More Precise Surrogate Markers for Clinical Response Are Needed

ROCHESTER, Minnesota—Accurate surrogate markers that would help researchers predict clinical response to systemic cancer chemotherapy and greatly speed development of new treatments may be on the way. Alex A. Adjei, MD, PhD, discussed these anticipated markers that will be much more precise than those currently in use. Dr. Adjei is consultant in oncology at the Mayo Clinic in Rochester, Minnesota.

"The ideal surrogate marker would be sensitive and specific, present in accessible tissue, measurable in a simple assay adaptable to clinical use, and would correlate with results in tumor tissue," Dr. Adjei said. Markers might measure pharmacodynamic effects such as topoisomerase I cleavable complex formation, decreased metabolism (perhaps measured using PET scans), increased apoptosis, or decreased blood flow/angiogenesis inhibition.

Potential uses of reliable surrogate markers include improving patient selection for treatment and early prediction of responses in clinical studies.

Identifying New Markers

Appropriate methods for identifying such markers, according to Dr. Adjei, include proteomics (immunoblotting), immunohistochemistry, commercially available enzyme inhibition assays, measurements of gene expression, magnetic resonance imaging (MRI), and functional imaging. "The problems with previous correlative studies have included use of nonstandardized methods and arbitrary interpretation of data," he said.

Dr. Adjei discussed the use of estrogen receptor (ER) expression in breast cancer as an example of these problems. "The key question is, what is the definition of ER-positivity?" he said.

A survey of a cohort of pathologists by the American College of Pathology revealed that the definition of estrogen receptor positivity by immunohistochemistry ranged from any cells staining positive to 50% of cells staining positive.

‘‘Given these data, it is amazing that we have been as successful as we have in using ER status as a marker," said Dr. Adjei.

Surrogate FTI Markers

Surrogate markers of farnesyl transferase inhibitor (FTI) activity have been investigated—first, in various human cancer cell lines, and subsequently in patient tissues, Dr. Adjei noted. Candidates include Ras expression, p21, and farnesylated proteins. Dr Adjei and his colleagues have generated antibodies against the prepeptide of prelamin A, which is a substrate for farnesyl transferase. Prelamin A is farnesylated, and this prepeptide is cleaved to form mature lamin A. The antibody therefore recognizes unfarnesylated prelamin A, which is a marker of FT inhibition. The antibody has been used in immunohistochemical assays to identify FT inhibition in relevant cells. Unfortunately, the immunohistochemical assay does not work with formalin-fixed tissue. In addition, lymphocytes do not contain lamin A, so it would not work as an assay in blood samples. As an alternative, the Mayo Clinic researchers have tested buccal mucosa cells.

"These cells are well suited for immunohistochemistry and gene expression studies. There is rapid turnover of the cell population, and the cells are easily accessible with noninvasive sampling methods," Dr. Adjei said.