scholarly journals Circulating Tumor DNA and Minimal Residual Disease (MRD) in Solid Tumors: Current Horizons and Future Perspectives

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Peng ◽  
Wuxuan Mei ◽  
Kaidong Ma ◽  
Changchun Zeng
Keyword(s):  
Solid Tumors ◽  
Clinical Decision Making ◽  
Residual Disease ◽  
Malignant Tumors ◽  
Circulating Tumor Dna ◽  
Detection Methods ◽  
Risk Of Recurrence ◽  
Increased Risk ◽  
Ctdna Analysis ◽  
Tumor Dna

Circulating tumor DNA (ctDNA) is cell-free DNA (cfDNA) fragment in the bloodstream that originates from malignant tumors or circulating tumor cells. Recently, ctDNA has emerged as a promising non-invasive biomarker in clinical oncology. Analysis of ctDNA opens up new avenues for individualized cancer diagnosis and therapy in various types of tumors. Evidence suggests that minimum residual disease (MRD) is closely associated with disease recurrence, thus identifying specific genetic and molecular alterations as novel MRD detection targets using ctDNA has been a research focus. MRD is considered a promising prognostic marker to identify individuals at increased risk of recurrence and who may benefit from treatment. This review summarizes the current knowledge of ctDNA and MRD in solid tumors, focusing on the potential clinical applications and challenges. We describe the current state of ctDNA detection methods and the milestones of ctDNA development and discuss how ctDNA analysis may be an alternative for tissue biopsy. Additionally, we evaluate the clinical utility of ctDNA analysis in solid tumors, such as recurrence risk assessment, monitoring response, and resistance mechanism analysis. MRD detection aids in assessing treatment response, patient prognosis, and risk of recurrence. Moreover, this review highlights current advancements in utilizing ctDNA to monitor the MRD of solid tumors such as lung cancer, breast cancer, and colon cancer. Overall, the clinical application of ctDNA-based MRD detection can assist clinical decision-making and improve patient outcomes in malignant tumors.

scholarly journals Circulating tumor DNA in neoadjuvant treated breast cancer reflects response and survival

2020 ◽  
Author(s):  
Mark Jesus M. Magbanua ◽  
Lamorna Brown-Swigart ◽  
Hsin-Ta Wu ◽  
Gillian L. Hirst ◽  
Christina Yau ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Circulating Tumor Dna ◽  
Patient Specific ◽  
Breast Cancer Patients ◽  
Metastatic Recurrence ◽  
Excellent Outcome ◽  
Increased Risk ◽  
Tumor Dna

AbstractPathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) is strongly associated with favorable outcome. We examined the utility of serial circulating tumor DNA (ctDNA) testing for predicting pCR and risk of metastatic recurrence in 84 high-risk early breast cancer patients treated in the neoadjuvant I-SPY 2 TRIAL. Cell-free DNA (cfDNA) was isolated from 291 plasma samples collected at pretreatment (T0), 3 weeks after initiation of paclitaxel (T1), between paclitaxel and anthracycline regimens (T2), or prior to surgery (T3). A personalized ctDNA test was designed to detect 16 patient-specific mutations (from whole exome sequencing of pretreatment tumor) in cfDNA by ultra-deep sequencing. At T0, 61 of 84 (73%) patients were ctDNA-positive, which decreased over time (T1-35%; T2-14%; T3-9%). Patients who remained ctDNA-positive at T1 were significantly more likely to have residual disease after NAC (83% non-pCR) compared to those who cleared ctDNA (52% non-pCR; OR 4.33, P=0.012). After NAC, all patients who achieved pCR were ctDNA-negative (n=17, 100%). For those who did not achieve pCR (n=43), ctDNA-positive patients (14%) had significantly increased risk of metastatic recurrence (HR 10.4; 95% CI, 2.3–46.6); interestingly, patients who did not achieve pCR but were ctDNA-negative (86%) had excellent outcome, similar to those who achieved pCR (HR 1.4; 95% CI, 0.15–13.5). Lack of ctDNA clearance was a significant predictor of poor response and metastatic recurrence, while clearance was associated with improved survival regardless of pCR status. Personalized monitoring of ctDNA during NAC may aid in real-time assessment of treatment response and help fine-tune pCR as a surrogate endpoint of survival.

