Sarcomas are a heterogeneous group of malignant tumors of connective tissue and bone with a propensity for local recurrence and distant metastases. Surgery and radiation are the mainstays of treatment for localized disease while the role of chemotherapy in this setting is controversial. Novel biomarkers that could predict therapeutic response to chemotherapy or that could prognosticate overall survival (OS) are needed to define the patients most likely to benefit from systemic treatment.
Serum protein acidic and rich in cysteine (SPARC), also known as osteonectin and BM-40, is a matricellular glycoprotein that is secreted by tumor and/or surrounding stroma. SPARC has been evaluated as a potential biomarker in numerous malignancies given its involvement in cell adhesion, proliferation, migration, and tissue remodeling [1]. Studies in different cancer types have demonstrated varying effects on tumorigenesis. For example, in ovarian and colorectal cancer as well as neuroblastoma, SPARC has demonstrated antitumorigenic properties inhibiting angiogenesis and functioning as a tumor suppressor. Conversely, in breast, melanoma, brain, colon, prostate, kidney, esophageal, lung, and pancreatic cancers, SPARC expression has been associated with a more aggressive phenotype, inhibiting apoptosis and promoting tumor invasiveness and metastases [2]. The reasons for these disparate results, even within the same type of cancer, are unknown but may be explained by different methodologies used to assess SPARC expression as well as its complex biology. Studies that have evaluated different types of specimens including cell lines, xenografts, and patient samples could account for some variability. Discrepancies may also be due to the reporting of expression of tumoral versus stromal SPARC as the protein may have differential effects depending on the site of expression. Also, the peptides of SPARC that are present and interacting with the tumor microenvironment could account for the varying effects between cancer types [3].
The prognostic and predictive potential of SPARC in cancer is controversial. In one study of advanced pancreatic cancer patients receiving gemcitabine and nab-paclitaxel, high stromal SPARC expressers had a statistically significant longer OS than low SPARC expressers on multivariate analysis [4]. However, this finding was not confirmed on a subsequent phase III study [5]. In resected pancreatic cancer, SPARC stromal and cytoplasmic overexpression was associated with statistically significant worse disease-free survival (DFS) and OS in those treated with adjuvant gemcitabine, and not 5-fluorouracil, suggesting that SPARC may have a role as a predictive marker [6].
In breast cancer, SPARC expression has largely been associated with a more aggressive phenotype and an unfavorable prognosis [7, 8]. In a large study of localized breast cancer, pre-treatment core biopsies were analyzed for SPARC expression by IHC. The highest expression rates were seen in triple-negative tumors (TNBC). In the overall population as well as in the TNBCs, high SPARC expression was associated with a greater likelihood of pathological complete response to neoadjuvant chemotherapy with docetaxel, doxorubicin, and cyclophosphamide +/- capecitabine and vinorelbine suggesting a role as a predictive biomarker. There was no significant correlation between SPARC expression and DFS or OS [9].
In sarcoma, SPARC has recently been suggested as a potential prognostic factor in a relatively small study. Twenty-seven sarcoma specimens were obtained at varying time points in the patients’ clinical courses and evaluated for SPARC expression. Staining intensity ranged from 1+ (low) to 3+ (strong). Patients were identified as high SPARC expressers if at least 50 % of the tumor cells displayed 2+ staining (56 %). The other patients were considered low SPARC expressers (44 %). SPARC levels did not correlate with specific histologies but did correlate with OS. Low SPARC expressers had a median survival of 22.1 months while in the high expressers, the median survival was 4.4 months [10].
In this report, we sought to evaluate SPARC expression in a more uniform population of patients with high risk soft tissue sarcoma. Specifically, we performed an exploratory analysis of SPARC expression in patients with available tumor specimens that were enrolled on a randomized phase II study examining patient outcomes from treatment with one of two neo/adjuvant chemotherapy regimens for soft tissue sarcoma, doxorubicin and ifosfamide (AI) and gemcitabine and docetaxel (GT). Using primary biopsy and resection specimens, SPARC expression was evaluated in terms of patient and tumor characteristics, treatment, and outcome including OS and time to recurrent disease.