Academic literature on the topic 'Adrenocortical carcinoma, tumor microenvironment, liquid biopsy'
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Journal articles on the topic "Adrenocortical carcinoma, tumor microenvironment, liquid biopsy"
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Ravensbergen, Cor J., Matthew Kuruc, Meaghan Polack, Stijn Crobach, Hein Putter, Hans Gelderblom, Devjit Roy, Rob A. E. M. Tollenaar, and Wilma E. Mesker. "The Stroma Liquid Biopsy Panel Contains a Stromal-Epithelial Gene Signature Ratio That Is Associated with the Histologic Tumor-Stroma Ratio and Predicts Survival in Colon Cancer." Cancers 14, no. 1 (December 29, 2021): 163. http://dx.doi.org/10.3390/cancers14010163.
Full textAbstract:
Liquid biopsy has emerged as a novel approach to tumor characterization, offering advantages in sample accessibility and tissue heterogeneity. However, as mutational analysis predominates, the tumor microenvironment has largely remained unacknowledged in liquid biopsy research. The current work provides an explorative transcriptomic characterization of the Stroma Liquid BiopsyTM (SLB) proteomics panel in colon carcinoma by integrating single-cell and bulk transcriptomics data from publicly available repositories. Expression of SLB genes was significantly enriched in tumors with high histologic stromal content in comparison to tumors with low stromal content (median enrichment score 0.308 vs. 0.222, p = 0.036). In addition, we identified stromal-specific and epithelial-specific expression of the SLB genes, that was subsequently integrated into a gene signature ratio. The stromal-epithelial signature ratio was found to have prognostic significance in a discovery cohort of 359 colon adenocarcinoma patients (OS HR 2.581, 95%CI 1.567–4.251, p < 0.001) and a validation cohort of 229 patients (OS HR 2.590, 95%CI 1.659–4.043, p < 0.001). The framework described here provides transcriptomic evidence for the prognostic significance of the SLB panel constituents in colon carcinoma. Plasma protein levels of the SLB panel may reflect histologic intratumoral stromal content, a poor prognostic tumor characteristic, and hence provide valuable prognostic information in liquid biopsy.
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Cantini, Giulia, Letizia Canu, Roberta Armignacco, Francesca Salvianti, Giuseppina De Filpo, Tonino Ercolino, Gabriella Nesi, et al. "Prognostic and Monitoring Value of Circulating Tumor Cells in Adrenocortical Carcinoma: A Preliminary Monocentric Study." Cancers 12, no. 11 (October 29, 2020): 3176. http://dx.doi.org/10.3390/cancers12113176.
Full textAbstract:
Adrenocortical carcinoma (ACC), a rare and aggressive neoplasia, presents poor prognosis when metastatic at diagnosis and limited therapies are available. Specific and sensitive markers for early diagnosis and a monitoring system of therapy and tumor evolution are urgently needed. The liquid biopsy represents a source of tumor material within a minimally invasive blood draw that allows the recovery of circulating tumor cells (CTCs). CTCs have been recently shown to be detectable in ACC. In the present paper, we evaluated the prognostic value of CTCs obtained by size-filtration in a small pilot cohort of 19 ACC patients. We found CTCs in 68% of pre-surgery and in 38% of post-surgery blood samples. In addition, CTC clusters (CTMs) and cancer associated macrophages (CAMLs) were detectable in some ACC patients. The median number of CTCs significantly decreased after the mass removal. Finally, stratifying patients in high and low pre-surgery CTC number groups, assuming the 75th percentile CTC value as cut-off, CTCs significantly predicted patients’ overall survival (log rank = 0.005), also in a multivariate analysis adjusted for age and tumor stage. In conclusion, though preliminary and performed in a small cohort of patients, our study suggests that CTC number may represent a promising marker for prognosis and disease monitoring in ACC.
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Abbott, Charles, Nikita Bedi, Jing Wang, Josette Northcott, Rachel Pyke, Robin Li, Lee McDaniel, et al. "20 Tumor-informed liquid biopsy monitoring of evolving therapeutic resistance mechanisms in head and neck squamous cell carcinoma patients receiving anti-PD-1 therapy." Journal for ImmunoTherapy of Cancer 9, Suppl 2 (November 2021): A22. http://dx.doi.org/10.1136/jitc-2021-sitc2021.020.
