Breast tumor `signatures` to help predict treatment response identified
Washington: Decoding the DNA of patients with advanced breast cancer has allowed scientists to identify distinct cancer “signatures” that could help predict which women are most likely to benefit from estrogen-lowering therapy, while sparing others from unnecessary treatment.
Researchers at Washington University School of Medicine in St. Louis uncovered mutations linked to whether or not women respond to aromatase inhibitors, drugs often prescribed to shrink large tumors before surgery.
These mutations also correlate with clinical features of breast tumors, including how likely they are to grow quickly and spread.
The research also involved physicians and scientists at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine and The Genome Institute.
“This is one of the first cancer genomics studies to move beyond cataloging mutations involved in cancer to finding those linked to treatment response and other clinical features,” said senior author Elaine Mardis, PhD, co-director of The Genome Institute.
“If our results are validated in larger studies, we think genomic information will be one more data point for physicians to consider when they select among several treatment options for their patients,” Mardis stated.
The study involved DNA from 77 post-menopausal women with stage 2 or 3 estrogen-receptor-positive breast cancer, the most common form of the disease. Estrogen stimulates the growth of these tumors, and all the women received aromatase inhibitors to lower estrogen in the body.
The drugs can reduce the size of breast tumors, enabling many women to receive breast-conserving surgery rather than a mastectomy. But aromatase inhibitors only work in some women, and doctors don``t know why.
To answer that question, the researchers compared the DNA in the tumor samples to matched DNA from the same patients`` healthy cells, which allowed them to identify mutations that only occurred in the cancer cells. This “unbiased” approach finds all the mutations underlying a patient`s cancer not just those that would be expected to occur.
The tumor samples came from women enrolled in one of two aromatase inhibitor clinical trials sponsored by the American College of Surgeons Oncology Group. As part of those trials, researchers had collected detailed information about the women’s tumors and whether they responded to a four-month course of aromatase inhibitor therapy before surgery. Twenty-nine of the tumor samples came from women whose tumors were resistant to aromatase inhibitors, and 48 came from patients whose tumors responded.
Over all, the scientists noted that tumors in women who responded to the estrogen-lowering drugs had relatively few mutations, while those whose cancers were resistant to the treatment had higher mutation rates and were genomically more complex.
“This makes sense in hindsight but it’s not something that we would have predicted,” Mardis said.
The researchers identified 18 significantly mutated genes in the tumor samples, meaning the genes were altered more often than would have been expected. Some of these genes were already known to be important in breast cancer but others were completely unexpected, including a handful that are well-recognized for their role in leukemia.
To evaluate the clinical significance of the 18 genes, the researchers expanded the study to include an additional 240 women with estrogen-receptor-positive breast cancer whose response to aromatase inhibitor therapy also had been documented.
They found several genes that were relatively common in many of the patients’ cancers that also appeared to be linked to treatment response. About 20 percent of women’s tumors had mutations in a potent tumor-suppressor gene called TP53.
These mutations were linked to a poor response to aromatase inhibitors and to fast-growing tumors that were more likely to metastasize. Women with TP53 mutations also were more likely to have a subtype of breast cancer called luminal B, which has a poor prognosis.
“Rather than give aromatase inhibitors to women with TP53 mutations knowing they are unlikely to be effective, these women may benefit from immediate surgery followed by chemotherapy,” said lead author Matthew Ellis, MD, PhD, the Anheuser Busch Professor of Medical Oncology, who treats patients at the Siteman Cancer Center and Barnes-Jewish Hospital.
In contrast, mutations in MAP3K1 and its “sister” gene MAP2K4 occurred in about 16 percent of patients and were linked to a good response to aromatase inhibitors. Women with mutations in these genes were more likely to have slow-growing tumors that did not spread, and they typically had luminal A breast cancer, which has a good prognosis.
Mutations in another gene, GATA3, also appeared to predict a good response to aromatase inhibitor therapy, while those in MALAT1, a long stretch of non-coding RNA, seemed to be associated with poor outcomes.
Mutations in most other significant genes occurred in frequencies too low to draw firm conclusions, but Ellis says it`s premature to dismiss their importance.
“Breast cancer is so common that mutations that recur infrequently may still involve thousands of women. Only through further genomic studies will we be able to determine whether they also have a role in treatment response,” Ellis stated.
The research has been published June 10 in the advance online edition of Nature.