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St. Louis Startup Hopes to Develop Dx to Predict Response to Neoadjuvant Aromatase Inhibitors


A St. Louis-based startup is working on a molecular diagnostic to determine how women with estrogen receptor-positive, node-negative breast cancer will respond to aromatase inhibitors, and therefore identify which women should be prescribed these kinds of drugs as neoadjuvant breast cancer therapies.

The company, University Genomics, hopes that within "a couple of years" its research may result in "a multigene diagnostic that predicts who gets excellent tumor regression with preoperative hormonal therapy so that this can become more of a standard of care, as opposed to chemotherapy" in post-menopausal, estrogen receptor-positive breast cancer patients, co-founder Matthew Ellis told Pharmacogenomics Reporter this week.

Ellis, an associate professor of medicine at Washington University School of Medicine in St. Louis, together with partners Chuck Perou, an assistant professor at the University of North Carolina, and Phil Bernard an assistant professor at the University of Utah, founded the company to develop and sell a diagnostic that could help predict an individual's response to aromatase inhibitors, such as Pfizer's Aromasin. The test was originally developed by Ellis and colleagues at St. Louis for neoadjuvant therapy, but the researchers believe it should also prove useful for predicting response in the adjuvant setting.

"What we're trying to do is replace chemotherapy with aromatase inhibitors" in the neoadjuvant setting, which means that women would be treated with an aromatase inhibitor before undergoing surgery, said Ellis. If chemotherapy is used, these women may otherwise lose a breast due to the size of the tumor. "To do that convincingly, we really need to know which tumors respond best to this treatment," he said.

Ellis said that the same diagnostic profile could "absolutely" be used in the adjuvant setting, which would see aromatase inhibitors used in concert with traditional chemotherapy. But in order to prove that the profile works in this setting, Ellis and colleagues must first transfer the profile to Roche's Q-PCR system so they can use RNA from formalin-fixed, paraffin-embedded breast cancer tumor samples. Once they do this they hope to establish their assay based on data from the approximately 6,500 samples that are part of the so-called MA-27 trial. This is a large, 5-year, multi-arm study of aromatase inhibitors.

Approximately 200,000 women in the Untied States are diagnosed with breast cancer every year, and the majority of these are early breast cancer cases who are treated with adjuvant therapy, Jodi Grabinski, an assistant professor in the University of Texas College of Pharmacy, told Pharmacogenomics Reporter this week. In many cases the adjuvant is tamoxifen.

Asked whether a diagnostic for identifying aromatase-inhibitor responders would be useful, Grabinski, who studies the effect of CYP450 2D6 and ER-alpha polymorphisms on tamoxifen effectiveness, speculated that clinicians would likely find it most useful to test a tumor's sensitivity to aromatase inhibitors and tamoxifen up front, in order to guide later therapy.

"What we're trying to do is replace chemotherapy with aromatase inhibitors in [a] particular clinical setting," in which women may otherwise lose a breast due to the size of the tumor. "To do that convincingly, we really need to know which tumors respond best to this treatment."

To attain its neoadjuvant results, University Genomics built its current profile using an Affymetrix GeneChip, which helped it identify genes that could predict how tumors may respond to aromatase inhibitors. The firm used the array in a trial of about 100 post-menopausal, estrogen receptor-positive breast cancer patients who had been treated with aromatase inhibitors for four months before surgery. The investigators gauged response by measuring the tumor size clinically, by ultrasound, and by mammography, and by studying the activity of cell cycle markers in the tumor. The group plans to publish results, which were positive, from this initial study within the next six to 12 months, Ellis said.

So far, there do not appear to be other diagnostics that may help predict a response to aromatase inhibitors. Ellis said he and his and colleagues are organizing a larger study, called Z-1031, this time with the American College of Surgeons Oncology Group. The study is currently enrolling the first of its planned 375 patients who will be randomized between Pfizer's Aromasin, Novartis' Femara, and AstraZeneca's Arimidex for four-month pre-operative treatments in order to find which is most effective in this setting.

"In addition, we'll be prospectively testing the multigene profile, which we've [previously found] to predict outcome," said Ellis. "So this is a validation set for the discoveries we've made in the first trial," in which the training set was established, he said.

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