Detection and prognostic role of heterogeneous populations of melanoma circulating tumour cells

Aya-Bonilla, Carlos; Morici, Michael; Hong, Xin; McEvoy, Ashleigh C.; Sullivan, Ryan J.; Freeman, James B.; Calapre, Leslie; Khattak, Muhammad A.; Meniawy, Tarek; Millward, Michael; Ziman, Mel; Gray, Elin S.

doi:10.1038/s41416-020-0750-9

Cited by 49 publications

(45 citation statements)

References 38 publications

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“…LDH levels were correlated with clinical response in two out of ve patients, and the number of CTCs seemed to re ect the response in four out of ve patients, suggesting that CTC count could be a useful biomarker for advanced melanoma treated with BRAF/MEK inhibitors. In a recent study that combined analysis of CTCs and ctDNA, CTC number was strongly associated with the level of ctDNA; moreover, the number of CTCs prior to systemic therapies was negatively correlated with overall and progression-free survival [12]. These observations, along with our results, indicate that detection of CTCs during treatment provides useful information that supports imaging studies, such as CT scans, in the prediction of drug response and prognosis.…”

Section: Discussionsupporting

confidence: 82%

“…In combination with negative selection for leukocyte speci c markers, various markers are used to detect melanoma cells in peripheral blood, including CD146, melanomaassociated chondroitin sulfate proteoglycan, ATP-binding cassette subfamily B member 5, CD271, and receptor activator of NF-κB. Assuming that the CTC population represents the distributed tumor burden and biological features, characterization of these cells could provide a complementary sample for the monitoring of tumor characteristics [11][12][13]. CTCs are a promising source of material because they can be obtained via routine blood sampling and can provide real-time information about the characteristics of tumors over time.…”

Section: Introductionmentioning

confidence: 99%

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Usefulness of Monitoring Circulating Tumor Cells as a Therapeutic Biomarker in Melanoma with BRAF Mutation

Okuyama

Kiniwa

Nakamura

et al. 2020

Preprint

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Background: Circulating tumor cells (CTCs) are non-invasive biomarkers that could be used to characterize changes in tumors. In this study, we monitored the number of CTCs, as well as the BRAF genotype of individual CTCs. Methods: CTCs were isolated from peripheral blood using a high-density dielectrophoretic microwell array, followed by labeling with melanoma-specific markers (MART-1 and/or gp100) and a leukocyte marker (CD45). Results: Examination of patients with stage 0–III melanoma detected CTCs even in patients with early disease (stage 0 or I). Next, we analyzed CTCs in five patients with stage IV melanoma during treatment with BRAF/MEK inhibitors. The number of CTCs fluctuated in association with the drug response in four of the five patients, suggesting that the total number of CTCs usually reflected the drug response. Interestingly, one of those patients had CTCs with seven different BRAF genotypes, and the mutated CTCs disappeared upon treatment with BRAF/MEK inhibitors, except for those harboring BRAFA598V.Conclusions: CTCs are present even in the early stage of melanoma, and the number of CTCs seems to reflect drug response during treatment with BRAF/MEK inhibitors. Furthermore, genetic heterogeneity of BRAF may contribute to drug resistance of BRAF/MEK inhibitor. Our findings demonstrate the usefulness of CTC analysis in melanoma for monitoring targeted therapies and understanding mechanism of drug resistance.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Usefulness of Monitoring Circulating Tumor Cells as a Therapeutic Biomarker in Melanoma with BRAF Mutation

Okuyama

Kiniwa

Nakamura

et al. 2020

Preprint

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“…CTC heterogeneity has been shown and described in other tumor entities (21)(22)(23)(24). We also found a diverse population of CTC in a pilot study of 20 EAC patients undergoing multimodal treatment (14).…”

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confidence: 64%

Cytopathological Heterogeneity of Circulating Tumor Cells in Non-metastatic Esophageal Adenocarcinoma

