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Background:
There is currently a lack of effective biomarkers to evaluate efficacy of neoadjuvant therapy (NAT) for resectable non-small cell lung cancer (NSCLC) patients. Circulating tumor DNA (ctDNA) has been investigated as a non-invasive tool for the assessment of tumor burden and minimal residual disease (MRD). The utility of ctDNA profiling...
Context in source publication
Context 1
... the neoadjuvant setting, 12 cases were treated with IO+Chemo, 4 with IO+IO, and 6 with Chemo. The clinicopathological characteristics of cases are summarized in Table 1. We performed NGS on baseline plasma and paired WBC samples, which identified 71 mutations from the entire cohort (n=22). ...Similar publications
![Patient demographics and tumor characteristics [n = 279]](publication/362785626/figure/tbl1/AS:11431281079802269@1660871754712/Patient-demographics-and-tumor-characteristics-n-279_Q320.jpg)
Introduction
Tumor agnostic circulating tumor DNA (ctDNA) is routinely used to guide treatment decisions in gastrointestinal (GI) cancers, especially metastatic cancers. The amount of ctDNA detected in plasma is affected by stage, tumor burden, and tumor vascularization. We hypothesized that peritoneal carcinomatosis (PC) is associated with lower c...
Noninvasive disease monitoring and risk stratification by circulating tumor DNA (ctDNA) profiling has become a potential novel strategy for patient management in B-cell lymphoma. Emerging innovative therapeutic options and an unprecedented growth in our understanding of biological and molecular factors underlying lymphoma heterogeneity have fundame...
Circulating tumor DNA (ctDNA) has contributed immensely to the management of hematologic malignancy and is now considered a valuable detection tool for solid tumors. ctDNA can reflect the real-time tumor burden and be utilized for analyzing specific cancer mutations via liquid biopsy which is a non-invasive procedure that can be used with a relativ...
Circulating tumor DNA (ctDNA) detection holds promise for genetic analyses and quantitative assessment of tumor burden. A systematic review and meta-analysis were conducted to investigate the clinical relevance of ctDNA among patients with localized non-small cell lung cancer (NSCLC). PubMed, EMBASE, and the Cochrane Library were searched for eligi...
Simple Summary
Early-stage disease non-small cell lung cancer has better outcomes than advanced disease, but 5-year survival rates can drop to approximately 50% in cases of increased tumor size, local extension, or nodal spread. The use of liquid biopsies to enhance diagnosis, optimize perioperative systemic treatments, and allow early detection of...
Citations
... In another small study, including 22 patients with tumors resected after chemotherapy, immunotherapy or a combination thereof, changes in ctDNA (measured as a RΔmean VAF) were also concordant with pathologic response. 59 In addition, in the single-arm phase II LCMC3 trial, ctDNA reductions post-atezolizumab correlated with pathologic response (P = 0.0001, r = 0.38). 60 These data highlight the possibility to use ctDNA in evaluating neoadjuvant therapy efficacy and its potential as a surrogate marker for pCR. ...
In around 30% of patients, non-small cell lung cancer is diagnosed at an advanced but resectable stage. Adding systemic therapy has shown clear benefit over surgery alone in locally advanced disease, and currently, chemo-immunotherapy in the adjuvant or neoadjuvant setting is the new standard for patients without targetable mutations. One major advantage of the neoadjuvant approach is the possibility of an immediate evaluation of the treatment effect, highlighting the role of pathology as an important contributor at the forefront of clinical decision-making and research. This review provides a summary and an update on current guidelines for histological evaluation of treatment effect after neoadjuvant therapy, also known as regression grading, and discusses newer data focusing on areas of evolving questions and controversies, such as the gross examination of the tumor and tumor bed, weighted versus unweighted evaluation approaches, discussion of histologic tumor type-specific cut-offs for major pathologic response, assessment of lymph nodes and regression grading after immunotherapy and targeted therapy. As no data or recommendations exist on regression grading of multiple tumor nodules, a practical approach is recommended. Lastly, we will touch on additional tissue biomarkers and summarize recent advances in the ardently discussed field of using circulating tumor DNA for the evaluation of treatment response.