Full textAbstract:
BackgroundTypical liquid biopsy panels offer a limited understanding of tumor biology, potentially under-representing the heterogeneity of resistance in late-stage cancers. Here, diminished scope can result in undetected, therapeutically-relevant biomarkers which respond dynamically to treatment, as well as potentially missed resistance mechanisms and pathway-level events. To address the challenges associated with identifying multiple concurrent heterogeneous resistance mechanisms in individual patients, we evaluated longitudinal exome-scale tumor-informed cell-free DNA (cfDNA) data from head and neck squamous cell carcinoma (HNSCC) patients receiving anti-PD1 therapy.MethodsPre- and post-intervention matched tumor, normal and plasma samples were retrospectively obtained from 15 stage II-IV HNSCC patients. Following baseline sample collection, all patients received a single dose of nivolumab or pembrolizumab. The primary tumor was then resected approximately one month later when possible, or a second biopsy collected where resection was impractical. Paired tumor and normal samples were then profiled using ImmunoID NeXT Platform®, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale cfDNA profiling of matched plasma samples was performed using the NeXT Liquid BiopsyTM platform to detect somatic variants.ResultsPatient neoantigen presentation score (NEOPSTM) rapidly and significantly contracted following therapy (p=.00098). Novel neoantigens arising post-treatment which were predicted to be presented on lost HLA alleles were significantly higher in patients with longer overall survival (p=.019). Variant detection across same-patient serial cfDNA samples revealed significantly correlated VAFs (R=.62, p<.0001) despite significant contraction of mutational burden in solid tumor (p=.0039), suggesting complex clonal/subclonal dynamics. Investigation of the evolving tumor and cfDNA subclonal architecture revealed significant association between decreasing cellular prevalence and NOTCH signaling (q=.001) and the innate immune system (q=.002), while increasing cellular prevalence was associated with p53 signalling (q=.02) and hypoxia (q=.02). These findings were complimented by transcriptomic data which showed significant enrichment of multiple immune pathways across treatment.ConclusionsWe found that immune checkpoint blockade precipitates rapid evolution of the HNSCC tumor microenvironment. By leveraging comprehensive, tumor-informed liquid biopsy data we were able to identify contracting cellular populations enriched for NOTCH pathway mutations. Longer OS following either intervention was associated with an expansion of novel neoantigens predicted to be presented by lost HLA alleles. Our results suggest that tumor-informed liquid biopsy provides a more robust understanding of therapeutic response and resistance mechanisms than that attainable with typical liquid biopsy panels alone.Ethics ApprovalThis study obtained ethics approval from Human Subjects Research at Stanford University. ID number is 40425. All participants gave informed consent prior to enrollment.
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Ramzy, George M., Thibaud Koessler, Eloise Ducrey, Thomas McKee, Frédéric Ris, Nicolas Buchs, Laura Rubbia-Brandt, Pierre-Yves Dietrich, and Patrycja Nowak-Sliwinska. "Patient-Derived In Vitro Models for Drug Discovery in Colorectal Carcinoma." Cancers 12, no. 6 (May 31, 2020): 1423. http://dx.doi.org/10.3390/cancers12061423.
Full textAbstract:
Lack of relevant preclinical models that reliably recapitulate the complexity and heterogeneity of human cancer has slowed down the development and approval of new anti-cancer therapies. Even though two-dimensional in vitro culture models remain widely used, they allow only partial cell-to-cell and cell-to-matrix interactions and therefore do not represent the complex nature of the tumor microenvironment. Therefore, better models reflecting intra-tumor heterogeneity need to be incorporated in the drug screening process to more reliably predict the efficacy of drug candidates. Classic methods of modelling colorectal carcinoma (CRC), while useful for many applications, carry numerous limitations. In this review, we address the recent advances in in vitro CRC model systems, ranging from conventional CRC patient-derived models, such as conditional reprogramming-based cell cultures, to more experimental and state-of-the-art models, such as cancer-on-chip platforms or liquid biopsy.
