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Oral Oncology Sep 2023Liquid biopsy has become a significant tool in personalized medicine, enabling real-time monitoring of cancer evolution and patient follow-up. This minimally invasive...
Liquid biopsy has become a significant tool in personalized medicine, enabling real-time monitoring of cancer evolution and patient follow-up. This minimally invasive procedure analyzes circulating tumor cells (CTCs) and circulating tumor-derived materials, such as ctDNA, miRNAs, and EVs. CTC analysis significantly impacts prognosis, detection of minimal residual disease (MRD), treatment selection, and monitoring of cancer patients. Liquid biopsy is an attractive option for mouth cancer detection and treatment progress monitoring in many countries. It is not invasive and requires no surgical expertise, making it an attractive option for mouth cancer detection. Liquid biopsy is a diagnostic repeatable test that can profile cancer genomes in real-time with minimal invasiveness and tailor oncological decision-making. It analyzes different blood-circulating biomarkers, with ctDNA being the preferred one. While tissue biopsy remains the gold standard for molecular evaluation of solid tumors, liquid biopsy is a complementary tool in various clinical settings, including treatment selection, monitoring response, cancer clonal evolution, prognostic evaluation, early disease detection, and minimal residual disease (MRD).
Topics: Humans; Neoplasm, Residual; Early Detection of Cancer; Head and Neck Neoplasms; Liquid Biopsy; Mouth Neoplasms; Biomarkers, Tumor
PubMed: 37399708
DOI: 10.1016/j.oraloncology.2023.106481 -
Blood Jan 2024Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated...
Assessment of measurable residual disease (MRD) by quantitative reverse transcription polymerase chain reaction is strongly prognostic in patients with NPM1-mutated acute myeloid leukemia (AML) treated with intensive chemotherapy; however, there are no data regarding its utility in venetoclax-based nonintensive therapy, despite high efficacy in this genotype. We analyzed the prognostic impact of NPM1 MRD in an international real-world cohort of 76 previously untreated patients with NPM1-mutated AML who achieved complete remission (CR)/CR with incomplete hematological recovery following treatment with venetoclax and hypomethylating agents (HMAs) or low-dose cytarabine (LDAC). A total of 44 patients (58%) achieved bone marrow (BM) MRD negativity, and a further 14 (18%) achieved a reduction of ≥4 log10 from baseline as their best response, with no difference between HMAs and LDAC. The cumulative rates of BM MRD negativity by the end of cycles 2, 4, and 6 were 25%, 47%, and 50%, respectively. Patients achieving BM MRD negativity by the end of cycle 4 had 2-year overall of 84% compared with 46% if MRD was positive. On multivariable analyses, MRD negativity was the strongest prognostic factor. A total of 22 patients electively stopped therapy in BM MRD-negative remission after a median of 8 cycles, with 2-year treatment-free remission of 88%. In patients with NPM1-mutated AML attaining remission with venetoclax combination therapies, NPM1 MRD provides valuable prognostic information.
Topics: Humans; Prognosis; Nucleophosmin; Mutation; Leukemia, Myeloid, Acute; Cytarabine; Neoplasm, Residual; Sulfonamides; Bridged Bicyclo Compounds, Heterocyclic
PubMed: 37647641
DOI: 10.1182/blood.2023021579 -
The Lancet. Haematology Nov 2023For patients with newly diagnosed multiple myeloma, reaching minimal residual disease (MRD) negativity after treatment is associated with improved outcomes; however, the...
BACKGROUND
For patients with newly diagnosed multiple myeloma, reaching minimal residual disease (MRD) negativity after treatment is associated with improved outcomes; however, the use of MRD to modulate therapy remains elusive. We present the final analysis of the MASTER trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) therapy in patients with newly diagnosed multiple myeloma, in which MRD status is used to modulate treatment duration and cessation.
METHODS
MASTER was a multicentre, single-arm, phase 2 trial conducted in five academic medical centres in the USA. Eligible participants were 18 years or older with newly diagnosed multiple myeloma (measurable by serum or urine protein electrophoresis or serum free light chains), a life expectancy of at least 12 months, and an Eastern Cooperative Oncology Group performance status of 0-2, and had received no previous treatment for multiple myeloma except up to one cycle of therapy containing bortezomib, cyclophosphamide, and dexamethasone. The study was enriched for participants with high-risk chromosome abnormalities (HRCAs). During the induction phase, participants received four 28-day cycles of Dara-KRd, each comprising daratumumab (16 mg/kg intravenously on days 1, 8, 15, and 22), carfilzomib (56 mg/m intravenously on days 1, 8, and 15), lenalidomide (25 mg orally on days 1-21), and dexamethasone (40 mg orally or intravenously on days 1, 8, 15, and 22); induction was followed by autologous haematopoietic stem-cell transplantation and up to two phases of consolidation with Dara-KRd. We assessed MRD by next-generation sequencing after or during each phase. The primary endpoint was reaching MRD negativity (<10). Participants who reached MRD negativity after or during two consecutive phases stopped treatment and began observation with MRD surveillance (MRD-SURE); participants who did not reach two consecutive MRD-negative results received maintenance lenalidomide. Secondary endpoints included progression-free survival and cumulative incidence of progression. All analyses were conducted in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03224507, and is complete.
