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Cancer Discovery Dec 2017Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies....
Identifying molecular residual disease (MRD) after treatment of localized lung cancer could facilitate early intervention and personalization of adjuvant therapies. Here, we apply cancer personalized profiling by deep sequencing (CAPP-seq) circulating tumor DNA (ctDNA) analysis to 255 samples from 40 patients treated with curative intent for stage I-III lung cancer and 54 healthy adults. In 94% of evaluable patients experiencing recurrence, ctDNA was detectable in the first posttreatment blood sample, indicating reliable identification of MRD. Posttreatment ctDNA detection preceded radiographic progression in 72% of patients by a median of 5.2 months, and 53% of patients harbored ctDNA mutation profiles associated with favorable responses to tyrosine kinase inhibitors or immune checkpoint blockade. Collectively, these results indicate that ctDNA MRD in patients with lung cancer can be accurately detected using CAPP-seq and may allow personalized adjuvant treatment while disease burden is lowest. This study shows that ctDNA analysis can robustly identify posttreatment MRD in patients with localized lung cancer, identifying residual/recurrent disease earlier than standard-of-care radiologic imaging, and thus could facilitate personalized adjuvant treatment at early time points when disease burden is lowest. .
Topics: Circulating Tumor DNA; Female; Humans; Lung Neoplasms; Male; Neoplasm, Residual
PubMed: 28899864
DOI: 10.1158/2159-8290.CD-17-0716 -
Molecular Diagnosis & Therapy Jun 2019Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are... (Review)
Review
Circulating tumor DNA (ctDNA) is a component of cell-free DNA that is shed by malignant tumors into the bloodstream and other bodily fluids. Levels of ctDNA are typically low, particularly in patients with localized disease, requiring highly sophisticated methods for detection and quantification. Multiple liquid biopsy methods have been developed for ctDNA analysis in solid tumor malignancies and are now enabling detection and assessment of earlier stages of disease, post-treatment molecular residual disease (MRD), resistance to targeted systemic therapy, and tumor mutational burden. Understanding ctDNA biology, mechanisms of release, and clearance and size characteristics, in conjunction with the application of molecular barcoding and targeted error correction, have increased the sensitivity and specificity of ctDNA detection techniques. Combinatorial approaches including integration of ctDNA data with circulating protein biomarkers may further improve assay sensitivity and broaden the scope of ctDNA applications. Circulating viral DNA may be utilized to monitor disease in some virally induced malignancies. In spite of increasingly accurate methods of ctDNA detection, results need to be interpreted with caution given that somatic mosaicisms such as clonal hematopoiesis of indeterminate potential (CHIP) may give rise to genetic variants in the bloodstream unrelated to solid tumors, and the limited concordance observed between different commercial platforms. Overall, highly precise ctDNA detection and quantification methods have the potential to transform clinical practice via non-invasive monitoring of solid tumor malignancies, residual disease detection at earlier timepoints than standard clinical and/or imaging surveillance, and treatment personalization based on real-time assessment of the tumor genomic landscape.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Genomics; High-Throughput Nucleotide Sequencing; Humans; Liquid Biopsy; Molecular Diagnostic Techniques; Neoplasm, Residual; Neoplasms
PubMed: 30941670
DOI: 10.1007/s40291-019-00390-5 -
Journal For Immunotherapy of Cancer Jun 2023Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable... (Review)
Review
Liquid biopsies using cell-free circulating tumor DNA (ctDNA) are being used frequently in both research and clinical settings. ctDNA can be used to identify actionable mutations to personalize systemic therapy, detect post-treatment minimal residual disease (MRD), and predict responses to immunotherapy. ctDNA can also be isolated from a range of different biofluids, with the possibility of detecting locoregional MRD with increased sensitivity if sampling more proximally than blood plasma. However, ctDNA detection remains challenging in early-stage and post-treatment MRD settings where ctDNA levels are minuscule giving a high risk for false negative results, which is balanced with the risk of false positive results from clonal hematopoiesis. To address these challenges, researchers have developed ever-more elegant approaches to lower the limit of detection (LOD) of ctDNA assays toward the part-per-million range and boost assay sensitivity and specificity by reducing sources of low-level technical and biological noise, and by harnessing specific genomic and epigenomic features of ctDNA. In this review, we highlight a range of modern assays for ctDNA analysis, including advancements made to improve the signal-to-noise ratio. We further highlight the challenge of detecting ultra-rare tumor-associated variants, overcoming which will improve the sensitivity of post-treatment MRD detection and open a new frontier of personalized adjuvant treatment decision-making.