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Wang, Sheng-Han, Shiou-Hwei Yeh, and Pei-Jer Chen. "Unique Features of Hepatitis B Virus-Related Hepatocellular Carcinoma in Pathogenesis and Clinical Significance." Cancers 13, no. 10 (May 18, 2021): 2454. http://dx.doi.org/10.3390/cancers13102454.
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Hepatitis B virus (HBV) infection is one of the important risk factors for hepatocellular carcinoma (HCC) worldwide, accounting for around 50% of cases. Chronic hepatitis B infection generates an inflammatory microenvironment, in which hepatocytes undergoing repeated cycles of damage and regeneration accumulate genetic mutations predisposing them to cancer. A striking male dominance in HBV-related HCC highlights the influence of sex hormones which interact with viral factors to influence carcinogenesis. HBV is also considered an oncogenic virus since its X and surface mutant proteins showed tumorigenic activity in mouse models. The other unique mechanism is the insertional mutagenesis by integration of HBV genome into hepatocyte chromosomes to activate oncogenes. HCC survival largely depends on tumor stages at diagnosis and effective treatment. However, early diagnosis by the conventional protein biomarkers achieves limited success. A new biomarker, the circulating virus–host chimera DNA from HBV integration sites in HCC, provides a liquid biopsy approach for monitoring the tumor load in the majority of HBV–HCC patients. To maximize the efficacy of new immunotherapies or molecular target therapies, it requires better classification of HCC based on the tumor microenvironment and specific carcinogenic pathways. An in-depth study may benefit both the diagnosis and treatment of HBV-related HCC.
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Cammarota, Antonella, Valentina Zanuso, Giulia Francesca Manfredi, Ravindhi Murphy, David James Pinato, and Lorenza Rimassa. "Immunotherapy in hepatocellular carcinoma: how will it reshape treatment sequencing?" Therapeutic Advances in Medical Oncology 15 (January 2023): 175883592211480. http://dx.doi.org/10.1177/17588359221148029.
Full textAbstract:
The treatment landscape of advanced hepatocellular carcinoma (HCC) has broadened with immune checkpoint inhibitors (ICIs) setting a novel standard of care. With the increased number of therapies either in first or in further line, disentangling the possible treatment sequences has become much more complex. Yet, all the second-line therapies have been evaluated after sorafenib. After ICIs, offering multikinase inhibitors is a widespread approach, either shifting forward sorafenib or lenvatinib, or choosing among regorafenib or cabozantinib, already approved in the refractory setting. Under specific circumstances, ICIs could be maintained beyond disease progression in patients with proven clinical benefit, as supported by some data emerging from phase III clinical trials with immunotherapy in HCC. Rechallenge with ICIs is an additional attractive alternative, although requiring careful and individual evaluation as efficacy and safety of such a strategy have not been yet clarified. Still, a considerable number of patients displays primary resistance to ICIs and might benefit from antiangiogenics either alone or in addition to ICIs instead. Hopefully, the ongoing clinical trials will enlighten regarding the most effective treatment pathways. The identification of predictive correlates of response to immunotherapy will help treatment allocation at each stage, thus representing an urgent matter to address in HCC research. With programmed death ligand 1 expression, tumor mutational burden, and microsatellite status being inadequate biomarkers in HCC, patient characteristics, drug safety profile, and regulatory approval remain key elements to acknowledge in routine practice. Despite the tissue remaining a preferred source, biomarkers discovery could take advantage of liquid biopsy to overcome the matter of tissue availability and track tumor changes. Lastly, tumor genetic phenotypes, tumor microenvironment features, gut microbiome, and markers of immune response and systemic inflammation are all potential emergent predictors of response to ICIs, pending validation in the clinical setting.
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Altieri, Barbara, Silke Appenzeller, Wiebke Arlt, Miriam Asia, Vasileios Chortis, Yasir S. Elhassan, Martin Fassnacht, et al. "OR04-5 Circulating Cell-Free DNA-Based Biomarkers For Prognostication and Disease Surveillance in Adrenocortical Carcinoma." Journal of the Endocrine Society 6, Supplement_1 (November 1, 2022): A81—A82. http://dx.doi.org/10.1210/jendso/bvac150.169.
