Although chemotherapy options for patients with sarcoma have expanded in recent months, efforts to advance treatment beyond a therapeutic plateau have long been hindered by a paucity of targetable genomic alterations and the rarity of these tumor types.
In the hopes of identifying new targets, researchers are focusing genomic sequencing studies on many different types of sarcomas. The insights gained have served to emphasize the significant heterogeneity and the unique molecular mechanisms underlying the development of these cancers. Moving forward may require the realization of truly individualized cancer therapy.
A Therapeutic Challenge
Encompassing more than 50 distinct histological subtypes, sarcomas are a rare group of cancers that arise in cells of mesenchymal origin. This type of cancer disproportionately affects children and adolescents; sarcomas account for an estimated 1% of adult cancers and 15% of childhood cancers, although the exact incidence remains unknown in part because of inexact classification and subtyping.
Broadly, they are classed as bone sarcomas and soft tissue sarcomas, depending upon the location of the primary tumor. More specifically, each subtype is named for the type of cell or tissue from which it develops. For example, rhabdomyosarcomas occur in the skeletal muscle, liposarcomas in the fat tissue, leiomyosarcomas in smooth muscle tissue. Among the bone sarcomas, osteosarcoma arises in the osteoid tissue and chondrosarcoma in the cartilaginous tissue. Ewing sarcoma forms in both the bone and the soft tissue, though the former is more common.
Despite their biological and histological differences, sarcomas are generally treated in the same manner, with a combination of surgery, chemotherapy, and radiation therapy. Unfortunately, many patients, particularly those diagnosed at advanced stages of disease, are not surgically treatable.
Although chemotherapy has vastly improved outcomes in some subtypes such as osteosarcoma, it has generated poor responses among patients with other subtypes and, even among those who do respond, recurrence often occurs.
In recent months, the FDA has approved two new chemotherapy agents expected to help improve outcomes among subsets of patients.
In January, eribulin mesylate (Halaven) became the first FDA-approved drug for patients with advanced or unresectable liposarcoma to demonstrate an improvement in overall survival (OS); the median OS was 15.6 months with the microtubule inhibitor versus 8.4 months with dacarbazine.
In October 2015, the FDA approved trabectedin (Yondelis), an alkylating agent, for patients with unresectable or metastatic liposarcoma or leiomyosarcoma who have received a prior anthracycline- containing regimen. The approval was based on a statistically significant improvement in median progression-free survival (PFS): 4.2 months with trabectedin versus 1.5 months with dacarbazine.
Nevertheless, response rates for both drugs were relatively low. The objective response rate was 4.0% (95% CI, 1.8-7.5) with eribulin and 7% (95% CI, 4.4-9.8) with trabectedin.
Although many molecularly targeted therapies have been tested, success has been limited. Imatinib (Gleevec), which the FDA approved for the treatment of KIT-positive gastrointestinal stromal tumors (GISTs), has proved particularly successful. Approximately half of the patients in one pivotal study responded to the TKI dosed at 400 mg and median OS was 49 months. In another study, the objective response rate hit 68.5%. Two other drugs, regorafenib (Stivarga) and sunitinib (Sutent), have been approved as GIST therapy on the basis of PFS and time to progression, respectively.
Pazopanib (Votrient) was approved in soft tissue sarcoma after demonstrating a median PFS of 4.6 months compared with 1.6 months for placebo in a clinical trial that had enrolled patients with leiomyosarcoma, synovial sarcoma, and other soft tissue subtypes not including GISTs.
Many Sides of the Genomic Coin
Thus far, large-scale genomic characterization of cancers has focused on epithelial and hematologic malignancies, and relatively few studies of sarcomas have been performed. That is slowly beginning to change as researchers are undertaking collaborative efforts to overcome the scarcity of samples. The Cancer Genome Atlas (TCGA) has also turned its attention to sarcoma and has included the study of these types of cancers in its Rare Tumor Characterization Project, although only a few types of sarcoma are being studied. The picture that is emerging from the limited studies that have been done is of at least two genomically distinct types of sarcoma. Some sarcomas have a very stable genome, with very few molecular alterations—in some cases, only a single defining abnormality that is maintained throughout the tumor’s evolution.