. Specifically, markedly increased understanding of molecular characteristics of AML, the expanded application of minimal/measurable residual diseases testing, and an increased armamentarium of leukemia-directed therapeutic agents have created a new paradigm for the medical care of patients with AML. An attempt is herein made to decipher the decision to proceed to transplant for patients with AML in first complete remission on the basis of the current best available evidence. The focus is on factors affecting the biology and treatment of AML itself, rather than on variables related to allo-HCT, an area characterized by significant advancements that have reduced overall therapy-related complications. This review seeks to focus on areas of particular complexity, while simultaneously providing clarity on how our current knowledge and treatment strategies may, or may not, influence the decision to pursue allo-HCT in patients with AML.
Topics: Adult; Humans; Leukemia, Myeloid, Acute; Hematopoietic Stem Cell Transplantation; Transplantation, Homologous; Remission Induction; Neoplasm, Residual; Retrospective Studies
PubMed: 37611216
DOI: 10.1200/JCO.22.02868 -
JAMA Oncology Feb 2024Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer...
IMPORTANCE
Addition of pembrolizumab to anthracycline-based chemotherapy improves pathologic complete response (pCR) and event-free survival (EFS) in triple-negative breast cancer (TNBC). The efficacy of anthracycline-free chemoimmunotherapy in TNBC has not been assessed.
OBJECTIVE
To assess the efficacy of the anthracycline-free neoadjuvant regimen of carboplatin and docetaxel plus pembrolizumab in TNBC.
DESIGN, SETTING, AND PARTICIPANTS
This was an open-label phase 2 clinical trial including a single group of patients with stage I to III TNBC enrolled at 2 sites who received neoadjuvant carboplatin and docetaxel plus pembrolizumab every 21 days for 6 cycles. Participants were enrolled from 2018 to 2022.
INTERVENTION OR EXPOSURE
Carboplatin (with an area under the free carboplatin plasma concentration vs time curve of 6) and docetaxel (75 mg/m2) plus pembrolizumab (200 mg) every 21 days for 6 cycles. Myeloid growth factor support was administered with all cycles.
MAIN OUTCOMES AND MEASURES
Primary end point was pathologic complete response (pCR) defined as no evidence of invasive tumor in breast and axilla. The secondary end points were residual cancer burden, EFS, toxicity, and immune biomarkers. RNA isolated from pretreatment tumor tissue was subjected to next-generation sequencing. Specimens were classified as positive or negative for the 44-gene DNA damage immune response (DDIR) signature and for the 27-gene tumor immune microenvironment (TIM; DetermaIO) signature using predefined cutoffs. Stromal tumor-infiltrating lymphocytes (sTILs) were evaluated using standard criteria. Programmed cell death-ligand 1 (PD-L1) testing was performed using a standard immunohistochemical assay.
RESULTS
Among the eligible study population of 115 female patients (median [range] age, 50 [27-70] years) who enrolled from September 2018 to January 2022, 39% had node-positive disease. pCR and residual cancer burden 0 + 1 rates were 58% (95% CI, 48%-67%) and 69% (95% CI, 60%-78%), respectively. Grade 3 or higher immune-mediated adverse events were observed in 3.5% of patients. sTILs, PD-L1, DDIR, and TIM were each predictive of pCR in multivariable analyses. The areas under curve for pCR were 0.719, 0.740, 0.699, and 0.715 for sTILs, PD-L1, DDIR, and TIM, respectively. Estimated 3-year EFS was 86% in all patients; 98% in pCR group and 68% in no-pCR group.
CONCLUSIONS AND RELEVANCE
The findings of the phase 2 clinical trial indicate that neoadjuvant carboplatin and docetaxel plus pembrolizumab shows encouraging pCR and 3-year EFS. The regimen was well tolerated, and immune enrichment as identified by various biomarkers was independently predictive of pCR. These results provide data on an alternative anthracycline-free chemoimmunotherapy regimen for patients who are not eligible for anthracycline-based regimens and support further evaluation of this regimen as a chemotherapy de-escalation strategy in randomized studies for TNBC.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03639948.
