Circulating tumor DNA as a liquid biopsy target for detection of pancreatic cancer

Most pancreatic cancer patients present with advanced metastatic disease, resulting in extremely poor 5-year survival, mainly because of the lack of a reliable modality for early detection and limited therapeutic options for advanced disease. Therefore, there is a need for minimally-invasive diagnostic tools for detecting pancreatic cancer at an early stage, when curative surgery and also novel therapeutic approaches including precision medicine may be feasible. The “liquid biopsy” addresses these unmet clinical needs based on the concept that simple peripheral blood sampling and detection of circulating tumor DNA (ctDNA) could provide diagnostic information. In this review, we provide an overview of the current status of blood-based tests for diagnosis of pancreatic cancer and the potential utility of ctDNA for precision medicine. We also discuss challenges that remain to be addressed in developing practical ctDNA-based liquid biopsy approaches for early diagnosis of pancreatic cancer.     

Liquid biopsy in patients with pancreatic cancer: Circulating tumor cells and cell-free nucleic acids

Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer(PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells(CTCs) and cell-free nucleic acids(cf NAs), such as DNA, m RNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called "liquid biopsy" has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfN As in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.     

Liquid biopsy leads to a paradigm shift in the treatment of pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is one of the most cancers. Its 5-year survival rate is very low. The recent induction of neoadjuvant chemotherapy and improvements in chemotherapy for patients with pancreatic cancer have resulted in improved survival outcomes. However, the prognosis of pancreatic cancer is still poor. To dramatically improve the prognosis, we need to develop more tools for early diagnosis, treatment selection, disease monitoring, and response rate evaluation. Recently, liquid biopsy (circulating free DNA, circulating tumor DNA, circulating tumor cells, exosomes, and microRNAs) has caught the attention of many researchers as a new biomarker that is minimally invasive, confers low-risk, and displays an overall state of the tumor. Thus, liquid biopsy does not employ the traditional difficulties of obtaining tumor samples from patients with advanced PDAC to investigate their molecular biological status. In addition, it allows for long-term monitoring of the molecular profile of tumor progression. These could help in identifying tumor-specific alterations that use the target structure for tailor-made therapy. Through this review, we highlighted the latest discoveries and advances in liquid biopsy technology in pancreatic cancer research and showed how it can be applied in clinical practice.     

Consistency of genotyping data from simultaneously collected plasma circulating tumor DNA and tumor-DNA in lung cancer patients

BackgroundTo clarify the rate of concordance between the results of concurrent sequencing of circulating tumor DNA (ctDNA) and tumor tissue samples based in clinic settings, and to explore potential factors influencing consistency.MethodsA retrospective analysis of 27 patients with lung cancer who underwent gene sequencing at the Department of Biotherapy of Tianjin Medical University Cancer Hospital from February 2016 to April 2019, was conducted by synchronous sequencing of tumor and plasma DNA samples and the concordance of mutations in nine known driver genes was calculated.ResultsThe overall concordance, sensitivity, and specificity for sequencing driver genes in plasma samples, were 85.2%, 87.0%, and 75%, respectively, relative to tumor samples. Concordance was 100% in patients with bone metastases, while the rate in those without bone metastases was 69.2%. Moreover, in patients where both the driver gene and TP53 mutations in plasma were detected, the findings of plasma sequencing of the driver gene were identical to those of tumor sequencing (concordance: 100%).ConclusionsOverall, our data show that circulating tumor DNA (ctDNA) was able to identify 75% of the identical information in driver genes, with higher rates of concordance in lung cancer patients with bone metastases or TP53 mutation-positive plasma samples.     

Liquid biopsy of gastric cancer patients:Circulating tumor cells and cell-free nucleic acids

To improve the clinical outcomes of cancer patients,early detection and accurate monitoring of diseases are necessary.Numerous genetic and epigenetic alterations contribute to oncogenesis and cancer progression,and analyses of these changes have been increasingly utilized for diagnostic,prognostic and therapeutic purposes in malignant diseases including gastric cancer(GC).Surgical and/or biopsy specimens are generally used to understand the tumor-associated alterations;however,those approaches cannot always be performed because of their invasive characteristics and may fail to reflect current tumor dynamics and drug sensitivities,which may change during the therapeutic process.Therefore,the importance of developing a non-invasive biomarker with the ability to monitor real-time tumor dynamics should be emphasized.This concept,so calledliquid biopsy,would provide an ideal therapeutic strategy for an individual cancer patient and would facilitate the development oftailor-madecancer management programs.In the blood of cancer patients,the presence and potent utilities of circulating tumor cells(CTCs)and cell-free nucleic acids(cfNAs)such as DNA,mRNA and microRNA have been recognized,and their clinical relevance is attracting considerable attention.In this review,we discuss recent developments in this research field as well as the relevance and future perspectives of CTCs and cfNAs in cancer patients,especially focusing on GC.     

