Overcoming Resistance

Editor’s Note: While this issue of Cancer Today was being completed, we learned that Emily Hunt had died of her illness. We last corresponded with Hunt in January 2025, when she acknowledged that she had few remaining treatment options. The story below appears as it was originally written prior to Hunt’s death, with some minor alterations.

WHEN EMILY HUNT of Phoenixville, Pennsylvania, first learned she had breast cancer in June 2013, her daughter, now 12, was an infant less than a year old. Hunt first felt the lump in her right breast while pumping breast milk and assumed it was a clogged milk duct. The lump was still there at her next gynecological appointment, so the doctor ordered a mammogram. The imaging test led to a biopsy that revealed estrogen receptor-positive, HER2-negative breast cancer. About 70% of breast cancers have this profile, making it the most common subtype by far.

Hunt had a sample of her tumor tested and learned that her cancer had a high risk for recurrence, so she opted for a double mastectomy and chemotherapy to treat the early-stage cancer as aggressively as possible. She also started on tamoxifen to block the effects of estrogen in hopes of preventing any lingering estrogen receptor-studded breast cancer cells from growing and spreading. Despite these efforts to reduce her recurrence risk, a screening CT scan in 2015 revealed enlarged lymph nodes in her right armpit, which a biopsy showed were positive for breast cancer. After radiation and chemotherapy in 2016, she had no evidence of disease. But in March 2018, she learned the cancer was in lymph nodes in her chest cavity near her lungs, which meant she had incurable stage IV disease.

When breast cancer is diagnosed at an early stage, it is highly treatable. In fact, five-year relative survival for locally advanced or early-stage breast cancer ranges from 90% to close to 100%. However, an estimated 20% to 40% of people diagnosed with early-stage estrogen receptor-positive breast cancer will develop metastatic disease. Those with metastatic breast cancer are living longer thanks to new treatments. Although the Surveillance, Epidemiology, and End Results Program, which is used to track U.S. cancer incidence and mortality statistics, does not capture metastatic recurrence after an early-stage diagnosis, research suggests that the five-year relative survival rate for people who are diagnosed with this metastatic hormone receptor-positive breast cancer is about 35%.

“The treatment goals for early-stage breast cancer were just to blast it,” Hunt said during an interview in December 2024. “Kill it and don’t worry about it coming back. Once you get into metastatic disease, it’s about controlling the disease—making sure it doesn’t spread—not just killing it.” Eradicating metastatic breast cancer completely is not an option. But several new therapies, including hormone treatments and drugs that target specific molecular features that drive cancer growth, have made it possible to keep the disease in check for longer periods of time.

Targeted Treatment Combinations

Tammy Uhl of Green Bay, Wisconsin, had a similarly harrowing journey with breast cancer that returned. In 2014, the then 42-year-old learned she had stage IIB hormone receptor-positive, HER2-negative breast cancer. Her treatment consisted of surgery, radiation and chemotherapy, followed by hormone therapy to reduce her chance of recurrence. But in September 2020, an MRI showed signs that breast cancer had spread to her bones.

The standard of care for those newly diagnosed with hormone receptor-positive metastatic breast cancer is usually an aromatase inhibitor, which is a hormone therapy that blocks an enzyme to lower estrogen levels. In addition, most people with metastatic breast cancer will receive one of three approved CDK4/6 inhibitors, according to medical oncologist Erika Hamilton, who specializes in breast cancer at Sarah Cannon Research Institute in Nashville, Tennessee. CDK stands for cyclin-dependent kinase, a family of proteins including CDK4 and CDK6 that are vital in cell growth and division. Drugs targeting these proteins are intended to make it harder for breast cancer cells to multiply.

In February 2015, the Food and Drug Administration (FDA) approved Ibrance (palbociclib) as the first CDK4/6 inhibitor for postmenopausal women with metastatic breast cancer after a clinical trial showed that it could keep cancer from progressing longer than an aromatase inhibitor alone. In the study, the progression-free survival for the people taking the combination was 20.2 months, compared with 10.2 months for people taking the aromatase inhibitor letrozole alone. Oncologists now have two additional choices of CDK4/6 inhibitors, Kisqali (ribociclib) and Verzenio (abemaciclib), both of which have been shown to extend median overall survival a year or more in patients with metastatic breast cancer. For example, one study found that people who took Kisqali and letrozole had a median overall survival of 63.9 months, compared with 51.4 for those who took letrozole and a placebo.