Topics: Humans; Female; Middle Aged; Docetaxel; Carboplatin; Triple Negative Breast Neoplasms; Neoadjuvant Therapy; B7-H1 Antigen; Neoplasm, Residual; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Biomarkers; Anthracyclines; Tumor Microenvironment; Antibodies, Monoclonal, Humanized
PubMed: 37991778
DOI: 10.1001/jamaoncol.2023.5033 -
Clinical Cancer Research : An Official... Nov 2023Breast cancer remains a leading cause of cancer-related death in women despite screening and therapeutic advances. Early detection allows for resection of local disease;... (Review)
Review
Breast cancer remains a leading cause of cancer-related death in women despite screening and therapeutic advances. Early detection allows for resection of local disease; however, patients can develop metastatic recurrences years after curative treatment. There is no reliable blood-based monitoring after curative therapy, and radiographic evaluation for metastatic disease is performed only in response to symptoms. Advances in circulating tumor DNA (ctDNA) assays have allowed for a potential option for blood-based monitoring. The detection of ctDNA in the absence of overt metastasis or recurrent disease indicates molecular evidence of cancer, defined as molecular residual disease (MRD). Multiple studies have shown that MRD detection is strongly associated with disease recurrence, with a lead time prior to clinical evidence of recurrence of many months. Importantly, it is still unclear whether treatment changes in response to ctDNA detection will improve outcomes. There are currently ongoing trials evaluating the efficacy of therapy escalation in the setting of MRD, and these studies are being conducted in all major breast cancer subtypes. Additional therapies under study include CDK4/6 inhibitors, PARP inhibitors, HER2-targeted therapies, and immunotherapy. This review will summarize the underlying scientific principles of various MRD assays, their known prognostic roles in early breast cancer, and the ongoing clinical trials assessing the efficacy of therapy escalation in the setting of MRD.
Topics: Humans; Female; Breast Neoplasms; Neoplasm Recurrence, Local; Circulating Tumor DNA; Prognosis; Neoplasm, Residual; Biomarkers, Tumor
PubMed: 37477704
DOI: 10.1158/1078-0432.CCR-23-0757 -
Journal of Clinical Oncology : Official... Jul 2023In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with...
PURPOSE
In GLOW, fixed-duration ibrutinib + venetoclax showed superior progression-free survival (PFS) versus chlorambucil + obinutuzumab in older/comorbid patients with previously untreated chronic lymphocytic leukemia (CLL). The current analysis describes minimal residual disease (MRD) kinetics and any potential predictive value for PFS, as it has not yet been evaluated for ibrutinib + venetoclax treatment.
METHODS
Undetectable MRD (uMRD) was assessed by next-generation sequencing at <1 CLL cell per 10,000 (<10) and <1 CLL cell per 100,000 (<10) leukocytes. PFS was analyzed by MRD status at 3 months after treatment (EOT+3).
RESULTS
Ibrutinib + venetoclax achieved deeper uMRD (<10) rates in bone marrow (BM) and peripheral blood (PB), respectively, in 40.6% and 43.4% of patients at EOT+3 versus 7.6% and 18.1% of patients receiving chlorambucil + obinutuzumab. Of these patients, uMRD (<10) in PB was sustained during the first year post-treatment (EOT+12) in 80.4% of patients receiving ibrutinib + venetoclax and 26.3% receiving chlorambucil + obinutuzumab. Patients with detectable MRD (dMRD; ≥10) in PB at EOT+3 were more likely to sustain MRD levels through EOT+12 with ibrutinib + venetoclax versus chlorambucil + obinutuzumab. PFS rates at EOT+12 were high among patients treated with ibrutinib + venetoclax regardless of MRD status at EOT+3: 96.3% and 93.3% in patients with uMRD (<10) and dMRD (≥10) in BM, respectively, versus 83.3% and 58.7% for patients receiving chlorambucil + obinutuzumab. PFS rates at EOT+12 also remained high in patients with unmutated immunoglobulin heavy-chain variable region (IGHV) receiving ibrutinib + venetoclax, independent of MRD status in BM.
CONCLUSION
Molecular and clinical relapses were less frequent during the first year post-treatment with ibrutinib + venetoclax versus chlorambucil + obinutuzumab regardless of MRD status at EOT+3 and IGHV status. Even for patients not achieving uMRD (<10), PFS rates remained high with ibrutinib + venetoclax; this is a novel finding and requires additional follow-up to confirm its persistence over time.
Topics: Humans; Aged; Progression-Free Survival; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasm, Residual; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Chlorambucil
PubMed: 37279408
DOI: 10.1200/JCO.22.02283 -
No Shinkei Geka. Neurological Surgery Sep 2023In the 5 edition of the WHO classification, medulloblastomas, which are representative pediatric brain tumors, are categorized into four groups: WNT, SHH-TP53 wild,...
