CORR Insights®: Assessment of Predictive Biomarkers of the Response to Pazopanib Based on an Integrative Analysis of High-grade Soft-tissue Sarcomas: Analysis of a Tumor Sample from a Responder and Patients with Other Soft-tissue Sarcomas

Where Are We Now?

In orthopaedic practice, a key determinant in our treatment decisions is a prediction of how the patient will respond to that treatment. Is the fracture going to heal? Is the pain going to improve? What would happen without intervention? In musculoskeletal oncology, those predictions often relate to the patient’s overall survival. Some great advances in survival prognostication have been developed over the past several years for metastatic carcinoma [1] and sarcoma [5, 7]. Unfortunately, for patients with advanced metastatic soft-tissue sarcomas, the prognosis for long-term survival remains poor.

A meta-analysis of patients with localized, resectable soft-tissue sarcomas demonstrated marginal improvement in overall survival with doxorubicin and ifosfamide-based chemotherapy [8]. However, with a number needed to treat of 10, the data would suggest that these cytotoxic agents would not yield a benefit in the overall recurrence rate in 90% of such treated patients. In advanced soft-tissue sarcoma, only 22.5% of patients demonstrated any clinical response to treatment with multiagent chemotherapy [13]. Predicting which of these patients will benefit from standard chemotherapy remains of utmost importance. Identifying which nine of 10 patients with localized disease will not benefit from medication may avoid severe toxicity in most of these patients. Similarly, understanding which patients with metastatic sarcoma are likely to respond to multiagent, conventional chemotherapy may help direct us towards either palliative care or more-targeted treatment options.

Although metastatic carcinomas like renal cell carcinoma and lung carcinoma generally have dismal prognoses, modern treatment with receptor tyrosine kinase inhibitors have markedly improved the duration of survival [6, 10]. But for patients with metastatic soft-tissue sarcomas administered with multiagent chemotherapy, few good choices remain, although tyrosine kinase inhibitors have emerged as a potential next line of therapy. The Pazopanib Explored in Soft Tissue Sarcoma Phase 3 trial demonstrated 3-month improvement in progression-free survival in patients with metastatic sarcomas treated with pazopanib, a tyrosine kinase inhibitor, compared with controls who were given a placebo [12]. Although the drug was approved for this indication by the FDA, none of the 369 patients in this trial demonstrated a complete response, and only 6% of those treated with pazopanib exhibited even a partial response.

In the current study by Suehara et al. [11], the authors presented the case of a patient who demonstrated at least a high-grade, partial response during a brief treatment course of pazopanib. Considering this favorable response, the authors performed integrative analyses to help understand some of the genomic and protein-level factors that may be associated with the treatment effect. Interestingly, this study was done in a somewhat reversed fashion. Typically, a hypothesis-driven series of research foci start with a proposed mechanism of action, which is then tested in vitro and in small-animal models before attempted translation into the clinical setting. Although we already know the overall mechanism of action of pazopanib, this study worked backwards to determine the specific genetic and proteomic aspects of the patient’s particular tumor that may have contributed to pazopanib's early efficacy.

Where Do We Need To Go?

In reality, soft-tissue sarcoma is not a single disease entity, but rather a family of diseases that share some similar characteristics. More than 50 soft-tissue sarcoma subtypes are recognized by the WHO [4], and they are currently distinguished mostly by histopathologic evaluation. Is the role of histopathology overstated in the classification and management of sarcomas? Of the CD99-positive, small, round, blue cell tumors that do not demonstrate an EWSR1 gene rearrangement, many will carry CIC-DUX4 gene fusion, which is associated with a more-aggressive clinical course and decreased overall survival compared with others in the Ewing sarcoma family [2]. Many have come to recognize these CIC-DUX4 sarcomas as representing a unique clinical entity from Ewing sarcoma, with a diagnosis based entirely on cytogenetics, despite histopathologic similarities. Which other sarcomas may have a prognosis or management dictated by cytogenetic profiling?

In breast carcinoma, a 70-gene signature can help predict oncologic outcomes and direct treatment decisions [3]. Advances in next-generation sequencing, in vitro cytotoxicity assays, and patient-derived xenograft models have opened the door to a new era of oncologic care for sarcomas as well. These platforms help us learn more about individual sarcomas, and each platform is designed to help predict which medications are likely to demonstrate clinical efficacy. The current study by Suehara, et al. [11] gives us reason to believe that pazopanib in soft-tissue sarcomas may have some clinical efficacy for dedifferentiated liposarcomas as well, and potentially even for well-differentiated liposarcomas, based on the expression of CDK4 and MDM2. A previous study has demonstrated some improvement in progression-free survival in patients with advanced liposarcomas, most of which were classified as dedifferentiated liposarcomas [9]. Although these studies suggest that there may be an identifiable subpopulation of patients with sarcomas for whom next-generation sequencing can help predict the treatment response, the next step will be to clarify which patients warrant further investigation.

Despite the tremendous advances that have been made, we do not fully understand the biology and pharmacology of these rare tumors. To truly push the needle regarding the treatment response, as has been done in melanoma, lung cancer, and renal cell carcinoma, we need to have a better understanding as to which medications are going to work for which patients. This can start with some early studies on GLI1 and platelet-derived growth factor receptor beta, as in the current analysis [11]. However, these may not be relevant to most patients with soft-tissue sarcomas. Nonetheless, this study’s findings may benefit those with other malignancies in terms of additional or specific pathways to target. As we now recognize from treating visceral malignancies, tyrosine kinase inhibitors will eventually lose clinical efficacy in patients treated with them. We need to better understand the failure modes or resistance mechanisms, not only for sarcomas.

How Do We Get There?

Soft-tissue sarcomas are not an orphan disease, but rather a family of even-rarer orphan diseases. We tend to group them together because few centers have enough patients with individual characteristics to adequately study each one. Suehara et al. [11] helped demonstrate the power of the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets trial (https://www.cbioportal.org/) by recognizing the molecular profiles of malignant tumors. However, the authors also highlight how even a large sarcoma center, such as the Memorial Sloan Kettering Cancer Center, cannot sequence enough sarcomas themselves to fundamentally transform clinical care alone. The promise of shared clinical data and outcomes from the Musculoskeletal Tumor Registry is now coming to fruition [11]. Ultimately, the vision of matching registry data with patient-level sequencing analyses on a national or international scale may launch sarcoma clinical care to once-unimaginable heights. By improving access to next-generation sequencing analyses, that goal is not far away. We can start by integrating the sequencing data we have into the Musculoskeletal Tumor Registry. Although some insurers currently only cover the expenses of next-generation sequences for patients who have not responded to multiple lines of systemic therapy, hope remains that information from further publications such as the current study [11] can help improve survival. A national sarcoma tissue bank may be a more-ambitious target, although the seeds of collaboration are already sprouting to conceive of the possibility.