Examining ESR1 in cancer treatment resistance

LONDON—Given tumors' ability to mutate to evade the immune system and protect themselves from attack, treatment resistance is leading problem in all cancer types. While tumors might initially shrink or go into remission, as the cancer cells mutate, previously effective treatments can cease to have any impact. But a team of scientists from the U.K. has developed a highly sensitive blood test capable of detecting when certain types of breast cancer become resistant to standard hormone treatment.

The work was conducted by scientists at The Institute of Cancer Research, London, and The Royal Marsden NHS Foundation Trust, and funded by a number of organizations, including NIHR Biomedical Research Centre at The Royal Marsden and The Institute of Cancer Research (ICR), Breast Cancer Now, The Cridlan Ross Smith Charitable Trust and Cancer Research UK. The results were published in Science Translational Medicine in a paper titled “Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.”

The cancer type in question is estrogen receptor (ER)-positive breast cancer, which is the most common type, and the treatment focused on is aromatase inhibitors, the typical treatment approach for this cancer. According to Breastcancer.org, aromatase inhibitors halt the production of estrogen in postmenopausal women by blocking the enzyme aromatase, which converts androgen into small amounts of estrogen. This in turn means “that less estrogen is available to stimulate the growth of hormone-receptor-positive breast cancer cells.”

When looking at women treated with aromatase inhibitors, the team found that their test could detect mutations of the estrogen receptor gene ESR1, which conveys resistance to hormone treatment, in women undergoing treatment with aromatase inhibitors. They took blood samples from 171 women with ER-positive breast cancer, then validated the results in three independent patient groups. Their results showed that ESR1 mutations could be detected via multiplexed digital PCR analysis, which is capable of reading the genetic code of the minute amounts of DNA released from tumors. In addition, this approach proved capable of detecting DNA errors as sensitively as tumor biopsies, with 97 percent matching between the two methods.

“Looking for cancer DNA in the blood allows us to analyze the genetic changes in cancer cells without the need for invasive biopsies. Our study demonstrates how these so-called liquid biopsies can be used to track the progress of treatment in the most common type of breast cancer,” said study leader Dr. Nicholas Turner, team leader in Molecular Oncology at The Institute of Cancer Research, London, and Consultant Medical Oncologist at The Royal Marsden NHS Foundation Trust. “The test could give doctors an early warning of treatment failure and, as clinical trials of drugs that target ESR1 mutations are developed, help select the most appropriate treatment for women with advanced cancer.”

This research also showed that one ESR1 mutations were detected, the mutated cancer cells multiplied and became the dominant type, leading to increased cancer aggressiveness and progression. In fact, women who presented with ESR1 mutations in their cancers were three times more likely to progress than those without. As noted on My Cancer Genome, nine ESR1 mutations have been identified so far as playing a role in acquired resistance to anti-estrogen therapy. All are located on the ligand binding domain, and vary in frequency from 3 percent up to 36 percent within ER-positive metastatic breast cancer. The full list can be viewed here.

The timing of treatment also had a significant impact on how the cancers developed resistance to this treatment, which is generally used after surgery in postmenopausal women with ER-positive breast cancer. The research team found that ESR1 mutations occurred in only 6 percent of patients treated with aromatase inhibitors before their cancers had begun to spread, but they occurred in 36 percent of patients when the cancer had already spread by the time aromatase inhibitor treatment began.

“We are in a new era of personalized cancer medicine, and liquid biopsies offer the hope that treatment can be monitored and adapted according to the evolution of an individual patient’s cancer. In the space of the last couple of years, there has been astonishingly rapid progress in the development of liquid biopsies to detect specific cancer mutations in the bloodstream. I am excited by the prospects of these new tests and would like to see them assessed in clinical trials as soon as possible, so we can show that their use to adapt treatment can offer real benefits for cancer patients,” Prof. Paul Workman, chief executive of The Institute of Cancer Research, London, commented in a press release.