-
Lancet (London, England) Jun 2023Progress in acute myeloid leukaemia treatment is occurring at an unprecedented pace. The past decade has witnessed an increasingly improved scientific understanding of... (Review)
Review
Progress in acute myeloid leukaemia treatment is occurring at an unprecedented pace. The past decade has witnessed an increasingly improved scientific understanding of the underlying biology of acute myeloid leukaemia, leading to enhanced prognostication tools and refined risk assessments, and most especially incorporating measurable residual disease (MRD) into longitudinal risk assessments. The classification of acute myeloid leukaemia has recently been updated by WHO and the International Consensus Classification (ICC). Recommendations for prognostic stratification, response assessment, and MRD determination have also been updated by the European LeukemiaNet. Treatment options have evolved substantially in the last 5 years for patients with newly diagnosed acute myeloid leukaemia, leading to improved outcomes in intensively treated patients and those more appropriate for non-intensive chemotherapy. More effective targeted treatment options in the relapsed setting are also available, further advancing the treatment armamentarium and improving patient outcomes.
Topics: Humans; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute; Treatment Outcome; Prognosis; Risk Assessment; Neoplasm, Residual
PubMed: 37068505
DOI: 10.1016/S0140-6736(23)00108-3 -
Cancer Discovery Dec 2021Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results... (Review)
Review
UNLABELLED
Growing evidence demonstrates that circulating tumor DNA (ctDNA) minimal residual disease (MRD) following treatment for solid tumors predicts relapse. These results suggest that ctDNA MRD could identify candidates for adjuvant therapy and measure response to such treatment. Importantly, factors such as assay type, amount of ctDNA release, and technical and biological background can affect ctDNA MRD results. Furthermore, the clinical utility of ctDNA MRD for treatment personalization remains to be fully established. Here, we review the evidence supporting the value of ctDNA MRD in solid cancers and highlight key considerations in the application of this potentially transformative biomarker.
SIGNIFICANCE
ctDNA analysis enables detection of MRD and predicts relapse after definitive treatment for solid cancers, thereby promising to revolutionize personalization of adjuvant and consolidation therapies.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Humans; Neoplasm Recurrence, Local; Neoplasm, Residual
PubMed: 34785539
DOI: 10.1158/2159-8290.CD-21-0634 -
Nature Reviews. Clinical Oncology Jul 2019Liquid biopsy has been introduced as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in... (Review)
Review
Liquid biopsy has been introduced as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in particular, cell-free tumour DNA (ctDNA). Highly sensitive liquid biopsy assays have been developed that can now be applied to detect and characterize minimal residual disease (MRD), which reflects the presence of tumour cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumour cells left behind after local therapy that eventually lead to local recurrence. This application is the new frontier of liquid biopsy analyses, which are challenged by the very low concentrations of CTCs and ctDNA in blood samples. In this Review, we discuss the key technologies that can be used to detect and characterize CTCs in surveillance of MRD and provide a brief overview of similar roles of ctDNA analyses. We then focus on the current clinical data on the use of CTCs and ctDNA in the detection and monitoring of MRD and in obtaining information on therapeutic targets and resistance mechanisms relevant to the management of individual patients with cancer.
Topics: Cell-Free Nucleic Acids; Humans; Liquid Biopsy; Neoplasm, Residual; Neoplastic Cells, Circulating; Precision Medicine; Prognosis
PubMed: 30796368
DOI: 10.1038/s41571-019-0187-3 -
Journal of Hematology & Oncology Dec 2019The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most... (Review)
Review
The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells' ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity-the driving force behind minimal residual disease-is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.
Topics: Biomarkers, Tumor; Drug Resistance, Neoplasm; Genetic Heterogeneity; Humans; Lung Neoplasms; Neoplasm, Residual; Prognosis; Protein Kinase Inhibitors
PubMed: 31815659
DOI: 10.1186/s13045-019-0818-2 -
Annals of Oncology : Official Journal... Feb 2023Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed... (Randomized Controlled Trial)
Randomized Controlled Trial
Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer.
BACKGROUND
Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)].
PATIENTS AND METHODS
c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961).
RESULTS
Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance.
CONCLUSIONS
c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.
Topics: Humans; Biomarkers, Tumor; Mutation; Neoplasm Recurrence, Local; Prospective Studies; Triple Negative Breast Neoplasms; Neoplasm, Residual; Antineoplastic Agents, Immunological; Circulating Tumor DNA
PubMed: 36423745
DOI: 10.1016/j.annonc.2022.11.005 -
Clinical Cancer Research : An Official... Aug 2022We assessed whether perioperative circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of...
PURPOSE
We assessed whether perioperative circulating tumor DNA (ctDNA) could be a biomarker for early detection of molecular residual disease (MRD) and prediction of postoperative relapse in resected non-small cell lung cancer (NSCLC).
EXPERIMENTAL DESIGN
Based on our prospective, multicenter cohort on dynamic monitoring of ctDNA in lung cancer surgery patients (LUNGCA), we enrolled 950 plasma samples obtained at three perioperative time points (before surgery, 3 days and 1 month after surgery) of 330 stage I-III NSCLC patients (LUNGCA-1), as a part of the LUNGCA cohort. Using a customized 769-gene panel, somatic mutations in tumor tissues and plasma samples were identified with next-generation sequencing and utilized for ctDNA-based MRD analysis.
