About three-quarters of all breast cancers are fueled by the hormone estrogen. Along with the standard treatments (surgery, radiation, and chemotherapy), drugs that block estrogen can cure many women with this disease.
Unfortunately, some women receiving even the best available treatments will eventually see their cancer return (recur) and spread (metastasize). When this happens, it is often only a matter of time before the cancer becomes resistant to additional therapies.
Research from scientists at Memorial Sloan Kettering and elsewhere has identified genetic mutations that promote resistance to hormone-blocking medications. In more than 40% of estrogen receptor-positive metastatic breast cancer cases, women are found to have changes in a protein called PI3K. The discovery has raised hopes among doctors and patients that mutated PI3K could be a potential drug target to prevent a recurrence. But so far, the results of clinical trials testing PI3K inhibitors have been somewhat disappointing.
Now, using a type of blood test called a liquid biopsy, researchers at MSK have identified mutations in two additional genes that promote resistance to estrogen-blocking medications.
The blood test analyzes very small quantities of tumor DNA floating in the bloodstream, called circulating tumor DNA. Women who participated in a clinical trial of a combination of PI3K inhibitors and hormone blockers were given the blood test before, during, and after treatment. The investigators then looked to see whether any genetic changes had become more common over this time span. They found that mutations in two genes, PTEN and ESR1, indeed became more common.
“From previous studies, we knew that ESR1 mutations led to resistance to antiestrogen therapy,” says Sarat Chandarlapaty, a physician-scientist at MSK and a corresponding author on the new paper, which was published in the journal Nature Cancer. “We now know that they can foil the combination of antiestrogens and PI3K inhibitors, too.”
He continues: “Likewise, we found that PTEN loss is another major cause of resistance to this combination.”
The investigators say that liquid biopsy could be used to tailor treatments to those patients most likely to benefit. For example, women who are found to have mutations in PTEN or ESR1 at the time of diagnosis may be better off receiving other drugs, such as AKT inhibitors or selective estrogen receptor degraders (SERDs), rather than PI3K inhibitors and hormone blockers.
“This study testifies to the power of liquid biopsies to monitor tumor evolution during cancer treatment,” says Pedram Razavi, a physician-scientist at MSK and the paper’s other corresponding author. “We were surprised by how quickly these resistance mutations appeared and how much metastatic breast cancer could evolve in such short intervals.”
The findings raise the possibility that doctors could use liquid biopsies to make changes to a person’s treatment in real time, matching the cancer’s evolution step by step.