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Estrogen-Positive Breast Tumors Show Mutational Shifts Following Hormone Therapy

NEW YORK (GenomeWeb) – A study appearing online this week in Nature Communications is highlighting the clonal complexity involved as estrogen receptor-positive breast cancers evolve after hormone reduction therapy.

A team led by investigators at Washington University School of Medicine's McDonnell Genome Institute and the Baylor College of Medicine did whole-genome sequencing on primary tumor samples taken before and after neoadjuvant aromatase inhibitor hormone therapy in 22 post-menopausal women with stage II or III breast cancer. The group also sequenced the genomes of matched normal samples, along with RNA sequencing on tumor samples.

From these data, the researchers identified significant heterogeneity in the mutational patterns and clonal populations present before and after treatment and in different parts of a given tumor. Together with treatment response clues, the findings highlight the genetic diversity found in estrogen receptor-positive breast cancers as well as the range of mutations that can spring up after hormone therapy.

"[U]nder the environmental stress of the treatment, the tumors are spawning new sub-clones that subsequently can survive and grow despite therapy, and that is why we are having difficulty in the end treating ER-positive breast cancer. We found this result in the majority of tumors we studied," co-corresponding author Matthew Ellis, a researcher affiliated with the Baylor College of Medicine's Lester and Sue Smith Breast Center and Washington University, said in a statement.

The researchers focused on 22 postmenopausal individuals with ER-positive luminal A or luminal B breast cancers, including a dozen individuals with aromatase inhibitor sensitive tumors and 10 representatives of aromatase inhibitor resistance.

Tumors from the individuals had been sequenced for a prior study, though the team did additional genome sequencing of surgical resection samples to get a look at genetic patterns present in tumors before and after about four months of neoadjuvant aromatase inhibitor treatment.

The researchers also did RNA sequencing on 20 baseline tumors and 18 tumor samples taken at the time of surgery, along with targeted gene panel sequencing on tumors from a few dozen more cases.

While mutation patterns remained relatively stable before and after treatment in two of the original 22 breast cancer patients, samples from the remaining 20 cases were much more complicated.

In two cases, the team uncovered so-called 'collision tumors' — genetically distinct, intersecting tumors in the same individual that stem from different founder clones.

A breast tumor classified as ER-positive prior to neoadjuvant aromatase inhibitor treatment contained both ER-positive and –negative segments after treatment, according to RNA sequence and tumor immunohistochemistry data.

Another 18 cases involved tumors with markedly different tumor mutation patterns and complicated clonal shifts before and after treatment. In one patient, for example, the sub-clone that accounted for most of the cells detected at baseline was nearly replaced in the post-treatment tumor by a sub-clone that started out in just 2 percent of cells.

Such complexity was recapitulated in the team's targeted sequencing or existing whole-genome sequence data for 57 more breast cancer cases. In post-treatment tumor sequences, the group also saw a jump in proposed resistance mutations, including alterations in the ESR1 gene.

"This study demonstrates that reducing estrogen levels in estrogen-receptor-positive breast cancer changes the genetics of the tumor, and these changes may be important for deciding how best to treat a patient after the surgical removal of the tumor," co-corresponding author Elaine Mardis said in a statement.

In particular, she noted that "patients who undergo aromatase inhibitor therapy for several months prior to surgery should be re-evaluated immediately before their operation to determine how the tumor may have changed in response to the therapy."

"Such information can help indicate whether further estrogen suppression treatment is likely to contribute to a lower risk of relapse," said Mardis, who was co-director of the McDonnell Genome Institute when the study was done. She was recently recruited to the Nationwide Children's Hospital in Columbus, Ohio to help set up a clinical sequencing pipeline at that center.

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