Viral oncoprotein antibodies as a marker for recurrence of Merkel cell carcinoma: A prospective validation study

Abstract

Background Merkel cell carcinoma (MCC) is an aggressive skin cancer with a recurrence rate of >40%. Of the 2000 MCC cases/year in the USA, most are caused by the Merkel cell polyomavirus (MCPyV). Antibodies to MCPyV-oncoprotein (T-antigens) have been correlated with MCC tumor burden. We prospectively validated the clinical utility of MCPyV oncoprotein antibody titers for MCC prognostication and surveillance. Methods MCPyV-oncoprotein antibody detection was optimized in a clinical laboratory. A cohort of 219 patients with newly-diagnosed MCC were followed prospectively (median follow-up 1.9 years). Among seropositive patients, antibody titer and disease status were serially tracked. Results Antibodies to MCPyV-oncoproteins were rare among healthy individuals (1%) but present in most MCC patients (114 of 219, 52%, p<0.01). Seropositivity at diagnosis independently predicted decreased recurrence risk (HR=0.58; p=0.04) in multivariate analyses adjusted for age, sex, stage, and immunosuppression. Following initial treatment, seropositive patients whose disease did not recur had rapidly falling titers that became negative by a median of 8.4 months. Among seropositive patients who underwent serial evaluation (71 patients; 282 timepoints), an increasing oncoprotein titer had a positive predictive value of 66% for clinically evident recurrence while a decreasing titer had a negative predictive value of 97%. Conclusions Determination of oncoprotein antibody titer assists in the clinical management of newly diagnosed MCC patients by stratifying them into a higher risk seronegative cohort in whom radiologic imaging may play a more prominent role, and into a lower-risk seropositive cohort whose disease status can be tracked in part via oncoprotein antibody titer.

Merkel cell carcinoma

“…The titres of antibodies against MCPyV T antigens (which are present in 52% of patients with MCC) have been shown to correlate with disease burden 108 . In another prospective validation study of 219 patients, measuring anti-ST antibodies provided useful clinical guidance 109 . Patients in whom no anti-ST antibodies could be detected had a 42% greater risk of recurrence, perhaps indicating either a less-robust immune response or an MCPyV − tumour status.…”

“…By contrast, if the titre increased, 88% of patients either had detectable disease at the time of the blood draw or subsequently developed recurrent disease. However, validation of the results of this study in different patient cohorts and laboratories is required before antibody titres can be adopted for routine use in MCC surveillance 109 .…”

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC

“…Seropositivity at the time point of diagnosis is not only associated with a reduced risk of recurrence, but can be used diagnostically. To this end, a falling (< 20% to last sample) or negative titer has a negative predictive value of 97%, while rising titers (> 20%) has a positive predictive value of 66% for the occurrence of recurrence [57]. b Interfering with the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling pathway by inhibitory antibodies achieve response rate of > 50% in the first line setting and about 30% in patients previously treated with chemotherapy [3, 4]…”

“…The observation that antibodies to the MCPyV oncoprotein fluctuate with disease burden is the basis for a blood test to detect early recurrence [57]. This test has recently been validated in a prospective cohort of several hundred patients.…”

“…The first group consists of patients not producing these antibodies, which need to be followed-up closely with imaging studies as they are at a 42% higher risk of recurrence than antibody-positive patients. The second group of patients who produce these antibodies can be followed-up with this blood test as dropping antibody titers correlate with an improved prognosis and increasing titers indicate reoccurrence of the disease [57] (Fig. 3a).…”