FINDINGS
Between Mar 21, 2018, and Oct 23, 2020, 123 participants were recruited to the study, of whom 70 (57%) were men, 53 (43%) were women, 94 (76%) were non-Hispanic White, 25 (20%) were non-Hispanic Black, and four (3%) were of another race or ethnicity. The median age of participants was 61 years (IQR 55-68), and 24 (20%) were aged 70 years or older. The median duration of follow up was 42·2 months (IQR 34·5-46·0). Of the 123 participants, 53 (43%) had no HRCAs, 46 (37%) had one HRCA, and 24 (20%) had two or more HRCAs. For 118 (96%) of 123 participants, MRD was evaluable by next-generation sequencing; the remaining five had an absence of sufficiently unique clonogenic sequences to enable tracking by the assay. Of these 118 participants, 96 (81%, 95% CI 73-88) reached MRD of less than 10 (comprising 39 [78%, 64-88] of 50 participants with no HRCAs, 38 [86%, 73-95] of 44 participants with one HRCA, and 19 [79%, 58-93] of 24 participants with two or more HRCAs) and 84 (71%, 62-79) reached MRD-SURE and treatment cessation. 36-month progression-free survival among all 123 participants was 88% (95% CI 78-95) for participants with no HRCAs, 79% (67-88) for those with one HRCA, and 50% (30-70) for those with two or more HRCAs. For the 84 participants reaching MRD-SURE, the 24-month cumulative incidence of progression from cessation of therapy was 9% (95% CI 1-19) for participants with no HRCAs, 9% (1-18) for those with one HRCA, and 47% (23-72) for those with two or more HRCAs. 61 participants (comprising 52% of 118 MRD-evaluable participants and 73% of 84 participants who reached MRD-SURE) remain free of therapy and MRD-negative as of Feb 7, 2023. The most common grade 3-4 adverse events were neutropenia (43 patients, 35%), lymphopenia (28 patients, 23%), and hypertension (13 patients, 11%). Three treatment-emergent deaths were recorded: two sudden deaths and one due to viral infection, none of which were judged to be treatment-related.
INTERPRETATION
This approach provided positive outcomes and a pathway for treatment cessation in most patients with newly diagnosed multiple myeloma. Outcomes for patients with ultra-high-risk multiple myeloma, defined as those with two or more HRCAs, remain unsatisfactory, and these patients should be prioritised for trials with early introduction of therapies with novel mechanisms of action.
FUNDING
Amgen and Janssen Pharmaceuticals.
Topics: Male; Humans; Female; Middle Aged; Aged; Multiple Myeloma; Lenalidomide; Neoplasm, Residual; Treatment Outcome; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone
PubMed: 37776872
DOI: 10.1016/S2352-3026(23)00236-3 -
American Journal of Hematology Aug 2023Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in...
Reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL); however, RT-PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay (sensitivity of 10 ) and its correlation with RT-PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT-PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long-term detectable BCR::ABL1 by PCR, six were PCR+/NGS-. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse-free survival and overall survival were similar in patients who were PCR+/NGS- and PCR-/NGS-, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS-based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low-level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.
Topics: Humans; Fusion Proteins, bcr-abl; Prognosis; Reverse Transcriptase Polymerase Chain Reaction; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Neoplasm, Residual; High-Throughput Nucleotide Sequencing; Recurrence
PubMed: 37183966
DOI: 10.1002/ajh.26949 -
Current Hematologic Malignancy Reports Dec 2023The utility of analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and disease in the bone marrow as an adjunctive tool in caring for hematologic... (Review)
Review
PURPOSE OF REVIEW
The utility of analyzing circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and disease in the bone marrow as an adjunctive tool in caring for hematologic cancer patients is expanding. This holds true for lymphoma where these biomarkers are being explored as a means of genotyping and quantifying disease. Regarding the latter, they can be used to monitor measurable residual disease (MRD) during and after treatment. This holds potential for aiding clinical decisions amidst treatment, detecting earlier relapse, and improving prognostication. Here, we review the evidence to support these applications in a variety of lymphoma subtypes.
