Also in the Oct. 7 JNCI

October 07, 2008

Study Design Proposed to Improve Biomarker Development

Researchers propose a nested case-control study design aimed at determining the accuracy of biomarker classification. The new design is called PRoBE for prospective-specimen-collection and retrospective-blinded-evaluation.

Although scientists have identified numerous biomarkers that initially appear to be valuable for classifying patients during diagnosis, screening, and prognosis, few markers have proved reliable enough to be used in clinical practice. To improve biomarker development, Margaret Pepe, Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle and colleagues outlined in 2001 a series of questions that should be answered during the discovery of putative biomarkers.

In the current commentary, Pepe and colleagues focus on the second phase of biomarker development in which researchers evaluate the classification accuracy of a marker. Only the biomarkers that show robust classification accuracy should then be evaluated in a randomized controlled trial, according to the authors.

A key requirement for testing classification accuracy is the minimization of bias. The PRoBE design aims to minimize bias when testing the classification accuracy of a marker, and it includes four components that relate to the clinical context in which the test will be used, the criteria for measuring biomarker performance, the biomarker test itself, and the sample size necessary for the study.

"The design can be applied to studies of biomarkers intended for use in disease diagnosis, screening, or prognosis. Common biases that pervade the biomarker research literature would be eliminated if these rigorous standards were followed," the authors write.

In an accompanying editorial, David Ransohoff, M.D., of the University of North Carolina at Chapel Hill notes that the PRoBE study builds on the previous proposal by Pepe and colleagues and will help further biomarker development in cancer. "By putting research design and bias squarely on the table, the PRoBE proposal invites a larger discussion about other ways to improve the process of discovery and development of biomarkers for cancer," the editorialist writes.


Nonsteroidal Anti-inflammatory Drug Use Associated with Reduced Risk of Breast Cancer

Regular NSAID use is associated with a reduced risk of breast cancer.

The results of previous studies aimed at evaluating the association between NSAIDs and breast cancer have been inconsistent. To get a more complete assessment of the association, Bahi Takkouche, M.D., Ph.D., of the University of Santiago de Compostela in Spain and colleagues performed a meta-analysis of data from 38 studies that in total involved 2,788,715 women.

Regular use of any NSAID was associated with a relative risk reduction of 12 percent compared with non-users. A separate analysis for aspirin showed a 13 percent relative risk reduction, and an analysis for ibuprofen showed a 21 percent relative reduction in risk.

"The large number of studies included, the magnitude of the associations found, the consistency of the results through settings, and the existence of a mechanism that gives strong biologic plausibility to the relationship, provide evidence that NSAID use is associated with reduced risk for breast cancer," the authors conclude.

In an accompanying editorial, Louise R. Howe, Ph.D., of Weill Cornell Medical College in New York and Scott Lippman, M.D., of the University of Texas M. D. Anderson Cancer Center in Houston, discuss the likely reasons for inconsistencies between individual studies of NSAIDs and breast cancer risk. "Moving forward, analyses of associations between NSAID use and breast cancer risk will likely gain clarity from stratification based on the biology of NSAID action," they write.


Blocking Tumor Cell Expression of Monocyte Chemoattractant Protein-1 Reduced Malignant Pleural Effusion in Mice

Injecting of tumor cells engineered to overexpress monocyte chemoattractant protein-1 (MCP-1) increased fluid accumulation in the chest due to cancer, called malignant pleural effusion, in mice and reduced their overall survival.

Malignant pleural effusion occurs frequently in lung and breast cancer patients. Researchers hypothesize that tumor cells produce MCP-1 locally and that the protein increases fluid collection.

In the current experiment, Georgios Stathopoulos, M.D., Ph.D., of the National and Kapodistrian University of Athens, Greece, and colleagues engineered a mouse melanoma cell line, B16, to overexpress MCP-1 and a mouse lung cancer cell line, LLC, to express a short-hairpin RNA that blocks MCP-1 expression.

Mice injected with LCC cells in which MCP-1 expression was inhibited had a smaller volume of pleural effusion and survived longer than animals injected with control cells. By contrast, injection of the B16 cells that overexpressed MCP-1 increased fluid collection, vascular perme¬ability, immune cell recruitment, and blood vessel development in animals relative to that observed in mice injected with cells that did not express high levels of the protein.

"Our results demonstrate that MCP-1 is a power¬ful inducer of [malignant pleural effusion] when secreted by cancer cells in the pleural cavity," the authors conclude.

Contact: Georgios Stathopoulos,, +302107235521 (office), +306947932967 (cell)

Risk Factors Associated with Male Breast Cancer Identified in Prospective Study

Men who had a first-degree relative with breast cancer were at increased risk of developing the disease, as were those individuals who had a history of bone fracture, were obese, or had little physical activity.

Scientists have previously studied risk factors associated with male breast cancer in retrospective studies, which may be adversely influenced by participants' limited recall.

In the current study, Louise Brinton, Ph.D., of the National Cancer Institute in Rockville, Md., and colleagues analyzed risk factors associated with male breast cancer in the prospective National Institutes of Health-AARP Diet and Health Study. A total of 324,920 men enrolled in the study and completed detailed questionnaires on lifestyle, diet, and medical and family history. Of those, 121 developed breast cancer.

Men with either a male or female first-degree relative with breast cancer had an increased risk of breast cancer compared with men who did not have an affected relative. Unexpectedly, a history of bone fracture was also associated with of an increased risk, an association that has not been seen in previous studies. An increased risk was also associated with obesity and a lack of physical activity, even after accounting for body mass. Alcohol consumption was not associated with risk of breast cancer in men.

"The identified risk factors show some commonalities with female breast cancer and indicate the importance of hormonal mechanisms. Differences in risk factors may reflect unique mechanisms associated with androgens and their ratio to bioavailable estrogens," the authors write.

Contact: National Cancer Institute office of media relations,, (301) 496-6641 Also in the October 7 JNCI:
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