... The correlation of ctDNA to the treatment response and prognostic significance in the context of neoadjuvant therapy or definitive radiation therapy have also been explored in NSCLC patients. Yue et al. reported a robust correlation between ctDNA dynamics during neoadjuvant therapy and the pathological response with pre-and post-surgery ctDNA levels associated with low RFS (HR = 7.41 and 5.37, respectively) [57]. Another study showed that ctDNA levels following neoadjuvant treatment were significantly linked to OS and surpassed radiological evaluations for survival prediction [58]. ...
Circulating tumor DNA (ctDNA) is the fraction of cell-free DNA in patient blood that originates from a tumor. Advances in DNA sequencing technologies and our understanding of the molecular biology of tumors have increased interest in exploiting ctDNA to facilitate detection of molecular residual disease (MRD). Analysis of ctDNA as a promising MRD biomarker of solid malignancies has a central role in precision medicine initiatives exemplified by our CIRCULATE-Japan project involving patients with resectable colorectal cancer. Notably, the project underscores the prognostic significance of the ctDNA status at 4 weeks post-surgery and its correlation to adjuvant therapy efficacy at interim analysis. This substantiates the hypothesis that MRD is a critical prognostic indicator of relapse in patients with colorectal cancer. Despite remarkable advancements, challenges endure, primarily attributable to the exceedingly low ctDNA concentration in peripheral blood, particularly in scenarios involving low tumor shedding and the intrinsic error rates of current sequencing technologies. These complications necessitate more sensitive and sophisticated assays to verify the clinical utility of MRD across all solid tumors. Whole genome sequencing (WGS)-based tumor-informed MRD assays have recently demonstrated the ability to detect ctDNA in the parts-per-million range. This review delineates the current landscape of MRD assays, highlighting WGS-based approaches as the forefront technique in ctDNA analysis. Additionally, it introduces our upcoming endeavor, WGS-based pan-cancer MRD detection via ctDNA, in our forthcoming project, SCRUM-Japan MONSTAR-SCREEN-3.
... Among the 11 prospective observational studies selected for the present meta-analysis, 4 studies (Provencio et al. 2022;Gale et al. 2022;Tan et al. 2021;Waldeck et al. 2022) were conducted with the European population and 7 studies (Xia et al. 2022;Peng et al. 2020;Qiu et al. 2021;Li et al. 2022;Zhang et al. 2022;Yue et al. 2022;Chen et al. 2022) were conducted with the Asian population. Irrespective of the pathological types of NSCLC, LUAD accounted for a significant proportion (73%) in the study population, while lung squamous carcinoma (LUSC) accounted for just 20%. ...
... Irrespective of the pathological types of NSCLC, LUAD accounted for a significant proportion (73%) in the study population, while lung squamous carcinoma (LUSC) accounted for just 20%. In regard to NSCLC staging, Provencio et al. (2022) focused only on stage III NSCLC patients, Chen et al. (2022) limited their evaluation to patients with stage I NSCLC, and the remaining nine studies (Gale et al. 2022;Xia et al. 2022;Tan et al. 2021;Waldeck et al. 2022;Peng et al. 2020;Qiu et al. 2021;Li et al. 2022;Zhang et al. 2022;Yue et al. 2022) included patients with stage I-III NSCLC. In addition to surgery, neoadjuvant therapy (NAT) was stated in the full text of three studies (Provencio et al. 2022;Zhang et al. 2022;Yue et al. 2022), among which the study of Zhang et al. (2022) was excluded due to a lack of detailed data. ...
... In regard to NSCLC staging, Provencio et al. (2022) focused only on stage III NSCLC patients, Chen et al. (2022) limited their evaluation to patients with stage I NSCLC, and the remaining nine studies (Gale et al. 2022;Xia et al. 2022;Tan et al. 2021;Waldeck et al. 2022;Peng et al. 2020;Qiu et al. 2021;Li et al. 2022;Zhang et al. 2022;Yue et al. 2022) included patients with stage I-III NSCLC. In addition to surgery, neoadjuvant therapy (NAT) was stated in the full text of three studies (Provencio et al. 2022;Zhang et al. 2022;Yue et al. 2022), among which the study of Zhang et al. (2022) was excluded due to a lack of detailed data. Postoperative AT was stated in the full text of ten studies (Provencio et al. 2022;Gale et al. 2022;Xia et al. 2022;Tan et al. 2021;Waldeck et al. 2022;Peng et al. 2020;Qiu et al. 2021;Zhang et al. 2022;Li et al. 2022;Chen et al. 2022), among which four studies (Gale et al. 2022;Xia et al. 2022;Waldeck et al. 2022;Qiu et al. 2021) were finally included in the meta-analysis based on the availability of raw data. ...
