Medical Oncologist Chris O’Brien Lifehouse Camperdown, New South Wales, Australia
Objective: Adolescent and young adult (AYA) patients with unresectable, recurrent or metastatic sarcoma have a poor prognosis and present clinical challenges that necessitate tailored therapeutic approaches. Next Generation Sequencing (NGS) can be used to clarify the diagnosis by identifying somatic mutations, structural variations and genetic alterations that drive tumorigenesis. However, in the majority of high risk AYA patients, NGS is predominantly used as a tool to identify targetable mutations and biomarkers such as tumor mutational burden (TMB) which may have therapeutic implications. In early years, patients were required to self-fund NGS testing, but through new programs testing has now become part of routine care at no cost to the patient. This study aimed to assess the clinical utility of NGS in an AYA sarcoma population at a major sarcoma referral center.
Methods: We retrospectively analyzed AYA sarcoma patients aged 15-39 years who underwent NGS between January 2015 and December 2023 at Chris O’Brien Lifehouse in Sydney, Australia. The primary outcomes were actionable mutations identified by the NGS panel, utilization of treatments recommended by the molecular tumor board (MTB), TMB and the clinical response to treatment. A variety of NGS panels were used depending on their availability over time.
Results: There were 106 AYA patients with sarcoma identified. Median age at the time of screening was 26 years of age. Of these patients, 59 (55.7%) were male and 45 (42.5%) were female. 16 (15.1%) patients had osteosarcoma, 15 (14.2%) had Ewing Sarcoma, 14 (13.2%) had rhabdomyosarcoma, 9 (8.5%) had synovial sarcoma, 7 (6.6%) had alveolar soft part sarcoma, 5 (4.7%) had desmoplastic small round cell tumor, 4 (3.8%) had undifferentiated pleomorphic sarcoma and the remaining 36 (34%) had a variety of other sarcomas. 98 (92.5%) patients had a successful NGS panel. 8 (7.6%) patients had a failed or unsuccessful NGS panel. From analysis of the NGS panel information, 35 (33%) patients had a potentially actionable mutation identified.
From the successful NGS panels, 14 (14.3%) patients had a targetable mutation or biomarker identified and all patients received NGS directed therapy as recommended by the MTB. Of these patients, 9 (64.3%) received treatment through a clinical trial, 3 (21.4%) via self-funding and 2 (14.3%) via compassionate access. In assessment of response, 12 (85.7%) patients developed progressive disease and 2 (14.3%) demonstrated stable disease.
Of the 98 patients with a successful NGS panel, TMB was reported in 79 (80.6%) patients. Of these patients, 73 (74.5%) had a low TMB identified and 6 (6.1%) had a high TMB identified. 4 (66.7%) of patients with a high TMB were able to access immune checkpoint inhibition but all of these patients developed progressive disease.
Conclusion: Of the total 106 AYA patients with sarcoma who underwent NGS, 2 (1.9%) had a favorable outcome with MTB recommended treatment which in these cases was stable disease. Based on this study, the likelihood of a favorable clinical outcome using NGS in this population is low, and this data could inform counseling of AYA sarcoma patients when NGS is being recommended.
