Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma

Pal, Sumanta K.; Sonpavde, Guru; Agarwal, Neeraj; Vogelzang, Nicholas J.; Srinivas, Sandy; Haas, Naomi B.; Signoretti, Sabina; McGregor, Bradley A.; Jones, Jeremy O.; Lanman, Richard B.; Banks, Kimberly C.; Choueiri, Toni K.

doi:10.1016/j.eururo.2017.03.046

Cited by 108 publications

(92 citation statements)

References 27 publications

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“…We recently reported outcomes from 224 patients with advanced RCC who received circulating tumor DNA (ctDNA) profiling as a part of routine clinical care [6]. Our data indicates key distinctions from TCGA data, such as a lower rate of VHL alteration (32% versus 53%), and a higher rate of TP53 alteration (30% versus 2%).…”

Section: Introductionmentioning

confidence: 77%

Association of Circulating Tumor DNA (ctDNA) Detection in Metastatic Renal Cell Carcinoma (mRCC) with Tumor Burden

Maia

Bergerot

Dizman

et al. 2017

KCA

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Background: In a series of 224 patients with advanced renal cell carcinoma (RCC), we have previously reported circulating tumor DNA (ctDNA) detection in 79% of patients. Clinical factors associated with detection are unknown.Methods: Data was obtained from patients with radiographically confirmed stage IV RCC who received ctDNA profiling as a part of routine clinical care using a CLIA-certified platform evaluating 73 genes. Detailed clinical annotation was performed, including assessment of International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, previous and current treatments and calculation of tumor burden using scan data most proximal to ctDNA assessment. Tumor burden was equated to the sum of longest diameter (SLD) of all measurable lesions.Results: Thirty-four patients were assessed (18 male and 16 female) with a median age of 62 (range, 34–84). Twenty-six patients, 4 patients and 4 patients had clear cell, sarcomatoid and papillary histologies, respectively. IMDC risk was good, intermediate and poor in 14, 19 and 1 patient, respectively. ctDNA was detected in 18 patients (53%) with a median of 2 genomic alterations (GAs) per patient. No associations were found between IMDC risk, histology or treatment type and presence/absence of ctDNA. However, patients with detectable ctDNA had a higher SLD compared to patients with no detectable ctDNA (8.81 vs 4.49 cm; P = 0.04). Furthermore, when evaluated as a continuous variable, number of GAs was correlated with SLD (P = 0.01).Conclusions: With the caveat of a limited sample size, it appears that SLD (a surrogate for tumor burden) is higher in mRCC patients with detectable ctDNA. Confirmation of these findings in larger series is ongoing and may suggest a capability for ctDNA to either complement or supplant radiographic assessment.

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Section: Introductionmentioning

confidence: 77%

Association of Circulating Tumor DNA (ctDNA) Detection in Metastatic Renal Cell Carcinoma (mRCC) with Tumor Burden

Maia

Bergerot

Dizman

et al. 2017

KCA

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“…We choose the top 50 predict molecules in each group and identified a total of 5 common molecules. To narrow the field of prospective candidates, we further analyzed the potential candidates by overlapping this result with most mutation molecules in ccRCC [7, 10], and gave evidence that ARID1A could be a potential target (Fig. 3A).…”

Section: Resultsmentioning

confidence: 99%

“…Comprehensive molecular studies revealed that ARID1A mutations exist in 3% of ccRCC [52]. But recent articles show that 12% mRNA mutation in genomic alterations (GAs) [10] and 51% protein loss of ARID1A [13] in ccRCC. It indicated that someone down-regulated ARID1A in translation, yet did not only interfere on the genetic level.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Several studies have shown that is closely associated with a series gene mutations such as TP53, VHL, PBRM1, ARID1A, PTEN, SDHB in cancer tissues [7-9], as well as TP53, VHL, NF1, ARID1A, PTEN mutation when treated with first-line and later line vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors (sunitinib, pazopanib, axitinib, sorafenib) in circulating tumor DNA [10, 11]. ARID1A is one of the commonest mutant genes and has equal frequencies when treated with first-line versus postfirst-line regimens in ccRCC [10], and it may play a key role in chemoresistance. At the same time, the lower protein of ARID1A represents a worse prognosis of clear cell renal cell carcinoma [12, 13], since ARID1A plays a role of tumor suppressor in various cancers such as ovarian cancer [14], lung adenocarcinoma [15], pancreatic cancer [16], and liver cancer [17].…”

Section: Introductionmentioning

confidence: 99%

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Mir-144-3p Promotes Cell Proliferation, Metastasis, Sunitinib Resistance in Clear Cell Renal Cell Carcinoma by Downregulating ARID1A

Xiao

Lou

Ruan

et al. 2017

Cell Physiol Biochem

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Background/Aims: We previously performed microRNA (miRNA) microarray to identify effective indicators of clear cell renal cell carcinoma (ccRCC) tissue samples and preoperative/postoperative plasma in which we identified miR-144-3p as an oncomiRNA. However, the molecular mechanism of miR-144-3p remains unclear. This study aims to explore the roles of miR-144-3p in the invasion, migration and Sunitinib-resistance in ccRCC and to elucidate the underlying mechanisms. Methods: Gain and loss of function approaches were used to investigate the cell proliferation, cycle distribution, clonogenicity, migration, invasion, chemosensitivity of miR-144-3p in vitro. The xenograft model was used to assess the effects of miR-144-3p overexpression on tumorigenesis. Bioinformatics analysis and dual-luciferase reporter assay were used to indentify AT-rich interactive domain 1A (ARID1A) as a direct target gene of miR-144-3p. Quantitative RT-PCR, Western blotting, and immunohistochemical (IHC) staining were used to explore ARID1A expression level of the mRNA and protein. Results: We found that miR-144-3p overexpression enhanced cell proliferation, clonogenicity, migration, invasion, and chemoresistance in ccRCC cells. Notably, the oncotumor activities of miR-144-3p were mediated by repressing the expression of ARID1A. The downregulation of ARIDIA could promote the function of miR-144-3p in cell proliferation, metastasis and chemoresistance. Consistently, ARID1A mRNA and protein levels were decreased in ccRCC and in nude mice, and they negatively correlated with miR-144-3p. Conclusion: Higher miR-144-3p may enhance malignancy and resistance to Sunitinib in ccRCC by targeting ARID1A, the observations may uncover novel strategies of ccRCC treatment.

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Genomic Strategies for Personalized Cancer Therapy

Dudek

Baxstrom

Bharadwaj

et al. 2020

Precision Medicine in Oncology

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Evolution of Circulating Tumor DNA Profile from First-line to Subsequent Therapy in Metastatic Renal Cell Carcinoma

Cited by 108 publications

References 27 publications

Association of Circulating Tumor DNA (ctDNA) Detection in Metastatic Renal Cell Carcinoma (mRCC) with Tumor Burden

Association of Circulating Tumor DNA (ctDNA) Detection in Metastatic Renal Cell Carcinoma (mRCC) with Tumor Burden

Mir-144-3p Promotes Cell Proliferation, Metastasis, Sunitinib Resistance in Clear Cell Renal Cell Carcinoma by Downregulating ARID1A

Genomic Strategies for Personalized Cancer Therapy

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