Topics: Humans; Circulating Tumor DNA; Neoplasm, Residual; Genomics
PubMed: 37349125
DOI: 10.1136/jitc-2022-006284 -
The Journal of Urology Mar 2022The oncologic benefit of postchemotherapy (PC) residual tumor resection (RTR) in patients with germ cell tumors and elevated serum tumor markers (STMs) remains unclear....
PURPOSE
The oncologic benefit of postchemotherapy (PC) residual tumor resection (RTR) in patients with germ cell tumors and elevated serum tumor markers (STMs) remains unclear. This analysis was performed to better define patients who benefit from surgery in this setting.
MATERIALS AND METHODS
Of 575 PC-RTR procedures (July 2008-July 2019) 153 were performed in patients with elevated STMs (human chorionic gonadotropin [HCG] >2.0 mIU/ml, alpha-fetoprotein [AFP] >7.0 µg/l), including 55 after first line and 98 after second or later line chemotherapy.
RESULTS
Viable cancer in the resected specimen was significantly more common in the salvage group than in the first line group (48.98% vs 16.36%, p=0.0001988) and was a predictor of survival in both groups. A preoperative serum level of AFP ≥30 µg/l was a significant predictor of viable cancer in the first line and salvage groups (55.56% [p=0.0157] and 66.67% [p=0.0017], respectively). The overall relapse-free survival rate (22.7% and 50%, p=0.00032) and overall survival rate (37.8% and 65%, p=0.0059) were significantly worse in the salvage group than in the first line group. A preoperative serum level of AFP ≥30 µg/l and viable cancer/teratoma found in the histological examination of the RTR specimens were significant predictors of relapse after first line chemotherapy. Serum AFP ≥30 µg/l and HCG ≥20 mIU/ml were significant factors affecting survival in the first line group.
CONCLUSIONS
Patients with AFP serum levels >30 µg/l and HCG ≥20 mIU/ml after first line chemotherapy should receive salvage chemotherapy instead of surgery. After second or later line therapy, the prognosis of patients with elevated markers and surgery is poor regardless of the tumor marker levels. However, 38% of these patients are long-term survivors, which justifies PC-RTR in this setting.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Chorionic Gonadotropin; Humans; Male; Middle Aged; Neoplasm, Residual; Neoplasms, Germ Cell and Embryonal; Prognosis; Salvage Therapy; Survival Rate; Testicular Neoplasms; alpha-Fetoproteins
PubMed: 34694152
DOI: 10.1097/JU.0000000000002270 -
Experimental Oncology Nov 2022The aim of the study was to examine the prognostic value of immunobiological markers (tumor-infiltrating lymphocytes (TILs) and their subpopulations) in residual...
UNLABELLED
The aim of the study was to examine the prognostic value of immunobiological markers (tumor-infiltrating lymphocytes (TILs) and their subpopulations) in residual tumor after neoadjuvant chemotherapy (NACT) completion in patients with triple negative (TNBC) and luminal B HER2-neu negative breast cancer (LBBC).
MATERIALS AND METHODS
The analysis of the treatment results of 59 patients with TNBC and 56 patients with LBBC with stage IIB-IIIB who received NACT was performed. The levels of TILs and their subpopulations (FOXP3+, CD4+, CD8+) in patients at the time of diagnosis in core-needle biopsy material and in residual tumor in postoperative material were studied by immunohistochemical method.
RESULTS
The risk of recurrence in patients with LBBC who received NACT before surgery is associated mainly with 4 factors: FOXP3+ lymphocytes, Ki-67 index in residual tumor, the number of affected axillary lymph nodes after NACT and viable residual tumor volume. Analysis of the treatment outcome in patients with TNBC revealed that the lack of pathologic complete response (pCR) after NACT increases the risk of disease recurrence by 2.9 times, hazard ratio (HR) = 2.9 (95% confidence interval (CI) 1.4-6.1; p = 0.005) compared with patients in which pCR was achieved after NACT. It was also found that the presence of residual tumor in patients with TNBC after NACT increases the risk of death from this disease by 2.7 times (95% CI 1.0-7.1; p = 0.05). Increased intratumoral and stromal CD8+ lymphocyte counts in the residual tumor after NACT significantly reduces the risk of death from TNBC, HR = 0.6 (95% CI 0.5-0.9; p = 0.01) and HR = 0.6 (95% CI 0.4-0.9; p = 0.008), respectively. Increase in intratumoral CD4+ lymphocytes in residual tumor in the non-pCR group reduces by half the risk of death from TNBC, HR = 0.5 (95% CI 0.3-1.0; p = 0.05).