“CDK4/6 inhibitors show improved overall survival in the first line,” Hamilton says, and those findings established these drugs as the standard of care for people diagnosed with metastatic breast cancer. “Women who get them live longer than women who don’t.”

CDK4/6 inhibitors are taken orally and generally have more tolerable side effects than chemotherapy. Many women who take a CDK4/6 inhibitor with endocrine therapy live for two years on average before their cancer becomes resistant and progresses, Hamilton says. “That’s a pretty big deal in metastatic breast cancer,” she notes. “Some don’t do as well, but others may be on it more than five years in the first-line [setting], which is really encouraging. This is becoming a disease where people live for quite some time.”

“Everybody gets to chemotherapy eventually—it’s not as though that is off the table—but you’re delaying the time until many patients have to receive chemo,” says William Gradishar, a medical oncologist at the Robert H. Lurie Comprehensive Cancer Center in Chicago. “The quality of life on these drugs is better by and large, and what you end up doing when you add a CDK4/6 inhibitor to antihormone therapy is you’re prolonging, in some cases by a year or two, the duration of therapy before you have to switch to something else. The disease stays stable for a prolonged time.”

More Targeted Options

While metastatic breast cancer that develops resistance to first-line treatments remains difficult to treat, oncologists now have more options, including targeted therapies based on the molecular features of the cancer. Treatment decisions at this point are often individualized for each patient, Gradishar says. Oncologists typically order a biomarker test, using tumor tissue or blood samples, when metastatic breast cancer progresses. Testing can reveal alterations in genes within cancer cells, Hamilton says. For example, patients whose metastatic breast cancer carries a PIK3CA mutation, which is found in approximately 40% of women with hormone receptor-positive breast cancer, may benefit from the targeted therapy Piqray (alpelisib) combined with hormone therapy after earlier treatment has stopped working. Piqray works by blocking the PI3K pathway, which helps cancer cells get energy needed to survive and grow.

Over time, hormone therapy in metastatic breast cancer can lead to changes in the cancer cells, including an increase in cancer cells with mutations in a gene called ESR1, which encodes an estrogen receptor. In fact, about 50% of women whose hormone receptor-positive metastatic breast cancer becomes endocrine resistant—which means it is not responsive to hormone therapy—have a mutation in this gene. For people who have progressed on prior endocrine therapy and have cancer with this mutation, Orserdu (elacestrant) can help to bind and degrade estrogen receptors on cancer cells. Afinitor (everolimus), which targets a protein known as mTOR, is yet another option when hormone therapy stops working. Afinitor doesn’t require that a cancer carry any particular “actionable” mutation. Women whose cancers have alterations in one of a few genes related to endocrine resistance, including PIK3CA, AKT1 or PTEN, may be treated with the targeted drug Truqap (capivasertib) plus the endocrine therapy fulvestrant. There is also some emerging evidence that switching from one CDK4/6 inhibitor to another when the first one stops working can sometimes be effective.

Oncologists must weigh many factors for a given treatment, including treatment side effects and cancer burden. “Mutations [also] help decide what endocrine option or combination is appropriate for a patient,” Hamilton says, but the most important factor is how long the benefit of the previous endocrine therapy lasted. Rapid progression on endocrine therapy suggests that the cancer may be increasingly resistant to this type of treatment, Hamilton explains, making it less likely that another endocrine-targeted option will benefit the patient.