Circulating tumor DNA to detect minimal residual disease, response to adjuvant therapy, and identify patients at high risk of recurrence in patients with stage I-III CRC.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 4009-4009
Author(s):  
Noelia Tarazona ◽  
Tenna V Henriksen ◽  
Juan Antonio Carbonell-Asins ◽  
Thomas Reinert ◽  
Shruti Sharma ◽  
...  
Keyword(s):  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Multivariable Analysis ◽  
Circulating Tumor Dna ◽  
Stage I ◽  
Plasma Samples ◽  
Risk Of Recurrence ◽  
Tumor Dna ◽  
Minimal Residual

4009 Background: The clinical utility of tracking circulating tumor DNA (ctDNA) as a non-invasive biomarker for detecting minimal residual disease (MRD) and stratifying patients based on their risk of developing relapse has been well established in colorectal cancer (CRC). This study evaluates the detection and longitudinal monitoring of ctDNA in CRC patients pre- and post-operatively, during and after adjuvant chemotherapy (ACT). Methods: The prospective, multicenter cohort study recruited patients (n = 193) diagnosed with resected stage I-III CRC. Plasma samples (n = 1052) were collected at various timepoints with a median follow up of 21.6 months (4.6-38.5 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic mutations identified. Multiplex PCR assays were designed to 16 tumor-specific single-nucleotide variants to track ctDNA in plasma samples. The study evaluated the relationship between ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by ctDNA status postoperatively and post-ACT. Multivariable analysis was performed with all clinical variables. Best model was selected according to Akaike Information Criterion. Results: Pre-operatively ctDNA was detected in 90% (n = 166/185) of the patients. Post-operative ctDNA status prior to ACT was assessed in 152 patients, of which 9.2% (14/152) were identified to be MRD-positive and 78.5% (11/14) eventually relapsed. In contrast, 10.1% (14/138) of MRD-negative cases relapsed (HR: 16.53; 95% CI: 7.19-38.02; p < 0.001). Longitudinal ctDNA-positive status, post-ACT (n = 84) and post definitive therapy (n = 139) was associated with a 27.92 HR (95% CI: 9.16-85.11; p < 0.001) and a 47.52 HR (95% CI: 17.34-130.3.; p < 0.001), respectively. In the multivariable analysis, longitudinal ctDNA status was the only significant prognostic factor associated with RFS (HR: 53.19, 95% CI: 18.87-149.90; p < 0.001). Serial ctDNA analysis detected MRD up to a median of 9.08 months (0.56-16.5 months) ahead of radiologic relapse with a sensitivity of 79.1% and specificity of 99%. Conclusions: Postoperative ctDNA analyses detect patients with high-risk of recurrence, with near 100% specificity. Early detection of MRD and longitudinal monitoring of ctDNA could guide treatment decisions. Intervention trials to assess the clinical benefit of ctDNA use are underway.

Landscape of genomic alterations of circulating tumor DNA in advanced genitourinary cancer patients: SCRUM-Japan MONSTAR SCREEN Project.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 152-152
Author(s):  
Nobuaki Matsubara ◽  
Taigo Kato ◽  
Takao Fujisawa ◽  
Masaki Shiota ◽  
Masatoshi Eto ◽  
...  
Keyword(s):  
Success Rate ◽  
Solid Tumors ◽  
Circulating Tumor Dna ◽  
Advanced Solid Tumors ◽  
Genomic Alterations ◽  
Tumor Mutational Burden ◽  
Somatic Alterations ◽  
Ctdna Analysis ◽  
Tumor Types ◽  
Tumor Dna

