Serial monitoring of circulating tumor DNA in patients with primary breast cancer for detection of occult metastatic disease.
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ABSTRACT:
SUBMITTER: Olsson E
PROVIDER: S-EPMC4551342 | biostudies-literature | 2015 Aug
REPOSITORIES: biostudies-literature
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Project description:Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) significantly improve progression-free survival and have become the standard therapy for estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer patients. Treatment surveillance by radiological imaging has some limitations in detection and repeated biopsy genomic profiling is not clinically feasible. Serial circulating tumor DNA (ctDNA) analysis may provide insights into treatment response. Here we performed serial ctDNA analysis (n = 178) on 33 patients. Serial ctDNA analysis identified disease progression with sensitivity of 75% and specificity of 92%. In eight of 12 patients (61%) responding to CDK4/6i who eventually developed progressive disease, serial sampling every 3 or 6 months captured the initial rise of ctDNA with an average lead time of 3 months. In three of eight patients that did not respond to CDK4/6i (progressive disease at first radiological assessment, 3 months), biweekly sequencing within the first cycle of CDK4/6i treatment (1 month) detected sustained ctDNA levels (≥0.2% variant allele frequency), with lead time of 2 months. Serial ctDNA analysis tracked RECIST response, including clinically challenging scenarios (bone metastases or small-sized target lesions), as well as detecting acquired genetic alterations linked to CDK4/6i resistance in the G1 to S transition phase. Circulating tumor DNA analysis was more sensitive than carcinoembryonic antigen or cancer antigen 15-3 serum tumor markers at monitoring tumor response to CDK4/6i treatment. Our findings indicated the possible clinical utility of serial ctDNA analysis for earlier progressive disease detection and real-time monitoring of CDK4/6i response.
| S-EPMC9128178 | biostudies-literature
Project description:Early biomarkers of therapeutic responses can help optimize the treatment of metastatic colorectal cancers (mCRC). In this prospective exploratory study, we examined serial changes of plasma-circulating tumor DNA (ctDNA) in 41 mCRC patients receiving first-line chemotherapies and tested its association with treatment outcomes according to radiological assessments. Using next-generation sequencing technologies, we profiled somatic mutations in 50 cancer-related genes in ctDNA before each of the first four treatment cycles. We observed mutations in 95.7% of pre-treatment ctDNA samples. Using mutations of the maximal frequency in each pre-treatment plasma ctDNA sample as the candidate targets, we computed log2 fold changes of ctDNA levels between adjacent treatment cycles. We found that ctDNA reductions as early as prior to cycle 2 predicted responses after cycle 4. Log2 fold changes of ctDNA after cycle 1 (ctDNA log2 (C1/C0)) > -0.126 predicted progressive disease, with an accuracy of 94.6%. These patients also showed significantly worse progression-free survival than those with ctDNA log2 (C1/C0) ≤ -0.126 (median 2.0 vs. 9.0 months; P = 0.007). Together, the present exploratory study suggests that early changes in ctDNA levels detected via targeted sequencing are potential biomarkers of future treatment responses in mCRCs.
| S-EPMC6536571 | biostudies-literature
Project description:BackgroundWe examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.MethodsSerial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.ResultsLatent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.ConclusionsWe identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.
| S-EPMC8023821 | biostudies-literature
Project description: Not available
| S-EPMC6976395 | biostudies-literature
Project description:AbstractBreast cancer (BC) represents the most commonly diagnosed cancer among females worldwide. Although targeted therapy has greatly improved the efficacy of treating BC, a large proportion of BC patients eventually develop recurrence or metastasis. Traditional invasive tumor tissue biopsy is short of comprehensiveness in tumor assessment due to heterogeneity. Liquid biopsy, an attractive non-invasive approach mainly including circulating tumor cell and circulating tumor DNA (ctDNA), has been widely utilized in a variety of cancers with the advances of sequencing technologies in recent years. The ctDNA that is found circulating in body fluids refers to DNA released from tumor cells and has shown clinical utility in metastatic breast cancer (MBC). With the results of genomic variants detection, ctDNA could be used to predict clinical outcomes, monitor disease progression, and guide treatment for patients with MBC. Moreover, the drug resistance problem may be addressed by ctDNA detection. In this review, we summarized the technological developments and clinical applications of ctDNA in MBC.
