Precision Oncology in Sarcomas

Divide and Conquer

Roberto Carmagnani Pestana, MD; Roman Groisberg, MD; Jason Roszik, PhD, MBA; Vivek Subbiah, MD

Disclosures

JCO Precis Oncol. 2019;2019(3) 

In This Article

Abstract and Introduction

Abstract

Sarcomas are a heterogeneous group of rare malignancies that exhibit remarkable heterogeneity, with more than 50 subtypes recognized. Advances in next-generation sequencing technology have resulted in the discovery of genetic events in these mesenchymal tumors, which in addition to enhancing understanding of the biology, have opened up avenues for molecularly targeted therapy and immunotherapy. This review focuses on how incorporation of next-generation sequencing has affected drug development in sarcomas and strategies for optimizing precision oncology for these rare cancers. In a significant percentage of soft tissue sarcomas, which represent up to 40% of all sarcomas, specific driver molecular abnormalities have been identified. The challenge to evaluate these mutations across rare cancer subtypes requires the careful characterization of these genetic alterations to further define compelling drivers with therapeutic implications. Novel models of clinical trial design also are needed. This shift would entail sustained efforts by the sarcoma community to move from one-size-fits-all trials, in which all sarcomas are treated similarly, to divide-and-conquer subtype-specific strategies.

Introduction

Sarcomas are a heterogeneous group of mesenchymal malignancies that comprise less than 1% of adult and 12% of pediatric cancers.[1,2] The WHO has defined more than 50 sarcoma subtypes, including a wide array of tumors that arise from adipose, muscular, bone, cartilage, and vascular tissues.[3] Treatment options for patients with advanced soft tissue sarcomas (STSs) are limited, and a one-size-fits-all paradigm has prevailed despite the diverse nature of STSs. For metastatic STSs, anthracycline-based chemotherapy remains the backbone of first-line treatment regimens.[4] However, efficacy is limited, with a median progression-free survival (mPFS) of approximately 6 months, and the incidence of treatment-associated adverse events (AEs) is high.[5] Therefore, more individualized treatment options are critical to improve the survival and quality of life of this patient population.

Reflecting STS heterogeneity, multiple molecular pathways are implicated in the development and progression of these cancers. The characterization of specific genetic aberrations has led to the identification of novel diagnostic, prognostic, and predictive biomarkers.[6] An understanding of the prevalence and function of specific genetic alterations in STS subtypes is critical to developing more-effective diagnostic tests and therapeutic approaches. Targeted therapies have the potential to produce significant tumor response by disrupting molecular pathways that drive oncogenesis, thus providing highly personalized treatment.[7] A recent report by Lucchesi et al[8] analyzed 584 patients with STS in the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database and identified that 41% of patients harbored a genetic alteration with potential to influence therapy. Accordingly, a single-center report by Boddu et al[9] analyzed 114 patients with sarcoma and identified that 49% carried a mutation deemed actionable; 15 patients had next-generation sequencing (NGS)–guided therapies, with 26% of these achieving clinical benefit (Table 1). This review focuses on how incorporation of NGS has affected drug development in sarcomas and strategies for optimizing precision oncology for these rare cancers.

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