BACKGROUND:Recent data suggest that patients with stage III melanoma are at high risk for developing central nervous system (CNS) metastases. Because a subset of patients with stage II melanoma experiences worse survival outcomes than some patients with stage III disease, the authors investigated the risk of CNS metastasis in stage II melanoma to inform surveillance guidelines for this population. METHODS: The authors examined clinicopathologic data prospectively collected from 1054 patients who had cutaneous melanoma. The χ 2 test, the cumulative incidence, and Cox multivariable regression analyses were performed to evaluate the association between baseline characteristics and the development of CNS metastases. RESULTS: Patients with stage III melanoma had a higher rate of developing brain metastases than those with stage II melanoma (100 of 468 patients [21.4%] vs. 82 of 586 patients [14.0%], respectively; p = .002). However, patients who had stage IIC melanoma had a significantly higher rate of isolated first recurrences in the CNS compared with those who had stage III disease (12.1% vs. 3.6%; p = .002). The risk of ever developing brain metastases was similarly elevated for patients who had stage IIC disease (hazard ratio [HR], 3.16; 95% CI, 1.77-5.66), stage IIIB disease (HR, 2.83; 95% CI, 1.63-4.91), and stage IIIC disease (HR, 2.93; 95% CI, 1.81-4.74), and the risk was highest in patients who had stage IIID disease (HR, 8.59;. CONCLUSIONS: Patients with stage IIC melanoma are at elevated risk for first recurrence in the CNS. Surveillance strategies that incorporate serial neuroimaging should be considered for these individuals until more accurate predictive markers can be identified.

9587 Background: Colitis and other gastrointestinal (GI) toxicity are a frequent and occasionally severe form of immune-related adverse events (irAEs) in patients treated with ICIs. To date, no definitive mechanism has been identified, and this area remains an active field of investigation. We hypothesized that activation of the RAGE axis, known to be implicated in inflammatory bowel disease through stimulation of signal transduction targeted by pro-inflammatory RAGE ligands, members of the S100 family and High Mobility Group Box 1 (HMGB1), might be associated with irAE- colitis. Methods: We examined sera from 111 advanced melanoma patients prospectively accrued and followed up at NYULH (treated with anti-PD-L1, n = 44; antiCTL4, n = 23; and combination, n = 44). 24 (22%) developed GI toxicity grade >2. Serum biomarkers of the ligand-RAGE pathways, soluble (s)RAGE, endogenous secretory (es)RAGE, S100B, and HMGB1, were measured in the patients’ sera during ICI treatment. Multivariable ordinal logistic regression analyses with all grades of GI toxicity as the primary outcome for all the recorded covariates (including serum biomarkers, clinical covariates) were performed. We then used ordinal multivariable logistic regression with stepwise variable selection. Similar analyses with GI toxicity as a binary outcome ((≥grade 1 vs no toxicity) were also conducted. Only those variables that jointly contributed to the odds of developing toxicity were included in the final stepwise model. No adjustments for multiplicity were included. As sRAGE and esRAGE are highly correlated (r = 0.86), esRAGE concentrations were not used in the joint models. Results: A significant association between GI toxicity and concentrations of sRAGE and S100B was identified. The final stepwise multivariable logistic model includes only sRAGE and S100B. The odds of having a one level increase in GI toxicity grade increase 1.100 times (95% CI: 1.008, 1.199; p = 0.029) for each unit decrease of sRAGE ( = sRAGE/100). The odds of a one level increase in GI toxicity increase 1.059 times (95% CI: 1.004, 1.116; p = 0.035) for each unit increase of S100B ( = s100B/100). All other analyses yielded comparable results. In contrast, concentrations of HMGB1 and other clinical covariates, including response and treatment category, were not associated with GI toxicity. Conclusions: Mediators of the RAGE axis, specifically sRAGE and S100B, might have a role in GI toxicity in patients receiving ICIs. The ligand-RAGE axis may be a novel target for irAE therapies for patients receiving ICIs to mitigate the severity of GI toxicity.

12087 Background: Aging is a nebulous concept with several definitions, but they all generally include physical and cognitive decline in function as a key component. We hypothesized that following cancer diagnosis, patients decline in physical and cognitive function would correspond with accelerated and/or accentuated aging trajectories. The magnitude of the functional changes could inform strategies to minimize impact of cancer diagnosis on trajectory of aging. Methods: We analyzed 32,935 participants >50 years enrolled between 1995-2018 in the Health and Retirement Study (HRS), a population-based, biennial longitudinal health interview survey of older adults in the United States. We assessed the changes in physical and cognitive function among cancer patients controlling for their pre-cancer trajectories and comparing it with aged population with no cancer diagnosis as control. The primary outcomes were change in physical function (Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL): range 0–11) and global cognitive function (Telephone Interview for Cognitive Status (TICS): range 0–27). The secondary outcome was change in self-rated health (SRH: range 1-5). We estimated the effect of acute change based on the immediate post-cancer outcome measurements compared to the trajectories before cancer; and the long-term effect as the per-year change in outcome decline post cancer compared to aging of cancer-free respondents adjusting covariates by linear mixed models. Results: 5,101 developed incident cancer: 1,514 in the 50-64 age group, 1,901 in the 65-74 age group, and 1,686 in the 75+ age group. 27,834 participants were cancer-free throughout. Cancer was associated with acute declines in physical function (0.06 [0.01– 0.10] and 0.25 [0.14– 0.36] points), cognitive function (0.22 [0.04–0.39] and 0.24 [0.01– 0.46] points), and SRH (0.19 [0.14–0.23] and 0.22 [0.12–0.33] points) for age of onset groups 50- and 75+ respectively. Moreover, participants with cancer demonstrated accelerated decline in physical function (0.02 [0.01–0.03], and 0.06 [0.05–0.07] points per year faster for 50-74 and 75+ age-of-onset groups respectively) compared to cancer-free participants, but not in cognitive and SRH. Lung, colorectal & breast cancer were associated with the highest acute and accelerated decline in functions, while prostate cancer was associated with moderate and insignificant decline. Conclusions: Using 24 years of nationally representative longitudinal data, this study provides, for the first time, evidence for the heterogeneous aging trajectories of cancer patients across varying age-of-onset and cancer types. Our results supported an accelerated aging trajectory of physical function with increased acceleration with increasing age-of-onset compared to the non-cancer population. It also provides evidence for accentuated aging trajectories of cognitive function and self-rated health.