| S-EPMC7244344 | biostudies-literature
Project description:Purpose: Circulating cell-free (ccf) human papillomavirus (HPV) DNA may serve as a unique tumor marker for HPV-associated malignancies, including cervical cancer. We developed a method to genotype and quantify circulating HPV DNA in patients with HPV16- or HPV18-positive metastatic cervical cancer for potential disease monitoring and treatment-related decision making.Experimental Design: In this retrospective study, HPV ccfDNA was measured in serum samples from 19 metastatic cervical cancer patients by duplex digital droplet PCR (ddPCR). Nine patients had received tumor-infiltrating lymphocyte (TIL) immunotherapy. ccfDNA data were aligned with the tumor HPV genotype, drug treatment, and clinical outcome.Results: In blinded tests, HPV ccfDNA was detected in 19 of 19 (100%) patients with HPV-positive metastatic cervical cancer but not in any of the 45 healthy blood donors. The HPV genotype harbored in the patients' tumors was correctly identified in 87 of 87 (100%) sequential patient serum samples from 9 patients who received TIL immunotherapy. In three patients who experienced objective cancer regression after TIL treatment, a transient HPV ccfDNA peak was detected 2-3 days after TIL infusion. Furthermore, persistent clearance of HPV ccfDNA was only observed in two patients who experienced complete response (CR) after TIL immunotherapy.Conclusions: HPV ccfDNA represents a promising tumor marker for noninvasive HPV genotyping and may be used in selecting patients for HPV type-specific T-cell-based immunotherapies. It may also have value in detecting antitumor activity of therapeutic agents and in the long-term follow-up of cervical cancer patients in remission. Clin Cancer Res; 23(22); 6856-62. ©2017 AACR.
| S-EPMC7885032 | biostudies-literature
Project description:BackgroundIn metastatic breast cancer (MBC), blood-based diagnostics have become a major focus of oncological research in the last 2 decades. Detection of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) has the potential to improve prognosis assessment and complement standard therapy monitoring tools.SummaryTo date, several large analyses have confirmed high CTC counts as an independent prognostic factor. Persistently high CTC numbers during systemic treatment are associated with early progression, but it remains to be clarified which therapeutic options should be offered to such patients since the SWOG 0500 trial failed to show benefit from early switch to another chemotherapy regimen in patients with CTC persistence. In comparison, evidence on the prognostic value of ctDNA is still limited. Most importantly, liquid biopsy-guided treatment interventions have been investigated in several trials. In patients with hormone receptor-positive and HER2-negative MBC, CTC-driven therapy choices resulted in similar PFS to physician's choice treatment. Recently, the DETECT III trial has shown that patients with HER2-negative MBC and HER2-positive CTCs may benefit from targeted anti-HER2 treatment with lapatinib. ctDNA-driven therapy selection has already been approved in clinical routine: alpelisib is the first targeted treatment indicated on the basis of a ctDNA test. Key Messages: CTCs and ctDNA predict clinical outcome and have a potential to improve therapy choices in MBC.
| S-EPMC8985043 | biostudies-literature
Project description:BACKGROUND:Occult metastatic tumors, below imaging thresholds, are a limitation of staging systems that rely on cross-sectional imaging alone and are a cause of the routine understaging of pancreatic ductal adenocarcinomas (PDACs). We investigated circulating tumor cells (CTCs) as a preoperative predictor of occult metastatic disease and as a prognostic biomarker for PDAC patients. EXPERIMENTAL DESIGN:A total of 126 patients (100 with cancer, 26 with benign disease) were enrolled in our study and CTCs were identified and enumerated from 4 mL of venous blood using the microfluidic NanoVelcro assay. CTC enumeration was correlated with clinicopathologic variables and outcomes following both surgical and systemic therapies. RESULTS:CTCs were identified in 78% of PDAC patients and CTC counts correlated with increasing stage (? = 0.42, p < 0.001). Of the 53 patients taken for potentially curative surgery, 13 (24.5%) had occult metastatic disease intraoperatively. Patients with occult disease had significantly more CTCs than patients with local disease only (median 7 vs. 1 CTC, p < 0.0001). At a cut-off of three or more CTCs/4 mL, CTCs correctly identified patients with occult metastatic disease preoperatively (area under the receiver operating characteristic curve 0.82, 95% confidence interval (CI) 0.76-0.98, p < 0.0001). CTCs were a univariate predictor of recurrence-free survival following surgery [hazard ratio (HR) 2.36, 95% CI 1.17-4.78, p = 0.017], as well as an independent predictor of overall survival on multivariate analysis (HR 1.38, 95% CI 1.01-1.88, p = 0.040). CONCLUSIONS:CTCs show promise as a prognostic biomarker for PDAC patients at all stages of disease being treated both medically and surgically. Furthermore, CTCs demonstrate potential as a preoperative biomarker for identifying patients at high risk of occult metastatic disease.
