Volume 7 Issue 6, June 2010

Prognostic models for patients with Hodgkin lymphoma are imperfect and do not allow a precise individualized therapy. A recent gene-expression profiling study, translated into a routine immunohistological test, identified genes of tumor-associated macrophages as being responsible for treatment outcome in patients with Hodgkin lymphoma. If this finding is confirmed by other investigators, it could be a major step towards personalized therapy for patients with Hodgkin lymphoma.

Imatinib 400 mg has been the first-line therapy for chronic myeloid leukemia (CML) since 2001 but may have been licensed at too low a dose. A recent study compared the standard dose with higher doses in patients with newly diagnosed CML and found no difference in response rates at 12 months. But, is the devil in the detail?

A recent landmark study reported the long-term results that compared a standard course of whole-breast irradiation (25 treatments over 5 weeks) with a hypofractionated course of radiation (16 treatments over 3.5 weeks) in patients with early-stage, node-negative breast cancer. The trial demonstrated equivalence of results with respect to overall survival, local control, toxicity and cosmetic outcomes.

Although high-dose methotrexate is widely accepted as the most effective chemotherapeutic agent for primary CNS lymphoma, no optimal dose or dosing strategy has been established. Researchers from the International Extranodal Lymphoma Study Group used clinical trial data to explore whether or not an area under the curve model might be useful to optimize methotrexate dosing. The results strongly suggest that effective methotrexate dose is an important variable in patient outcome.

Management of high-risk non-muscle-invasive bladder cancer represents a difficult challenge in clinical practice. The dilemma is to decide between an organ-sparing approach or radical cystectomy with the risk of undertreatment or overtreatment for this group of patients. This issue is especially important for patients who have failed previous intravesical therapy.

The validation of predictive and prognostic biomarkers and surrogate end points requires robust statistical analysis of data gathered from multiple, large, independent studies. In this Review, Marc Buyse and coauthors discuss this validation process and the nature of biomarkers and surrogate end points. Furthermore, they consider strategies for the pragmatic evaluation of biomarkers and surrogate end points in the absence of statistical validation.

Prognostic and predictive markers in colon cancer might help define which patients with stage II disease are likely to benefit from adjuvant therapy. In this Review, Tara Gangadhar and Richard Schilsky discuss the recent clinical development of such markers, including microsatellite instability and 18q loss of heterozygosity. Further validation of these markers could potentially lead to the individualization of adjuvant therapy in colon cancer.

Well-developed and validated genomic signatures can lead to personalized treatment decisions resulting in improved patient management. However, the pace of acceptance of these signatures in clinical practice has been slow because many of the signatures have been developed without clear focus on the intended clinical use, and proper independent validation studies establishing their medical utility have rarely been performed. The authors of this Review focus on guidelines that physicians could refer to when evaluating studies on prognostic gene-expression signatures.

Elevations in CA125 measurements often antedate any signs, symptoms or radiographic evidence of disease. Unfortunately, data favoring early therapeutic intervention for recurrent ovarian cancer are lacking. The results of a clinical trial suggest that withholding treatment in the event of isolated rising CA125 levels will not negatively impact overall survival. Women with no clinical evidence of disease should be informed about the usefulness and drawbacks of CA125 measurements, and offered the choice to pursue periodic measurements as well as other surveillance.

Two gene-expression-based reference laboratory tests, MammaPrint^® and Oncotype Dx^®, are available for prognostication of patients diagnosed with breast cancer. This Review provides a conceptual and practical overview of these two tests and describes the clinical contexts for which these assays were developed so oncologists can select the most appropriate assay based on specific clinical contexts.

The diagnostic utility of tumor size in breast cancer is dependent on multiple factors. In this Perspective, Foulkes and coauthors recommend that tumor size should not be automatically considered in treatment decisions for all breast cancer subtypes. The authors discuss how the correlation between size and survival is disrupted in triple-negative and basal-like breast cancers and propose two specific mechanisms that might be responsible for this disrupted relationship.

In this Focus issue, leaders in the field provide an update on the current status of prognostic and predictive biomarkers in oncology and debate the major challenges such as statistical validation, and appropriate use and validation of surrogate endpoints. The value of CA125 monitoring in treatment decision making for ovarian cancer, the clinical development of molecular markers to individualize adjuvant therapy in colon cancer, and guidance for physicians in critically evaluating published studies on prognostic gene-expression signatures are highlighted. This Focus provides a valuable and cutting-edge resource for clinicians and researchers.