Circulating tumor DNA secreted into the blood by tumors has been shown to be a potent liquid biomarker for cancer.
In this issue, Aadel Chaudhuri, Angela Hirbe, Jack Shern, and colleagues use circulating tumor DNA detected in plasma to distinguish neurofibromatosis patients from malignancy (in this case, malignant peripheral nerve schwannoma) and those containing only benign precursor lesions. This work and other articles in this special issue have the potential to unlock new technology for earlier cancer detection, which could facilitate earlier diagnosis and better survival for cancer patients all around the world.
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INTRODUCTION
Three studies presented in this special issue of PLOS Medicine focus on evaluating circulating bulk DNA (ctDNA) as a response biomarker in early-stage solid tumors. Both Yaqi Wang and Pradeep Chauhan and their colleagues evaluated ctDNA as a tool capable of predicting pathologic complete response (pCR) in locally advanced rectal cancer (LARC) and bladder cancer's muscle invasive phototherapy (MIBC), respectively. Jeanne Tie and colleagues focused on evaluating ctDNA in the risk of liver metastases from colorectal cancer (CRLM), both during neoadjuvant, post-operative, and adjuvant treatment [3]. In this brief perspective, we evaluate these advances in the broader context of recently published work.
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ctDNA AS A NEW ADJUNCTIVE THERAPY RESPONSE BIOMARKER
Quantifying ctDNA kinetics over time may act as a tumor biomarker with targeted therapies, immunotherapy, and radiotherapy [4-6]. With neoadjuvant treatment, ctDNA kinetics can guide changes in therapy in non-responders, or be used as a tool to cut the number of chemotherapy cycles. being performed or reduce the need for further treatment (including surgery).
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Regarding the latter point, Wang and colleagues draw attention to the possibility of postponing surgery in patients with a complete clinical response (cCR; that is, without clinical, endoscopic, or X-ray signs). disease) after adjuvant radiotherapy for LARC [2]. This is called the "watch and wait" strategy. In patients presenting with cCR after neoadjuvant therapy, the probability of LARC recurrence without further intervention is low [7].
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However, cCR is an imperfect proxy for pCR, so the authors sought to determine whether ctDNA assessment in neoadjuvant therapy could improve the accuracy of response determination treatment or not. Through evaluating an index called T234_cle clear (describing the absence of the underlying mutation with the highest mutant allele frequency at all 3 time points before surgery), the research team identified 20 of 89 patients lacking evidence of T234_cle clear after adjuvant therapy. Four of these patients demonstrated cCR based on Magnetic Resonance Imaging (MRI) evaluation [2]. This observation highlighted some discordance between cCR and ctDNA. One in four patients who showed cCR had disease recurrence. This suggests that ctDNA clearance may refine cCR assessment in LARC [2]. Another analysis demonstrated that incorporating multiple ctDNA features along with MRI response information in the prediction model improved the ability to distinguish pCR from non-pCR, compared with ctDNA features or response parameters. simple MRI effect [2].
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The study from Wang et al supports previous findings from Murahashi and colleagues, who also evaluated post-treatment ctDNA kinetics in patients undergoing neoadjuvant LARC therapy [8]. In the analysis by Murahashi et al., post-treatment ctDNA levels decreased in 11 of 12 patients who had a clinical response to neoadjuvant treatment (pCR or 12 months recurrence-free if a follow-up strategy was used). and wait); conversely, 7 of 39 patients without clinical response showed increased ctDNA levels [8]. Combining ctDNA reduction during treatment with endoscopic assessment of complete response improved response stratification of neoadjuvant therapy in this study [8]. Overall, these data suggest that ctDNA monitoring after neoadjuvant treatment for LARC has potential as an additional tool to improve the accuracy of current cCR measures.
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As with the application of ctDNA in LARC, Chauhan and colleagues asked whether assessment of urinary ctDNA (utDNA) could differentiate pCR from non-pCR in patients receiving neoadjuvant therapy for MIBC. no [1]. Developing an alternative to pCR in this setting may avoid cystectomy and diversion in patients with a good prognosis. The team determined that non-silent mutations (mutations that result in a change in the encoded amino acid sequence), but not silent mutations (mutations that do not change the amino acid sequence), are the weakest. precise determinant of pCR versus non-pCR and suggest that an effect in the bladder urothelium may underlie this difference (effect or cancer describes tissue that has been preconditioned by exposure with carcinogens, creating favorable conditions for the process of cancer formation [9]).