152 Background: Circulating tumor DNA in plasma (ctDNA) is an emerging resource for detecting genomic alterations in various cancers. However, the characteristics and clinical utility of ctDNA are not fully elucidated, especially in patients with genitourinary (GU) cancers. Methods: In April 2019, SCRUM-Japan started the MONSTAR-SCREEN project, which evaluates the ctDNA from patients with various advanced solid tumors. We collected plasma and tumor samples from patients with advanced prostate cancer (PC), urothelial carcinoma (UC), and renal cell carcinoma (RCC). Plasma ctDNA and tissue genomic DNA were analyzed using NGS-based cell-free DNA assay, a modified version of FoundationOne Liquid (F1L) including blood tumor mutational burden (TMB) analysis, and tissue-based panel, FoundationOne CDx (F1CDx), respectively. Success rate of ctDNA was defined as the percentage of patients whose sample quality control status was “pass” or “qualified”. Level of ctDNA was defined as the maximum allele fraction (AF) for all known somatic alterations detected. Results: As of June 18, 2020, ctDNA analysis results were available for 470 of 540 patients with advanced solid tumors. Among them, we analyzed 70 advanced GU cancers (35 PC, 17 UC, and 18 RCC) and 400 non-GU cancers. The success rate of ctDNA was significantly lower in GU cancers than in non-GU cancers (81.4% vs. 91.5%, P = 0.016). The levels of ctDNA in PC and UC were similar to those in non-GU cancers. RCC had the second lowest ctDNA level (median 0.13%) after that in malignant melanoma. The median TMB, as estimated by ctDNA, was 4.40, 0.88 and 0.44 mutations/Mb in UC, PC and RCC, respectively. The most frequently altered genes were TP53 (34%), AR (11%), BRCA2 (11%), ATM (8.6%), and CDK12 (8.6%) in PC, TP53 (59%), TERT (41%), and CHEK2 (18%) in UC, and TP53 (22%), ATM (11%), and MTOR (11%) in RCC. The mutation rate in genes related to DNA damage response (DDR) pathways was significantly higher in GU cancers compared to that in non-GU cancers (30.0% vs. 18.0%, P = 0.033). However, other pathways were less frequently altered in GU cancers versus non-GU cancers, including Wnt (5.7% vs. 16.8%, P = 0.017), PI3K (8.6% vs. 19.0%, P = 0.039) and RAS/MAPK (8.6% vs. 29.5%, P < 0.001). Conclusions: Our results reveal the genomic landscape of ctDNA in several advanced solid tumors, and highlight the differences between tumor types. Comprehensive analysis of ctDNA using the F1L assay reveled alterations in DDR-associated genes were significantly more frequent in GU cancers than in non-GU cancers. Clinical trial information: UMIN000036749.

scholarly journals Circulating Tumor DNA Testing Opens New Perspectives in Melanoma Management

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2914 ◽  
Author(s):  
Alessandra Sacco ◽  
Laura Forgione ◽  
Marianeve Carotenuto ◽  
Antonella De Luca ◽  
Paolo A. Ascierto ◽  
...  
Keyword(s):  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Prognostic Information ◽  
Skin Cancers ◽  
Highly Sensitive ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna

Malignant melanoma accounts for about 1% of all skin cancers, but it causes most of the skin cancer-related deaths. Circulating tumor DNA (ctDNA) testing is emerging as a relevant tool for the diagnosis and monitoring of cancer. The availability of highly sensitive techniques, including next generation sequencing (NGS)-based panels, has increased the fields of application of ctDNA testing. While ctDNA-based tests for the early detection of melanoma are not available yet, perioperative ctDNA analysis in patients with surgically resectable melanoma offers relevant prognostic information: i) the detection of ctDNA before surgery correlates with the extent and the aggressiveness of the disease; ii) ctDNA testing after surgery/adjuvant therapy identifies minimal residual disease; iii) testing ctDNA during the follow-up can detect a tumor recurrence, anticipating clinical/radiological progression. In patients with advanced melanoma, several studies have demonstrated that the analysis of ctDNA can better depict tumor heterogeneity and provides relevant prognostic information. In addition, ctDNA testing during treatment allows assessing the response to systemic therapy and identifying resistance mechanisms. Although validation in prospective clinical trials is needed for most of these approaches, ctDNA testing opens up new scenarios in the management of melanoma patients that could lead to improvements in the diagnosis and therapy of this disease.

scholarly journals Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 994
Author(s):  
Marisol Huerta ◽  
Susana Roselló ◽  
Luis Sabater ◽  
Ana Ferrer ◽  
Noelia Tarazona ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Residual Disease ◽  
Malignant Tumors ◽  
Circulating Tumor Dna ◽  
Ductal Adenocarcinoma ◽  
Epigenetic Alterations ◽  
Non Invasive ◽  
Droplet Pcr ◽  
Tumor Dna

