Aromatase inhibitors in human estrogen-receptor positive breast cancer can cause tumor mutations.
Human estrogen-receptor positive (ER-positive) breast cancer tumors treated with aromatase inhibitors cause the spectrum of mutations in the tumor population to change, a recent study revealed.
Aromatase inhibitors are an estrogen-deprivation therapy that lowers the levels of estrogen required for the tumor to grow. In prior studies, researchers extensively studied the genetic heterogeneity in breast cancer in untreated samples; however, how these aromatase inhibitors affect genetic diversity remained unclear.
To answer this question, researchers examined 22 human breast cancer tumors that were scheduled for surgery in a study published in Nature Communications.
“The majority of ER-positive breast cancers are not a single tumor but more like a family of related tumors referred to as ‘sub-clones,’” said senior study author Matthew Ellis. “The tumors are like a large family. A family has the same genetic origin — the same parents – but each family member has distinct genetic characteristics. The brothers and sisters are clearly individuals but they are also related.
“When we treat the tumor with aromatase inhibitors, and estrogen-deprivation therapy that lowers the levels of estrogen the tumor needs to grow, we are creating a situation where certain members in the tumor family are able to persist and grow while others perish. The surviving members of the tumor family are likely the ones that will cause future problems with recurrence.”
For the study, researchers treated the tumors with estrogen-deprivation therapy for 4 months in order to reduce the size of the tumor prior to surgery. Once the tumors were surgically removed, researchers examined the entire genomic structure of each of the tumors on biopsies taken before and after therapy, to analyze in-depth, the effect of estrogen-deprivation therapy on the gene mutation patterns of the tumors.
“In the post-treatment samples, we found many new mutations or enrichment of mutations present at low levels in the pre-treatment samples,” Ellis said. “This means that under the environmental stress of the treatment, the tumors are spawning new sub-clones which subsequently can survive and grow despite therapy, and that is why we are having difficulty treating ER-positive breast cancer. We found this result for a majority of ER-positive breast cancers we studied.”
Although a majority of breast cancer tumors were comprised of a number of sub-clones with a common origin, meaning they were all members of the same tumor family, researchers also found that some of the participants had more than 1 tumor of different origin.
“Even though each patient in this study was diagnosed only with a single tumor, looking at the cancer genome allowed us to see that in some cases the patient actually had 2 separate tumors growing closely together,” said first study author Christopher Miller. “We call these ‘collision tumors.’”
Collision tumors are completely separate tumors that grow in close proximity to each other. Those that go undiagnosed may explain why tumors with an initially good prognosis can have an unexpected relapse after surgical treatment, according to the study.
“(The 2 separate tumors were like) 2 unrelated families growing so close together they were originally incorrectly identified as a single family,” Ellis said.
After 4 months of therapy that caused the ER-positive tumors to shrink, researchers were able to identify a second ER-negative tumor. In fact, in 1 out of 22 tumors, they discovered ER-negative tumor cells that were hiding inside a mostly ER-positive tumor.
“Without this approach, that ER-negative tumor would have never been diagnosed early and treated,” Ellis said. “If a patient with breast cancer has the tumor surgically removed, it won’t be possible to detect the cells with the genetic makeup most likely to be driving relapse. But, if, on the other hand, we start by treating the tumor with aromatase inhibitors before surgery for a few months, so we can track the behavior of that tumor, we would get a more complete picture of the cancer. We can potentially detect sub-clones that can cause relapse in the future.”
Authors noted that the findings may help to improve cancer treatment in the future.
“Our results suggest that studying the genetic makeup of a tumor at diagnosis is not enough — periodically scanning the genome in several biopsy samples to understand how it is changing may help us evolve treatment strategies to match,” Miller said.