CtDNA: An emerging neoadjuvant biomarker in resectable solid tumors.
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ABSTRACT:
SUBMITTER: Abbosh C
PROVIDER: S-EPMC8509880 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The detection of circulating tumor DNA via liquid biopsy has become an important diagnostic test for patients with cancer. While certain commercial liquid biopsy platforms designed to detect circulating tumor DNA have been approved to guide clinical decisions in advanced solid tumors, the clinical utility of these assays for detecting minimal residual disease after curative-intent treatment of nonmetastatic disease is currently limited. Predicting disease response and relapse has considerable potential for increasing the effective implementation of neoadjuvant and adjuvant therapies. As a result, many companies are rapidly investing in the development of liquid biopsy platforms to detect circulating tumor DNA in the minimal residual disease setting. In this review, we discuss the development and clinical implementation of commercial liquid biopsy platforms for circulating tumor DNA minimal residual disease detection of solid tumors. Here, we aim to highlight the technological features that enable highly sensitive detection of tumor-derived genomic alterations, the factors that differentiate these commercial platforms, and the ongoing trials that seek to increase clinical implementation of liquid biopsies using circulating tumor DNA-based minimal residual disease detection.
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Project description:Definitive management of locoregionally advanced solid tumors presents a major challenge and often consists of a combination of surgical, radiotherapeutic and systemic therapy approaches. Upfront surgical treatment with or without adjuvant radiotherapy carries the risks of significant morbidities and potential complications that could be lasting. In addition, these patients continue to have a high risk of local or distant disease relapse despite the use of standard adjuvant therapy. Preoperative neoadjuvant systemic therapy has the potential to significantly improve clinical outcomes, particularly in this era of expanding immunotherapeutic agents that have transformed the care of patients with metastatic/unresectable malignancies. Tremendous progress has been made with neoadjuvant immunotherapy in the treatment of several locoregionally advanced resectable solid tumors leading to ongoing phase 3 trials and change in clinical practice. The promise of neoadjuvant immunotherapy has been supported by the high pathologic tumor response rates in early trials as well as the durability of these responses making cure a more achievable potential outcome compared with other forms of systemic therapy. Furthermore, neoadjuvant studies allow the assessment of radiologic and pathological responses and the access to biospecimens before and during systemic therapy. Pathological responses may guide future treatment decisions, and biospecimens allow the conduct of mechanistic and biomarker studies that may guide future drug development. On behalf of the National Cancer Institute Early Drug Development Neoadjuvant Immunotherapy Working Group, this article summarizes the current state of neoadjuvant immunotherapy of solid tumors focusing primarily on locoregionally advanced melanoma, gynecologic malignancies, gastrointestinal malignancies, non-small cell lung cancer and head and neck cancer including recent advances and our expert recommendations related to future neoadjuvant trial designs and associated clinical and translational research questions.
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Project description:The therapeutic landscape for patients with advanced malignancies has changed dramatically over the last twenty years. The growing number of targeted therapies and immunotherapeutic options available have improved response rates and survival for a subset of patients, however determining which patients will experience clinical benefit from these therapies in order to avoid potential toxicities and reduce healthcare costs remains a clinical challenge. Cell-free circulating tumor DNA (ctDNA) is shed by tumor cells into systemic circulation and is already an integral part of routine clinical practice for the non-invasive tumor genotyping in advanced non-small cell lung cancer as well as other malignancies. The short half-life of ctDNA offers a unique opportunity to utilize early on-treatment changes in ctDNA for real-time assessment of therapeutic response and outcome, termed molecular response. Here, we provide a summary and review of the use of molecular response for the prediction of outcomes in patients with advanced cancer, including the current state of science, its application in clinic, and next steps for the development of this predictive tool.
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Project description:The Abelson (ABL) tyrosine kinases were identified as drivers of leukemia in mice and humans. Emerging data has shown a role for the ABL family kinases, ABL1 and ABL2, in the progression of several solid tumors. This review will focus on recent reports of the involvement of the ABL kinases in tumor progression using mouse models as well as recent data generated from genomic and proteomic studies linking enhanced expression and hyper-activation of the ABL kinases to some human cancers. Preclinical studies on small molecule inhibitors of the ABL kinases suggest that their use may have beneficial effects for the treatment of selected solid tumors.
