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Trial and Error: Prognostic Gene Signature Study Design Altered

Rabiya S. Tuma

The first prospective randomized trial to test the efficacy of a prognostic microarray gene signature is scheduled to begin enrollment in September. However, in a meeting held at the St. Gallen conference in Switzerland in late January, the steering committee decided to substantially alter the trial's design. The changes are reflective of a field in flux, a situation highlighted by several new approaches designed to improve the value of molecular array data in cancer prognosis.

The trial in question, Microarray for Node-Negative Disease may Avoid Chemotherapy (MINDACT), was originally designed to compare the ability of a 70-gene prognostic profile versus clinical and pathological criteria to identify women with node-negative breast cancer who are unlikely to benefit from adjuvant chemotherapy. The hypothesis was that by using the 70-gene prognostic profile, the researchers could reduce the number of women exposed to chemotherapy by as much as 25% without increasing the group's risk of distant relapse.

"We assumed that women would do as well whether managed by the traditional clinical–pathological criteria or managed by the genomic signature," said Martine Piccart, M.D., Ph.D., from the Jules Bordet Institute in Brussels, Belgium. "But in statistics, proving noninferiority is very difficult."



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Martine Piccart

 
In the initial design, women with early-stage (T1 or T2), node-negative breast cancer were eligible for enrollment and would be randomly assigned to one of two arms. In the standard-care arm, physicians would determine whether or not a woman should receive adjuvant chemotherapy based on the clinical–pathological features of her disease, following standard treatment guidelines. In the second arm, the women's tumors would be analyzed using the 70-gene microarray signature. Those who were determined to be at high risk of distant relapse (about 60%) would receive adjuvant therapy, whereas those with the low-risk, "good" signature would not. The researchers would then compare the clinical outcomes of the two arms, ensuring that withholding chemotherapy from women with the "good" signature did not substantially increase the rate of distant relapse.

With the new design, the team will focus on the patients whose genetic signature data and clinical–pathological information are discordant, which, based on validation data reported at the San Antonio Breast Cancer Symposium, will be about 35% of the women. Thus, patients who are determined to be at high risk for relapse by both the gene signature and clinical–pathological criteria will be treated with chemotherapy, as is current standard practice. Those patients who are low risk by both criteria will not receive chemotherapy. However, the patients who are determined to be at high risk for distant relapse by one criterion and low risk by the other will be randomly assigned to one of two arms. In one arm, physicians will use clinical–pathological features to determine treatment. In the other arm, they will rely only on the prognostic criteria of the 70-gene signature to determine whether or not a woman receives chemotherapy.

"Everybody thinks now we have a much stronger design and we will be able to exactly answer all of the questions that we were initially interested in," said Piccart. "The primary goal of the trial is to prove that if we use this new tool we are going to treat [20% to 28%] fewer women with chemotherapy; that is still what we are going to prove with the new design."

Practically, however, the new design will make the trial more expensive and cumbersome. Initially, the researchers intended to enroll 5,000 women in the prospective phase of MINDACT. Now they need 6,000 participants to achieve sufficient statistical power. An estimated 2,100 women will end up being randomized, while 3,300 will fall into the high-risk arm by both criteria and 600 in the low-risk arm by concordant data. In addition, the scientists will now have to perform microarray analyses on all participants' samples, whereas previously they were obligated to perform the analysis only for those patients assigned to the gene array arm.

Validating the Signature

The first phase of the MINDACT trial is an independent validation of the 70-gene prognostic signature, known in shorthand as the Amsterdam signature, which was developed by Laura J. Van't Veer, Ph.D., head of molecular pathology at the Netherlands Cancer Institute in Amsterdam, and her team. They showed in a study published in 2002 that the signature accurately identified women with node-negative breast cancer who were at low risk of disease recurrence—and could, therefore, safely avoid chemotherapy—from those who were at high risk of recurrence.



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Laura J. Van't Veer

 
Currently, 95% of women with node-negative breast cancer in the United States and 85% in Europe are eligible to receive adjuvant chemotherapy, according to consensus treatment guidelines. This high rate of adjuvant therapy remains the standard of care, despite the fact that scientists know that many of these patients are unlikely to experience disease relapse if left untreated after only local therapy. If the signature's value is confirmed in the MINDACT trial, the Amsterdam signature could be the prognostic tool that the field currently lacks.

At the San Antonio Breast Cancer Symposium in December, Piccart reported preliminary results from the validation phase of MINDACT on behalf of TRANSBIG, the translational research network that is coordinating the trial. In the validation phase, researchers analyzed patient samples from six institutions in four countries. The samples were collected from women who were younger than 60 years at the time of diagnosis, had stage T1 or T2 node-negative disease, and had a follow-up time of more than 5 years.

With 291 samples analyzed—of a target of 400—the validation series has met both criteria required to proceed with the prospective phase of MINDACT. The hazard ratio for distant recurrence in the poor-prognosis patients, relative to those in the good-signature category, is above 2, which was the preset cutoff value. Also, more than 88% of the good-prognosis patients remain alive after 10 years, which was above the threshold value of 85%.

Despite the statistically significant hazard ratio for distant recurrence in this new validation series, it is less than half of what it was in the signature's original validation series. Jan G. M. Klijn, M.D., Ph.D., of Erasmus Medical Center, in Rotterdam, the Netherlands, offered two possible explanations for the difference. "First, this is a different series of tumors, and they are from six different institutions, while in the original study they only had samples from their own tumor bank and their own institution," he said. "But another, more logical, explanation is the fact that their methodology in the original study was not completely correct." Van't Veer's group used some of the same samples in both the discovery and validation phases. Researchers and statisticians have subsequently agreed that this practice can result in overfitting the data. That means that the signature will drop in performance when tested on an independent, unrelated set of samples.

Van't Veer does not dispute this interpretation but rather points out that this was the reason TRANSBIG researchers, including Van't Veer herself, wanted a validation phase built into the MINDACT trial.

Fatima Cardoso, M.D., of the Jules Bordet Institute in Brussels, Belgium, and scientific director of TRANSBIG, likens the drop in the hazard ratio to the drop in response rate that is frequently seen when researchers take a therapy from a phase II study to a randomized phase III trial. "There is less bias and less selection of patients [in phase III trials]," she said.

Cardoso said that the current hazard ratio, although acceptable enough to allow the trial to go forward, was part of the reason for the trial design changes. "We need to try to do the best trial we can at this time," though she also said that the challenge is complicated by the fact this is still an evolving science. "The statisticians love working with us because it's a constant challenge."


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