Pancreatic cancer (PC) is one of the most devastating malignant tumors, being the seventh leading cause of cancer-related death worldwide. Researchers and clinicians are endeavoring to develop strategies for the early detection of the disease and the improvement of treatment results. Adequate biopsy is still challenging because of the pancreas’s poor anatomic location. Recently, circulating tumor DNA (ctDNA) could be identified as a liquid biopsy tool with huge potential as a non-invasive biomarker in early diagnosis, prognosis and management of PC. ctDNA is released from apoptotic and necrotic cancer cells, as well as from living tumor cells and even circulating tumor cells, and it can reveal genetic and epigenetic alterations with tumor-specific and individual mutation and methylation profiles. However, ctDNA sensibility remains a limitation and the accuracy of ctDNA as a biomarker for PC is relatively low and cannot be currently used as a screening or diagnostic tool. Increasing evidence suggests that ctDNA is an interesting biomarker for predictive or prognosis studies, evaluating minimal residual disease, longitudinal follow-up and treatment management. Promising results have been published and therefore the objective of our review is to understand the current role and the future perspectives of ctDNA in PC.

The application of dynamic monitoring of circulating tumor DNA for detecting minimal residual disease and predicting recurrence in colorectal cancer patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15531-e15531
Author(s):  
Hiu Ting Chan ◽  
Satoshi Nagayama ◽  
Yoon Ming Chin ◽  
Masumi Otaki ◽  
Rie Hayashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Plasma Samples ◽  
Blood Samples ◽  
Clonal Hematopoiesis ◽  
Tumor Tissues ◽  
Ctdna Analysis ◽  
Tumor Dna ◽  
Minimal Residual

e15531 Background: Although the prognosis of colorectal cancer (CRC) has improved in the past decade, a subset of CRC patients may still suffer from relapse due to the progression from minimal residual disease (MRD) after surgical resection. A sensitive and non-invasive method to detect MRD and early diagnosis of recurrence disease is warranted to start therapeutic interventions at an earlier timing and improving the overall survival rate. In this study, we have evaluated the feasibility of circulating tumor DNA (ctDNA) analysis to detect MRD and early detection of recurrence in CRC patients. Methods: Plasma samples were collected prospectively from 38 CRC patients (stage I to IV), who underwent surgical resection. Preoperative blood samples were obtained just before surgery and post-operative samples were collected at multiple time-points to monitor the changes of tumor mutation profiles. Tumor-derived mutations were detected in preoperative blood samples as well as surgically resected-tumor tissues using ultradeep targeted next generation sequencing. Patient-paired peripheral blood cells (PBCs) were sequenced concurrently to exclude clonal hematopoiesis-related mutations. Results: Among the 38 patients, 74 non-synonymous mutations were identified in tumor tissues and 64 mutations in the preoperative plasma samples. Paired PBCs sequencing identified 11 mutations in plasma samples to be clonal hematopoiesis-related mutations. After the exclusion of clonal hematopoiesis-related mutations, 34 (89.5%) of the 38 patients harbors at least one somatic mutation either from tumor tissues or plasma samples to be monitored longitudinally. ctDNA was detectable in 5 of 14 (36%) post-surgical samples of patients who did not receive adjuvant chemotherapy and in 9 of 18 (50%) post-chemotherapy samples. Up to date, 6 patients have been detected with clinical recurrence and ctDNA analysis identified all 6 recurrences before imaging. Serial ctDNA analyses were able to detect disease recurrence up to 6 months before imaging tests. Furthermore, all patients that were ctDNA negative post-operative or post-chemotherapy showed no signs of clinical relapse. Conclusions: Our current results indicate that ctDNA analysis allows the detection of MRD in CRC patients. The integration of ctDNA analysis with current standard monitoring guidelines holds great promise in early detection of recurrence to allow clinical intervention to be applied promptly.

scholarly journals Feasibility and promise of circulating tumor DNA analysis in dogs with naturally-occurring sarcoma

2020 ◽  
Author(s):  
Patricia Filippsen Favaro ◽  
Samuel D. Stewart ◽  
Bradon R. McDonald ◽  
Jacob Cawley ◽  
Tania Contente-Cuomo ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Malignant Tumors ◽  
Cost Effective ◽  
Circulating Tumor Dna ◽  
Molecular Heterogeneity ◽  
Naturally Occurring ◽  
Cost Effective Approach ◽  
Ctdna Analysis ◽  
Development And Validation ◽  
Tumor Dna