Full textAbstract:
Abstract Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. Here, we investigated the role of circulating cell-free DNA (ccfDNA)-related biomarkers for prognostication and monitoring of ACC. We investigated 79 patients with ACC (29M/50F, 52±14yrs; 35 primary tumors [ACC-P] and 44 recurrences [ACC-R]); while 27 patients with adrenocortical adenomas [ACA] (9M/18F, 56±16yrs) and 19 healthy subjects (HS; 9M/10F, 37±9yrs) served as controls. We extracted ccfDNA from 1-4 ml EDTA-plasma using Nonacus Cell3 Xtract or Qiagen QIAamp MinElute kit and quantified by fluorimeter (ccfDNA concentrations, Biomarker 1). Targeted next-generation sequencing (Illumina NextSeq500) was performed in a first subgroup of 52 baseline ccfDNA samples (23 ACC-P, 20 ACC-R, 8 ACA) using a customised panel of 30 ACC-specific genes (Cell3 Target Nonacus). Leucocyte DNA was sequenced to discriminate germline from somatic variants (Biomarker 2). Sequencing data from matched tumor DNA were available for 28 ACC (20 ACC-P, 8 R-ACC). A combined Biomarker score was calculated for prediction of clinical outcome. ACC-P had the highest ccfDNA concentrations (mean±SD 1.08±1.50 ng/µl) compared to ACC-R (0.29±0.23 ng/µl, P<0.05), ACA (0.17±0.13 ng/µl, P<0.005) and HS (0.11±0.07 ng/µl, P<0.005). Using a cutoff of 0.204 (median HS+2SD), 68% of ACC-P were postitive for Biomarker 1 (vs. ACC-R 55%, ACA 28%, HS 5%; P<0.0001 by Chi square test). At ccfDNA sequencing, 43% of ACC-P showed at least one somatic mutation (=positive Biomarker 2), vs. 15% in ACC-R and 0% in ACA. Mutational status at ccfDNA level matched with tumor DNA in 80% of cases. In 23 ACC-P with available sequencing data, the combined Biomarker score was strongly associated with both progression-free and overall survival (P<0.0001, HR 8.56, 95%CI 2.55-58.7, and P=0.0008, HR 13.3, 95%CI 3.77-47.1, respectively). 10 ACC-P were followed up for at least 6 months: 6 patients tumor-free at last CT scan were negative for Biomarker 1 whereas 3 out of 4 patients with early disease relapse were positive. In two recurrent cases, somatic mutations in ACC driver genes, i.e. MEN1 and ZNRF3, observed at baseline in both tumour and ccfDNA, remained detectable during monitoring. In conclusion, ccfDNA-related biomarkers are frequently detected in patients with primary ACC. They may represent a promising, non-invasive tool to predict early disease progression and complement imaging in disease surveillance. Our findings on ccfDNA-based liquid biopsy will be validated in a larger cohort of ACCs with long-term follow up. Presentation: Saturday, June 11, 2022 12:30 p.m. - 12:45 p.m.
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Goudsmit, Christine, Felipe da Veiga Leprevost, Venkatesha Basrur, Lila Peters, Alexey Nesvizhskii, and Heather Walline. "Differences in Extracellular Vesicle Protein Cargo Are Dependent on Head and Neck Squamous Cell Carcinoma Cell of Origin and Human Papillomavirus Status." Cancers 13, no. 15 (July 23, 2021): 3714. http://dx.doi.org/10.3390/cancers13153714.