A systematic review and meta-analysis of circulating cell-free DNA as a diagnostic biomarker for non-small cell lung cancer

BackgroundEarly diagnosis of non-small cell lung cancer (NSCLC) is crucial for treatment. Circulating cell-free DNA (cfDNA) is an extracellular nucleic acid found in serum, and tumor cfDNA circulating in the blood may be used as a biomarker for early diagnosis. The purpose of this study was to evaluate the application value of cfDNA as a biomarker for the diagnosis of NSCLC through meta-analysis.MethodsWe searched the China National Knowledge Infrastructure (CNKI), Wanfang, VIP, PubMed, Cochrane Central Register of Controlled Trials, Embase, and Web of Science databases using the following search terms: lung cancer, NSCLC, biomarkers, circulating cfDNA, cfDNA, circulating tumor DNA (ctDNA), circulating cell-free tumor DNA, and diagnosis. The retrieval period was set until September 2021. According to PICOS (patients, intervention, comparison, outcomes, and study design) principles the inclusion criteria were: aged ≥18 years; at least 10 NSCLC cases; NSCLC patients diagnosed by histopathology or cytology; circulating cfDNA was detected; outcome data could be completely extracted. Bias risk assessment was conducted according to the QUADAS (Quality Assessment of Diagnostic Accuracy Studies). RevMan 5.3 was used for meta-analysis.ResultsEight studies met the inclusion criteria, including a total of 618 NSCLC patients and 635 healthy subjects. The overall sensitivity and specificity were 0.79 [95% confidence interval (CI): 0.75–0.82] and 0.81 (95% CI: 0.78–0.84), respectively. The area under the curve (AUC) of the summary receiving operating characteristic (SROC) curve was 0.8941. The pooled positive likelihood ratio, pooled negative likelihood ratio, and pooled diagnostic odds ratio were 5.37 (95% CI: 2.67–10.81), 0.24 (95% CI: 0.15–0.38), and 24.68 (95% CI: 8.85–68.84), respectively. The patient selection bias was high in two articles was high, unclear in one article, and low in the remaining five ones. The risk of bias in the research index test was unclear in one article, and low in the remaining seven articles. The reference standard bias, and flow and time bias of all articles was low.ConclusionsCirculating cfDNA is an efficacy biomarker in diagnosis of NSCLC. Its clinical application technology is worthy of further research.     

Emerging blood-based biomarkers for detection of gastric cancer

Early detection and efficient monitoring of tumor dynamics are prerequisites for reducing disease burden and mortality, and for improving the management of patients with gastric cancer(GC). Blood-based biomarker assays for the detection of early-stage GC could be of great relevance both for population-wide or risk groupbased screening programs, while circulating biomarkers that reflect the genetic make-up and dynamics of the tumor would allow monitoring of treatment efficacy, predict recurrences and assess the genetic heterogeneity of the tumor. Recent research to identify blood-based biomarkers of GC has resulted in the identification of a wide variety of cancer-associated molecules, including various proteins, autoantibodies against tumor associated antigens, cell-free DNA fragments, m RNAs and various non-coding RNAs, circulating tumor cells and cancer-derived extracellular vesicles. Each type of these biomarkers provides different information on the disease status, has different advantages and disadvantages, and distinct clinical usefulness. In the current review, we summarize the recent developments in blood-based GC biomarker discovery, discuss the origin of various types of biomarkers and their clinical usefulness and the technological challenges in the development of biomarker assays for clinical use.     

New challenges in perioperative management of pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)is the fourth leading cause of cancer-related death in the industrialized world.Despite progress in the understanding of the molecular and genetic basis of this disease,the5-year survival rate has remained low and usually does not exceed 5%.Only 20%-25%of patients present with potentially resectable disease and surgery represents the only chance for a cure.After decades of gemcitabine hegemony and limited therapeutic options,more active chemotherapies are emerging in advanced PDAC,like 5-Fluorouracil,folinic acid,irinotecan and oxaliplatin and nab-paclitaxel plus gemcitabine,that have profoundly impacted therapeutic possibilities.PDAC is considered a systemic disease because of the high rate of relapse after curative surgery in patients with resectable disease at diagnosis.Neoadjuvant strategies in resectable,borderline resectable,or locally advanced pancreatic cancer may improve outcomes.Incorporation of tissue biomarker testing and imaging techniques into preoperative strategies should allow clinicians to identify patients who may ultimately achieve curative benefit from surgery.This review summarizes current knowledge of adjuvant and neoadjuvant treatment for PDAC and discusses the rationale for moving from adjuvant to preoperative and perioperative therapeutic strategies in the current era of more active chemotherapies and personalized medicine.We also discuss the integration of good specimen collection,tissue biomarkers,and imaging tools into newly designed preoperative and perioperative strategies.     

