 Okay, so this is our first case of HER2-negative metastatic breast cancer. This is a 47-year-old premenopausal patient. She presented with a newly discovered mass in her left breast and palpable axillary lymph nodes. Her clinical workup included abdominal and chest-pelvic CT, which showed a mass in the upper outer quadrant and two metastases in the right hepatic lobe. According to the biopsy, it showed invasive ductal carcinoma: ER 100%, PR 89%, HER2 0; FISH is negative. So, she is not HER2-low, but she is HER2-zero. The Ki-67 was 64%, which is on the high side. A lumpectomy and sentinel biopsy were performed; the tumor was 5.8 cm with three positive lymph nodes for metastatic disease. So, how do we approach this patient in the first-line setting and what factors into our decision on how to treat the patient? When assessing the type of breast cancer and the burden of disease, and considering her performance status is 47, she is young. Her markers, ER 100% and PR 89%, indicate strong ER and PR positivity. Therefore, I would consider this tumor to be endocrine sensitive. As I have not treated her yet, I don't have any other markers of endocrine sensitivity, but the assumption is she will have a recurrence-sensitive disease. Looking at the burden of disease, she only has two foci of metastatic disease in her liver. In this case, we want to be more aggressive. The Ki-67 is 64%, indicating a high proliferative tumor. Single-agent endocrine therapy would not suffice; a combination with a CDK4/6 inhibitor would be a good option. Elizabeth, how do you decide between the three different CDK4/6 inhibitors in terms of adverse events?

 Well, palbociclib is generally easier to tolerate. Although ribociclib may be preferred based on data from last year, it should not be used in patients with liver or cardiac dysfunction, which may impact the choice. Some patients may have already benefitted from a cyclin in the agonist setting.

 Ribociclib is the one with an overall survival benefit. However, both palbociclib and abemaciclib have progression-free survival benefits. Regarding the toxicity profile, ribociclib and palbociclib tend to cause more neutropenia, while abemaciclib is associated with more diarrhea. All three are acceptable options, included in the NCCN guidelines, and FDA-approved for first-line therapy in the metastatic setting.

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Virginia Kaklamani, MD, presents the case of a 47-year-old premenopausal woman diagnosed with HR+/HER2- metastatic breast cancer for discussion.

Case Presentation: A 72-Year-Old Woman With HR+/HER2- mBC

program. I'm Dr. Virginia Kaklamani, professor of medicine at UT Health, San Antonio, MD Anderson Cancer Center. With me today is Elizabeth Diaz, who is one of our physician assistants. Elizabeth, would you like to introduce yourself?

 Hi, I'm Elizabeth Diaz. I'm a physician assistant. I work with metastatic breast cancer patients here at UT Health San Antonio in the MD Anderson Cancer Center.

Wonderful. Today, we are pleased to discuss our approach to treatment and management of patients with HER2-negative, metastatic breast cancer in our practice. Let's get started.

The first point to consider is how many patients with metastatic breast cancer in our practice have HER2-negative disease. This subtype of breast cancer is the most common. Although we have effective treatments in the neoadjuvant and adjuvant settings, patients still develop metastatic disease. Most likely, this metastatic disease will develop after the first 5 years from diagnosis. Approximately half of our practice, if not more, comprises patients with HER2-negative metastatic disease. Another topic to discuss is HER2-low breast cancer. This has been a point of discussion in the past year because we now have effective therapies for this subtype, which is not HER2-positive. Therefore, medications like trastuzumab deruxtecan (T-DXd) have proven to be effective in treating this type of breast cancer. We will discuss these therapies further during this program.

Now, Elizabeth, what is the standard of care for first-line therapy in patients with HER2-negative metastatic breast cancer?

The preferred first-line regimen involves a CDK4 inhibitor with either an aromatase inhibitor or fulvestrant. The first decision is to determine whether the patient has endocrine resistance. We use an aromatase inhibitor if they have de novo metastatic disease or if it has been more than 2 years since they received endocrine therapy. On the other hand, we would use fulvestrant if they had progression on an aromatase inhibitor or if it has been less than 2 years since they had a different therapy. For premenopausal women, we still use the CDK4 inhibitor and endocrine therapy but also with ovarian suppression. Another dilemma is selecting the appropriate CDK4 inhibitor because we do not have results from a head-to-head trial. We typically use ribociclib due to its overall survival benefit. However, these trials were not designed to examine overall survival and met their primary endpoint of progression-free survival. Therefore, all three CDK4 inhibitors are superior to endocrine therapy alone. Another option is endocrine therapy alone, although we typically do not use that in our practice; it might be more appropriate for patients with poor performance status.

 Yes, that's a great point. When CDK4/6 inhibitors first emerged in 2015, we were pleased to have a new treatment option for patients with HER2-negative metastatic breast cancer. However, we should not overlook the importance of endocrine monotherapy. When treating patients with metastatic disease, the two primary goals are to improve overall survival and quality of life. Administering treatments with high toxicity can compromise the latter. Therefore, for some patients, endocrine monotherapy may be extremely appropriate. Recent data suggest that using a CDK4/6 inhibitor at any point in the disease course still provides a benefit. As such, it doesn't necessarily have to be a first-line therapy; it could be reserved for second-line treatment, particularly for patients with slow-progressing or low-burden disease.

Virginia Kaklamani, MD, and Elizabeth Diaz, PA-C, offer an overview of HR+/HER2- metastatic breast cancer and detail the standard-of-care first-line therapy options.

Virginia Kaklamani, MD

Articles

Case Presentation: A 72-Year-Old Woman With HR+/HER2- mBC

Overview of HR+/HER2- Metastatic Breast Cancer (mBC)