A unique genetic signature can alert physicians to high-risk breast tumors that are masquerading as low-risk tumors, according to research at Washington University School of Medicine in St. Louis and collaborating institutions. Although these tumors are apparently estrogen-receptor positive - meaning they should depend on estrogen to grow - they don't respond well to anti-estrogen therapy.
Until now, doctors had no way to know these tumors would be unresponsive because their pathology is deceptive - the tumors appear to be more easily treatable estrogen-receptor-positive tumors, but they rapidly lose their estrogen receptors. The researchers demonstrated that the chance for cancer recurrence in such patients is significantly higher, and standard post-operative care with long-term anti-estrogen therapy is often not effective. The genetic signature defined by the researchers will permit doctors to identify their high-risk patients and direct them to more effective therapy.
"These tumors are like wolves in sheep's clothing," says Matthew Ellis, M.D., Ph.D., associate professor of medicine in the Division of Medical Oncology and a faculty member at the Siteman Cancer Center. "When these patients come in, their tumors test positive for estrogen receptors, so they are started on anti-estrogen treatment with the thought that they will do fine. But these tumors don't depend on estrogen at all for growth and will keep growing during the therapy. Now we have a robust way to identify such tumors soon after diagnosis."
The researchers findings will be presented June 2 at 10:45 a.m. CT at the 2008 American Society of Clinical Oncology Annual Meeting in Chicago.
"We've been interested in how to predict relapse in patients with estrogen-receptor-positive breast cancer," Ellis says. "So we looked for genetic expression profiles associated with relapse, but we took a very different approach from previous studies that addressed this question."
Instead of just profiling gene expression in patients' tumors at diagnosis, Ellis and colleagues at a number of other comprehensive cancer centers, also tested tumor gene expression one month after the start of treatment with letrozole, an aromatase inhibitor that blocks the body's estrogen production. All the study participants had been diagnosed with estrogen-receptor-positive tumors and were put on letrozole therapy to shrink tumors before surgery.
"It makes intuitive sense that the genetic features of the tumor in the presence of letrozole reflect the tumor's response to the drug and would be much more predictive of outcome than its features in the absence of the drug," explains Ellis, a Washington University oncologist at Barnes-Jewish Hospital.
The team first identified the 50-gene signature using pretreatment tumor samples. They compared gene expression in tumors of patients with estrogen-receptor-positive tumors who had good outcomes to those whose outcomes were poor.
Then they initiated a five-year clinical trial to assess the predictive ability of the gene expression profile when it was obtained after one month of letrozole therapy. In a study of 56 postmenopausal women with estrogen-receptor-positive stage 2 or 3 breast tumors, Ellis's group demonstrated that the post-letrozole genetic expression signature in the 50-gene set was much more predictive than the pretreatment genetic profile. Based on the post-letrozole profile, they found they could rank tumors as low-, medium- and high-risk.