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Project description:Irreversible electroporation (IRE), a novel non-thermal ablation technique, is utilized to ablate unresectable solid tumors and demonstrates favorable safety and efficacy in the clinic. IRE applies electric pulses to alter the cell transmembrane voltage and causes nanometer-sized membrane defects or pores in the cells, which leads to loss of cell homeostasis and ultimately results in cell death. The major drawbacks of IRE are incomplete ablation and susceptibility to recurrence, which limit its clinical application. Recent studies have shown that IRE promotes the massive release of intracellular concealed tumor antigens that become an "in-situ tumor vaccine," inducing a potential antitumor immune response to kill residual tumor cells after ablation and inhibiting local recurrence and distant metastasis. Therefore, IRE can be regarded as a potential immunomodulatory therapy, and combined with immunotherapy, it can exhibit synergistic treatment effects on malignant tumors, which provides broad application prospects for tumor treatment. This work reviewed the current status of the clinical efficacy of IRE in tumor treatment, summarized the characteristics of local and systemic immune responses induced by IRE in tumor-bearing organisms, and analyzed the specific mechanisms of the IRE-induced immune response. Moreover, we reviewed the current research progress of IRE combined with immunotherapy in the treatment of solid tumors. Based on the findings, we present deficiencies of current preclinical studies of animal models and analyze possible reasons and solutions. We also propose possible demands for clinical research. This review aimed to provide theoretical and practical guidance for the combination of IRE with immunotherapy in the treatment of malignant tumors.
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Project description:Neoadjuvant chemotherapy (NCT) is a standard care for esophageal squamous cell carcinoma (ESCC), but the efficacy is unsatisfactory. Cancer stem cells (CSCs) play key roles in chemotherapy resistance. Gene amplified in squamous cell carcinoma 1 (GASC1) is a neoteric gene in stemness maintaining of ESCC. We aimed to reveal whether GASC1 could be a predictive biomarker for NCT in ESCC. ESCC patients (T2-4N0-2M0) were evaluated for GASC1 expression using immunohistochemical staining and classified as GASC1-low group (GLG) and GASC1-high group (GHG). NCT was delivered in two cycles and then the surgery was completed. Primary endpoints were tumor regression grade (TRG) and objective response rate (ORR); secondary endpoints were radical surgical resection (R0) rate and three-year overall survival (OS). 60 patients were eligible with evaluable outcomes: 24 in GHG and 36 in GLG. Between GHG and GLG, TRG1, TRG2, TRG3, and TRG4 were 0 : 16.7%, 20.8% : 41.7%, 58.3% : 36.1%, and 20.8% : 5.6%, respectively (P=0.006); ORR and R0 rate were 33.3% : 69.4% (P=0.006) and 75% : 94.4% (P=0.046), respectively; the median OS was 20 : 32 (months) (P=0.0356). No significant difference in the three-year OS was observed between GHG and GLG: 29.2% : 41.7% (P=0.24). Furthermore, the GASC1 expression level was associated with poor OS independent of other factors by univariate and multivariate analyses. Therefore, GASC1 might be a potential biomarker to predict NCT efficacy for ESCC.
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Project description:ObjectiveCirculating tumor DNA (ctDNA) offers a minimally-invasive alternative to study genomic changes in recurrent malignancies. With a high recurrence rate, the overall survival in high-grade serous ovarian carcinoma (HGSC) has remained low. Our objectives were to determine whether ctDNA from plasma adequately represents HGSC, and to find mutational changes at relapse suggesting therapy options that could alter patient outcome.MethodsWe collected 152 longitudinal plasma and 92 fresh tissue samples from 29 HGSC patients, sequencing and detecting mutations with a gene panel of more than 700 cancer-related genes. Tumor content was measured using TP53 VAF. We analyzed the concordance between the mutations in tissue and plasma samples and calculated correlations to patient outcomes. We also searched for novel mutations appearing at relapse.ResultsThe concordance rate between mutations in plasma compared to tumor tissue was 83 % at diagnosis and 90 % at relapse. CtDNA was released similarly from the tubo-ovarian tumors, intra-abdominal metastases and ascites. CtDNA release was high when CA-125 level was elevated. The TP53 VAF in ctDNA from plasma samples before the third cycle of primary chemotherapy showed a negative correlation to patient outcome. At relapse, 19 novel, pathogenic DNA mutations appeared, suggesting possible actionable alterations and biological mechanisms related to chemoresistance.ConclusionRelapse ctDNA samples reflect tissue samples well and longitudinal sampling provides a timely source for mutational profiling. The emerging genetic mutations at recurrence propose that ctDNA accurately represents the widespread disease and provides possibilities for personalized therapy options.