et al. 2020

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Background/Aim: The presence of circulating tumor cells (CTC) has been reported to have an impact on prognosis in different tumor entities. Little is known about CTC morphology and heterogeneity. Patients and Methods: In a multicenter setting, pre-therapeutic peripheral blood specimens were drawn from patients with non-metastatic esophageal adenocarcinoma (EAC). CTCs were captured by size-based filtration (ScreenCell ®), subsequently Giemsa-stained and evaluated by two trained readers. The isolated cells were categorized in groups based on morphologic criteria. Results: Small and large single CTCs, as well as CTC-clusters, were observed in 69.2% (n=81) of the 117 specimens; small CTCs were observed most frequently (59%; n=69), followed by large CTCs (40%; n=47) and circulating cancer-associated macrophage-like cells (CAMLs; 34.2%, n=40). Clusters were rather rare (12%; n=14). CTC/CAML were heterogeneous in the cohort, but also within one specimen. Neither the presence of the CTC subtypes/CAMLs nor the exact cell count were associated with the primary clinical TNM stage. Conclusion: Morphologically heterogenic CTCs and CAMLs are present in patients with non-metastatic, non-pretreated EAC. Over the past decades the incidence of esophageal squamous cell carcinoma has decreased significantly in the U.S. and Europe. At the same time, the incidence of adenocarcinoma (EAC) has increased rapidly, especially among men (1). Although overall survival has improved over the years thanks to new treatment strategies, the prognosis is still limited (2). We still lack tools for better pre-therapeutic risk-stratification for cancer recurrence, which would enable us to design patientadapted treatment strategies. Currently, treatment decisions are being made based on CT-scans, endoscopic findings, endoscopic ultrasound and tumor biopsy. This momentary pretherapeutic "tumor-image" of the patient does not adequately reflect the actual tumor biology and aggressiveness. More than 50% of the patients initially considered curable will eventually relapse or develop metastasis after complete resection of the tumor (3). This relapse could be due to clinically invisible distant micro-metastases and tumor dissemination at an early time point, or due to lack of treatment response. A promising tool to evaluate these occult metastases for risk stratification and treatment surveillance is the use of liquid biopsy (4). Liquid biopsy summarizes the analysis of tumor cells and tumor-derived products in body fluids, like circulating tumor cells (CTC) (5-7), circulating tumor DNA (ctDNA) (8, 9) and extracellular vesicles (EVs) (10-12). In the case of EAC, there are very limited studies available regarding CTC presence and their significance in general (5, 13-16). CTC have been found in about 20% of patients using epithelial surface antigen (EpCAM)-dependent isolation devices in EAC. These patients 5679 This article is freely accessible online.

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“…LDH levels were correlated with clinical response in two out of five patients, and the number of CTCs seemed to reflect the response in four out of five patients, suggesting that CTC count could be a useful biomarker for advanced melanoma treated with BRAF/MEK inhibitors. In a recent study that combined analysis of CTCs and ctDNA, CTC number was strongly associated with the level of ctDNA; moreover, the number of CTCs prior to systemic therapies was negatively correlated with overall and progression-free survival [ 13 ]. These observations, along with our results, indicate that detection of CTCs during treatment provides useful information that supports imaging studies, such as CT scans, in the prediction of drug response and prognosis.…”

Section: Discussionmentioning

confidence: 99%

Usefulness of monitoring circulating tumor cells as a therapeutic biomarker in melanoma with BRAF mutation

et al. 2021

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Background While molecularly targeted therapies and immune checkpoint inhibitors have improved the prognosis of advanced melanoma, biomarkers are required to monitor drug responses. Circulating tumor cells (CTCs) are released from primary and/or metastatic tumors into the peripheral blood. We examined whether CTCs have potential as biomarkers by checking the number of CTCs, as well as the BRAF genotype of individual CTCs, in melanoma patients undergoing BRAF/MEK inhibitor treatment. Methods CTCs were isolated from peripheral blood using a high-density dielectrophoretic microwell array, followed by labeling with melanoma-specific markers (MART-1 and/or gp100) and a leukocyte marker (CD45). The numbers of CTCs were analyzed in fifteen patients with stage 0–III melanoma. Furthermore, changes in CTC numbers were assessed in five patients with stage IV melanoma at four time points during BRAF/MEK inhibitor treatment, and the BRAF genotype was analyzed in CTCs isolated from one patient. Results We examined CTCs in patients with stage 0–III (five samples per stage: stage 0–I, stage II, and stage III), and detected CTCs even in patients with early disease (stage 0 and I). Interestingly, recurrence occurred in the lymph nodes of one stage I patient 2 years after the detection of a high number of CTCs in the patient’s blood. The total number of CTCs in four of five patients with stage IV melanoma fluctuated in response to BRAF/MEK inhibitor treatment, suggesting that CTC number has potential for use as a drug response marker in advanced disease patients. Interestingly, one of those patients had CTCs harboring seven different BRAF genotypes, and the mutated CTCs disappeared upon BRAF/MEK inhibitor treatment, except for those harboring BRAFA598V. Conclusions CTCs are present even in the early stage of melanoma, and the number of CTCs seems to reflect patients’ responses to BRAF/MEK inhibitor treatment. Furthermore, genetic heterogeneity of BRAF may contribute to resistance to BRAF/MEK inhibitors. Our findings demonstrate the usefulness of CTC analysis for monitoring responses to targeted therapies in melanoma patients, and for understanding the mechanism of drug resistance.

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Detection and prognostic role of heterogeneous populations of melanoma circulating tumour cells

Cited by 49 publications

References 38 publications

Usefulness of Monitoring Circulating Tumor Cells as a Therapeutic Biomarker in Melanoma with BRAF Mutation

Usefulness of Monitoring Circulating Tumor Cells as a Therapeutic Biomarker in Melanoma with BRAF Mutation

Cytopathological Heterogeneity of Circulating Tumor Cells in Non-metastatic Esophageal Adenocarcinoma

Usefulness of monitoring circulating tumor cells as a therapeutic biomarker in melanoma with BRAF mutation

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