| S-EPMC5896564 | biostudies-literature
Project description:INTRODUCTION:The management of metastatic breast cancer needs improvement. As clinical evaluation is not very accurate in determining the progression of disease, the analysis of circulating tumor DNA (ctDNA) has evolved to a promising noninvasive marker of disease evolution. Indeed, ctDNA was reported to represent a highly sensitive biomarker of metastatic cancer disease directly reflecting tumor burden and dynamics. However, at present little is known about the dynamic range of ctDNA in patients with metastatic breast cancer. METHODS:In this study, 74 plasma DNA samples from 58 patients with metastasized breast cancer were analyzed with a microfluidic device to determine the plasma DNA size distribution and copy number changes in the plasma were identified by whole-genome sequencing (plasma-Seq). Furthermore, in an index patient we conducted whole-genome, exome, or targeted deep sequencing of the primary tumor, metastases, and circulating tumor cells (CTCs). Deep sequencing was done to accurately determine the allele fraction (AFs) of mutated DNA fragments. RESULTS:Although all patients had metastatic disease, plasma analyses demonstrated highly variable AFs of mutant fragments. We analyzed an index patient with more than 100,000 CTCs in detail. We first conducted whole-genome, exome, or targeted deep sequencing of four different regions from the primary tumor and three metastatic lymph node regions, which enabled us to establish the phylogenetic relationships of these lesions, which were consistent with a genetically homogeneous cancer. Subsequent analyses of 551 CTCs confirmed the genetically homogeneous cancer in three serial blood analyses. However, the AFs of ctDNA were only 2% to 3% in each analysis, neither reflecting the tumor burden nor the dynamics of this progressive disease. These results together with high-resolution plasma DNA fragment sizing suggested that differences in phagocytosis and DNA degradation mechanisms likely explain the variable occurrence of mutated DNA fragments in the blood of patients with cancer. CONCLUSIONS:The dynamic range of ctDNA varies substantially in patients with metastatic breast cancer. This has important implications for the use of ctDNA as a predictive and prognostic biomarker.
| S-EPMC4303230 | biostudies-literature
Project description:The availability of blood-based diagnostic testing using a non-invasive technique holds promise for real-time monitoring of disease progression and treatment selection. Circulating tumor cells (CTCs) have been used as a prognostic biomarker for the metastatic breast cancer (MBC). The molecular characterization of CTCs is fundamental to the phenotypic identification of malignant cells and description of the relevant genetic alterations that may change according to disease progression and therapy resistance. However, the molecular characterization of CTCs remains a challenge because of the rarity and heterogeneity of CTCs and technological difficulties in the enrichment, isolation and molecular characterization of CTCs. In this pilot study, we evaluated circulating tumor associated cells in one blood draw by size exclusion technology and cytological analysis. Among 30 prospectively enrolled MBC patients, CTCs, circulating tumor cell clusters (CTC clusters), CTCs of epithelial-mesenchymal transition (EMT) and cancer associated macrophage-like cells (CAMLs) were detected and analyzed. For molecular characterization of CTCs, size-exclusion method for CTC enrichment was tested in combination with DEPArray™ technology, which allows the recovery of single CTCs or pools of CTCs as a pure CTC sample for mutation analysis. Genomic mutations of TP53 and ESR1 were analyzed by targeted sequencing on isolated 7 CTCs from a patient with MBC. The results of genomic analysis showed heterozygous TP53 R248W mutation from one single CTC and pools of three CTCs, and homozygous TP53 R248W mutation from one single CTC and pools of two CTCs. Wild-type ESR1 was detected in the same isolated CTCs. The results of this study reveal that size-exclusion method can be used to enrich and identify circulating tumor associated cells, and enriched CTCs were characterized for genetic alterations in MBC patients, respectively.
| S-EPMC5085698 | biostudies-literature