Educated Patient® Metastatic Breast Cancer Summit Overview of Management of Hormone Receptor-positive Breast Cancer Presentation: November 12, 2022

Although certain treatments such as Ibrance (palbociclib), Kisqali (ribociclib) and Verzenio (abemaciclib) have become the standard first-line treatment option for hormone receptor-positive breast cancer, recent study findings have shown that they may no longer be interchangeable.

Now, according to Dr. Seth A. Wander, health care providers are actively debating as to why two drugs — in this instance, Ibrance and Kisqali — could elicit similar improvements in progression-free survival but drastic results in overall survival.

Of note, progression-free survival (time from the start of cancer treatment to disease progression or death) and overall survival (time from first treatment to death from any cause) are common endpoints that trial investigators assess when analyzing new treatments.

As part of a larger discussion, Wander, an assistant professor of medicine at Harvard Medical School and a medical oncologist at Massachusetts General Hospital in Boston, highlighted the first- and second-line management of hormone receptor-positive breast cancer during CURE®’s recent Educated Patient® Metastatic Breast Cancer Summit.

Most Common Cancer

Wander noted that breast cancer, according to statistics released by the American Cancer Society in 2020, is the most common type of malignancy diagnosed in women.

In fact, more than 275,000 new cases of breast cancer were expected to be diagnosed in women in the U.S. Of those cases, approximately 70% are hormone receptor positive.

He explained that treatment is divided into two groups — local or systemic therapy. Surgery and/or radiation are classified as localized therapy and are often used to manage symptoms, according to Wander. As for systemic therapy, that comprises chemotherapy, as well as hormonal treatments, targeted therapies, immunotherapy and antibody drug conjugates/ The goal with systemic therapy, Wander said, is to focus controlling the disease while limiting side effects.

If possible, Wander explained, oncologists aim to avoid using conventional chemotherapies unless other systemic therapies fail to induce tumor responses.

Hormone Therapy

One of the treatments Wander detailed was anti-estrogen therapy. He explained that some of the more common treatments in this space are tamoxifen, which is administered once a day for a continuous period, and once per month Faslodex (fulvestrant).

Some of the more common side effects patients may expect when receiving these treatments include, but are not limited to, menopausal symptoms as well as injection site reactions to Faslodex and slow but potential deteriorating bone density.

Patients receiving these types of treatments, according to Wander, are advised to seek routine follow-up visits with their care team to ensure none of these side effects are occurring.

CDK4/6 Inhibitors

Wander then highlighted the benefits associated with treatment using CDK4/6 inhibitors such as Ibrance and Kisqali. He noted that each can be prescribed to patients to be used once a day for three weeks, with a one week break every month. There’s also Verzenio which is given continuously twice a day. Similar to hormone therapy, these treatments are associated with side effects such as fatigue and diarrhea. The CDK4/6 inhibitors may also, on rare occasions, lead to rare heart issues as well as liver and lung concerns.

As a result, it is recommended that patients receiving CDK4/6 inhibitors undergo more frequent monitoring than patients being treated with hormone therapy.

Treatments such as Kisqali combined with letrozole as well as Ibrance plus Faslodex have been shown to elicit similar improvements in progression-free survival. However, as Wander mentioned, recent study findings have demonstrated differing survival outcomes for the two CDK4/6 inhibitors. For instance, a study presented at the 2021 San Antonio Breast Cancer Symposium showed that adding Ibrance to endocrine therapy likely failed to improve outcomes in hormone receptor-positive breast cancer. Whereas findings from the MONALEESA-3 trial showed that adding Kisqali to Faslodex was an effective second-line option while improving overall survival versus placebo plus Faslodex.

Mechanisms of Treatment Resistance

Although there are more treatment options available to patients than there were decades ago, treatment resistance is still a concern.

In fact, many cancer cells will eventually resist the effect of drugs rendering them useless.

Wander briefed the audience on work that has been done over the past five to six years to identify reasons for this resistance. He noted that alterations to proteins that regulate cell division as well as in pathways that promote cell growth may result in drug resistance. As a result, he said, investigators have been looking into new treatment approaches to either prevent or overcome this resistance.

One of those developments he referenced was the identification of the ESR1 gene. Through the use of genomic sequencing, investigators have observed that patients who have not yet been treated for breast cancer very rarely have mutations in the ESR1 gene. However, after prolonged treatment, up to a third of patients will develop a mutation, Wander explained.

He cited the findings from the PADA-1 trial as a prime example of this approach working. In this instance, patients who were receiving an aromatase inhibitor plus Ibrance as their initial treatment were followed at regular intervals to observe any changes to the ESR1 gene. If the patient developed a mutation, they were switched to receive Faslodex even before a scan determined disease progression.

Wander further explained that the findings showed the longer a patient remained on the aromatase inhibitor, the likelier they were to have an ESR1 mutation. Moreover, the switch to Faslodex may have been beneficial for patients, according to Wander.

Understanding the molecular drivers of resistance both to the hormone agents as well as to these targeted drugs can help us develop new therapeutic strategies in the clinic, which is an active area of research for all of us right now,” Wander concluded.

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