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To identify potential extracellular vesicle (EV) biomarkers in head and neck squamous cell carcinoma (HNSCC), we evaluated EV protein cargo and whole cell lysates (WCL) from HPV-positive and -negative HNSCC cell lines, as well as normal oral keratinocytes and HPV16-transformed cells. EVs were isolated from serum-depleted, conditioned cell culture media by polyethylene glycol (PEG) precipitation/ultracentrifugation. EV and WCL preparations were analyzed by LC-MS/MS. Candidate proteins detected at significantly higher levels in EV compared with WCL, or compared with EV from normal oral keratinocytes, were identified and confirmed by Wes Simple Western protein analysis. Our findings suggest that these proteins may be potential HNSCC EV markers as proteins that may be (1) selectively included in EV cargo for export from the cell as a strategy for metastasis, tumor cell survival, or modification of tumor microenvironment, or (2) representative of originating cell composition, which may be developed for diagnostic or prognostic use in clinical liquid biopsy applications. This work demonstrates that our method can be used to reliably detect EV proteins from HNSCC, normal keratinocyte, and transformed cell lines. Furthermore, this work has identified HNSCC EV protein candidates for continued evaluation, specifically tenascin-C, HLA-A, E-cadherin, EGFR, EPHA2, and cytokeratin 19.
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Agarwal, Shipra, Andrey Bychkov, and Chan-Kwon Jung. "Emerging Biomarkers in Thyroid Practice and Research." Cancers 14, no. 1 (December 31, 2021): 204. http://dx.doi.org/10.3390/cancers14010204.
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Thyroid cancer is the most common endocrine malignancy. Recent developments in molecular biological techniques have led to a better understanding of the pathogenesis and clinical behavior of thyroid neoplasms. This has culminated in the updating of thyroid tumor classification, including the re-categorization of existing and introduction of new entities. In this review, we discuss various molecular biomarkers possessing diagnostic, prognostic, predictive and therapeutic roles in thyroid cancer. A comprehensive account of epigenetic dysregulation, including DNA methylation, the function of various microRNAs and long non-coding RNAs, germline mutations determining familial occurrence of medullary and non-medullary thyroid carcinoma, and single nucleotide polymorphisms predisposed to thyroid tumorigenesis has been provided. In addition to novel immunohistochemical markers, including those for neuroendocrine differentiation, and next-generation immunohistochemistry (BRAF V600E, RAS, TRK, and ALK), the relevance of well-established markers, such as Ki-67, in current clinical practice has also been discussed. A tumor microenvironment (PD-L1, CD markers) and its influence in predicting responses to immunotherapy in thyroid cancer and the expanding arena of techniques, including liquid biopsy based on circulating nucleic acids and plasma-derived exosomes as a non-invasive technique for patient management, are also summarized.
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Hong, David S., Shiraj Sen, Haeseong Park, Rebecca Suk Heist, Shirish M. Gadgeel, Zachary Franklin Zimmerman, and Lyudmila Bazhenova. "A phase I, open-label, multicenter, first-in-human study of the safety, tolerability, pharmacokinetics, and antitumor activity of TPX-0022, a novel MET/CSF1R/SRC inhibitor, in patients with advanced solid tumors harboring genetic alterations in MET." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): TPS3663. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.tps3663.
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TPS3663 Background: Alterations in the MET gene, including amplifications, chromosomal translocations, and activating mutations (kinase domain [KD] or exon 14 [Δex14]), occur across various tumors and may function as oncogenic drivers. SRC family kinases function as a key downstream node for MET signaling. CSF1R is a receptor tyrosine kinase associated with tumor progression and suppression of the immune response in the tumor microenvironment. TPX-0022 is a type I kinase inhibitor with a novel macrocyclic structure that potently inhibits MET, CSF1R and SRC to simultaneously target oncogenic MET signaling, its key downstream mediators, and the tumor microenvironment. Methods: This is a multicenter phase 1 first-in-human, open-label study to determine the safety, tolerability, PK, and preliminary efficacy of TPX-0022 in adults with advanced solid tumors harboring genetic alterations in MET. TPX-0022 will be administered orally in continuous 28-day cycles. The primary endpoint is the incidence of DLTs and determination of recommended phase 2 dose (RP2D). Secondary endpoints include ORR by blinded independent central review, intra-cranial response rate, PFS and OS (dose expansion only). In the dose escalation portion, ~30 subjects age ≥18 with solid tumors harboring MET gene amplifications, Δex14, fusions or KD mutations as determined by local tissue-based or liquid biopsy will be enrolled in a 3+3 design. Intrasubject dose escalation will also be allowed. Once the RP2D has been determined, a food effect sub-study will be conducted and ~80 subjects will be enrolled in a dose expansion portion of the study into the following cohorts: I: non-small cell lung cancer (NSCLC) Δex14 (MET therapy naïve), II: NSCLC Δex14 (MET therapy pre-treated), III: MET amplified NSCLC, gastric, or hepatocellular carcinoma, IV: solid tumors with MET KD mutations or fusions. Correlative studies will include analysis of circulating cell-free DNA to identify genomic alterations that may predict activity of TPX-0022 as well as circulating protein biomarkers such as s-MET, HGF, CSF1 and serum cytokines. The study is open and enrolling in the dose escalation portion at the time of submission. Clinical trial information: NCT03993873 .
