Researchers have used whole-genome sequencing to catalog the genetic alterations in tumors from 50 patients with estrogen receptor (ER)-positive breast cancer. The goal of the study, which was presented at the AACR annual meeting, was to identify genetic factors that explain why some tumors respond to estrogen-lowering drugs and others do not.
Women with ER-positive breast cancer take estrogen-lowering drugs, such as tamoxifen or aromatase inhibitors, to slow the growth of tumors, make the tumors easier to remove surgically, or prevent the regrowth of tumors after surgery or radiation. But the treatment does not always work, and resistant tumors are associated with a poor prognosis. The genetic factors underlying resistance to estrogen-lowering therapy are not clear.
To investigate this question, Dr. Matthew Ellis of the Washington University School of Medicine in St. Louis and his colleagues studied the tumor genomes and normal genomes of 50 women with ER-positive breast cancer. The women were participants from two clinical trials testing aromatase inhibitors as neoadjuvant therapy. Patients received one of three types of aromatase inhibitors following a biopsy and prior to treatment with surgery. Twenty-six of the 50 patients had tumors that responded to aromatase inhibitors, and 24 had tumors that did not respond.
The analysis, which included approximately 10 trillion chemical bases of DNA, revealed a “constellation of mutations,” including some that are common and some that are rare, noted Dr. Ellis. The vast majority of potential cancer-related mutations detected in the study were found in less than 5 percent of tumors.
“Breast cancer is extraordinarily complicated,” said Dr. Ellis, “and the sequencing revealed a lot of new biology that we had not seen before.” The researchers have begun the process of relating the mutations discovered in the study to the responses to estrogen-lowering therapies.
The commonly mutated genes included PIK3CA and TP53. In addition, MAP3K1, a tumor-suppressor gene, was defective in 10 percent of patients. This gene has been implicated in other cancers, but this is the first time the gene has been associated with breast cancer, according to the researchers.
The finding that half the tumors had mutations in PIK3CA was important because it underscores the opportunities to inhibit the effects of these changes in breast cancer, noted Dr. Matthew Meyerson of the Dana-Farber Cancer Institute, who discussed the results at the meeting.
Dr. Meyerson also said that his group has independently found frequent inactivating mutations in MAP3K1 in breast cancer, thereby “validating the remarkable results by Dr. Ellis.” The current study, he noted, demonstrates the feasibility of conducting genomic analyses of breast cancer using next-generation sequencing in the context of cancer clinical trials.
NCI Cancer Bulletin for April 5, 2011 - National Cancer Institute
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