RECENT FINDINGS
Numerous clinical trials across a variety of lymphomas have demonstrated value in MRD monitoring. MRD monitoring is often prognostic for progression free survival (PFS) and even overall survival (OS) at several time points in a disease course, particularly when utilizing serial measurements. With regards to tailoring treatment, there are a growing number of trials examining MRD-adaptive treatment strategies to intensify or de-escalate treatment to individualize care. Lastly, MRD monitoring has been utilized successfully in detecting earlier relapse when compared to more standard methods of clinical surveillance such as radiographic assessment. Although not routinely implemented into clinical practice, MRD monitoring in lymphoma is helping shape the future landscape of this disease by aiding in prognostication, guiding therapy, and detecting earlier relapse. Steps to standardize and further examine this technology prospectively are being taken to bring MRD monitoring to the forefront of the field.
Topics: Humans; Neoplasm Recurrence, Local; Lymphoma; Prognosis; Circulating Tumor DNA; Recurrence; Neoplasm, Residual
PubMed: 37930608
DOI: 10.1007/s11899-023-00715-6 -
Trends in Cancer Jul 2023Tumor recurrence following potentially curative therapy constitutes a major obstacle to achieving cures in patients with cancer. Recurrent tumors frequently arise from a... (Review)
Review
Tumor recurrence following potentially curative therapy constitutes a major obstacle to achieving cures in patients with cancer. Recurrent tumors frequently arise from a population of residual cancer cells - also referred to as minimal residual disease (RD) or persister cells - that survive therapy and persist for prolonged periods prior to tumor relapse. While there has been significant recent progress in deciphering tumor-cell-intrinsic pathways that regulate residual cancer cell survival and recurrence, much less is known about how the tumor microenvironment (TME) of residual tumors impacts persister cancer cells or tumor recurrence. In this review, we highlight recent studies exploring the regulation and function of immune cells in RD and discuss therapeutic opportunities to target immune cells in residual tumors.
Topics: Humans; Neoplasm, Residual; Neoplasm Recurrence, Local; Cell Line, Tumor; Cell Survival; Tumor Microenvironment
PubMed: 37150627
DOI: 10.1016/j.trecan.2023.04.001 -
Annals of Oncology : Official Journal... May 2024KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
KEYNOTE-522 demonstrated statistically significant improvements in pathological complete response (pCR) with neoadjuvant pembrolizumab plus chemotherapy and event-free survival (EFS) with neoadjuvant pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab in patients with high-risk, early-stage triple-negative breast cancer (TNBC). Prior studies have shown the prognostic value of the residual cancer burden (RCB) index to quantify the extent of residual disease after neoadjuvant chemotherapy. In this preplanned exploratory analysis, we assessed RCB distribution and EFS within RCB categories by treatment group.
PATIENTS AND METHODS
A total of 1174 patients with stage T1c/N1-2 or T2-4/N0-2 TNBC were randomized 2 : 1 to pembrolizumab 200 mg or placebo every 3 weeks given with four cycles of paclitaxel + carboplatin, followed by four cycles of doxorubicin or epirubicin + cyclophosphamide. After surgery, patients received pembrolizumab or placebo for nine cycles or until recurrence or unacceptable toxicity. Primary endpoints are pCR and EFS. RCB is a prespecified exploratory endpoint. The association between EFS and RCB was assessed using a Cox regression model.
RESULTS
Pembrolizumab shifted patients into lower RCB categories across the entire spectrum compared with placebo. There were more patients in the pembrolizumab group with RCB-0 (pCR), and fewer patients in the pembrolizumab group with RCB-1, RCB-2, and RCB-3. The corresponding hazard ratios (95% confidence intervals) for EFS were 0.70 (0.38-1.31), 0.92 (0.39-2.20), 0.52 (0.32-0.82), and 1.24 (0.69-2.23). The most common first EFS events were distant recurrences, with fewer in the pembrolizumab group across all RCB categories. Among patients with RCB-0/1, more than half [21/38 (55.3%)] of all events were central nervous system recurrences, with 13/22 (59.1%) in the pembrolizumab group and 8/16 (50.0%) in the placebo group.
CONCLUSIONS
Addition of pembrolizumab to chemotherapy resulted in fewer EFS events in the RCB-0, RCB-1, and RCB-2 categories, with the greatest benefit in RCB-2. These findings demonstrate that pembrolizumab not only increased pCR rates, but also improved EFS among most patients who do not have a pCR.
