DAR FINKELSTEIN WOKE in the middle of the night in June 2019 with a sharp pain across her chest and suspected she was having a heart attack. “I woke my husband and said, ‘I think we need to get to the emergency department,’” she recalls.
At the hospital, near Finkelstein’s home in Fort Mill, South Carolina, doctors ruled out a heart condition but ordered a computerized tomography (CT) scan of the chest, which showed three spots on her ribs.
Finkelstein had previously been treated for stage II breast cancer in 2006. Thirteen years later, the health care team in the emergency room explained that the location of the spots on her bones was a site where breast cancer often spreads. They told Finkelstein, who was 65 years old at the time, that they suspected she had stage IV breast cancer, also known as metastatic breast cancer. This diagnosis, quickly confirmed by her oncologist, came as a shock to Finkelstein; a mammogram had shown normal results just a month before.
Whether it appears in the breast or not, breast cancer that has spread to other parts of the body is “typically not something that we think of as curable,” says Virginia Borges, a medical oncologist who specializes in breast cancer at the University of Colorado Anschutz Medical Campus in Aurora. “We expect that patients will be on treatment and dealing with this breast cancer for the rest of their lives.” But as researchers learn more about the characteristics of breast cancer cells, new treatments, including targeted medications, are giving people with metastatic breast cancer more options to keep cancer at bay.
One Cancer, Many Features
Physicians characterize breast cancer by the presence or absence of certain markers on cancer cells. All breast cancers, whether diagnosed at an early or advanced stage, are assigned to subtypes based on their distinctive features. A tumor’s hormone receptor status, which indicates the presence or absence of receptors for certain hormones, such as estrogen and progesterone, can help physicians choose a treatment course. Hormone receptor-positive breast cancer is the most common form of breast cancer, accounting for 60% to 75% of cases. In addition to chemotherapy, radiation and surgery, treatments for hormone receptor-positive breast cancer often incorporate hormonal therapy that reduces the amount of estrogen in the body or blocks its effects, which can stop cancer’s growth.
Abigail M. Johnston was diagnosed with metastatic breast cancer in 2017. She shares her strategies for making treatment decisions.
It’s been more than 25 years since the FDA approval of Herceptin (trastuzumab). A post in the AACR blog Cancer Research Catalyst traces Herceptin’s continuing impact on people whose cancer expresses the HER2 protein.
Some breast cancers contain increased amounts of the HER2 protein, which prompts cancer cells to rapidly divide. HER2-positive breast cancer, which accounts for about 20% of cases, tends to spread quickly. However, HER2-positive breast cancer can respond to targeted therapies, including the monoclonal antibody Herceptin (trastuzumab), which was approved by the Food and Drug Administration (FDA) in 1998 to treat patients with HER2-positive metastatic breast cancer but is now also approved for people with early-stage HER2-positive breast cancer.
If breast cancer lacks hormone receptors and an abundance of HER2 protein, it is typically known as triple-negative breast cancer. This subtype makes up about 10% to 15% of breast cancer cases. “It’s one of the smallest subsets, but … particularly in the metastatic disease setting, it’s a cancer where we don’t have as many treatment options,” Borges explains, although newer treatments include immunotherapy and antibody-drug conjugates, which link a chemotherapy drug to an antibody that delivers the chemotherapy straight to a cancer cell.
A Targeted Approach
While metastatic breast cancer remains incurable, evolving knowledge of these subtypes has led to newer treatments that extend lives.
Since its FDA approval in 1998, Herceptin has been a beneficial therapy for many people with HER2-positive breast cancer. The monoclonal antibody binds to the HER2 receptors on breast cancer cells to prevent the cells from growing in number.
Borges notes that when she began her career in the 1990s, HER2-positive metastatic breast cancer was a grave diagnosis, and Herceptin proved a valuable addition to treatment options. Some of Borges’ first patients with metastatic breast cancer who took Herceptin in clinical trials before the drug was approved are still alive today. “We have watched each other grow up and seen our kids grow up,” Borges says.