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Project description:The relatively low success rate of phase II oncology trials in predicting success of novel drugs in phase III trials and in gaining regulatory approval may be due to reliance on the endpoint of response rate defined by the RECIST. The neoadjuvant treatment paradigm allows the antitumor activity of a novel therapy to be determined on a pathologic basis at the time of surgery instead of by RECIST, which was not developed to guide clinical decision making or correlate with long-term outcomes. Indeed, the FDA endorsed pathologic complete response (pCR) as a surrogate for overall survival (OS) in early-stage breast cancer and granted accelerated approval to pertuzumab based on this endpoint. We propose that pCR is a biologically rational method of determining treatment effect that may be more likely to predict OS. We discuss some advantages of the neoadjuvant trial design, review the use of neoadjuvant therapy as standards of care, and consider the neoadjuvant platform as a method for drug development. Clin Cancer Res; 22(10); 2323-8. ©2016 AACR.
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Project description:BackgroundNeoadjuvant therapy for resectable gastric cancer/gastroesophageal junction tumors is progressing slowly. Although immunotherapy for advanced gastric cancer/gastroesophageal junction tumors has made great progress, the efficacy and safety of neoadjuvant immunotherapy for locally resectable gastric cancer/gastroesophageal junction tumors have not been clearly demonstrated. Here, we conducted a systematic review and meta-analysis to assess the efficacy and safety of neoadjuvant immunotherapy and advance the current research.MethodsOriginal articles describing the safety and efficacy of neoadjuvant immunotherapy for resectable gastric cancer/gastroesophageal junction tumors published up until October 15, 2023 were retrieved from PubMed, Embase, the Cochrane Library, and other major databases. The odds ratios (OR) and 95% confidence intervals (CIs) were calculated for heterogeneity and subgroup analysis.ResultsA total of 1074 patients from 33 studies were included. The effectiveness of neoadjuvant immunotherapy was mainly evaluated using pathological complete remission (PCR), major pathological remission (MPR), and tumor regression grade (TRG). Among the included patients, 1015 underwent surgical treatment and 847 achieved R0 resection. Of the patients treated with neoadjuvant immunotherapy, 24% (95% CI: 19%-28%) achieved PCR and 49% (95% CI: 38%-61%) achieved MPR. Safety was assessed by a surgical resection rate of 0.89 (95% CI: 85%-93%), incidence of ≥ 3 treatment-related adverse events (TRAEs) of 28% (95% CI: 17%-40%), and incidence of ≥ 3 immune-related adverse events (irAEs) of 19% (95% CI: 11%-27%).ConclusionNeoadjuvant immunotherapy, especially neoadjuvant dual-immunotherapy combinations, is effective and safe for resectable gastric/gastroesophageal junction tumors in the short term. Nevertheless, further multicenter randomized trials are required to demonstrate which combination model is more beneficial.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=358752, identifier CRD42022358752.
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Project description:Neoadjuvant chemotherapy (NAC) significantly improved the prognosis of patients with locally advanced resectable gastric cancer but, despite important progresses, relapse-related death remains a major challenge. Therefore, it appears crucial to understand which patients will benefit from peri-operative treatment. Biomarkers such as human epidermal growth factor receptor-2 (HER2), microsatellite instability (MSI), and Epstein-Barr Virus (EBV) have been widely studied; however, they do not yet guide the choice of perioperative treatment in clinical practice. We performed a narrative review, including 23 studies, addressing the value of tissue- or blood-based biomarkers in the neoadjuvant setting. Ten studies (43.5%) were prospective, and more than half were conducted in East-Asia. Biomarkers were evaluated only post-NAC (on surgical samples or blood) in seven studies (30.4%), only pre-NAC (on endoscopic specimens or blood) in 10 studies (43.5%), and both pre- and post-NAC (26.1%) in six studies. Among the high variety of investigated biomarkers, some of these including MSI-H or enzymatic profile (as TS, UGT1A1, MTHFR, ERCC or XRCC) showed promising results and deserve to be assessed in methodologically sound clinical trials. The identification of molecular biomarkers in patients treated with NAC for locally advanced resectable gastric or EGJ cancer remains crucial.
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