Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

The response rates upon neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma are higher as compared with stage IV disease. Given that successful ICB depends on systemic immune response, we hypothesized that systemic immune suppression might be a mechanism responsible for lower response rates in late-stage disease, and also potentially with disease recurrence in early-stage disease. Plasma and serum samples of cohorts of patients with melanoma were analyzed for circulating proteins using mass spectrometry proteomic profiling and Olink proteomic assay. A cohort of paired samples of patients with stage III that progressed to stage IV disease (n = 64) was used to identify markers associated with higher tumor burden. Baseline patient samples from the OpACIN-neo study (n = 83) and PRADO study (n = 49; NCT02977052) were used as two independent cohorts to analyze whether the potential identified markers are also associated with disease recurrence after neoadjuvant ICB therapy. When comparing baseline proteins overlapping between patients with progressive disease and patients with recurrent disease, we found leucine-rich alpha-2-glycoprotein 1 (LRG1) to be associated with worse prognosis. Especially nonresponder patients to neoadjuvant ICB (OpACIN-neo) with high LRG1 expression had a poor outcome with an estimated 36-month event-free survival of 14% as compared with 83% for nonresponders with a low LRG1 expression (P = 0.014). This finding was validated in an independent cohort (P = 0.0021). LRG1 can be used as a biomarker to identify patients with high risk for disease progression and recurrence, and might be a target to be combined with neoadjuvant ICB. Significance: LRG1 could serve as a potential target and as a biomarker to identify patients with high risk for disease recurrence, and consequently benefit from additional therapies and intensive follow-up

Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

UNLABELLED: The response rates upon neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma are higher as compared with stage IV disease. Given that successful ICB depends on systemic immune response, we hypothesized that systemic immune suppression might be a mechanism responsible for lower response rates in late-stage disease, and also potentially with disease recurrence in early-stage disease. Plasma and serum samples of cohorts of patients with melanoma were analyzed for circulating proteins using mass spectrometry proteomic profiling and Olink proteomic assay. A cohort of paired samples of patients with stage III that progressed to stage IV disease (n = 64) was used to identify markers associated with higher tumor burden. Baseline patient samples from the OpACIN-neo study (n = 83) and PRADO study (n = 49; NCT02977052) were used as two independent cohorts to analyze whether the potential identified markers are also associated with disease recurrence after neoadjuvant ICB therapy. When comparing baseline proteins overlapping between patients with progressive disease and patients with recurrent disease, we found leucine-rich alpha-2-glycoprotein 1 (LRG1) to be associated with worse prognosis. Especially nonresponder patients to neoadjuvant ICB (OpACIN-neo) with high LRG1 expression had a poor outcome with an estimated 36-month event-free survival of 14% as compared with 83% for nonresponders with a low LRG1 expression (P = 0.014). This finding was validated in an independent cohort (P = 0.0021). LRG1 can be used as a biomarker to identify patients with high risk for disease progression and recurrence, and might be a target to be combined with neoadjuvant ICB. SIGNIFICANCE: LRG1 could serve as a potential target and as a biomarker to identify patients with high risk for disease recurrence, and consequently benefit from additional therapies and intensive follow-up

The promise of neoadjuvant immunotherapy and surgery for cancer treatment

Cancer immunotherapies utilizing immune checkpoint inhibitors (ICI) have demonstrated durable efficacy in a proportion of patients with advanced/metastatic cancers. More recently, the use of ICIs for the adjuvant treatment of patients with surgically resectable melanoma has also demonstrated efficacy by improving relapse-free survival and in the case of ipilimumab (anti–CTLA-4) also improving overall survival. Although promising, the effective scheduling of surgery and immunotherapy and its duration is not well elucidated. Recent preclinical studies suggest that surgery followed by adjuvant therapy might be suboptimal as compared with an approach in which immunotherapy is applied before surgery (neoadjuvant immunotherapy). Encouraging findings from early-phase clinical trials in melanoma, non–small cell lung carcinoma, and glioblastoma support the idea that neoadjuvant immunotherapy might have improved clinical efficacy over an adjuvant application. In this review, we discuss the existing rationale for the use of neoadjuvant immunotherapy, its apparent strengths and weaknesses, and implications for the design of future clinical trials

Table S3 from Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Table S3 shows the patient characteristics PRADO</p

Figure S1 from Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Figure S1 shows a flowchart of patients OpACIN-neo study</p

Figure S5 from Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Figure S5 shows that complement factor B (CFB), component 7 (C7) and alpha-1B-glycoportein (A1BG) expression are increased upon melanoma progression and recurrence.</p

Figure S3 from Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Figure S3 shows that SAA1, CRP and LDHB are associated with melanoma disease progression.</p

Figure S6 from Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Figure S6 shows that neutrophil count and neutrophil-to-lymphocyte ratio (NLR) are not associated with recurrence in non-responding patients</p

Table S2 from Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence

Table S2 shows the patient characteristics OpACIN-neo</p