More recently, researchers have built on their knowledge and the success of Herceptin to develop treatments that link a potent chemotherapy drug to the same antibody that is used in Herceptin. One of these new treatments, an antibody-drug conjugate called Enhertu (trastuzumab deruxtecan), was approved in 2019 for people whose cancer expresses high levels of HER2 if they already received two HER2-targeted medications. But that approval has now expanded to include breast cancer with lower levels of HER2 expression, which is now being categorized as “HER2-low.” As a result, among patients whose cancer would have previously been classified and treated as HER2-negative, about 60% have cancer that is categorized as HER2-low and could benefit from Enhertu.
“We have always thought of breast cancer in a binary classification, so it was either HER2-positive or HER2-negative,” says Shanu Modi, a breast oncologist at Memorial Sloan Kettering Cancer Center in New York City. “That’s because HER2-positive breast cancers were the only cancers that seemed to benefit from the most commonly used HER2-targeted therapies.”
Biopsies can identify important features to guide treatment in metastatic breast cancer.
National Comprehensive Cancer Network guidelines recommend that all patients with metastatic breast cancer receive a biopsy whether their initial diagnosis is metastatic disease or they are diagnosed with metastatic disease after an early-stage breast cancer diagnosis.
However, a study presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting found that many patients with recurrent metastatic breast cancer did not receive a biopsy. Using patient data collected from across Washington state, researchers from the Fred Hutchinson Cancer Center in Seattle identified more than 700 women diagnosed with recurrent metastatic breast cancer between 2008 and 2017. They found that more than half of the women did not receive the recommended biopsy to confirm their metastatic breast cancer diagnosis and check their tumor pathology.
“We’ve gotten better at identifying specific niches for drugs, so we really need more information about your tumor,” says medical oncologist Hannah Linden, a specialist in breast cancer at Fred Hutchinson Cancer Center who helped conduct the study. “We want to know, ‘Well, should I treat you with endocrine therapy or HER2-directed therapy?’ And you can’t know unless you’ve sampled the metastases.”
Sometimes the cancer’s molecular characteristics change from the time a person is first diagnosed with early-stage breast cancer to the onset of metastatic disease. Other times, what looks like a metastasis is a different type of cancer unrelated to breast cancer, Linden adds.
If a repeat biopsy is too dangerous due to the tumor’s location, such as deep in the lung or in a bone that is particularly fragile, “you can go back to any prior biopsy,” says Virginia Borges, a medical oncologist who specializes in breast cancer at the University of Colorado Anschutz Medical Campus in Aurora. If new tissue is unavailable, she recommends sending archived tissue to the pathology lab “and get fresh testing done so that we’re not missing anyone who could benefit from targeted therapies.”
Tumor testing, whether through a blood biopsy or tissue biopsy, is also important for people with breast cancer who have a progression while taking hormone therapy. Because an ESR1 mutation can develop at any point during endocrine therapy, ASCO now recommends a blood biopsy whenever a patient who has taken endocrine therapy has a new progression.
A study called DESTINY-Breast04, published July 7, 2022, in the New England Journal of Medicine, assessed Enhertu in 557 patients whose advanced breast cancer expressed low levels of HER2. When compared with patients given chemotherapy, those who took Enhertu lived 4.8 months longer without their cancer progressing.
“Equally important is that patients getting that drug, in general, ended up living longer with stage IV disease than the group that was unable to get it,” Modi says, with a median overall survival of 23.4 months in the Enhertu group compared with 16.8 months in the chemotherapy control group. Patients in the study had previously received one or two treatment lines of chemotherapy and one or more lines of endocrine therapy (if they were also hormone receptor-positive).