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Excluding silent mutations, the utDNA MRD threshold was optimized based on analysis of healthy participants and non-pCR patients. Applying this threshold to the cohort showed a sensitivity of 81% and specificity of 81% for prediction of non-pCR. Based on these findings Chauhan and colleagues suggest that utDNA could be used to complement new clinical predictors of cPR, such as MRI-based response criteria, and attract interest. Attention to the Alliance study (clingov: NCT03609216) will provide a framework to validate the research team's results. This work highlights the potential of urinary utDNA to be used as a biomarker in bladder cancer, building on previous work using the same ctDNA platform (uCAPP-seq) by Dudley and colleagues. Industry has demonstrated that utDNA has the ability to identify localized early-stage bladder cancer and monitor disease recurrence after local bladder cancer treatment [10].
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Tie and colleagues explored ctDNA as a treatment-therapy response biomarker in CRLM. In a cohort of patients undergoing neoadjuvant chemotherapy, they noted a mean 40.93-fold decrease in ctDNA levels during treatment with 13 of 18 evaluable patients demonstrating lack of prior ctDNA detection treatment cycle 4. However, ctDNA clearance during adjuvant chemotherapy had no impact on 5-year recurrence-free survival (RFS) when compared with lack of ctDNA clearance. In contrast, the team determined that postoperative ctDNA detection was a strong predictor of reduced RFS in post-therapy ctDNA-positive patients (surgery +/- adjuvant therapy ) showed a 5-year RFS rate of 0% compared with 75.6% in ctDNA negative patients. These data highlight the importance of combining ctDNA clearance kinetics during neoadjuvant treatment with postoperative survival endpoints, as in this study, ctDNA clearance with chemotherapy Adjuvants do not reduce the risk of disease recurrence after surgery.
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Supporting ctDNA as a neoadjuvant response biomarker in other tumor types, non-small cell lung cancer (NSCLC) data from the CheckMate-816 study, a randomized, phase-in study III compared platinum chemotherapy with or without nivolumab in stage IB-IIIA NSCLC, highlighting ctDNA clearance at cycle day 3 after combination chemotherapy and checkpoint inhibitor treatment immunity associated with pCR [11]. Patients with stage II-III early breast cancer treated with standard adjuvant chemotherapy or neoadjuvant chemotherapy plus MK-2206 (an AKT inhibitor) underwent analyzes ctDNA using the tumor-informed assay in the I-SPY2 platform trial [12]. ctDNA clearance after cycle 1 of therapy was associated with increased pCR (24 of 29 [83%] patients without pCR had residual ctDNA detected after cycle 1 of therapy compared with 14 above 27 [52%] had ctDNA deletion after cycle 1 of therapy [12]). In this study, the authors stratified patients according to pCR status and ctDNA status after neoadjuvant therapy and determined that patients who were ctDNA-negative but did not achieve pCR were at risk of recurrence. metastases were similar compared to patients who achieved pCR, suggesting that ctDNA clearance may divide non-pCR patients into high-risk and low-risk groups [12].
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CONCLUSION
In summary, the findings presented in this special issue add to a new literature highlighting the need to explore the translational potential to evaluate ctDNA as a response biomarker in novel adjuvant settings. . These data are particularly relevant in LARC and MIBC where treatment response biomarkers independent of pathological examination of resected tumor specimens are required to guide management decisions. no surgery. Data from Tie and colleagues suggest that the ability of adjuvant chemotherapy-induced ctDNA clearance to act as a proxy for long-term survival benefit from targeted therapy is limited in CLRM . It is conceivable that the utility of ctDNA as a novel adjuvant response biomarker may vary by treatment type and solid tumor type. To address this issue, it will be important for pretrials to incorporate ctDNA clearance kinetics as endpoints to alternatively define these measures of survival across solid tumor types. Finally, to understand the relative merits and disadvantages of ctDNA-based response measures compared with conventional clinical response measures (such as endoscopy and imaging-based assessments), it is necessary to compare Direct comparison of ctDNA clearance with these methods.
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Translator: Hai Anh – Phacogen Institute of Technology;
(Biotechnology Engineer - Hanoi University of Science and Technology)
Referral:
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