Most ER-positive breast cancer patients are given hormone therapies that work to reduce tumor size and lessen their risk of dying from their cancer. However, a relapse risk remains constant in these patient for many years, even decades, probably because some tumor cells become resistant to the therapy and stay in the body as dormant tumors.
The mechanisms that lead to acquired resistance and cause a dormant tumor to start growing again are unknown and difficult to examine.
Researchers at the University of Edinburgh studied 62 breast cancer patients who did not undergo surgery – either because they declined or were unfit – and were treated with Femara (letrozole), a common hormone therapy, for at least four months and up to 45 months (almost four years).
They took tumor samples before the women started therapy, and again within the first few weeks and then after four months of treatment, and evaluated the gene expression of each sample to see how the treatment affected tumors over time. (Gene expression refers to the process by which information in a gene is synthesized to create a working product, like a protein.)
Investigators noted specific changes in gene expression that started at the beginning of the treatment and became more clear with time. Particularly, relapsing tumors had more epigenetic modifications — changes in the DNA conformation that alter the expression of specific genes — than did tumors that remained dormant.
“Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples,” the researchers wrote.
“Treatment resistance is hard to study and laboratory experiments often do not closely resemble the situation in patients. This is the first time we have been able to investigate genetic changes in individual patients’ tumors over time,” Andy Sims, the study’s lead author, said in a press release.
“We hope the findings will help to develop new tests that predict which women on hormone therapy are likely to relapse so that they can be offered alternative treatments.”
The findings also suggest that inhibitors of epigenetic modifications might serve as second-line treatment of tumors with acquired resistance to hormone therapy, although more research is needed.
“This is a promising early finding that could help us better understand how some breast cancers become resistant to therapy and what we can do about it. Drug resistance is a major hurdle that we must overcome if we are to finally stop women dying from breast cancer,” said Simon Vincent, director of research at Breast Cancer Now, which helped fund the study.
“Through research like this, we hope to one day be able to identify when therapies are becoming less effective and when a change of treatment might be appropriate.”