CONCLUSION
The results of our study indicate a favorable prognostic value of TILS in residual tumor in TNBC. It is also reasonable to include the determination of the level of FOXP3+ lymphocytes in the residual tumor in the standard algorithms for stratification of risk groups.
Topics: Female; Humans; Breast Neoplasms; Forkhead Transcription Factors; Lymphocytes, Tumor-Infiltrating; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Neoplasm, Residual; Prognosis; Triple Negative Breast Neoplasms
PubMed: 36325708
DOI: 10.32471/exp-oncology.2312-8852.vol-44-no-3.18377 -
The Urologic Clinics of North America Aug 2019The introduction of cisplatin-based chemotherapy has revolutionized the care of patients with disseminated testicular germ cell tumors. Although a majority are cured... (Review)
Review
The introduction of cisplatin-based chemotherapy has revolutionized the care of patients with disseminated testicular germ cell tumors. Although a majority are cured with chemotherapy alone, surgical resection continues to play a role because one-third will have residual mass after chemotherapy. In this article, we review the current indications for postchemotherapy resection in nonseminomatous germ cell tumors, including masses greater than 1 cm, resection after salvage chemotherapy, with elevated markers, after late relapse, and for growing teratoma syndrome. We also highlight technical considerations of this often-challenging surgery, including the need for adjunctive procedures, extraretroperitoneal resections, and modern techniques to minimize morbidity.
Topics: Biomarkers, Tumor; Disease-Free Survival; Humans; Laparoscopy; Lymph Node Excision; Lymphatic Metastasis; Male; Neoplasm, Residual; Neoplasms, Germ Cell and Embryonal; Robotic Surgical Procedures; Salvage Therapy; Testicular Neoplasms
PubMed: 31277733
DOI: 10.1016/j.ucl.2019.04.004 -
Nature Reviews. Clinical Oncology Jul 2019Liquid biopsy has been introduced as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in... (Review)
Review
Liquid biopsy has been introduced as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in particular, cell-free tumour DNA (ctDNA). Highly sensitive liquid biopsy assays have been developed that can now be applied to detect and characterize minimal residual disease (MRD), which reflects the presence of tumour cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumour cells left behind after local therapy that eventually lead to local recurrence. This application is the new frontier of liquid biopsy analyses, which are challenged by the very low concentrations of CTCs and ctDNA in blood samples. In this Review, we discuss the key technologies that can be used to detect and characterize CTCs in surveillance of MRD and provide a brief overview of similar roles of ctDNA analyses. We then focus on the current clinical data on the use of CTCs and ctDNA in the detection and monitoring of MRD and in obtaining information on therapeutic targets and resistance mechanisms relevant to the management of individual patients with cancer.
Topics: Cell-Free Nucleic Acids; Humans; Liquid Biopsy; Neoplasm, Residual; Neoplastic Cells, Circulating; Precision Medicine; Prognosis
PubMed: 30796368
DOI: 10.1038/s41571-019-0187-3 -
Signal Transduction and Targeted Therapy Sep 2021Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other... (Clinical Trial)
Clinical Trial
Surgery is the common treatment for early lung cancer with multiple pulmonary nodules, but it is often accompanied by the problem of significant malignancy of other nodules in non-therapeutic areas. In this study, we found that a combined treatment of local radiofrequency ablation (RFA) and melatonin (MLT) greatly improved clinical outcomes for early lung cancer patients with multiple pulmonary nodules by minimizing lung function injury and reducing the probability of malignant transformation or enlargement of nodules in non-ablated areas. Mechanically, as demonstrated in an associated mouse lung tumor model, RFA not only effectively remove treated tumors but also stimulate antitumor immunity, which could inhibit tumor growth in non-ablated areas. MLT enhanced RFA-stimulated NK activity and exerted synergistic antitumor effects with RFA. Transcriptomics and proteomics analyses of residual tumor tissues revealed enhanced oxidative phosphorylation and reduced acidification as well as hypoxia in the tumor microenvironment, which suggests reprogrammed tumor metabolism after combined treatment with RFA and MLT. Analysis of residual tumor further revealed the depressed activity of MAPK, NF-kappa B, Wnt, and Hedgehog pathways and upregulated P53 pathway in tumors, which was in line with the inhibited tumor growth. Combined RFA and MLT treatment also reversed the Warburg effect and decreased tumor malignancy. These findings thus demonstrated that combined treatment of RFA and MLT effectively inhibited the malignancy of non-ablated nodules and provided an innovative non-invasive strategy for treating early lung tumors with multiple pulmonary nodules. Trial registration: www.chictr.org.cn , identifier ChiCTR2100042695, http://www.chictr.org.cn/showproj.aspx?proj=120931 .