阻塞性睡眠呼吸暂停的个体化治疗：机遇与挑战

阻塞性睡眠呼吸暂停(OSA)是一种异质性疾病,其在临床表现、发病机制及治疗反应等方面存在个体差异。基于临床特征和病理生理机制分型可更好地识别不同患者,从而针对不同病因开展个体化综合治疗以提高治疗效果。目前,OSA的个体化治疗在国内的应用仍处于初级阶段,机遇与挑战并存。     

Prognostic and predictive blood biomarkers in gastric cancer and the potential application of circulating tumor cells

Gastric cancer(GC), with its high incidence and mortality rates, is a highly fatal cancer that is common in East Asia particularly in China. Its recurrence and metastasis are the main causes of its poor prognosis. Circulating tumor cells(CTCs) or other blood biomarkers that are released into the circulating blood stream by tumors are thought to play a crucial role in the recurrence and metastasis of gastric cancer. Therefore, the detection of CTCs and other blood biomarkers has an important clinical significance; in fact, they can help predict the prognosis, assess the staging, monitor the therapeutic effects and determine the drug susceptibility. Recent research has identified many blood biomarkers in GC, such as various serum proteins, autoantibodies against tumor associated antigens, and cell-free DNAs. The analysis of CTCs and circulating cell-free tumor DNA(ctDNA) in the peripheral blood of patients with gastric cancer is called as liquid biopsy. These blood biomarkers provide the disease status for individuals and have clinical meaning. In this review, we focus on the recent scientific advances regarding CTCs and other blood biomarkers, and discuss their origins and clinical meaning.     

Neoadjuvant therapy for pancreatic ductal adenocarcinoma: Opportunities for personalized cancer care

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is best treated in a multidisciplinary fashion using surgery, chemotherapy, and radiation. Adjuvant chemotherapy has shown to have a significant survival benefit in patients with resected PDAC. However, up to 50% of patients fail to receive adjuvant chemotherapy due to postoperative complications, poor patient performance status or early disease progression. In order to ensure the delivery of chemotherapy, an alternative strategy is to administer systemic treatment prior to surgery. Precision oncology refers to the application of diverse strategies to target therapies specific to characteristics of a patient’s cancer. While traditionally emphasized in selecting targeted therapies based on molecular, genetic, and radiographic biomarkers for patients with metastatic disease, the neoadjuvant setting is a prime opportunity to utilize personalized approaches. In this article, we describe the current evidence for the use of neoadjuvant therapy (NT) and highlight unique opportunities for personalized care in patients with PDAC undergoing NT.     

Modified FOLFIRINOX for resected pancreatic cancer: Opportunities and challenges

Pancreatic cancer is one of the leading causes of cancer death worldwide.Adjuvant chemotherapy has been developed based on the experiences made with palliative chemotherapy, and advocated to improve long-term survival of patients with this disease. However, the optimal chemotherapeutic regimen remains controversial. Recently, Conroy et al demonstrated the impressive benefits of modified FOLFIRINOX over gemcitabine alone in the multicenter Partenariat de Recherche en Oncologie Digestive 24(PRODIGE-24) trial. The remarkable results mark a new milestone in treating resectable pancreatic cancer and have now changed the standard of care for this patient population. In this commentary, we discuss an issue of difference of tumor grade between the PRODIGE-24 trial and previous phase III trials. We also discuss potential biomarkers predicting therapeutic response to modified FOLFIRINOX. Finally,we summarize several ongoing clinical trials of replacing part of the FOLFIRINOX regimen with Xeloda/S-1/nanoliposomal irinotecan for pancreatic cancer.     

Genomic testing for pancreatic cancer in clinical practice as real-world evidence

Background

Precision medicine guided by comprehensive genome sequencing represents a potential treatment strategy for pancreatic cancer. However, clinical sequencing for pancreatic cancer entails several practical difficulties. We have launched an in-house clinical sequencing system and started genomic testing for patients with cancer in clinical practice. We have analyzed the clinical utility of this system in pancreatic cancer.

