Approximately one‐third of Merkel cell carcinoma (MCC) patients eventually develop distant metastatic disease. Little is known about whether the location of the primary lesion is predictive of initial distant metastatic site, or if survival likelihood differs depending on the metastatic site. Such data could inform imaging/surveillance practices and improve prognostic accuracy. Multivariate and competing‐risk analyses were performed on a cohort of 215 MCC patients with distant metastases, 31% of whom had two or more initial sites of distant metastasis. At time of initial distant metastasis in the 215 patients, metastatic sites (n = 305) included non‐regional lymph nodes (present in 41% of patients), skin/body wall (25%), liver (23%), bone (21%), pancreas (8%), lung (7%), and brain (5%). Among the 194 patients who presented with MCC limited to local or regional sites (stage I‐III) but who ultimately developed distant metastases, distant progression occurred in 49% by 1 year and in 80% by 2 years following initial diagnosis. Primary MCC locations differed in how likely they were to metastasize to specific organs/sites (P < .001). For example, liver metastases were far more likely from a head/neck primary (43% of 58 patients) versus a lower limb primary (5% of 39 patients; P < .0001). Skin‐only distant metastasis was associated with lower MCC‐specific mortality as compared to metastases in multiple organs/sites (HR 2.7; P = .003), in the liver (HR 2.1; P = .05), or in distant lymph nodes (HR 2.0; P = .045). These data reflect outcomes before PD1‐pathway inhibitor availability, which may positively impact survival. In conclusion, primary MCC location is associated with a pattern of distant spread, which may assist in optimizing surveillance. Because it is linked to survival, the site of initial distant metastasis should be considered when assessing prognosis.

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Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with a high risk of local recurrence and distant metastasis. Optimal care of this potentially life-threatening cancer is critical but challenging because: physicians are often unfamiliar with its management due to rarity, and MCC management remains controversial, in part because it is rapidly evolving across multiple specialties. While guidelines offer a broad overview of management, they are often not sufficient when making decisions for individual patients. Herein, we present a literature review as well as practical approaches adopted at our institutions for staging, surveillance and therapy of MCC. Each of these areas are discussed in light of how they can be appropriately customized for prevalent but challenging situations. We also provide representative examples of MCC patient scenarios and how they were managed by a multidisciplinary team to identify suitable evidence-based, individualized treatment plans.

9566 Background: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of 40%. Early detection of recurrence can improve outcomes, and effective surveillance is crucial for management of patients with MCC. While Merkel cell polyomavirus (MCPyV) oncoprotein serology is useful in surveillance for MCPyV-positive MCC tumors, patients with MCPyV-negative tumors have no available blood biomarkers and require frequent imaging. This prospective, multicenter study assessed whether circulating tumor DNA (ctDNA) can assess disease burden and detect recurrence regardless of virus status. Methods: A total of 328 blood samples were collected from 125 patients at various time points with a median follow-up of 6 months (range: 0-21 months) between April 2020 to January 2022. Whole-exome sequencing was performed on tumor tissue and matched normal blood to identify a set of somatic, clonal single nucleotide variants, which were tracked in subsequent blood (plasma) samples using a personalized and multiplex PCR-NGS based ctDNA assay (Signatera). Clinically evident disease was defined as MCC noted either by physical exam or by imaging, and molecular evidence of disease was defined as a positive ctDNA test. Surveillance phase began once there was no clinically evident or molecular evidence of disease. Results: Among 125 patients, 47 (38%) had clinically evident MCC and all were found to be ctDNA-positive at the first time point (sensitivity: 100%; 95% CI: 91-100%). Of the 47, 24 were newly diagnosed with MCC and had a median primary tumor size of 2.2 cm (range 0.5-8.5 cm) and a median ctDNA value of 26 mean tumor molecules (MTM)/mL (range: 0.08-1470 MTM/mL). Primary tumor diameter and ctDNA value were strongly correlated (Spearman’s r = 0.81, p < 0.001). Of the 125 patients, 73 (58%) patients were assessed in the surveillance setting and had a total of 152 plasma samples available for longitudinal ctDNA testing. Over this period, 7 ctDNA tests were positive while 145 were negative. After a positive test, 5/7 developed a clinically evident recurrence (4 within 60 days). Of the remaining 2 without clinical recurrence, one had < 60 days of follow-up at time of data analysis. The estimated risk of recurrence, accounting for incomplete follow-up, was 57% within 60 days of a positive ctDNA test (n = 7 tests). In contrast, after a negative ctDNA test (n = 145 tests), the risk of recurrence was 0% within 60 days and 3% between 60-90 days. Conclusions: To our knowledge, this is the largest study to explore ctDNA testing in MCC patients. This study demonstrates that ctDNA testing can detect MCC recurrence early and is a promising clinical surveillance tool regardless of tumor viral status.