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Circulating Tumor Cells and Early Relapse in Node-Positive Melanoma Anthony Lucci1, Carolyn S

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Circulating Tumor Cells and Early Relapse in Node-Positive Melanoma Anthony Lucci1, Carolyn S Published OnlineFirst February 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2670 CLINICAL CANCER RESEARCH | PRECISION MEDICINE AND IMAGING Circulating Tumor Cells and Early Relapse in Node-positive Melanoma Anthony Lucci1, Carolyn S. Hall2, Sapna P. Patel3, Boomadevi Narendran1, Jessica B. Bauldry1, Richard E. Royal4, Mandar Karhade1, Joshua R. Upshaw1, Jennifer A. Wargo4, Isabella C. Glitza3, Michael K.K. Wong3, Rodabe N. Amaria3, Hussein A. Tawbi3, Adi Diab3, Michael A. Davies3, Jeffrey E. Gershenwald4, Jeffrey E. Lee4, Patrick Hwu3, and Merrick I. Ross4 ABSTRACT ◥ Purpose: There is a need for sensitive, reproducible biomarkers Results: At least one baseline CTC was identified in 90 of for patients with stage III melanoma to guide clinical decision 243 (37%) patients. Forty-five (19%), 67 (28%), 118 (49%), and making. Circulating tumor cells (CTCs) can be detected in patients 13 (5%) patients were stage IIIA, IIIB, IIIC, or IIID, respectively. with melanoma; however, there are limited data regarding their CTC detection was not associated with substage, or primary significance in stage III disease. The aim of this study was to tumor characteristics. Multivariable analysis demonstrated determine whether CTCs are associated with early relapse in stage that the detection of ≥1 baseline CTC was significantly asso- III melanoma. ciated with decreased 6-month RFS [log-rank, P < 0.0001; Experimental Design: We prospectively assessed CTCs at first HR, 3.62, 95% confidence interval (CI), 1.78–7.36; P < 0.0001] presentation in clinic (baseline) for 243 patients with stage III and 54-month RFS (log-rank, P ¼ 0.01; HR, 1.69; 95% CI, 1.13–2.54; melanoma. CTCs were measured using the CellSearch System. P ¼ 0.01). Relapse-free survival (RFS) was compared between patients with Conclusions: ≥1 CTC was independently associated with mel- one or more baseline CTC versus those with no CTCs. Log-rank test anoma relapse, suggesting that CTC assessment may be useful to and Cox regression analysis were applied to establish associations of identify patients at risk for relapse who could derive benefit from CTCs with RFS. adjuvant therapy. Introduction Circulating tumor cells (CTCs) have been studied for more than 30 years in patients with melanoma, although most studies Cutaneous melanoma results in 75% of skin cancer–related deaths primarily used PCR methodologies (3, 4). Although some of these (1), and the incidence has been increasing worldwide over the last studies have demonstrated that CTC presence has prognostic decade. This trend is also seen in the United States, with an estimated significance (5–11), the varied methodologies employed and the 96,480 new melanoma cases and more than 7,200 deaths expected in lack of standardization have impeded the utilization of CTCs as a 2019 (1). Despite the development of several targeted and immune- melanoma biomarker in the clinic. The semiautomated CellSearch based therapies for patients with melanoma, the prognosis is quite system (Menarini Silicon Biosystems) is a standardized, FDA- heterogeneous for patients with stage III melanoma overall, with 5-year approved methodology for CTC detection for metastatic breast, survival rates ranging from 93% to 32% for patients with stage IIIA– colon, and prostate cancers. The CellSearch CTC Assay has been IIID, respectively, according to the American Joint Commission on studied extensively for a variety of patients with solid tumors. Cancer (AJCC) 8th edition (2). These survival statistics highlight the However, to date, only three studies have reported on the prog- need for better prognostic markers to identify patients at increased nostic significance of CTCs in patients with melanoma using the risk for relapse. Because adjuvant therapies are approved for all recently developed melanoma-specific CellSearch CTC Assay; these patients with stage III melanoma (not necessarily just high-risk studies included only patients with stage IV melanoma (12–14). patients), there is the potential to overtreat those with low-relapse risk. In this study, we utilized a melanoma-specificCTCkittoevaluate the identification rate and prognostic significance of CTC detection in patients with stage III cutaneous melanoma. We present one of 1Department of Breast Surgical Oncology, The University of Texas MD Anderson the first prospective studies designed to determine whether CTCs 2 Cancer Center, Houston, Texas. Department of Breast Surgery-Research, The are significantly associated with relapse in patients with stage III 3 University of Texas MD Anderson Cancer Center, Houston, Texas. Department melanoma. We hypothesized that identification of CTCs within the of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. 