Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to Sunitinib in metastatic renal cancer

Rossi, Elisabetta; Fassan, Matteo; Aieta, Michele; Zilio, Francesca; Celadin, R; Borin, Marcello; Grassi, Angela; Troiani, Laura; Basso, Umberto; Barile, Carmen; Sava, Teodoro; Lanza, Cristiano; Miatello, L; Jirillo, Antonio; Rugge, Massimo; Indraccolo, Stefano; Cristofanilli, Massimo; Amadori, Alberto; Zamarchi, Rita

doi:10.1038/bjc.2012.388

Cited by 53 publications

(54 citation statements)

References 38 publications

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“…The prognostic role of circulating tumour cells (CTCs) have been demonstrated in breast cancer [26] and other neoplasms, while their significance in RCC is still debated. In an exploratory study conducted at our Institution, a fluctuation of CTC values has been observed in RCC patients during treatment with sunitinib, and the balance of live and apoptotic cells appeared to correlate with longer disease control [27].…”

Section: Discussionmentioning

confidence: 99%

First-Line sunitinib in patients with renal cell carcinoma (RCC) in von Hippel–Lindau (VHL) disease: clinical outcome and patterns of radiological response

et al. 2014

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rate of radiological response, patterns of responses in different organs, treatment-related toxicities. We performed a retrospective analysis of sunitinib therapy in genetically-confirmed VHL patients treated at our Institution for multifocal or advanced RCC. From February 2007 to July 2012, 14 VHL patients started first-line sunitinib for recurrent or progressing RCC, mean age 48 years (27-71). Nine patients achieved a partial RECIST response (64.3%); responses were noted not only in renal and hepatic lesions but also in pancreatic nodules. Most lesions showed density reduction, while all CNS haemangioblastoma lesions remained stable. At a median follow-up of 37 months, six patients have progressed and three patients died, with a progression-free rate at 2 years of 71.4%. Sunitinib may therefore achieve a fairly good disease control in VHL patients. Radiological responses may be obtained not only in renal tumors but also in synchronous VHL-related lesions, especially pancreatic solid nodules whose exact nature (metastatic RCC or neuroendocrine tumor) cannot be ruled out without invasive biopsy.

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Section: Discussionmentioning

confidence: 99%

First-Line sunitinib in patients with renal cell carcinoma (RCC) in von Hippel–Lindau (VHL) disease: clinical outcome and patterns of radiological response

et al. 2014

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“…Statistical Analysis-The cumulative changes of live and apoptotic CTCs were expressed as described previously (27) by the parameter ⌬AUC; the detected numbers of M30-negative and M30-positive CTCs were separately plotted in relation to time, and the area under the curve (AUC) of longitudinal graphs was calculated (by the trapezoidal rule) following a procedure that is commonly adopted to evaluate cumulative changes of serological tumor markers. The difference between live and apoptotic CTC concentration-time area was calculated in all patients according to Equation 1,…”

Section: Methodsmentioning

confidence: 99%

Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy

Gong

Liu

Yao

et al. 2015

Journal of Biological Chemistry

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“…We recognize and acknowledge in the manuscript that detection of all apoptotic CTCs may not be necessary to demonstrate clinical response to therapy. Instead we propose, as previously stated in the original manuscript, that the detection of any apoptotic cells within the CTC population is a potential indicator of therapy response, as has been elegantly demonstrated by previous work by Rossi et al (3,4). Building on their previous studies, this Communication has afforded Rossi et al the opportunity to publish a small amount of additional data that demonstrates (not surprisingly) that a 2-marker apoptosis assay (M-30/gH2AX) may have more utility than M-30 alone on the CellSearch, at least in spiked samples.…”

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confidence: 96%

Response to Rossi et al.

et al. 2013

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THANK you for providing us with the opportunity to respond to the Communication regarding our published, peerreviewed Cytometry Part A paper entitled ''User-defined protein marker assay development for characterization of circulating tumor cells using the CellSearch Ò system'' [Cytometry A 2012;81A:983-995; doi: cyto.a.22158]. We appreciate the interest in our work and will address the three specific concerns of Rossi and colleagues in this response.(1) Optimization conducted on spiked samples only, without further validation in ex vivo samples:Rossi et al. express concern regarding our use of only spiked samples throughout the study and question the soundness of our approach based on lack of validation in clinical samples (1). As is clearly stated in the Introduction of the original article, the primary objective of our study was not to demonstrate the clinical significance of our developed assays but instead to provide a detailed description of the process of user-defined protein marker development and optimization using the CellSearch system such that it may act as a reference guide for other users of this platform. Rossi et al. subsequently state that in order to prove the clinical significance of a new method, optimization must be undertaken in the setting of a pilot set of patients. We could not agree more with this statement, and as we move forward with implementing these assays in our own lab, this is exactly our course of action.Our interpretation of our study outcomes was based solely on the assays' expected performance when using highly controllable models (cell lines with known expression of the user-defined marker). We hypothesized that if optimized results could not be obtained in these ''best case scenario'' model systems, then the assays would be unlikely to work with a high degree of efficiency in more variable samples obtained from patients. At no point do we assert that our model system replicates the heterogeneous nature of patient samples but instead that our findings be utilized as a starting point for developing user-defined markers on the CellSearch that will subsequently be considered for use in a clinical setting. This is evidenced by our use of multiple cell lines when optimizing the CD44 protocol. This approach allowed us to examine differences in assay performance when presented with varying degrees of marker expression (high/low/negative). These results could not have been obtained from patient samples since the level of marker expression and the presence or absence of a marker would not be known. We, therefore strongly agree with Rossi et al. that clinical validation of all developed assays of this nature, regardless of the platform utilized, is absolutely necessary. However, initial assay validation with known controls (as is described in our article) is always required first in order to ensure appropriate quality control and the sensitivity/specificity of the assay before implementing it for use in patient samples.(2) The choice of FCM as a reference method:The second concern of...

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Dynamic changes of live/apoptotic circulating tumour cells as predictive marker of response to Sunitinib in metastatic renal cancer

Cited by 53 publications

References 38 publications

First-Line sunitinib in patients with renal cell carcinoma (RCC) in von Hippel–Lindau (VHL) disease: clinical outcome and patterns of radiological response

First-Line sunitinib in patients with renal cell carcinoma (RCC) in von Hippel–Lindau (VHL) disease: clinical outcome and patterns of radiological response

Potentiated DNA Damage Response in Circulating Breast Tumor Cells Confers Resistance to Chemotherapy

Response to Rossi et al.

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