Dissertations / Theses on the topic "Adrenocortical carcinoma, tumor microenvironment, liquid biopsy"
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Armignacco, Roberta. "Evolution and progression of adrenocortical carcinoma: the potential role of the adipose microenvironment and the isolation and characterization of circulating tumor cells." Doctoral thesis, 2018. http://hdl.handle.net/2158/1118771.
Full textAbstract:
Adrenocortical carcinoma (ACC) is a rare endocrine malignancy affecting the adrenal cortex, presenting high heterogeneity and aggressiveness, often with an unfavorable outcome. Despite several novel biomarkers of diagnostic and prognostic relevance have been identified, the molecular mechanism underlying the pathology has still to be fully elucidated and the available therapeutic options show limited specificity and efficacy. Molecular alterations, including driver gene mutations, epigenetic alterations and dysregulation of signaling pathways related to cell survival, growth and proliferation, play a crucial role in determine malignancy. However, this cannot exhaustively enucleate the mechanisms by which cancer cells acquire the ability to migrate and metastasize to distant sites, thus resulting in cancer progression. Tumor microenvironment constitutes the ideal soil to establish a dynamic crosstalk between tumor and stromal cells, inducing reciprocal metabolic and functional alterations. In particular, adipocytes and adipose progenitors have been demonstrated to play a pivotal role in supporting tumor growth and progression. Since the adrenal glands present a substantial component of adipose tissue, the adipose microenvironment may be involved in the mechanisms underlying adrenal tumorigenesis and cancer evolution.
The first objective of this thesis was to was reproduce an in vitro tumor microenvironment by co-culturing the adrenocortical cancer cells NCI-H295R with cells of the adipose lineage, particularly adipose-derived stem cells (ASCs) and in vitro differentiated adipocytes, in order to evaluate the reciprocal paracrine effects on cell behavior. This was achieved by using a culturing system in which the two cell types were physically separated but a constant exchange of soluble factors was assured by the presence of a porous membrane. Through this method we demonstrated that an active crosstalk was established between the two cell types, leading to cancer cell increased proliferation and migration ability, but also to a altered morphological and functional features in adipose cells, acquiring a phenotype more prone to sustain cancer growth. Studying the dynamics of such interactions would help in elucidating adrenocortical cancer biology and in developing more specific and effective treatments.
Identifying specific features of more aggressive cancer cells could also allow to monitor tumor progression, preventing tumor dissemination and metastasis. In this scenario, the "liquid biopsy" may represent the possibility to follow tumor evolution: the detection and characterization of circulating tumor cells (CTCs) in blood samples of cancer patients represents a promising way to profile cancer disease complexity at any stage of tumor progression, by a minimally-invasive procedure. As shown in the present study, CTCs can be isolated and identified for their cancer and adrenal nature in blood samples of ACC patients. Moreover, an experimental workflow was designed in order to compare CTC genetic profile to that of the primary tumor. In particular, DNA extraction and amplification methods were tested on CTC samples to assess feasibility for downstream applications, such as next generation sequencing and digital-droplet PCR.
The identification of specific traits characterizing the pool of cancer cells retaining the metastatic potential would be particularly meaningful in advanced adrenocortical carcinoma, aiding to monitoring disease evolution and to develop therapeutic strategies patient-centered.