Background
Several recent studies have reported the increasing application of preoperative circulating tumor DNA (ctDNA) as a biomarker of tumor burden for guiding potential postoperative treatment strategies.
Methods
A meta-analysis of prospective/retrospective cohort studies was conducted to compare the prognosis of preoperatively genetically positive and genetically negative NSCLC patients. The endpoints used in the included studies were overall survival (OS) and recurrence-free survival (RFS). The objective of the meta-analysis was to comprehensively explore the prognostic value of preoperative ctDNA for patients with non-small-cell lung cancer (NSCLC) and its significance in guiding postoperative adjuvant therapy (AT) in patients with NSCLC.
Results
The preliminary analysis identified 1565 studies, among which only 11 studies fulfilled the eligibility criteria and were finally included in the present systematic review and meta-analysis. The statistical results revealed that the expression of preoperative ctDNA was associated with worse RFS (HR = 3.00; 95% CI 2.26–3.98; I² = 0%) and OS (HR = 2.77; 95% CI 1.67–4.58; I² = 0%), particularly in lung adenocarcinoma (LUAD) patients (RFS: HR = 3.46; 95% CI 2.37–5.05; I² = 0%; OS: HR = 3.52; 95% CI 1.91–6.49; I² = 0%) and patients with I–II stage of NSCLC (RFS: HR = 2.84; 95% CI 1.88–4.29; I² = 0%; OS: HR = 2.60; 95% CI 1.43–4.74; I² = 0%). Moreover, compared to patients with negative preoperative ctDNA, patients with positive preoperative ctDNA presented greater survival benefits (HR = 0.39; 95% CI 0.22–0.67; I² = 2%) from postoperative AT.
Conclusion
The evaluation of the prognostic value of preoperative ctDNA revealed that preoperative ctDNA might be used as a prognostic biomarker for patients with LUAD or those with stage I–II NSCLC. In addition, postoperative AT is recommended for NSCLC patients with positive preoperative ctDNA, regardless of the disease stage and subtype.
... Questions remain with regards to which patients will benefit the most, especially since PD-L1 status and pathological response seem to be related to outcome. Furthermore, compelling evidence have demonstrated the role of circulating tumour DNA as a potential biomarker to predict neoadjuvant immunotherapy efficacy and to predict recurrence free-survival in resectable disease (67)(68)(69). Another ongoing challenge is the precise identification of NSCLC patients that could benefit from adjuvant chemotherapy. ...
Lung cancer is the leading cause of cancer mortality in the world. It greatly affects the patients’ quality of life, being a challenge for the daily practice in Respiratory Medicine. Advances in the genetic knowledge of thoracic tumours mutational landscape, the development of targeted therapies and immune checkpoint inhibitors, led to a paradigm shift in the treatment of lung cancer and pleural mesothelioma. During the annual ERS Congress in Milan, Italy, experts from all over the world presented their high-quality research and reviewed best clinical practices. Lung cancer screening, management of early-stages of lung cancer, application of artificial intelligence and biomarkers were discussed and they will be summarised here.
... 28 Recent studies indicate ctDNA may be a valuable tool in assessing response to neoadjuvant therapies. 29,30 miRNA is another biomarker which has recently emerged as a promising candidate for fast and minimally invasive detection of early-stage lung cancers. 31 As assays for detecting biomarkers via liquid biopsy continue to improve, analysis of ctDNA and miRNA are likely to play a larger role in screening and caring for early-stage lung cancers. ...
Many changes have occurred in the field of thoracic surgery over the last several years. In this review, we will discuss new diagnostic techniques for lung cancer, innovations in surgery, and major updates on latest treatment options including immunotherapy. All these have significantly started to change our approach toward the management of lung cancer and have great potential to improve the lives of our patients afflicted with this disease.
... Recently, this question has been investigated. Some publications with comparatively small sample sizes fail to identify the prognostic role of ctDNA [9][10][11]. Nevertheless, most of the studies present positive results. ...
