When Cancer Evolves

Cancer is an intelligent disease. Tumor cells often find ways to outsmart therapies that once kept disease from progressing. Some genes develop changes, or mutations, that allow cancer to grow unchecked.

Such is the case with the ESR1 mutation, a genetic change that occurs in approximately 20% to 40% of people who have hormone receptor (HR)-positive breast cancer and are treated with certain hormone (endocrine) therapies.

“The majority of breast cancers — about two- thirds — have this protein called estrogen receptor,” says Suzanne Fuqua, a professor at the Lester and Sue Smith Breast Center at Baylor College of Medicine in Houston. “That receptor becomes the driver for the majority of breast cancers in women. If your tumor has the estrogen receptor present, it fuels the cells to grow and proliferate.”

Oncologists use a variety of endocrine therapies to treat patients with HR-positive cancers before and after surgery. When making treatment decisions, they evaluate a patient’s breast cancer type, whether they are pre- or postmenopausal and which treatments they have already received. They may treat Or patients may be treated with drugs that reduce the amount of estrogen in their body, known as aromatase inhibitors (AI), that are only effective in patients who are postmenopausal because the source of estrogen in this case is from the conversion of androgens to estrogens mediated by the enzyme aromatase. AIs include Femara (letrozole), Arimidex (anastrozole) and Aromasin (exemestane).

Fuqua says that during the past two decades, emerging science has led to increased use of AIs, adding that these agents seem to delay cancer recurrence “a little bit better” than SERMs.

“Everyone around the world pretty much switched their patients to aromatase inhibitors,” she says.

However, as the use of AIs in treating patients with breast cancer increased, clinicians noted a key change in those whose cancer had spread, or metastasized. When endocrine therapies denied estrogen receptor (ER)-positive cancers the hormone they needed to grow, certain genes mutations were favored selectively through the process of tumor evolution.

“The ESR1 gene is the gene that encodes for the estrogen receptor, a key driver of tumor initiation and tumor progression in hormone receptor-positive breast cancers,” says Dr. Rinath Jeselsohn, an assistant professor of medicine at Dana-Farber Cancer Institute in Boston. Estrogen receptors without a mutation need both estrogen and proteins known as coactivators to become activated, she says.

But when the ESR1 gene has a mutation, the estrogen receptor in the cancer cell changes and allows coactivators to bind to it without estrogen. In short, the estrogen receptor no longer needs estrogen to become active and help cancer grow. “This means that drugs such as aromatase inhibitors that block the production of estrogen will not be effective in the presence of an ESR1 mutation,” Jeselsohn says.

ESR1 mutations allow cancer to spread in patients being treated with certain endocrine therapies, according to Jeselsohn. “In patients who have primary hormone receptor-positive breast cancer, these mutations are very rare,” she says. “They really evolve when patients are treated with aromatase inhibitors.

In particular, they evolve during treatment with aromatase inhibitors in metastatic disease.”

For patients with metastatic breast cancer, ESR1 gene mutations require a therapeutic change to stop cancer from worsening.

Dr. Kelly Shanahan, 63, of South Lake Tahoe, California, is one of those people.

An Evolving Cell

In April 2008, Shanahan was 47 and had her own busy obstetrics/ gynecology practice. After a routine mammogram revealed early-stage, HR-positive, HER2-negative breast cancer, she considered her options. As a busy doctor and mom to a then-9-year-old daughter, “I didn’t have time to drive 45 minutes each way, five days a week, for five to seven weeks for radiation therapy,” she says. Instead, Shanahan opted for a bilateral mastectomy.

When a biopsy confirmed cancer in one of her lymph nodes, she began a 16-week course of chemotherapy followed by an AI. But when the drug caused arthritis symptoms that made performing surgery difficult for her, she stopped taking it.

Later, excruciating back pain sent Shanahan for a PET scan and MRI. The results shocked her.

“I had cancer in every bone in my body,” she says.

She spent the next 14 months on a regimen of intravenous chemotherapy. When her treatment ended, Shanahan — by then retired from her medical practice — began taking Aromasin, an oral AI.

For six years, she had no evidence of active disease. But in April 2021, her disease progressed. A blood test known as liquid biopsy confirmed a mutation in the ESR1 gene and a mutation in the PIK3CA gene. Aromasin was no longer working.

“Most people get two years on an AI alone,” Shanahan says. “I got six years out of it.”

ESR1 mutations are not unexpected in people with metastatic breast cancer who have been treated with AIs. The mutation was first identified by Fuqua in the 1990s when she examined laboratory samples of metastatic breast tumors. She hypothesized that mutations in the estrogen receptor were allowing cancer cells to bypass the therapies used at the time and driving the metastatic behavior of cells.

Her research was controversial, she says. She notes that she was using metastatic tumors, whereas other breast cancer research focused on primary tumors.

“Now the field has changed to where we know that the metastatic tumor is different from the primary tumor,” Fuqua says.

Larger studies done in 2013 and 2014 used next-generation sequencing to study metastatic samples, including research led by Jeselsohn, helped researchers “really start to understand the significance of ER mutations,” Jeselsohn says. “Since then, we’ve been learning more about them in the lab. In the clinic, we’re understanding more about the resistance they cause.”

Today, biopsies of metastatic tumors, liquid biopsies and tumor sequencing allow oncologists to target drug treatments to specific mutations such as ESR1. Previously, clinicians would typically treat people with a cancer recurrence in the same way their primary cancer had been treated.

With a liquid biopsy, Fuqua says, doctors can determine whether mutations are developing during treatment. “What we’ve found is that patients with ESR1 mutations quickly have another recurrence when they’re on an aromatase inhibitor alone,” she says.

