Sarcoma – Divide and Conquer with Precision Oncology

Keerthi Ranganathan

Scientific Content Developer
4baseCare

Sarcomas are a heterogeneous category of rare cancers with over 80 subtypes identified to date. Specific driver genomic aberrations have been found in a considerable proportion of soft tissue sarcomas (STS), which account for up to 40% of all sarcomas. Currently, the diagnosis of sarcoma is based on morphology through immunohistochemistry (IHC) and clinicopathological correlation. However, advances in next-generation sequencing (NGS) technology have led to the discovery of genetic events in these mesenchymal tumors, which has opened up new options for molecularly targeted therapy and immunotherapy, in addition to improving our understanding of biology.

NGS has the potential to become an established platform of choice for sarcoma researchers in the future years. Many researchers have used NGS-based comprehensive genomic profiling (CGP) to try to find recurring abnormalities so far. The majority of discovered mutations in cancer-related pathways are secondary mutations that emerge later in the carcinogenesis process. Identification of these mutations is critical, and with so much variety in the molecular pathways involved, appropriate sarcoma therapy necessitates an individualized strategy.

Precision medicine not only enables a better diagnosis in sarcomas but also allows for the identification of better therapeutic targets for different subtypes of sarcomas. Imatinib and other tyrosine kinase inhibitors in gastrointestinal stromal tumors, neurotrophic tyrosine receptor kinase inhibitors in infantile fibrosarcoma, and crizotinib in inflammatory myofibroblastic tumors are all examples of targeted therapy that have had considerable success in sarcomas. As a result, sarcoma treatment has shifted from conventional chemotherapy-based therapies to modern targeted therapy.

As our capability to examine the genome, proteome, transcriptome, and immunophenotype of malignancies advances, clinical trial design and, as a result, treatment strategies must also evolve. The moment has come to divide and conquer as our understanding of the molecular basis of sarcoma grows. This will enable us to move away from the one-size-fits-all or fruit bowl theory (the present paradigm), in which most sarcoma patients receive conventional treatment that is not based on genetic testing to individual, customized therapy for specific sarcoma subtypes on the basis of biology (the future paradigm). 

Studying rare subgroups of an already rare illness might be a difficulty under this new methodology. It is conceivable to establish effectiveness with small patient numbers, as has recently been established in other rare tumor forms that have led to FDA-approved therapies. Vemurafenib, for example, was recently authorized for BRAFV600-positive Erdheim-Chester disease based on outcomes from a small number of patients. Although, when mutations are uncommon and occur in a variety of histologies, evaluating targeted therapies might be difficult. To establish the therapeutic value of new therapies in patients with rare STS subtypes, novel clinical trial designs are necessary.

Basket trials are an emerging model of trial design based on the assumption that the existence of a specific molecular aberration or biomarker (NTRK fusion) predicts the benefit of targeted therapies, regardless of the type of cancer tissue. One example is the basket trial of vemurafenib for tumors that harbor a BRAFV600 mutation. Vemurafenib is an orally available tyrosine kinase inhibitor (TKI) of BRAF, with higher selectivity for the BRAFV600 mutant form that had been approved previously for patients with BRAFV600E mutation-positive metastatic melanoma.

There was one anecdotal response in a patient with clear-cell sarcoma in this experiment with six pre-specified cohorts. The ongoing National Cancer Institute Molecular Analysis for Therapy Choice trial is another example of novel trial strategies for the development of precision oncology; patients will be paired with a targeted drug that has demonstrated activity against their specific driver pathway abnormality, regardless of tumor histology.