In the 5 edition of the WHO classification, medulloblastomas, which are representative pediatric brain tumors, are categorized into four groups: WNT, SHH-TP53 wild, SHH-TP53 mutant, and non-WNT/non-SHH, based on their molecular background. While the histopathological findings still hold importance in predicting prognosis, the histopathological classification is no longer utilized in this edition. SHH medulloblastomas are further subdivided into two groups based on the presence or absence of TP53 mutation, as their clinical characteristics and prognosis differ. Group 3 and Group 4 medulloblastomas, recognized as distinct molecular groups in clinical practice, are combined into a single group called "non-WNT/non-SHH", because they lack specific molecular pathway activation. Furthermore, based on methylation profiling, dividing SHH medulloblastoma into four subgroups and non-WNT/non-SHH medulloblastoma into eight subgroups was proposed. Understanding the unique clinical characteristics and prognosis associated with each group is crucial. However, it is important to acknowledge that our current understanding of prognosis is based on treatment approaches guided by clinical risk factors such as postoperative residual tumor volume and the presence of metastatic disease. This molecular-based classification holds promise in guiding the development of optimal treatment strategies for patients with medulloblastoma.
Topics: Child; Humans; Medulloblastoma; Brain Neoplasms; Mutation; Neoplasm, Residual; Cerebellar Neoplasms
PubMed: 37743337
DOI: 10.11477/mf.1436204827 -
Blood Dec 2023The early thymic precursor (ETP) immunophenotype was previously reported to confer poor outcome in T-cell acute lymphoblastic leukemia (T-ALL). Between 2009 and 2014,... (Clinical Trial)
Clinical Trial
The early thymic precursor (ETP) immunophenotype was previously reported to confer poor outcome in T-cell acute lymphoblastic leukemia (T-ALL). Between 2009 and 2014, 1256 newly diagnosed children and young adults enrolled in Children's Oncology Group (COG) AALL0434 were assessed for ETP status and minimal residual disease (MRD) using flow cytometry at a central reference laboratory. The subject phenotypes were categorized as ETP (n = 145; 11.5%), near-ETP (n = 209; 16.7%), or non-ETP (n = 902; 71.8%). Despite higher rates of induction failure for ETP (6.2%) and near-ETP (6.2%) than non-ETP (1.2%; P < .0001), all 3 groups showed excellent 5-year event-free survival (EFS) and overall survival (OS): ETP (80.4% ± 3.9% and 86.8 ± 3.4%, respectively), near-ETP (81.1% ± 3.3% and 89.6% ± 2.6%, respectively), and non-ETP (85.3% ± 1.4% and 90.0% ± 1.2%, respectively; P = .1679 and P = .3297, respectively). There was no difference in EFS or OS for subjects with a day-29 MRD <0.01% vs 0.01% to 0.1%. However, day-29 MRD ≥0.1% was associated with inferior EFS and OS for patients with near-ETP and non-ETP, but not for those with ETP. For subjects with day-29 MRD ≥1%, end-consolidation MRD ≥0.01% was a striking predictor of inferior EFS (80.9% ± 4.1% vs 52.4% ± 8.1%, respectively; P = .0001). When considered as a single variable, subjects with all 3 T-ALL phenotypes had similar outcomes and subjects with persistent postinduction disease had inferior outcomes, regardless of their ETP phenotype. This clinical trial was registered at AALL0434 as #NCT00408005.
Topics: Child; Humans; Young Adult; Disease-Free Survival; Neoplasm, Residual; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Prognosis
PubMed: 37556734
DOI: 10.1182/blood.2023020678 -
Blood May 2024Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of... (Review)
Review
Experts from the European Leukemia Net (ELN) working group for adult acute lymphoblastic leukemia have identified an unmet need for guidance regarding management of adult acute lymphoblastic leukemia (ALL) from diagnosis to aftercare. The group has previously summarized their recommendations regarding diagnostic approaches, prognostic factors, and assessment of ALL. The current recommendation summarizes clinical management. It covers treatment approaches, including the use of new immunotherapies, application of minimal residual disease for treatment decisions, management of specific subgroups, and challenging treatment situations as well as late effects and supportive care. The recommendation provides guidance for physicians caring for adult patients with ALL which has to be complemented by regional expertise preferably provided by national academic study groups.
Topics: Humans; Adult; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Europe; Disease Management; Neoplasm, Residual; Prognosis
PubMed: 38306595
DOI: 10.1182/blood.2023023568