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'On-Treatment' Breast Cancer Signature Could Help Predict Treatment Response

NEW YORK (GenomeWeb News) – Testing the expression of a specific set of genes early in breast cancer therapy can predict which seemingly low-risk tumors are destined to become high risk — and help guide treatment accordingly, new research suggests.
 
During a phase II clinical trial, a team of researchers was able to classify estrogen-receptor positive tumors into low-, medium-, and high-risk groups depending on the genetic signature in the tumors a month after patients started treatment. Washington University School of Medicine oncologist Matthew Ellis is expected to present the findings at the American Society of Clinical Oncology annual meeting in Chicago on June 2.
 
In general, physicians classify breast cancer tumors as either estrogen-receptor positive or estrogen-receptor negative, depending on whether they grow in response to the hormone estrogen. Typically, estrogen-receptor positive tumors, which are more common in older women, can be treated with drugs that inhibit estrogen production.
 
Even so, not all tumors that start out estrogen-receptor positive remain so. Some estrogen-receptor positive tumors respond to anti-estrogen therapy at first, but eventually become estrogen-receptor negative — and resistant to these drugs. This transition is associated with patient relapse and poor overall outcomes.   
 
“We identified a group of about ten to 15 percent of estrogen-receptor positive tumors that behave in a completely hormone refractory way,” Ellis told GenomeWeb Daily News. “That’s why we call it the wolf in sheep’s clothing.”
 
During a phase II clinical trial involving 56 postmenopausal women with stage 2 or 3 estrogen receptor positive tumors, Ellis and his team identified these high-risk tumors using a slightly unconventional approach: rather than just looking for the specific gene signature in tumors before treatment, they also tested gene expression after treatment with Femara (letrozole), a Novartis drug that blocks estrogen production.
 
The idea was that tumors destined to become aggressive and drug resistant would have telltale genetic signs after treatment that would differ from those of sensitive tumors. “This is not an intellectual leap of much faith, because it’s exactly what you’d expect,” Ellis said.
 
Researchers at Washington University in St. Louis, Duke University, the University of North Carolina at Chapel Hill, the Cleveland Clinic, the University of Chicago, and the Dana-Farber Cancer Institute in Boston participated in the study.
 
They measured the expression of 50 genes at baseline and again after one month and four months of letrozole therapy. Based on post-letrozole gene expression after a month for the “on-treatment” genetic signature, the team ranked each individual’s tumor as low-, medium-, or high-risk. Then they assessed how these classifications predicted treatment response and relapse.
 
After a follow up of between one and five years, about 81 percent of patients in the low-risk group had a complete or partial response to letrozole treatment. That dropped to 70 percent in the medium-risk group, while only a quarter of the high-risk patients responded to therapy. Some 15 percent of those tested started with estrogen-receptor positive tumors that became estrogen-receptor negative.
 
This new knowledge may eventually change the way that physicians design estrogen-receptor positive breast cancer therapies, Ellis said. For instance, it may be possible to target aggressive, post-surgery chemotherapy to those with higher-risk tumors.
 
Researchers are currently entering into discussions about larger, prospective trials of the on-treatment genetic signature, he added, but that trial has not been scheduled yet.
 
The University of Utah’s Associated Regional and University Pathologists Inc. national reference laboratory also plans to offer a homebrew qPCR clinical test based on this study later this year. There is no indication at this time how much the test will cost, Ellis said.
 
Meanwhile, University Genomics, a company owned by Washington University and the Universities of Utah and North Carolina, holds a provisional patent for the gene-expression profile test.
 
Although the on-treatment genetic signature was only tested for letrozole, Ellis said, he’s confident that it can help predict treatment response and relapse for estrogen-receptor positive patients taking other anti-estrogen drugs as well.

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