Research Progress and Cancer Progression
When Finkelstein was first diagnosed with stage II hormone receptor-positive, HER2-negative breast cancer in July 2006, she had a lumpectomy followed by radiation. She then took an aromatase inhibitor called Femara (letrozole) for five years to decrease the amount of estrogen in her body and lower the chance of breast cancer recurrence.
When Finkelstein’s cancer recurred in 2019, scans revealed extensive bone metastases. A biopsy of the cancer in her pelvis confirmed her cancer status had not changed, and it was still hormone receptor positive. Doctors recommended she start with Femara along with Ibrance (palbociclib), a targeted therapy known as a CDK4/6 inhibitor, which blocks proteins that lead to the uncontrolled growth and division of cancer cells. The FDA had approved this CDK4/6 inhibitor for hormone receptor-positive, HER2-negative metastatic breast cancer in 2015 after a study showed patients taking the combination lived 20.2 months without their cancer getting worse, compared with 10.2 months for those taking Femara alone.
The combination kept Finkelstein’s cancer in check until August 2021, when she experienced a number of cancer progressions. She switched to a different type of hormonal therapy called Faslodex (fulvestrant), which is a selective estrogen receptor degrader (SERD). In April 2022, she started using another CDK4/6 inhibitor called Kisqali (ribociclib). In both cases, Finkelstein had radiation to treat new cancer growth on her bones.
In February 2023, she switched to Orserdu (elacestrant), a SERD approved by the FDA in January 2023 for people whose cancer develops a mutation called ESR1. This mutation, which indicates resistance to hormone therapy, develops in 20% to 40% of patients with metastatic breast cancer after they are treated with aromatase inhibitors such as Femara. Studies showed that Orserdu could extend the time without progression to 3.8 months, compared with 1.9 months with other standards of care in postmenopausal women and adult men whose cancer developed this mutation after taking at least one line of endocrine therapy.
In May 2023, Finkelstein learned the cancer had metastasized to her liver, so she switched to a targeted PI3K inhibitor called Piqray (alpelisib), a drug for people whose cancer harbors a mutation in the PIK3CA gene that causes the PI3K protein to be overactive and spur excessive cell growth. Piqray blocks PI3K. The drug was approved for use with Faslodex in 2019 after studies showed patients with PIK3CA-mutated advanced breast cancer who took the combination lived 11 months without their cancer progressing, compared with 5.7 months for those who took Faslodex plus a placebo. This drug caused Finkelstein’s blood glucose levels to rise to the point that she needed daily insulin injections to continue the treatment. Still, she liked Piqray because it did not sap her energy the way other treatments have.
Finkelstein, now 70, is grateful for the range of treatment options that have been available to her over the years—developments that have often kept pace with each of her cancer progressions. Ibrance was approved in 2015, a few years before she started on it, and Orserdu received approval in January 2023, just weeks before she took her first dose. The pace of discovery and FDA approvals “gives you hope that you can hold it steady as long as possible,” Finkelstein says.
But with these options also comes decisions and disappointment. In September 2023, she learned she had a mass in her liver. She stopped taking Piqray and started to take Xeloda (capecitabine), which is an oral chemotherapy drug. She is also looking into clinical trials.
Finkelstein urges people with metastatic breast cancer to find an approachable, collaborative oncologist. About two years after she was diagnosed with metastatic disease, she switched to an oncologist who she felt did a better job discussing treatment options and describing her rationale for making changes.
Choosing to see a new oncologist “was the best thing I ever did,” she says. “Having open, honest discussions with my oncologist has been key. She has a good understanding of my approach to my treatment,” Finkelstein says.
While the ultimate goal of treatment is to eradicate breast cancer, for now, a more attainable goal for patients with metastatic disease is to “at least keep it under control and turn it into a disease that patients can live with for a long time,” says Modi of Memorial Sloan Kettering Cancer Center. “Having a lot of [treatment] options is important. And the fact that we’re now seeing gains in prolonging the survival of stage IV patients with the newer drugs leaves me hopeful that we are moving the needle.”
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