Topics: Humans; Female; Antibodies, Monoclonal, Humanized; Triple Negative Breast Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Neoplasm, Residual; Middle Aged; Paclitaxel; Carboplatin; Neoadjuvant Therapy; Neoplasm Staging; Cyclophosphamide; Aged; Adult; Doxorubicin; Epirubicin; Progression-Free Survival; Chemotherapy, Adjuvant; Antineoplastic Agents, Immunological; Double-Blind Method
PubMed: 38369015
DOI: 10.1016/j.annonc.2024.02.002 -
Annals of Oncology : Official Journal... Dec 2023Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor...
Tumor-agnostic plasma assay for circulating tumor DNA detects minimal residual disease and predicts outcome in locally advanced squamous cell carcinoma of the head and neck.
BACKGROUND
Forty to fifty percent of patients with locally advanced squamous cell carcinoma of the head and neck (LA SCCHN) relapse despite multimodal treatment. Circulating tumor DNA (ctDNA) has the potential to detect minimal residual disease (MRD) after curative-intent therapy and to identify earlier which patients will progress. We developed a tumor-agnostic plasma ctDNA assay to detect MRD in unselected LA SCCHN with the aim of predicting progression-free survival (PFS) and overall survival without the need for tumor sequencing.
PATIENTS AND METHODS
A 26-gene next-generation sequencing panel was constructed that included the most frequently mutated genes in SCCHN and two HPV-16 genes. MRD was assessed in each patient through an in-house informatic workflow informed by somatic mutations identified in the corresponding pre-treatment plasma sample. The presence of MRD was defined as the detection of ctDNA in one plasma sample collected within 1-12 weeks of the end of curative treatment. The primary endpoint was the PFS rate at 2 years. At least 32 patients were planned for inclusion with the hypothesis that PFS at 2 years was >80% in MRD-negative patients and <30% in MRD-positive patients (α = 0.05, β = 0.9).
RESULTS
We sequenced DNA from 116 plasma samples derived from 53 LA SCCHN patients who underwent curative-intent treatment. ctDNA was detected in 41/53 (77%) patients in the pre-treatment samples. Out of these 41 patients, 17 (41%) were MRD positive after treatment. The 2-year PFS rate was 23.53% (9.9% to 55.4%) and 86.6% (73.4% to 100%) in MRD-positive and MRD-negative patients, respectively (P < 0.05). Median survival was 28.37 months (14.30 months-not estimable) for MRD-positive patients and was not reached for the MRD-negative cohort (P = 0.011).
CONCLUSIONS
Our ctDNA assay detects MRD in LA SCCHN and predicts disease progression and survival without the need for tumor sequencing, making this approach easily applicable in daily practice.
Topics: Humans; Squamous Cell Carcinoma of Head and Neck; Circulating Tumor DNA; Neoplasm, Residual; Neoplasm Recurrence, Local; Head and Neck Neoplasms; Biomarkers, Tumor
PubMed: 37879442
DOI: 10.1016/j.annonc.2023.09.3102 -
British Journal of Haematology Dec 2023
Review
Topics: Humans; Aged; Leukemia, Myeloid, Acute; Neoplasm, Residual
PubMed: 37822071
DOI: 10.1111/bjh.19135 -
Expert Review of Molecular Diagnostics 2023The advance of diagnostics and treatments has greatly improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, relapse and metastasis are still... (Review)
Review
INTRODUCTION
The advance of diagnostics and treatments has greatly improved the prognosis of non-small cell lung cancer (NSCLC) patients. However, relapse and metastasis are still common problems encountered by NSCLC patients who have achieved complete remission. Therefore, overcoming the challenge of relapse and metastasis is particularly important for improving the prognosis of NSCLC patients. Research has shown that minimal residual disease (MRD) was a potential source of tumor relapse and metastasis, and circulating tumor DNA (ctDNA) MRD has obvious advantages in predicting the relapse and metastasis of NSCLC and evaluating treatment effectiveness. Therefore, dynamic monitoring of MRD is of great significance for NSCLC patient management strategies.
AREAS COVERED
We have reviewed articles related to NSCLC MRD included in PubMed and describes the biological significance and historical context of MRD research, reasons for using ctDNA to evaluate MRD, and potential value and challenges of ctDNA MRD in assessing relapse and metastasis of NSCLC, ultimately guiding clinical therapeutic strategies and management.
EXPERT OPINION
The standardized scope of ctDNA MRD detection for NSCLC requires more clinical research evidence to minimize study differences, making it possible to include in the clinical staging as a reliable indicator.
Topics: Humans; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Lung Neoplasms; Neoplasm, Residual; Recurrence; Biomarkers, Tumor
PubMed: 37702546
DOI: 10.1080/14737159.2023.2252334