Topics: Adult; Aged; Aged, 80 and over; Animals; Cell Proliferation; Combined Modality Therapy; Female; Hedgehog Proteins; Heterografts; Humans; Kaplan-Meier Estimate; Killer Cells, Natural; Lung Neoplasms; Male; Melatonin; Mice; Middle Aged; Mitogen-Activated Protein Kinase Kinases; Multiple Pulmonary Nodules; NF-kappa B; Neoplasm, Residual; Progression-Free Survival; Radiofrequency Ablation; Treatment Outcome; Wnt Signaling Pathway
PubMed: 34471091
DOI: 10.1038/s41392-021-00745-7 -
Clinical Advances in Hematology &... Jul 2022The analysis of circulating tumor DNA (ctDNA) has multiple uses in oncology. In the past few years, studies with varying designs, methods, and quality have emerged that... (Review)
Review
The analysis of circulating tumor DNA (ctDNA) has multiple uses in oncology. In the past few years, studies with varying designs, methods, and quality have emerged that show promise for the use of ctDNA as a tool to detect minimal residual disease (MRD) across luminal gastrointestinal malignancies. This review of the current literature looks at ctDNA in relation to detecting MRD, predicting patient prognosis, and assessing risk for recurrence.
Topics: Biomarkers, Tumor; Circulating Tumor DNA; Gastrointestinal Neoplasms; Humans; Neoplasm, Residual; Prognosis
PubMed: 35802877
DOI: No ID Found -
Neurosurgery Mar 2020Preservation of functional integrity during vestibular schwannoma surgery has become critical in the era of patient-centric medical decision-making. Subtotal tumor...
BACKGROUND
Preservation of functional integrity during vestibular schwannoma surgery has become critical in the era of patient-centric medical decision-making. Subtotal tumor removal is often necessary when dense adhesions between the tumor and critical structures are present. However, it is unclear what the rate of tumor control is after subtotal resection (STR) and what factors are associated with recurrence.
OBJECTIVE
To determine the rate of residual tumor growth after STR and identify clinical and radiographic predictors of tumor progression.
METHODS
A single-institution retrospective study was performed on all sporadic vestibular schwannomas that underwent surgical resection between January 1, 2002 and December 31, 2015. Clinical charts, pathology, radiology, and operative reports were reviewed. Volumetric analysis was performed on all pre- and postoperative MR imaging. Univariate and multivariate logistic regression was performed to identify predictors of the primary endpoint of tumor progression. Kaplan-Meier analysis was performed to compare progression free survival between 2 groups of residual tumor volumes and location.
RESULTS
In this cohort of 66 patients who underwent primary STR, 30% had documented progression within a median follow up period of 3.1 yr. Greater residual tumor volume (OR 2.0 [1.1-4.0]) and residual disease within the internal auditory canal (OR 3.7 [1.0-13.4]) predicted progression on multivariate analysis.
CONCLUSION
These longitudinal data provide insight into the behavior of residual tumor, helping clinicians to determine if and when STR is an acceptable surgical strategy and to anchor expectations during shared medical decision-making consultation with patients.
Topics: Adult; Aged; Disease Progression; Female; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasm, Residual; Neuroma, Acoustic; Retrospective Studies; Tumor Burden
PubMed: 31232426
DOI: 10.1093/neuros/nyz200