Novel serum biomarkers that detect ovarian cancer recurrence earlier than CA125

Despite a complete clinical response to primary surgery and chemotherapy, 80% of patients with advanced stage (III-IV) ovarian cancer recur. The serum biomarker CA125 is widely used to monitor patients for recurrence. Doubling of CA125 outside the normal range detects recurrent ovarian cancer in 70% of cases with a lead time of 3 - 4.8 months. Here we report novel biomarkers that detect recurrence missed by CA125 and that detect recurrence at an earlier interval than elevation of CA125. Novel biomarkers for recurrent OC were measured with the Olink multiplexed proximity extension assay. In a previous study, >1,196 Olink biomarkers were screened to identify 21 that detected disease recurrence including MUC16 (CA125), HE4 and 19 novel candidates (Ren et al., Cancer Research 80.16_Supplement (2020): 5144-5144). The 21 biomarkers were measured in 309 serial serum samples from 51 OC patients with advanced stage ovarian cancer who had been placed in complete clinical remission with primary surgery and chemotherapy and then monitored for recurrence with CA125 for an average of 4 years (range 1 - 8).Among the 51 OC cases, recurrence was observed in 31 cases with 17 exhibiting elevated CA125 (>35 U/mL) at the time of recurrence and 14 experiencing recurrence without CA125 elevation. Overall, 20 cases remained in remission during the observation period. We identified four biomarkers (DEFB4A, SULT1A1, TBCB, and TCL1A) that detected OC recurrence more than three months prior to clinical confirmation. In cases where biomarkers increased, TCL1A was elevated 131 days, TBCB 104 days, SULT1A1 242 days and DEFB4A 265 days prior to clinical recurrence. A combination of the four markers detected 14 of 31 (45%) recurrent cases at least three months earlier than standard clinical diagnosis. The four-biomarker combination identified 6 of 14 (43%) CA125-negative recurrent cases more than three months in advance. In summary, this study identifies a four-biomarker serum panel that improves early detection of OC recurrence compared to CA125 alone. The panel offers a more than three months lead time for detection of recurrence and detected patients with normal CA125 levels.