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Clinical Significance of Early Changes in Circulating Tumor Cells from Patients Receiving First-Line Cisplatin-Based Chemotherapy for Metastatic Urothelial Carcinoma.

ABSTRACT: Background: The therapeutic paradigm of metastatic urothelial carcinoma (UC) is rapidly shifting and new biomarkers are needed to enhance patient selection. Objective: Early identification of dynamic predictors of outcome may be a key to optimize the sequence of effective therapies in metastatic UC patients. Methods: Blood samples from patients receiving first-line MVAC chemotherapy were collected at baseline (T₀) and after 2 cycles (T₂). Samples were processed by immunomagnetic beads (AdnaTest ProstateCancerSelect kit) and the expression of EPCAM, MUC1 and ERBB2 was studied using multiplex-PCR. Circulating tumor cell (CTC) positivity and cutoffs, obtained by receiver operator characteristic (ROC) curve analysis in healthy donors, were: ?1 positive marker among EPCAM (?0.40?ng/?l), MUC1 (?0.10?ng/?l) and ERBB2 (?0.20?ng/?l). CTC variation (T₀/T₂) was split in favorable (+/-, -/-, -/+) and unfavorable groups (+/+). Cox regression analyses evaluated associations with clinical factors. Results: In this pilot study to assess a new CTC detection method, among 31 evaluable patients, 17 (54.8%) were CTC-positive at T₀. No association was found between CTC and objective response to MVAC. CTC dynamic changes better predicted 3-year progression-free (PFS) and overall survival (OS) compared to CTC status assessed at single time points. Unfavorable trend was univariably detrimental on 3-year PFS (10% vs. 49.2%, p?=?0.006) and OS (20% vs. 63.5%, p?=?0.017). Significance was maintained after controlling for liver metastases (p?=?0.031 and p?=?0.025 for PFS and OS) and MSKCC score (p?=?0.014 and 0.025). Conclusions: Newly described early CTC changes during chemotherapy might be useful to improve our prognostic ability. Pending validation, these results could fulfill the promise to help accelerating therapeutic sequences.

SUBMITTER: Fina E

PROVIDER: S-EPMC5181661 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Clinical Significance of Early Changes in Circulating Tumor Cells from Patients Receiving First-Line Cisplatin-Based Chemotherapy for Metastatic Urothelial Carcinoma.

Fina Emanuela E Necchi Andrea A Giannatempo Patrizia P Colecchia Maurizio M Raggi Daniele D Daidone Maria Grazia MG Cappelletti Vera V

Bladder cancer (Amsterdam, Netherlands) 20161027 4

Background: The therapeutic paradigm of metastatic urothelial carcinoma (UC) is rapidly shifting and new biomarkers are needed to enhance patient selection. Objective: Early identification of dynamic predictors of outcome may be a key to optimize the sequence of effective therapies in metastatic UC patients. Methods: Blood samples from patients receiving first-line MVAC chemotherapy were collected at baseline (T0) and after 2 cycles (T2). Samples were p ...[more]

PMID: 28035320

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Project description:Urothelial carcinoma (UC) is a frequently diagnosed tumor and an important cause of cancer deaths worldwide. Until a few years ago, despite the unquestioned role of platinum-based chemotherapy, therapeutic choices beyond the first line were limited and related to unsatisfactory outcomes. Metastatic UC has always been associated with a poor prognosis, with overall survival only slightly above a year. In the recent past, huge progress has been made in our understanding of the molecular and genomic disease characteristics, to enable stratification of patients in terms of prognosis and treatment responses. Unfortunately, we still do not have the perfect combination of clinical biomarkers to tailor the optimal treatment for each patient, despite making several efforts in this direction. The therapeutic arsenal has been augmented by immune checkpoint inhibitors (ICIs), which nowadays represent the backbone of the second-line setting. Equally revolutionary was the FDA's approval of erdafitinib, a potent fibroblast growth factor receptor (FGFR) inhibitor, the use of which is reserved for patients whose tumor harbors specific FGF pathway alterations. Recently, the therapeutic landscape of metastatic UC has been enhanced by the introduction of novel compounds, consisting of antibody-drug conjugates (ADCs). Enfortumab vedotin is an antibody targeting nectin-4, a cell adhesion molecule highly expressed in UC, conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Sacituzumab govitecan is a humanized monoclonal antibody targeting Trop-2, a transmembrane glycoprotein, conjugated to the active metabolite of irinotecan. These two compounds have received accelerated approval by the FDA in patients pretreated with platinum-based chemotherapy and immunotherapy. Several ongoing trials are investigating the role of ICIs combined with chemotherapy, antiangiogenic drugs, or other ICIs, as well as the efficacy of PARP inhibitors and target therapies, hoping to provide information for some important unmet needs. In this review, we aim to evaluate the current potential treatment options after first-line chemotherapy.

Project description:BackgroundLimited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown.ObjectiveTo compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy.Design, setting, and participantsWe conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database.Outcome measurements and statistical analysisThe primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness.Results and limitationsIPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0-45.3%] vs 46.1% [95% CI 43.4-48.8%]) but higher at 36 mo (28.3% [95% CI 21.8-34.7%] vs 13.3% [95% CI 11.1-15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15-1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30-0.85). Limitations include retrospective design and potential unmeasured confounding.ConclusionsIn the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy.Patient summaryTo determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.

Project description:BackgroundThe available prognostic models for overall survival (OS) in patients with metastatic urothelial carcinoma (UC) have been derived from clinical trial populations of cisplatin-treated patients.ObjectiveTo develop a new model based on real-world patients.Design, setting, and participantsIndividual patient-level data from 29 centers were collected, including metastatic UC and first-line cisplatin- or carboplatin-based chemotherapy administered between January 2006 and January 2011.InterventionFirst-line, platinum-based, combination chemotherapy.Outcome measurements and statistical analysisThe population was randomly split into a development and a validation cohort. Generalized boosted regression modelling was used to screen out irrelevant variables and address multivariable analyses. Two nomograms were built to estimate OS probability, the first based on baseline factors and platinum agent, the second incorporating objective response (OR). The performance of the above nomograms and that of other available models was assessed. We plotted decision curves to evaluate the clinical usefulness of the two nomograms.Results and limitationsA total of 1020 patients were analyzed (development: 687, validation: 333). In a platinum-stratified Cox model, significant variables for OS were performance status (p<0.001), white blood cell count (p=0.013), body mass index (p=0.003), ethnicity (p=0.012), lung, liver, or bone metastases (p<0.001), and prior perioperative chemotherapy (p=0.012). The c-index was 0.660. The distribution of the nomogram scores was associated with OR (p<0.001), and incorporating OR into the model further improved the c-index in the validation cohort (0.670).ConclusionsWe developed and validated two nomograms for OS to be used before and after completion of first-line chemotherapy for metastatic UC.Patient summaryWe proposed two models for estimating overall survival of patients with metastatic urothelial carcinoma receiving first-line, platinum-based chemotherapy. These nomograms have been developed on real-world patients who were treated outside of clinical trials and may be used irrespective of the chemotherapeutic platinum agent used.

Dataset Information

Clinical Significance of Early Changes in Circulating Tumor Cells from Patients Receiving First-Line Cisplatin-Based Chemotherapy for Metastatic Urothelial Carcinoma.

Publications

Clinical Significance of Early Changes in Circulating Tumor Cells from Patients Receiving First-Line Cisplatin-Based Chemotherapy for Metastatic Urothelial Carcinoma.

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