4Department of Surgical Oncology, The University of blood at baseline would independently predict shorter survival, Texas MD Anderson Cancer Center, Houston, Texas. irrespective of standard primary tumor (T), distant metastases (M), regional nodes (N; TNM) factors, or the extent of lymph node Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). metastases. If this hypothesis is validated, it would warrant larger studies to facilitate the incorporation of easily obtained, blood- Corresponding Author: Anthony Lucci, UT MD Anderson Cancer Center, 1515 based CTC assessments into standard practice. This would be of Holcombe Blvd., Unit 1484, Houston, TX 77030. Phone: 713-563-1871; Fax: 713- fi 745-1462; E-mail: [email protected] great clinical interest as there are currently no melanoma-speci c, blood biomarker tests approved by the National Comprehensive Clin Cancer Res 2020;26:1886–95 Cancer Network or by the American Society of Clinical Oncology doi: 10.1158/1078-0432.CCR-19-2670 (ASCO) to identify patients with stage III melanoma who are at Ó2020 American Association for Cancer Research. high risk for relapse. AACRJournals.org | 1886 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst February 3, 2020; DOI: 10.1158/1078-0432.CCR-19-2670 Circulating Tumor Cells and Relapse in Stage III Melanoma Assay. CTC assessments were performed within 72 hours of blood Translational Relevance collection at the University of Texas MD Anderson Cancer Center In this prospective study of 243 patients with cutaneous mel- (Houston, TX), following the manufacturer's protocol as described anoma, the detection of one or more CTCs per 7.5-mL tubes of previously (12). Briefly, the CellSearch Circulating Melanoma Cell blood at first presentation in clinic (baseline) independently pre- test uses ferrofluids coated with CD146 antibodies to immunomag- dicted relapse within 6 months of baseline, as well as at 54-month netically enrich melanoma cells, and a fluorescently labeled mela- follow-up. CTC assessment at first presentation in clinic may be noma-specific antibody (HMW-MAA; clone 9.2.27) for CTC detec- useful to identify patients with stage III melanoma who could tion, as well as anti-CD45, and CD34 for white blood cell and derive benefit from rigorous imaging surveillance, or adjuvant endothelial cell exclusion. A semiautomated fluorescence-based þ systemic therapy. These data support future trials to further microscope system is utilized to identify CTCs: CD146 ,HMW- þ À À þ identify the predictive value for liquid biopsy in the optimal MAA ,CD45 ,CD34 , and nucleated (DAPI ) cells. All results treatment of patients with melanoma. were reviewed by a trained and highly experienced laboratory scientist (C. Hall) who was blinded to all patient clinical data. In a previously published study, we observed negligible tube-to-tube variability in melanoma CTC detection for each patient sample Materials and Methods using CellSearch; the CTC detection rate kappa inter-rater agree- Patients ment was 0.88 between three 7.5-mL tubes of blood (15). Therefore, CTC detection levels in this study are reported as the number of This study included patients diagnosed with stage III cutaneous CTCs per single 7.5-mL tube of blood. To date, we have assessed melanoma between February 2012 and June 2017 at The University CTC positivity in 91 healthy control samples and found CTCs are of Texas MD Anderson Cancer Center (Houston, TX). Patients rare; CTCs were detected in two of 91 (2.2%) of healthy control with mucosal and uveal melanoma and patients with metastatic blood samples (mean 0.04 Æ 0.2 cells per 7.5-mL tubes of blood). disease proven by biopsy and/or PET/CT imaging were ineligible to participate in this study. We obtained informed consent from Statistical analyses all patients prior to blood collection and this study was conducted We used x2 or Fisher exact tests to evaluate associations between in accordance with ethical guidelines set forth by the Belmont presence of CTCs and clinical factors. Relapse-free survival (RFS) was Report. Individual patient results were blinded from investigators defined as the time elapsed between date of baseline CTC assessment by use of a random number system as the unique patient identifier. and either the date of clinical disease relapse, death, or the last follow- The Institutional Review Board (IRB) at The University at Texas up. A Cochran–Armitage test was used to identify relapse trends in MD Anderson Cancer Center (Houston, TX) approved this pro- patients with 0, ≥1, ≥2, and ≥3 CTCs. Log-rank tests were used to spective study (LAB-11-0314; principal investigator: A. Lucci). The compare RFS
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