... Among them, 7 abstract studies without specified survival data were included in the systematic review, [15][16][17][18][19][20][21]. 15 fulllength articles were included in the IPD-based synthesis, [10][11][12][13][22][23][24][25][26][27][28][29][30][31][32] and 20 studies with detailed survival data were included in the conventional synthesis of HRs (95% CI) [9][10][11][12][13][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. A full-length study by Zhao X et al. [22], which reported survival outcomes of 7 patients without HR (95% CI), was only included in the IPD-based synthesis. ...
... Among them, 7 abstract studies without specified survival data were included in the systematic review, [15][16][17][18][19][20][21]. 15 fulllength articles were included in the IPD-based synthesis, [10][11][12][13][22][23][24][25][26][27][28][29][30][31][32] and 20 studies with detailed survival data were included in the conventional synthesis of HRs (95% CI) [9][10][11][12][13][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37]. A full-length study by Zhao X et al. [22], which reported survival outcomes of 7 patients without HR (95% CI), was only included in the IPD-based synthesis. ...
Background
This reconstructed individual patient data (IPD)-based meta-analysis is aimed to summarize the current findings and comprehensively investigate the predictive value of circulating tumor DNA (ctDNA) in operable non-small cell lung cancer (NSCLC).
Methods
PubMed, Cochrane and Embase were searched to include potentially eligible studies. The primary outcomes included progression-free survival (DFS) by ctDNA status at baseline, postoperative, and longitudinal timepoints. The IPD-based survival data was retracted and used in reconstructed IPD-based meta-analysis. Subgroup analysis was implemented based on the baseline characteristics.
Results
Totally, 28 studies were involved, including 15 full-length articles (1686 patients) for IPD-based synthesis and 20 studies for conventional meta-analysis. The IPD-based meta-analysis discovered that patients with positive ctDNA status at the baseline (hazard ratio, HR = 3.73, 95% confidential interval, CI: 2.95–4.72), postoperative (3.96, 2.19–7.16), or longitudinal timepoints (12.33, 8.72–17.43) showed significantly higher risk of recurrence. Patients with persistent ctDNA-negative status had the lowest recurrence rate, and the negative conversion of ctDNA from baseline to postoperative timepoints was correlated with elevated DFS. Subgroup analyses suggested that stage II–III patients with ctDNA-positive status may achieve preferable therapeutic outcomes.
Conclusions
Plasm ctDNA monitoring shows excellent clinical significance at the tested timepoints. Perioperative conversion of ctDNA status may indicate the therapeutic effect of radical surgery. Postoperative adjuvant therapy may be determined according to the ctDNA status.
Trail registration
CRD42022304445.
... De-escalation of chemotherapy via utilizing cfDNA monitoring is a strategy under investigation in multiple cancer types 7 . In the neoadjuvant setting, clearance of ctDNA after neoadjuvant therapy correlates with pathologic complete response 37,38 . Our patient's rapid initial decline in tumorassociated variants was reassuring for a good clinical response to chemotherapy and contributed to the decision to transition to maintenance immunotherapy. ...
The rising utilization of circulating tumor DNA (ctDNA) assays in Precision Oncology may incidentally detect genetic material from secondary sources. It is important that such findings are recognized and properly leveraged for both diagnosis and monitoring of response to treatment. Here, we report a patient in whom serial cell-free DNA (cfDNA) monitoring for his known prostate adenocarcinoma uncovered the emergence of an unexpected FGFR3-TACC3 gene fusion, a BRCA1 frameshift mutation, and other molecular abnormalities. Due to the rarity of FGFR3 fusions in prostate cancer, a workup for a second primary cancer was performed, leading to the diagnosis of an otherwise-asymptomatic urothelial carcinoma (UC). Once UC-directed treatment was initiated, the presence of these genetic abnormalities in cfDNA allowed for disease monitoring and early detection of resistance, well before radiographic progression. These findings also uncovered opportunities for targeted therapies against FGFR and BRCA1. Overall, this report highlights the multifaceted utility of longitudinal ctDNA monitoring in early cancer diagnosis, disease prognostication, therapeutic target identification, monitoring of treatment response, and early detection of emergence of resistance.