RESULTS
Preoperative ctDNA positivity was associated with lower recurrence-free survival (RFS; HR = 4.2; P < 0.001). The presence of MRD (ctDNA positivity at postoperative 3 days and/or 1 month) was a strong predictor for disease relapse (HR = 11.1; P < 0.001). ctDNA-based MRD had a higher relative contribution to RFS prediction than all clinicopathologic variables such as the TNM stage. Furthermore, MRD-positive patients who received adjuvant therapies had improved RFS over those not receiving adjuvant therapy (HR = 0.3; P = 0.008), whereas MRD-negative patients receiving adjuvant therapies had lower RFS than their counterparts without adjuvant therapy (HR = 3.1; P < 0.001). After adjusting for clinicopathologic variables, whether receiving adjuvant therapies remained an independent factor for RFS in the MRD-positive population (P = 0.002) but not in the MRD-negative population (P = 0.283).
CONCLUSIONS
Perioperative ctDNA analysis is effective in early detection of MRD and relapse risk stratification of NSCLC, and hence could benefit NSCLC patient management.
Topics: Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Circulating Tumor DNA; Humans; Lung Neoplasms; Mutation; Neoplasm Recurrence, Local; Neoplasm, Residual; Prospective Studies
PubMed: 34844976
DOI: 10.1158/1078-0432.CCR-21-3044 -
Lancet (London, England) Jan 2023S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
S-1 has shown promising efficacy with a mild toxicity profile in patients with advanced biliary tract cancer. The aim of this study was to evaluate whether adjuvant S-1 improved overall survival compared with observation for resected biliary tract cancer.
METHODS
This open-label, multicentre, randomised phase 3 trial was conducted in 38 Japanese hospitals. Patients aged 20-80 years who had histologically confirmed extrahepatic cholangiocarcinoma, gallbladder carcinoma, ampullary carcinoma, or intrahepatic cholangiocarcinoma in a resected specimen and had undergone no local residual tumour resection or microscopic residual tumour resection were randomly assigned (1:1) to undergo observation or to receive S-1 (ie, 40 mg, 50 mg, or 60 mg according to body surface area, orally administered twice daily for 4 weeks, followed by 2 weeks of rest for four cycles). Randomisation was performed by the minimisation method, using institution, primary tumour site, and lymph node metastasis as adjustment factors. The primary endpoint was overall survival and was assessed for all randomly assigned patients on an intention-to-treat basis. Safety was assessed in all eligible patients. For the S-1 group, all patients who began the protocol treatment were eligible for a safety assessment. This trial is registered with the University hospital Medical Information Network Clinical Trials Registry (UMIN000011688).
FINDINGS
Between Sept 9, 2013, and June 22, 2018, 440 patients were enrolled (observation group n=222 and S-1 group n=218). The data cutoff date was June 23, 2021. Median duration of follow-up was 45·4 months. In the primary analysis, the 3-year overall survival was 67·6% (95% CI 61·0-73·3%) in the observation group compared with 77·1% (70·9-82·1%) in the S-1 group (adjusted hazard ratio [HR] 0·69, 95% CI 0·51-0·94; one-sided p=0·0080). The 3-year relapse-free survival was 50·9% (95% CI 44·1-57·2%) in the observation group compared with 62·4% (55·6-68·4%) in the S-1 group (HR 0·80, 95% CI 0·61-1·04; two-sided p=0·088). The main grade 3-4 adverse events in the S-1 group were decreased neutrophil count (29 [14%]) and biliary tract infection (15 [7%]).
INTERPRETATION
Although long-term clinical benefit would be needed for a definitive conclusion, a significant improvement in survival suggested adjuvant S-1 could be considered a standard of care for resected biliary tract cancer in Asian patients.
FUNDING
The National Cancer Center Research and the Ministry of Health, Labour, and Welfare of Japan.
Topics: Humans; Neoplasm, Residual; Chemotherapy, Adjuvant; Neoplasm Recurrence, Local; Biliary Tract Neoplasms; Proportional Hazards Models; Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36681415
DOI: 10.1016/S0140-6736(22)02038-4 -
Nature Biotechnology Dec 2021Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for...
Circulating tumor-derived DNA (ctDNA) is an emerging biomarker for many cancers, but the limited sensitivity of current detection methods reduces its utility for diagnosing minimal residual disease. Here we describe phased variant enrichment and detection sequencing (PhasED-seq), a method that uses multiple somatic mutations in individual DNA fragments to improve the sensitivity of ctDNA detection. Leveraging whole-genome sequences from 2,538 tumors, we identify phased variants and their associations with mutational signatures. We show that even without molecular barcodes, the limits of detection of PhasED-seq outperform prior methods, including duplex barcoding, allowing ctDNA detection in the ppm range in participant samples. We profiled 678 specimens from 213 participants with B cell lymphomas, including serial cell-free DNA samples before and during therapy for diffuse large B cell lymphoma. In participants with undetectable ctDNA after two cycles of therapy using a next-generation sequencing-based approach termed cancer personalized profiling by deep sequencing, an additional 25% have ctDNA detectable by PhasED-seq and have worse outcomes. Finally, we demonstrate the application of PhasED-seq to solid tumors.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; High-Throughput Nucleotide Sequencing; Humans; Mutation; Neoplasm, Residual
PubMed: 34294911
DOI: 10.1038/s41587-021-00981-w -
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