Prior to the mid-1970s, the prognosis for patients diagnosed with high-grade, central osteosarcoma was poor, with an overall survival rate that ranged from 10% to 20%. However, the introduction of neoadjuvant chemotherapy regimens resulted in marked improvement in the survival of patients with osteosarcoma, and the current overall survival rates range from 60% to 70% for patients with a localized tumor. Nonetheless, despite numerous organized trials and combinations of chemotherapeutic agents, the survival rate for these patients has plateaued, and the prognosis for patients with disseminated osteosarcoma remains extremely poor. Recent advances have shed light on basic molecular mechanisms driving the biology of these tumors and have led to a push to discover additional novel biomarkers that might be exploited for therapeutic means.
Numerous osteosarcoma biomarkers have been studied during the past twenty-five years; perhaps the two most publicized are P-glycoprotein and the HER-2/neu gene product. P-glycoprotein, the product of the multidrug resistance gene MDR1, is a transmembrane efflux pump that removes chemotherapeutic agents from tumor cells. One drug that this protein is known to effectively remove from tumor cells is doxorubicin, a first-line agent used in the treatment of osteosarcoma. In 1995, Baldini et al. reported that increased P-glycoprotein levels in patients with osteosarcoma, detected with immunohistochemical methods, was associated with an increased risk for adverse clinical behavior independent of the effect of neoadjuvant chemotherapy1. Thereafter, numerous studies have produced conflicting results on whether elevated P-glycoprotein levels are associated with adverse outcomes in patients with high-grade osteosarcoma. What appears clear is that any potential for an adverse outcome related to P-glycoprotein expression does not correlate with actual MDR1-gene expression2 or response to chemotherapy3, and ultimately the issue of P-glycoprotein expression and its relationship to survival remains unresolved.
Similar findings have been reported regarding the HER-2/neu oncogene product. Two studies in the mid-1990s showed that elevated expression of HER-2/neu in biopsy samples was associated with a poor histologic response to neoadjuvant chemotherapy and significantly decreased event-free survival4,5. These studies suggested the possibility of utilizing monoclonal antibodies, such as trastuzumab (Herceptin), as an adjuvant chemotherapeutic agent. However, a subsequent study by Kilpatrick et al. suggested that immunohistochemical evidence of HER-2/neu expression did not correlate with histologic subtype, grade, response to chemotherapy, metastasis, or survival in patients with osteosarcoma6. Finally, Akatsuka et al. reported that elevated HER-2/neu expression was associated with an increased probability of event-free and overall survival7. All of these investigators utilized immunohistochemical or immunoblot methods to detect the presence of HER-2/neu on tumor cells. When Zhou et al. attempted to correlate gene amplification with immunoreactivity, they found modest correlation between gene expression and the presence of the protein, as one of seven immunostain-positive tumors lacked any associated gene amplification and two of five immunostain-negative tumors demonstrated gene amplification8. Similar to the case with P-glycoprotein, the exact relationship between HER-2/neu expression and prognosis in patients with osteosarcoma remains unresolved. Nonetheless, several studies have suggested that the use of anti-HER-2/neu monoclonal antibodies is inappropriate given the lack of gene expression by these tumors9,10.
In the second March 2011 issue of The Journal, Kubo et al. reported another potential biomarker—interferon-α/ß receptor. Much like the case with HER-2/neu, the identification of interferon-α/ß receptors as a biomarker has strong therapeutic implications. The Cooperative Oncology Group's current trial AOST0331 contains an arm in which patients who have a good response to induction chemotherapy can also receive subcutaneous injections of interferon-α-2b. Therefore, demonstrating that interferon-α/ß receptors not only are prognostically important but also serve as a potential therapeutic target is extremely important. In their study, Kubo et al. performed immunohistochemical studies for interferon-α/ß receptors and correlated the presence or absence of the receptors with survival. A univariate analysis showed that American Joint Committee on Cancer surgical stage IIA, a good response to chemotherapy (>90% necrosis), and expression of interferon-α/ß receptors all predicted favorable disease-free survival. However, in a multivariate analysis, interferon-α/ß receptor expression was the only independently significant parameter related to better outcome. While the results appear promising, it is necessary to confirm them in a substantially larger cohort. Additionally, it remains unclear whether the identification of the interferon-α/ß receptors with simple immunohistochemical methods is related in any way to gene expression; whether this finding relates to interferon-α-2b binding to the osteosarcoma cells, thus resulting in apoptosis through a p53 pathway; or whether this is a spurious finding similar to observations related to P-glycoprotein—i.e., that detection of the protein appears unrelated to the mechanism by which it should theoretically affect prognosis.
Regardless of the exact mechanism of action, the data reported by Kubo et al. suggest that interferon-α/ß receptors might be a novel biomarker for osteosarcomas. Given the small sample size in this study, further validation of these results and further examination of the pathways by which interferon-α/ß receptors affect the prognosis in patients with osteosarcoma should prove useful. Further study is also necessary to determine whether these receptors are simply a novel biomarker related to prognosis, or whether they can be exploited for therapeutic purposes. It will be extremely interesting to follow future studies of these receptors to monitor whether their prognostic significance and relevance to therapeutic targeting are able to withstand further scrutiny, unlike the several once-promising biomarkers that seem to have fallen by the wayside.