AbstractComparative studies of naturally-occurring canine cancers have provided new insight into many areas of cancer research. The inclusion of pet dogs in the development and validation of circulating tumor DNA (ctDNA) diagnostics may be uniquely informative for human translation for many reasons, including: high incidence of certain spontaneous cancers, repeated access to blood and tumor from the same individuals during the course of disease progression, and molecular heterogeneity of naturally-occurring cancers in dogs. Here, we present a feasibility study of ctDNA analysis performed in 9 healthy dogs and 39 dogs with either benign or malignant splenic tumors (hemangiosarcoma) using shallow whole genome sequencing (sWGS) of cell-free DNA. To enable detection and quantification of ctDNA using sWGS, we adapted two informatic approaches and compared their performance for the canine genome. At presentation, mean ctDNA tumor fraction in dogs with malignant splenic tumors was 11.2%, significantly higher than dogs with benign lesions (3.2%; p 0.001), achieving an AUC of 0.84. ctDNA tumor fraction was 14.3% and 9.0% in dogs with metastatic and localized disease, respectively although this difference was not statistically significant (p 0.227). In paired analysis, ctDNA fraction decreased from 11.0% to 7.9% after resection of malignant tumors (p 0.047). Our results demonstrate that ctDNA analysis is feasible in dogs with hemangiosarcoma using a cost-effective approach such as sWGS. Future studies are underway to validate these findings, and further evaluate the role of ctDNA to assess burden of disease and treatment response during drug development.

Predicting response to radical (chemo)radiotherapy (R-CRT) with circulating HPV DNA and tumor DNA (ctDNA) analysis in locally-advanced head and neck squamous cell carcinoma (LAHNC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 6043-6043
Author(s):  
Shreerang Bhide ◽  
Jen Lee ◽  
Isaac Garcia-Murillas ◽  
Ros Cutts ◽  
Tara Hurley ◽  
...  
Keyword(s):  
Dna Analysis ◽  
Residual Disease ◽  
Locally Advanced ◽  
Digital Pcr ◽  
Circulating Tumor Dna ◽  
Surgical Biopsy ◽  
Hpv Dna ◽  
Pet Ct ◽  
Ctdna Analysis ◽  
Tumor Dna

6043 Background: Following R-CRT for human papilloma virus positive (HPV+) and negative (HPV-) LAHNC, patients frequently undergo unnecessary neck dissection (ND) and/or repeated biopsies for abnormal PET-CT findings even in the presence of a complete pathological response (pCR), which causes significant morbidity. We assessed the role of circulating tumor DNA analysis in identifying patients with true residual disease. Methods: We prospectively recruited development (DC, n=55) and test (TC, n=33) cohorts of LAHNC patients having R-CRT. For HPV+ tumors we developed a novel amplicon based next generation sequencing assay (HPV-detect) to detect circulating HPV DNA and for HPV- tumors we used personalised droplet digital PCR assays of somatic mutations. Circulating tumor DNA levels at 12 weeks post-R-CRT were correlated to residual disease assessed by PET-CT and surgery. Results: In the DC (27 HPV+), baseline HPV-detect demonstrated 100% sensitivity and 93% specificity, confirmed in the TC (20 HPV+). 37 HPV+ patients (DC&TC) had complete samples-set. 36 had a negative HPV-detect at end of treatment, including 6 patients who underwent ND (3) and repeat primary site biopsies (3) for positive PET-CT but had pCR on surgical/biopsy specimen. 1 patient had positive HPV-detect and positive biopsy, indicating 100% agreement for HPV-detect and residual cancer. In a 10 HPV- patients with complete sample-set, there was 90% agreement between ctDNA and residual disease in HPV- tumors (3 ctDNA positive and tumor present, 1 ctDNA negative but tumor present, and 6 negative ctDNA negative tumor) with 80% sensitivity for residual disease and 100% specificity. Combined agreement between ctDNA testing (HPV+ and -) & residual disease was 98% (Table). Conclusions: Circulating HPV DNA quantified using HPV-detect and ctDNA identifies patients with residual disease post-R-CRT in LAHNC. Further studies are required to validate these findings. [Table: see text]

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