Tumor gene profiles predict breast cancer response to letrozole

NEW YORK (Reuters Health) - Gene expression profiles based on analysis of tumor DNA microarrays can differentiate between breast cancers that are responsive to letrozole, an oral, non-steroidal, highly selective aromatase inhibitor, and those that are resistant to the drug. These results are from a study by an international group of researchers published online February 17 by the Journal of Clinical Oncology.

Investigators say this is the first study to describe genetic covariables and molecular processes that discriminate between tumors that are clinically responsive or resistant to an aromatase inhibitor.

"Our research is designed to discover tumour genetic signatures that will identify cancers most likely to respond to treatment (currently only 50% of unselected tumour respond), so saving those with resistant tumors unnecessary therapy," Dr. William R. Miller of the University of Edinburgh, UK, told Reuters Health. "Additionally, we believe that it might be possible to identify the genetic mechanism for resistance in nonresponding tumours so that circumventing treatments may be developed."

"While no single variable completely distinguished between clinical responders and nonresponders," the researchers write, "it can be seen that there are different patterns of expression in letrozole-responsive and -resistant tumors."

They also note that tumors responding to letrozole comprised a relatively homogenous group that was "clearly dissimilar genetically" from tumors resistant to the drug. The report pointed out, however, that no single genetic parameter can distinguish between the two types of tumors.

In an analysis of the gene probes for 205 covariables that differentiated between clinical responders and nonresponders, the most significantly involved processes were macromolecular biosynthesis, cellular biosynthesis and translation. These had higher basal expression in letrozole-responsive tumors and increased expression with treatment in the nonresponding tumors. Data on molecular function showed that structural components of ribosomes were most significantly enriched.

The study population consisted of 79 consecutive patients, all postmenopausal, presenting to a single breast cancer unit over a 2-year period. All had large primary, histologically confirmed, invasive, estrogen receptor-positive breast cancer.

Patients received a neoadjuvant regimen that included letrozole 2.5 mg daily for 3 months. Fifty-two patients had both usable microarray results and an assessable clinical response, based on tumor volume measurements over the 3-month treatment period. Of these 52 women, 37 patients were classified as clinical responders (at least 50% tumor volume reduction) and 15 were considered clinical nonresponders.

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