Achievements

Background: Desmoid tumors are soft-tissue neoplasms, which, although unable to metastasize, can cause significant morbidity due to local invasion. Currently, the first-line approach is active surveillance. For tumors that progress during surveillance, systemic therapies can be used, including nirogacestat, sorafenib, pazopanib, and cytotoxic chemotherapy. However, their optimal duration is unknown. Here, we aim to assess the risk of treatment failure after discontinuing sorafenib before one year. Methods: We analyzed all patients with desmoid tumors treated with sorafenib at three academic centers from 01/01/2000-12/01/2021. We included patients who discontinued sorafenib not due to radiological or clinical progression and had documented no intention to start the next line of therapy at the time of discontinuation. The primary endpoint was 2-year treatment-free survival between patients who stopped sorafenib before and after 1 year. The secondary endpoint was the rate of toxic effects recorded according to the Common Terminology Criteria for Adverse Events during treatment. We calculated treatment-free survival using the Kaplan-Meier method with the Log-Rank Test to estimate the 95% confidence interval. All patients were censored at the 2-year mark. Fischer’s Exact T-test was performed to assess between-group differences. Results: 40 patients received sorafenib and discontinued it with no intention to start a next line of therapy. The main reasons for discontinuation were side effects (n=21, 52%) and physician-patient preference (n=10, 25%). 27 (67%)were women, and median age at diagnosis was 36.Regarding race and ethnicity,27 (47%)were White, 8 (20%)were Black, and 16 (40%) were Latino. The tumor was in the lower extremity in 10 (25%) cases, trunk in 3 (7%) cases, abdominal wall in 10 (25%), intra-abdominal in 5 (12%), upper extremity in 5 (12%) head-neck in 1 and breast in 1. 20 patients stopped treatment before one year and 20 after one year, with 7 and 3 patients requiring a next line of therapy in each group, respectively. The 2-year treatment-free survival was 60% (95% confidence interval [CI], 0.35 to 0.85) in the prior to 1-year group and 87.5% (95% CI, 0.71 to 1.0) in the post-1-year group (P = 0.046). The most frequently reported adverse events while on sorafenib were grade 1 or 2 events of palmar-plantar erythrodysesthesia (40%) and diarrhea (40%), with no difference between groups on therapy discontinuation due to side effects (p=0.1). Conclusions: Discontinuing sorafenib prior to 1 year was associated with a higher risk of requiring further therapy within the following two years. Still, most patients did not require additional therapy. This finding underscores the complexity of determining the optimal duration for sorafenib therapy, and multiple features should be considered, including side effects, symptom improvement, fertility planning, tumor cellularity (evaluated by T2 MRI signal), and physician-patient shared decision.

Background: Oncolytic viruses (OV) are viruses that preferentially destroy cancer cells while sparing healthy cells. Currently, talimogene laherparepvec (TVEC) is the sole FDA-approved OV product; however, resistance to therapy often emerges. To further understand OV resistance mechanisms, we performed transcriptome and mutational analysis on patient samples using a discordant lesion approach. Methods: An 80-year-old woman was diagnosed with Merkel cell carcinoma of the right lower extremity and underwent wide local excision. Her disease recurred, and she developed multiple metastatic lesions over three years. During that time, she was further treated with radiation, immunotherapy, and intralesional TVEC. Despite the different treatments, her disease eventually progressed, leading to her death. We analyzed the primary lesion and four discordant lesions that either persisted or recurred following treatment. Treatment data were extracted from medical records, and lesions were classified based on their resistance to therapies. DNA and RNA were extracted from tissue, and whole exome sequencing and bulk RNA sequencing were performed. Whole exome data was compared between specimens to determine mutation enrichment over time. Gene Set Enrichment Analysis was used to interpret bulk RNA sequencing data and compare transcriptional states of lesions. Results: Lesions four and five recurred following TVEC treatment and were, therefore, classified as TVEC resistant. Whole exome sequencing of all five lesions identified a heterozygous point mutation (P521L) in the SH2B3 gene in lesions four and five only. Additionally, the variant allelic fraction of this point mutation increased from 33% in lesion four to 44% in lesion five, where it was the highest frequency variant. When comparing lesion five to lesion one, Gene Set Enrichment Analysis showed an increase in both the hallmark inflammatory response gene signature and the hallmark interferon alpha response gene signature. SH2B3 is a gene that encodes the LNK protein, which functions as a negative regulator of the JAK-STAT signaling pathway and is, therefore, a negative regulator of interferon signaling. A mutation leading to a loss of function in SH2B3 would conceptually lead to upregulation of interferon signaling, which has previously been shown to promote an antiviral state within the tumor microenvironment and limit the effectiveness of OV treatment. Conclusions: Sequencing of discordant MCC lesions revealed enrichment in the mutational fraction of SH2B3 associated with an increase in interferon alpha and inflammatory signaling among lesions that were resistant to TVEC treatment. This is the first study to report a possible genetic driver for OV resistance. We introduced using CRISPR-HDR P521L SH2B3 in MCC cell lines to investigate its impact on LNK expression and its role as a mechanism of OV treatment resistance, with results to be presented.