Liquid biopsy is a valuable tool in the diagnosis and management of lung cancer

Liquid biopsy refers to the use of various body fluids to test for circulating biological elements derived from the tumor. Liquid biopsy has taken on an increasingly important role in lung cancer diagnosis, molecular characterization, surveillance, monitoring, and determining mechanisms of resistance. These assays can utilize various sources of cell-free DNA (cfDNA) including blood, pleural fluid, urine, and others to detect tumor associated alterations. With the increasing power of next-generation sequencing technologies and the development of assays such as digital droplet PCR, rare tumor alleles can be detected in cfDNA to determine key characteristics of the tumor. Current assays, while effective, are still challenged by limited sensitivity and capacity to single genes or small panels of genes, though this is rapidly expanding. Nevertheless, testing of cfDNA has been shown to be valuable in detecting resistance to targeted inhibitors, particularly for detection of T790M in EGFR and monitoring response to therapy. With the continued development of more powerful and sensitive assays, these techniques will empower clinicians to better characterize early stage disease and can be used in the screening of high-risk patients, which may eliminate the requirement for tissue diagnosis in some settings. That said, since the majority of these alterations are not specific to lung cancer, there will continue to be a need for tissue in at least the initial diagnosis. Used in conjugation with tissue sampling, these assays will assist the treating clinician and the pathologist to better characterize individual tumors, even in the setting of limited tissue.     

Recent advances in blood-based and artificial intelligence-enhanced approaches for gastrointestinal cancer diagnosis

Gastrointestinal (GI) cancers are among the most common cancer types and leading causes of cancer-related deaths worldwide. There is a tremendous clinical need for effective early diagnosis for better healthcare of GI cancer patients. In this article, we provide a short overview of the recent advances in GI cancer diagnosis. In the first part, we discuss the applications of blood-based biomarkers, such as plasma circulating cell-free DNA, circulating tumor cells, extracellular vesicles, and circulating cell-free RNA, for cancer liquid biopsies. In the second part, we review the current trends of artificial intelligence (AI) for pathology image and tissue biopsy analysis for GI cancer, as well as deep learning-based approaches for purity assessment of tissue biopsies. We further provide our opinions on the future directions in blood-based and AI-enhanced approaches for GI cancer diagnosis, and we think that these fields will have more intensive integrations with clinical needs in the near future.     

Liquid biopsy in colorectal cancer: No longer young,but not yet old

Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. The treatment strategy employed in CRC patients is becoming highly dependent on molecular characteristics present at diagnosis and during treatment. Liquid biopsy is an emerging field in the management of this cancer, and its relevance as a potential diagnostic, prognostic, monitoring, and therapeutic tool makes it a viable strategy in the clinical management of CRC patients. Liquid biopsy also has certain limitations, but these limitations seem to be at the reach of near-future technological development. In this letter, we focus on the clinical perspectives of liquid biopsy in CRC with particular regard to the various biomarkers recently identified that have been shown to be potentially useful in multiple aspects of early stage or metastatic CRC.     

New blood markers detection technology: A leap in the diagnosis of gastric cancer

Gastric cancer(GC) is still one of the malignant tumors with high morbidity and mortality in the world, with a 5-year survival rate of less than 30%. GC is often either asymptomatic or causes only nonspecific symptoms in its early stages, whereas when the symptoms manifest, the cancer has usually reached an advanced stage, which is one of the main causes of its relatively poor prognosis. Hence, the main focus of GC research has been on discovering new tools and technology to predict, screen and diagnose g C at an early stage which would prompt early treatment. With the tremendous advances in the OMICS technology, serum proteomics has been in the limelight of cancer research over the last few decades and has steered the development of several methods helping to understand the mechanisms underlying gastric carcinogenesis, resulting in the identification of a large number of molecular targets such as circulating tumor cells(CTCs), cell free DNA(cf DNA) and cell tumor DNA(ct DNA) and their sub-molecular components such as mi RNA, that show great promise as GC biomarkers. In this review, we are underlying the recent breakthroughs about new blood markers technology for GC while scrutinizing the potential clinical use of CTCs, cf DNA, ct DNA and the role of the methylation of their submolecular components in the pathogenesis, diagnosis and management of GC.     

Monitoring clinical outcomes in aggressive B-cell lymphoma: From imaging studies to circulating tumor DNA

Recent guidelines have de-emphasized the role of routine surveillance computed tomography (CT) scans for diffuse large B-cell lymphoma (DLBCL) patients who achieve a complete response to front-line therapy. This shift in practice recommendations was prompted by retrospective studies that failed to demonstrate clear clinical utility for surveillance CT in unselected DLBCL patients. Controversy remains, however, over the role of routine surveillance CT in the highest risk patients for treatment failure who would remain candidates for aggressive salvage therapies. Novel high-throughput sequencing methods can non-invasively monitor tumor-specific DNA in the blood and offers clear advantages designed to overcome fundamental limitations of CT scans. This review will discuss the current controversies surrounding monitoring clinical outcomes in aggressive B-cell lymphomas, with a specific emphasis on DLBCL. Fundamental limitations of imaging scans will be addressed and the potential of monitoring circulating tumor DNA as an adjunct or replacement for CT scans will be discussed.