Characterizing the Genetic Landscape of Radiation Associated Cutaneous Angiosarcomas

David Shultz, MD, PhD,  Princess Margaret Cancer Centre (Canada)
Recipient of the: $50,000 Race to Cure Sarcoma Research Award

Radiation-associated cutaneous angiosarcoma (RAA) is a highly aggressive malignancy that arises in breast cancer patients approximately 5-10 years following treatment with adjuvant radiotherapy (RT). The median survival of patients diagnosed with RAA is 32 months due to high rates of local and distant failure. As with most sarcomas, surgery is the primary treatment, and adjuvant radiotherapy and chemotherapy are commonly used. Although the significance of RAA as a threat to breast cancer survivorship is increasingly appreciated, fundamental questions regarding RAA’s biology remain unanswered. Principally, the pathogenic molecular mechanisms involved have not been characterized. Furthermore, although it has been reported that 70% of RAAs present as multiple foci arising within the irradiated field, it is not known whether or not such foci tend to be genetically distinct tumours with unique molecular targets. This knowledge could lead to more effective preventative, screening, or management paradigms.

The objectives of our study are to (1) differentiate the mutational signature in radiation associated cutaneous angiosarcoma (RAA) from non-radiation associated (sporadic) cutaneous angiosarcomas (non-RAA), using whole genome sequencing (WGS), in order to determine if there are targetable pathways that differ between RAA and non-RAA that may impact treatment algorithms and define RAA-specific pathogenic molecular mechanisms; (2) Assess RAA genetic heterogeneity by comparing separately biopsied tumour foci that arose simultaneously in the same patient. Through this, we seek to determine if intra-tumoural heterogeneity impacts the biology of multifocal RAA such that mutiple agents might be needed to adequately treat locally confined disease.

Because there are currently about 3.4 million BC survivors in North America alone, most of whom received adjuvant radiotherapy, thousands of women will be diagnosed with RAA over the next several decades. Thus, focused research on this treatment-related malignancy is paramount. Funding for this project will enable us to begin identifying key, therapeutic targets for RAA and ultimately design clinical trials needed to establish more effective treatment protocols.