... A retrospective study of 22 patients with stage IB-IIIA NSCLC who received neoadjuvant therapy showed that the results of ctDNA dynamic analysis were highly consistent with postoperative pathologic evaluation; that patients with positive ctDNA at 3 to 8 days after surgery had relatively high recurrence risk (HR = 5.37); and that the molecular recurrence prediction based on ctDNA NGS detection was 6.83 months earlier, compared with the median time of assessment by imaging criteria. 33 Therefore, more studies with larger patient populations and multiple different post-treatment time points are needed to better understand ctDNA MRD and its predictive association with NSCLC recurrence and survival. ...
Molecular residual disease (MRD), detected by circulating tumor DNA (ctDNA) can be involved in the entire process of solid tumor management, including recurrence prediction, efficacy evaluation, and risk stratification. Currently, the detection technologies are divided into two main categories, as follows: tumor-agnostic and tumor informed. Tumor-informed assay obtains mutation information by sequencing tumor tissue samples before blood MRD monitoring, followed by formulation of a personalized MRD panel. Tumor-agnostic assays are carried out using a fixed panel without the mutation information from primary tumor tissue. The choice of testing strategy may depend on the level of evidence from ongoing randomized clinical trials, investigator preference, cost-effectiveness, patient economics, and availability of tumor tissue. The review describes the difference between tumor informed and tumor agnostic detection. In addition, the clinical application of ctDNA MRD in solid tumors was introduced, with emphasis on lung cancer, colorectal cancer, Urinary system cancer, and breast cancer.
... While there might be variations in results across different RCTs, it is generally observed that PD-L1, TMB, and MSI-H have a positive correlation with response rates, while ctD-NA shows a negative correlation. In particular, it has been shown that ctDNA detected before and after surgery is closely associated with relapse [53,54]. There is a potential benefit for patients who have ctDNA detected after surgery to maintain adjuvant ICIs treatment following neoadjuvant ICIs treatment [55]. ...
Lung cancer is a dismal disease as a leading cause of overall cancer death, but the development of immune checkpoint inhibitors (ICIs) in driver gene mutation negative metastatic non-small cell lung cancer (NSCLC) is changing the paradigm of lung cancer treatment. Recently, ICIs are expanding their treatment area to early-stage NSCLC and ICIs have also changed their treatment strategies of such patients. And it is important to appropriately select patients with resectable early-stage lung cancer through a multidisciplinary team approach and decrease the tumor relapse rate in the ICIs era. In this review article, we discuss the recently released neoadjuvant and adjuvant data of ICIs, their treatment rationale, and unmet needs in the treatment of early-stage NSCLC.
... Such insights are crucial to avoid prescribing costly and potentially harmful treatments to patients unlikely to benefit (7), and to prevent unnecessary surgical delays that could exacerbate cancer progression (57). Among the myriad of current biomarkers, PD-L1 and ctDNA (14,58,59) have demonstrated significant promise in recent clinical studies. However, their application is not without challenges that warrant in-depth examination. ...
Immune checkpoint inhibitors (ICIs) have emerged as a revolutionary paradigm in oncology, offering a potent arsenal against various malignancies by harnessing the body's own immunological prowess. In a whirlwind of advancement, an abundance of new ICIs have come to light, rendering it a Herculean task for physicians to remain au courant with the rapidly evolving landscape. This comprehensive review meticulously explores the crescendo of clinical investigations and FDA approvals that have come to light during 2022 and 2023, showcasing the metamorphic impact of ICIs in cancer therapeutics. Delving into the pith of pivotal Phase 3 trials across diverse cancer types - including lung, renal, melanoma, and more - the review illuminates the significant strides made in enhancing patient outcomes, alongside the unveiling of novel ICIs that have garnered attention in the oncological community. The analysis extends to the notable presentations at the esteemed ESMO and ASCO conventions, providing a panoramic view of the contemporary advancements in ICI technology. Furthermore, the review underscores the imperative of continuous exploration in overcoming the extant challenges, such as the quest for reliable predictive biomarkers and the optimization of combinatorial strategies to surmount resistance and augment therapeutic efficacy. Through a holistic lens, this article elucidates the monumental impact of ICIs, marking a significant epoch in the odyssey towards rendering cancer a conquerable adversary.
