Medical Device Daily Staff Writer

Much of the trauma of breast cancer is in the treatments used to attack the disease and, despite those increasingly effective treatments, the fear that the cancer will recur and metastasize.

However, it may not be too far into the future when women diagnosed with breast cancer may be able to avoid such difficult treatments as chemotherapy with all its side effects, depending on the type of cancer they have. That is, if recent efforts by the National Cancer Institute (NCI; Bethesda, Maryland), Exagen Diagnostics (Albuquerque, New Mexico) and others come to fruition.

An initial validation study, presented by Exagen Diagnostics at the recent San Antonio Breast Cancer Symposium, suggests it soon may be possible to distinguish good prognosis from poor prognosis in any newly diagnosed breast cancer patient, based on DNA changes in the patient's tumor. Those patients identified as having a very good prognosis may do well without chemotherapy or hormonal therapy after their tumors have been removed.

"The tests that we are in the process of validating are two tests that work as one panel to indicate, for any breast cancer patient who's newly diagnosed, what's their prognosis; in other words, are they going to have a poor or a good prognosis?" Suzanne Mattingly, PhD, vice president of business development and marketing, told Medical Device Daily.

What needs to be done now, she said, is a second validation test on a separate cohort of patients. At that point, the two tests would be considered validated.

In a retrospective study of 308 patients conducted with the Cancer Research and Treatment Center at the Health Sciences Center of the University of New Mexico (Albuquerque), Exagen reported the discovery of two, three-gene sets of markers that were prognostic in testing archived specimens from hormone receptor (HR)-positive and hormone receptor-negative patients. The two sets of markers form a panel for use in testing tumor tissue from breast cancer patients, providing a same- or next-day result.

In independent test sets, each of the three-gene markers accurately identified 91% of HR-negative and HR-positive specimens from patients who did not experience recurrence of disease. In patients who were also node negative, the negative predictive value was 100%.

The study population consisted of white and Hispanic patients with invasive ductal carcinoma diagnosed between 1986 and 1999 at the University of New Mexico Health Sciences Center. A minimum of four years of follow-up clinical information was available for each of the patients, with an average follow-up of 8.9 years.

Poor prognosis was clinically defined as development of recurrence, as evidenced by either distant metastasis or death from breast cancer. Good prognosis was clinically defined as the absence of recurrence (or death from breast cancer) as of the last date of follow-up.

"What we're trying to do is make sure the right patients get the right treatment at the right time, and that's why we've worked to develop two tests," Mattingly said. "One is for hormone receptor positive patients, and one is for hormone receptor negative patients, so that all patients could be identified as to prognosis."

That's where Exagen is creating a first - no other company has so far created a genomic test for HR-negative patients, she said. Any effort to change treatment patterns over time would have to include prognoses for both HR-positive and HR-negative breast cancer patients.

Currently, there are tests for HR-positive breast cancer patients; however, they are "complex tests" that are typically done by one central lab in each case, Mattingly said.

"What we're trying to do is create tests that can be done by any testing lab, and so in the context of doing that, we will be providing our assay as a FISH [fluorescence in situ hybridization] assay . . . and that's a technique that's done by just about any reference lab."

Exagen expects the product to be on the market by late 2005 or early 2006.

"With this approach, we are seeking to define a new standard of care by becoming the first company to offer a prognostic panel of tests that examines the patient's tumor tissue to detect changes in DNA copy number in any patient. This is a more practical method than currently available tests using RNA," said Waneta Tuttle, PhD, Exagen CEO.

"Today, we are treating almost any woman as though her cancer is aggressive, which puts patients who don't actually need treatment at risk for side effects of therapy that is not necessary," said Ian Rabinowitz, MD, the primary UNM clinician involved in Exagen's initial study. "For early stage breast cancer there are about 70% to 80% of patients who are cancer-free and don't actually require therapy after they receive a lumpectomy. At this point in time," he said, "we have no way of identifying which patients fall into that category."

In related news on this front, the National Cancer In-stitute (NCI), part of the National Institutes of Health (both Bethesda, Maryland), said that a new test can predict both the risk of breast cancer recurrence and may identify women who will benefit most from chemotherapy. That was the conclusion of research performed by the NCI in collaboration with the National Surgical Adjuvant Breast and Bowel Project and Genomic Health (Seattle).

These results suggest that almost half of 43,000 U.S. women diagnosed with estrogen-dependent, lymph-node negative breast cancer every year are at low risk for recurrence and may not need to go through the discomfort and side effects of chemotherapy.

The test is based on the expression levels of a panel of cancer-related genes and used to predict whether estrogen-dependent breast cancer will come back, according to a study published online Friday by the New England Journal of Medicine.

The researchers used tissue samples and medical records from women enrolled in clinical trials of the cancer drug tamoxifen, which blocks the effect of estrogen on breast cancer cells. These women had a kind of breast cancer defined as estrogen receptor-positive, lymph-node negative. Each year, 43,000 women are diagnosed with this kind of breast cancer, which needs estrogen to grow but has not spread to the lymph nodes. Currently, many women with this type of breast cancer in the U.S. do receive chemotherapy in addition to hormonal therapy.

Using samples from 447 patients and a collection of 250 genes in three independent preliminary studies, 16 cancer-related genes were found that worked best. The scientists created a formula that generates a "recurrence score" - from 1 to 100 - based on the expression patterns of those genes and offering a measure of the risk of a given cancer's recurrence.

Prior to that research, analysis of the expression of genes was performed on tumor specimens that were frozen rather than tissue-prepared for routine pathologic evaluation. The expression analysis depended on measurement of RNA (the molecule necessary for the translation of a gene into a protein, and RNA is altered when tissues are fixed and embedded).

Frozen tissues are generally not readily available in routine practice, according to the NCI, but researchers at Genomic Health developed a method for performing such analyses on tissues embedded in paraffin wax and allowing them to use the altered RNA found in fixed tissue.

Published: December 16, 2005