PURPOSE: The role of circulating tumor DNA (ctDNA) monitoring in predicting treatment response and survival outcomes in early-stage and metastatic solid tumors has shown promising results. The value of early ctDNA dynamics in solid tumors treated with immune checkpoint inhibitors (ICIs) merits further investigation. Our study aims to assess the role of early ctDNA changes, measured 3-4 weeks after initiating ICI therapy, in predicting clinical outcomes in patients with advanced-stage melanoma. METHODS: We performed a multi-institutional analysis of real-world data from testing patients with unresectable stage III/IV melanoma using a personalized, tumor-informed ctDNA assay (Signatera) during the course of treatment with anti–PD-1-based therapy. ctDNA levels were assessed before the start of treatment and at 3-4 weeks before the second treatment dose. The change in ctDNA (decrease v increase) between the two points was assessed to evaluate the odds of objective response and disease control and to evaluate the risk of progression-free survival (PFS) and overall survival (OS). RESULTS: One hundred seventeen patients were evaluated. Regression analysis revealed that a decrease in ctDNA was associated with increased odds of disease control (odds ratio [OR], 30.56 [95% CI, 10.64 to 87.84], P < .001) and objective response (OR, 23.54 [95% CI, 8.58 to 64.57], P < .001). Patients with a decrease in ctDNA had an increased PFS (hazard ratio [HR], 0.18 [95% CI, 0.11 to 0.31], P < .001) and OS (HR, 0.28 [95% CI, 0.13 to 0.56], P < .001) probability. CONCLUSION: We found that early ctDNA dynamics after only 3-4 weeks of ICI initiation in patients with advanced-stage melanoma appears to be a candidate strategy to predict overall treatment response, risk of progression, and long-term survival. Larger prospective studies are warranted to validate the utility of early ctDNA changes in treatment monitoring.

Cardiac paragangliomas are extremely rare tumors derived from chromaffin cells of the neural crest. Succinate dehydrogenase B (SDHB) mutations are associated with metastatic potential and potentially worse prognosis. Here we describe the case of a 64-year-old man who presented with chest pain, fatigue, and weight loss. Cardiac workup revealed a nearly 7-cm cardiac mass in the right lateral wall. Incisional biopsy demonstrated paraganglioma. Plasma free normetanephrine and chromogranin A were elevated. A DOTATATE positron emission tomography/computed tomography (PET/CT) revealed avidity of the mass with no evidence of distant metastases. Next-generation sequencing of the specimen demonstrated a variant of unknown significance of SDHB at H244D. Germline testing was negative. Surgical resection was aborted due to involvement of critical structures of the heart. Systemic treatment with the multi-tyrosine kinase inhibitor cabozantinib was initiated with subsequent improvements in biochemical markers as well as reductions in maximum standardized uptake value (SUVmax) on Ga-68 DOTATATE PET/CT. After 5 months of cabozantinib, he was unable to tolerate the side effects and external beam radiation therapy was completed. In this case, we report a novel somatic SDHB mutation at H244D in a sympathetic paraganglioma presenting as a cardiac mass.

Oncocytic adrenal carcinoma (OAC) is a rare histologic subtype of adrenal cortical carcinoma (ACC) characterized by >90% oncocytic cells. Unlike ACC, OACs have a reduced incidence of adrenal hormone production, larger size, and longer time to recurrence (17.5 months vs 8 months). Genetic mutations in CTNNB1 are associated with decreased survival in ACC but their role in OAC is unknown. Here, we present a case of OAC highlighting the importance of comprehensive genomic profiling in predicting time to recurrence. A 72-year-old woman presented with rapidly progressive muscle weakness, new-onset type 2 diabetes mellitus, resistant hypertension associated with hypokalemia, and profound cognitive decline. Hormonal evaluation was consistent with ACTH-independent Cushing syndrome. A computed tomography scan of the abdomen showed a 7.1-cm heterogenous left adrenal mass. Pathology confirmed OAC after an en bloc left adrenalectomy. Next-generation sequencing revealed somatic mutations in CTNNB1, CDKN2A, and CDKN2B. Disease progression at 5 months after left adrenalectomy was comparable to other histopathological types of ACC, emphasizing the impact of genomic alterations in OAC.

In the phase 2 trial SWOG S1616 (NCT03033576), patients with advanced melanoma with primary resistance to anti-PD-1/L1 therapies had improved outcomes on the combination of the anti-CTLA-4 antibody ipilimumab with continued anti-PD-1 with nivolumab, over ipilimumab alone. Baseline biopsies from patients responsive to combination therapy had increased transcriptomic expression of complement by myeloid cells, interferon pathways by endothelial cells, and oxidative phosphorylation and lipid metabolism by melanoma cells. Using spatial proteomics, some on-therapy biopsies from patients responding to combination therapy had networks of activated CD8 T cells nearby melanoma cells, while others had T cells and myeloid cells, reflective of different timepoints in a dynamic antitumor response. Conversely, biopsies from patients progressing on combination immunotherapy displayed impaired T-cell infiltration adjacent to plasma cells. Our results define cellular neighborhoods and transcriptomes in melanoma biopsies when reversing resistance to anti-PD-1 with the addition of anti-CTLA4, and plasma cell sheets in non-responding biopsies.

Supplementary Figure S7 shows the evaluation of TLS signatures in RNAseq and MIBI samples.

Supplementary Figure S6 shows the TCR/BCR repertoire metrics in RNAseq data from biopsies from patients nonresponsive to combination therapy.