Treating Patients With ESR1 Mutations

There are other treatment options for people who develop resistance to AIs. Many get a monthly injection of Faslodex (fulvestrant). This selective estrogen receptor degrader (SERD) binds to the cell’s estrogen receptor and breaks it down, disrupting the cell’s signaling pathway. Shanahan was taking Faslodex and Ibrance (palbociclib), a CDK 4/6 inhibitor and a type of targeted therapy that blocks the CDK4 and CDK6 enzymes that fuel cell division, until September, due to progression of her disease. She is currently enrolled in an endocrine therapy clinical trial.

“When a patient develops an ESR1 mutation on an aromatase inhibitor in the second-line and beyond setting, we tend to use (Faslodex)-based therapy,” says Dr. Aditya Bardia, director of the breast cancer research program at Massachusetts General Hospital Cancer Center in Boston. “Some physicians would use (Faslodex) alone. Some would use (Faslodex) plus a CDK 4/6 inhibitor, and some would use (Faslodex) plus Piqray (alpelisib), a PI3 kinase inhibitor, if a patient has PIK3CA-mutant breast cancer.”

Postmenopausal women and adult men with ER-positive, HER2-negative, ESR1-mutated metastatic breast cancer whose cancer has progressed after at least one line of endocrine therapy also now have access to a new FDA-approved oral estrogen receptor degrader.

In January 2023, the FDA approved Orserdu (elacestrant) for these patients.

“(Orserdu) has shown activity that’s superior to standard endocrine therapy, including (Faslodex) in a randomized phase 3 clinical trial,” Bardia says, referring to the EMERALD trial, in which participants taking the drug showed improved progression-free survival, which is the amount of time a patient lives without their disease progressing. He expects its approval to mark a practice change, as it may be used over agents such as Faslodex. Shanahan says she has looked forward to another treatment option for people with ESR1 mutations. “A lot of my friends are on (Faslodex),” she says. “Some of them have a lot of problems with the injections. They have pain and develop lumps on their (buttocks from the injection). I have zero problems with (Faslodex).” She says hydrating before her injection, exercising the day she’s getting the shot and turning on the seat heaters in her car helped to keep her comfortable.

Bardia notes there’s significant interest in other emerging therapies to treat patients with ESR1 mutations. He mentioned the new SERDs giredestrant and camizestrant as well as the PROTAC ARV471— all of which are being studied in clinical trials — as novel endocrine agents to watch.

Judy Morgan, 66, of Lafayette, Louisiana, has had breast cancer since 1993. Her initial treatment, which she calls “aggressive,” included chemotherapy, radiation and an autologous bone marrow transplant. Seven years later, cancer spread to her sternum. Surgeons removed the tumor, and she began taking Arimidex.

In 2017, Morgan needed a hip replacement. The news wasn’t good: Cancer had spread to her hip, and a subsequent liquid biopsy revealed an ESR1 mutation. She began a regimen of the CKD 4/6 inhibitor Ibrance and monthly Faslodex injections. But by 2021, the cancer had again progressed.

Morgan’s oncologist at The University of Texas MD Anderson Cancer Center in Houston recommended she enroll in the ELAINE 2 study, a clinical trial to evaluate the selective estrogen receptor modulator lasofoxifene in combination with the CDK 4/6 inhibitor Verzenio (abemaciclib).

The trial was open to postmenopausal and premenopausal women on ovarian suppression with locally advanced or metastatic HR-positive, HER2-negative breast cancer with an ESR1 mutation.

Morgan says she’s done well on the combined therapy, with the most notable side effect being diarrhea. “To me, the gain is worth more than any side effects that you may have to deal with,” she says. “I felt better, like there was an improvement in my overall health.”

Educate Yourself

Bardia encourages people with ESR1 mutations to ask their doctor if a clinical trial is right for them.

“Any time there is disease progression, we recommend having a discussion with the physician about the standard options and clinical trial options available,” he says. “The advantage of a clinical trial is that it offers access to something that’s otherwise not available. In the metastatic setting, we often use therapy sequentially. The advantage of a trial is it increases the number of potential options.”

He also recommends that patients ask their doctors about getting a liquid biopsy. “It’s less invasive, and you can check it serially over time,” he says.

Fuqua encourages patients to have their tumors sequenced. “The challenge is making patients aware of the potential for targeted therapy,” she says. “We call it precision therapy. That’s the sexy word people like to use, but it’s finding the mutation in the patient’s sample and looking for what drugs we can use. That knowledge is your strength. Knowledge gives you your way forward with targeted therapy.”

Morgan encourages others with metastatic breast cancer and an ESR1 mutation to avoid being passive. “Don’t be afraid to try new things,” she says. “When you’re battling something like breast cancer, you want the latest and greatest.”

For Shanahan, self-advocacy means asking questions and being clear about what you want.

She told her doctor she didn’t want to take a medication targeting the PIK3CA mutation. When her doctor wanted to use Verzenio, the CDK 4/6 inhibitor known to cause diarrhea, before Shanahan’s road trip with her daughter, she declined.

“Our doctors and care teams should educate us and point us in the right direction, but so much of the time, we have to do it ourselves,” Shanahan says, noting that she now advocates for others with metastatic breast cancer. “I think it’s incumbent upon us to educate ourselves because not everybody is going to have a care team that prioritizes that,” she says.

Her advice is not to be afraid to ask questions or to get a second opinion.

“As a doctor, when a patient told me she wanted to get a second opinion, I’d feel really smart if she came back and that person had agreed with my recommendation. And if they didn’t agree, then I learned something. A good doctor will welcome you getting a second opinion. We (patients) have to put ourselves first,” Shanahan says.

Editor's Note: Judy Morgan died shortly after this feature was posted online on Dec. 20, 2023. Our thoughts go out to her family and friends.

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.