The role of whole-genome sequencing for guiding systemic therapy in patients with soft tissue sarcoma.

Abstract

BACKGROUND

The analysis of tumor DNA by whole-genome sequencing (WGS) is increasingly utilized for the identification of clinically relevant DNA aberrations. We aim to assess whether WGS improves the guidance of individualized systemic therapy in soft tissue sarcoma (STS).

CONCLUSION

WGS identified actionable targets in 46% of STS cases, leading to WGS-informed therapy in 14% of patients. Improving the timing of the WGS request and a more appropriate patient selection upfront could increase this relatively low percentage. Complex genome sarcomas seem to be the STS group for which WGS is most likely to add value by opening the way to tumor-agnostic therapies.

PATIENTS AND METHODS

WGS results of STS patients were retrieved from electronic patient records and pathology reports from clinical studies and routine diagnostics. WGS was carried out in primary STS with an unfavorable prognosis, metastatic STS, or STS where broad molecular diagnostics were deemed necessary. Actionable targets were defined as genomic alterations identified by WGS for which specific systemic therapy was indicated in routine care or clinical trials available at time of the WGS analysis.

RESULTS

WGS was carried out on 161 STS patients. The most common histological subtypes were leiomyosarcoma (22%), undifferentiated pleomorphic sarcoma/sarcoma not otherwise specified (17%) and dedifferentiated liposarcoma (14%). The majority of WGS analyses were requested at the time of recurrence or metastasis (41%), At least one actionable target was found by WGS in 74 (46%) of patients. Actionable targets were more frequently seen for complex genome sarcomas compared with simple genome sarcomas (50% versus 28%). Eventually, 23 patients (14%) received matched experimental therapy based on their WGS results. Non-availability of WGS directed treatment or lack of clinical necessity for systemic therapy (n = 17) and rapid disease progression causing poor performance score (n = 10) were the main reasons to not start WGS-informed therapy.