Molecular Targets Remain Elusive in Most Sarcomas

Andrew S. Brohl, MD

OncLive: What are some of the key genomic events underlying the development of sarcomas?

Andrew S. Brohl, MD, is a medical oncologist at Moffitt Cancer Center, specializing in sarcomas. His research focuses on the study of sarcoma genomics and the application of genomic data for personalized cancer therapy. He is also a member of The Cancer Genome Atlas (TCGA) sarcoma project. Here, in an interview with OncLive, he discusses some of the recent findings of genomic studies of sarcomas.Brohl: Given the heterogeneity of sarcomas, there is a wide range of genomic underpinnings to different sarcoma subtypes. Genomic findings in sarcomas to date can range anywhere from subtypes with relatively simple genomes with few somatic events, in particular fusion-driven subtypes such as Ewing sarcoma, to those with extreme genomic instability and extensive structural rearrangements.

Has the identification of these molecular alterations translated into changes in the clinical treatment of these cancers?

In several sarcoma subtypes, key recurrent driver events have been identified, such as in KIT or PDGFRα in gastrointestinal stromal tumors (GISTs), inactivating mutations in members of the polycomb repressive complex 2 (PRC2) in malignant peripheral nerve sheath tumors (MPNST), and several angiogenesis signaling genes in angiosarcoma, among others.GIST is one of the poster children for molecularly targeted therapy. The successful targeting of KIT and PDGFRα with tyrosine kinase inhibitors led to dramatically improved outcomes in the early 2000s for patients with advanced GIST.

For a more recent example, ALK inhibitors have shown very promising activity in case reports and a small series of ALK-rearranged inflammatory myofibroblastic tumors. As a final example, the CDK4/6 inhibitor palbociclib showed modest activity in a phase II trial in CDK4-amplified liposarcoma subtypes and is listed as an option for systemic therapy for this tumor type in current National Comprehensive Cancer Network guidelines.

How does the rarity of sarcomas impact our understanding of their genomic features?

What are the most significant unanswered questions or challenges in the field of sarcoma genomics?

For most other subtypes of sarcoma, however, the identification of molecular alterations has not yet led to significant advances in standard clinical management, and cytotoxic chemotherapy remains the norm for the treatment of advanced disease.The rarity and heterogeneity of sarcomas pose significant challenges for research and clinical efforts. Specific to genomics, it is likely that each of the >100 subtypes of sarcoma has a unique pattern of underlying genomic events. We therefore will need to individually study each of these subtypes to understand the full spectrum of genomic events that underlie sarcoma. Many of these subtypes are quite rare, which makes collection of sufficient numbers of samples for testing a major issue and typically requires collaboration across many sites.I would say that sarcoma genomics is still in the early stages. In most sarcoma subtypes, we haven’t yet completed the initial cataloging of the most common recurrent genomic events and so this will be the first step. Even large collaborative efforts like TCGA are currently only targeting a handful of the more common sarcoma subtypes for analysis, so we as a community will need to provide the momentum to go after the remaining rarer subtypes that are the most difficult to come by.

Looking ahead, for most non-GIST sarcoma subtypes, thus far we are not finding a high frequency of immediately targetable mutations such as activating kinase mutations. I therefore think that the most important challenge moving forward will be figuring out how to translate other types of genomic findings, such as dysregulation of transcription factors or loss of tumor suppressors, toward clinical use.