When endocrine therapy and targeted therapies are not able to control the disease, many oncologists recommend the oral drug Xeloda (capecitabine) as a chemotherapy choice. In addition to its convenient pill form, Xeloda doesn’t cause hair loss. Hamilton notes that some patients can benefit from what she calls “chemo substitutes,” which are antibody-drug conjugates (ADCs) that use proteins expressed on the cancer cells to deliver a chemotherapy drug straight to a tumor. The first ADC, Enhertu (trastuzumab deruxtecan), was initially approved for patients whose cancer cells express an abundance of the HER2 protein—since the drug uses the HER2 protein to gain access to the cells. However, Enhertu has been found to be effective in cases with much lower levels of the protein. Since its initial approval, the FDA has expanded the use of Enhertu. In 2022, it was approved for cancer with some HER2 expression, called HER2-low breast cancer. Then, in January 2025, it was approved for cases with minimal levels of HER2 detected, called HER2-ultralow. (Read more about the expanded FDA approval for HER2-ultralow breast cancer.)

In February 2023, the FDA also approved a second ADC called Trodelvy (sacituzumab govitecan), which targets a protein called Trop-2 for HER2-negative metastatic breast cancer in patients who’ve had endocrine-based therapy and at least two other systemic therapies. The approval was based on evidence that the drug could extend progression-free and overall survival slightly compared with chemotherapy.

Holding Hope

Hunt’s first treatment for metastatic breast cancer in 2018 consisted of the CDK4/6 inhibitor Ibrance with endocrine therapy. This approach kept her cancer from progressing for 18 months with a few side effects, including mouth sores and low blood counts, which caused fatigue and made her more susceptible to getting sick. After she started having hip pain, she had scans that showed the cancer had spread to her bones. She recalled 16 months of no disease progression after taking Piqray, the targeted therapy for cancer with PIK3CA mutations, along with hormone therapy.

Over the years and through numerous cancer progressions, Hunt tried many therapies, including radiation, targeted therapies and the oral chemotherapy Xeloda. She also tried Avastin (bevacizumab), which blocks blood vessel growth, with the chemotherapy drug Taxol (paclitaxel) and Orserdu, which is a drug prescribed for patients when other endocrine therapy stops working. When scans showed Orserdu wasn’t working, Hunt started a different chemotherapy in December 2024.

Uhl started treatment for her metastatic breast cancer in 2020. She too started with a CDK4/6 inhibitor and endocrine therapy, which kept her cancer in check for two years. By early 2022, scans showed signs of cancer progression into her hip. When her oncologist suggested weekly IV chemotherapy as the only remaining treatment option, Uhl sought a second opinion and found a breast cancer specialist who recommended a liquid biopsy to look for genetic alterations that might expand her treatment options. When the test didn’t uncover any actionable mutations, Uhl continued on her CDK4/6 inhibitor combination before moving on to the oral chemotherapy Xeloda.

That’s when a special type of PET scan, called 18F-Fluoroestradiol PET (FES PET), revealed her cancer included a mix of hormone receptor-positive and hormone receptor-negative cells. FES PET uses a radioactive tracer that binds to estrogen receptor cells in cancer, allowing doctors to visualize them. Uhl’s previous biopsy results had already revealed her cancer expressed very low levels of HER2, so she opted to try the ADC Enhertu in spring 2024. For the first time since before her stage IV diagnosis, scans in August 2024 showed no evidence of active disease—news that Uhl wasn’t expecting to hear after her cancer had quickly progressed on two previous treatments.

The inevitability of disease progression remains a difficult reality for people with metastatic breast cancer, Gradishar acknowledges, but he remains optimistic that the number of treatment options for advanced-stage breast cancer will continue to grow. “Even if we can’t cure the disease, the promise is we’ll be able to switch from one treatment approach to another and have a series of therapies that may be helpful to extend life and hopefully maintain quality of life,” he says. Even as Hunt explained, via email in January 2025, that her own treatment opportunities were dwindling, she encouraged people with metastatic breast cancer to stay focused on new treatment options.

Uhl plans to stay on Enhertu for as long as it continues working. She advises others facing these complex treatment decisions to find a health care team they trust while learning all they can about the latest research advances so they can ask informed questions.

“You have to first and foremost trust your team because that, to me, is everything,” says Uhl, whose decision to seek out a second opinion led her to additional testing and treatment that is currently keeping her cancer in check. “It’s knowledge, it’s trust, it’s faith about what’s next and to keep the hope that there is something else that’s out there.”

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