A graph-based approach unveils complex patterns of melanoma distant metastases

Abstract

The administration of immune checkpoint blockade (ICB) therapies in patients with stage III and IV melanomas has revolutionised the field, resulting in durable responses. Recent work has shown that different metastatic sites have distinct response rates to ICB therapies, suggesting that the distribution of anatomical locations in each patient plays a role in treatment response and overall survival. In order to explore the association between anatomical patterns of distant disease, response and survival outcomes, we collated and manually curated the progression history of distant metastases in a cohort of 6,031 patients with melanoma. This cohort includes untreated patients as well as patients exposed to ICB therapies and BRAF/MEK inhibitors. For each patient, the temporal and spatial distribution of distant metastatic events occurring from primary disease was captured in a directed acyclic graph model. A distance metric between the progression histories of any two patients based on their graph representation was calculated. The resulting distances were used to pursue clustering of these 6,031 metastatic progression histories. This approach identifies subsets of patients with similar histories of metastatic disease progression. These subsets present significant survival differences among them and capture varying levels of complexity. Specifically, our preliminary results identify that (i) haematogenous spread is associated with worse survival compared to distant lymphatic spread, (ii) patients with combinations of liver, lung and bone are among those groups with worst overall survival, (iii) patients with parallel metastatic events have worse survival than patients with events occurring in series and involving the same sites, and (iv) some clusters are enriched with patients exposed with ICB therapies.