A Patient's Guide to Treating Hormone-Positive Metastatic Breast Cancer

Table of Contents

• Introduction: Understanding Your Cancer Type
• The Current Standard of Care: CDK 4/6 Inhibitors
• Clinical Considerations: Do All CDK 4/6 Inhibitors Behave the Same?
• Treatment Considerations for Special Populations
• Does Your Tumor's Biology Matter? The Role of Biomarkers
• Future Directions and New Treatments on the Horizon
• Conclusion and Key Takeaways
• Source Information

Introduction: Understanding Your Cancer Type

Estrogen receptor-positive, HER2-negative breast cancer (often called luminal-type) is the most frequent form of the disease, accounting for about 70% of all breast cancer cases. Despite receiving the best possible treatment after initial diagnosis, between 5% and 25% of patients will experience a recurrence. This cancer can sometimes return many years after the original diagnosis.

A smaller percentage of patients are diagnosed with de novo metastatic breast cancer (MBC), meaning the cancer has already spread to other parts of the body at the time of first diagnosis. In recent major clinical trials, these patients made up around 30% of participants. It is crucial to understand that metastatic breast cancer is currently considered incurable.

The primary goals of treatment are to help patients live longer, maintain or improve their quality of life, manage symptoms, and respect their personal wishes and goals for care.

The Current Standard of Care: CDK 4/6 Inhibitors

The established first choice for managing advanced luminal breast cancer is a combination of endocrine therapy (ET) and cyclin-dependent kinase (CDK) 4/6 inhibitors. This is true regardless of how far the disease has spread. The standard approach involves using multiple lines of endocrine and targeted treatments until the cancer develops resistance, at which point palliative chemotherapy is considered.

Understanding why cancer becomes resistant to hormone therapy and developing new treatment options are among the biggest challenges in current cancer research. Another area of intense focus is improving treatments for after endocrine therapy stops working. The development of antibody-drug conjugates (ADCs) is particularly promising, and some of these drugs are expected to soon become part of the standard arsenal against this disease.

Clinical Considerations: Do All CDK 4/6 Inhibitors Behave the Same?

Based on the results of several large Phase III clinical trials, three CDK 4/6 inhibitors—palbociclib (Ibrance), abemaciclib (Verzenio), and ribociclib (Kisqali)—are used in combination with endocrine treatment. This combination is not only a standard treatment but is considered one of the major breakthroughs in breast cancer oncology in the last twenty years.

The main results of these pivotal trials are summarized in the table below. Current medical guidelines recommend that nearly every patient with advanced luminal breast cancer be treated with a CDK 4/6 inhibitor. This recommendation is based on a clinically meaningful progression-free survival (PFS) benefit seen across all trials.

Key Trial Results:

• PALOMA-2 (Palbociclib + Letrozole): Median PFS was 24.8 months vs. 14.5 months with placebo (Hazard Ratio [HR] 0.58).
• MONALEESA-2 (Ribociclib + Letrozole): Median PFS was 25.3 months vs. 16.0 months with placebo (HR 0.56). Overall Survival (OS) benefit was also significant (HR 0.76).
• MONARCH-3 (Abemaciclib + NSAI): Median PFS was 28 months vs. 14.7 months with placebo (HR 0.54).
• Similar significant benefits were seen in second-line settings and in premenopausal women when combined with other endocrine agents like fulvestrant.

Although the results are overall similar, some differences exist. A significant overall survival (OS) benefit was observed in trials using ribociclib (MONALEESA-2, -3, -7) and abemaciclib (MONARCH-2), but not in the two major trials using palbociclib (PALOMA-2 and -3). The reason for this difference is not entirely clear but could be related to patient selection or how the disease behaves after progression on these drugs.

The best sequence of different endocrine backbone agents depends on which drugs a patient has previously received, how long they responded to them, the extent of the disease, patient preference, and drug availability. The longest PFS is generally achieved when these combinations are used as a first-line treatment.

Treatment Considerations for Special Populations

Historically, premenopausal women were underrepresented in cancer trials. The MONALEESA-7 trial specifically focused on this group (672 patients) and showed that the benefit of adding a CDK 4/6 inhibitor to endocrine therapy (with ovarian suppression) was comparable to that seen in postmenopausal women. A separate study even found that premenopausal patients had a longer PFS with palbociclib + ET (20 months) than with chemotherapy (14.4 months), endorsing the use of these combinations in younger patients.

Elderly patients are also often underrepresented. A joint analysis of palbociclib trials that included 304 patients aged 65 or older found that the efficacy of the treatment was maintained, with a median PFS of 27.5 months for patients aged 65-74. Quality of life was also maintained. However, data for patients over 75 or those with significant frailty are still limited, and doctors must pay special attention to potential drug interactions in this population.

Male patients were eligible for only one major trial (MONALEESA-3), and while recruitment was fast, ultimately none were enrolled. A separate real-world study did include a small number of men (1.2%, 39 patients), but this number is too low to draw specific conclusions. Despite the lack of data, current guidelines recommend that men be offered the same treatment options as women.

Does Your Tumor's Biology Matter? The Role of Biomarkers

The most common molecular alterations in this type of breast cancer are mutations in the ESR1 and PIK3CA genes. An ESR1 mutation is often found after previous treatment with an aromatase inhibitor (in 30%-40% of patients) and is typically associated with a worse prognosis. A PIK3CA alteration occurs in about 40% of patients and seems to be linked to worse overall survival and resistance to chemotherapy.

Importantly, the benefit from adding a CDK 4/6 inhibitor to endocrine therapy appears to hold regardless of whether these specific mutations are present. Researchers are making unprecedented efforts to find biomarkers that predict who will respond best to these drugs using advanced genetic testing.

For example, a large pooled analysis suggested that patients with alterations in certain genes (FRS2, PRKCA, MDM2, ERBB2, AKT1_E17K, BRCA1/2) might have a greater benefit from ribociclib, while alterations in other genes (CHD4, BCL11B, ATM, CDKN2A/2B/2C) might be linked to resistance. However, these findings are still considered hypothesis-generating and not yet ready for use in everyday clinical practice.

Monitoring cancer DNA in the blood (ctDNA) during treatment may be a better way to predict long-term outcomes than a single test at the beginning. The PADA-1 trial showed that patients whose ctDNA showed a rise in ESR1 mutations could benefit from switching their treatment early, before the cancer showed visible signs of progression.

In conclusion, while a huge effort has been made to find biomarkers, none are currently used to decide on treatment. However, the presence of certain mutations and their changes over time do have a clear prognostic value, meaning they can help indicate the likely course of the disease.

Future Directions and New Treatments on the Horizon

When cancer progresses on CDK 4/6 inhibitors, molecular profiling often shows new genetic changes, such as alterations in the FGFR pathway or, in about 5% of cases, RB1 gene mutations. Understanding these resistance mechanisms is key to developing the next line of therapies.

One of the most promising areas of development is for antibody-drug conjugates (ADCs). These are sophisticated drugs designed to deliver a potent chemotherapy agent directly to cancer cells by attaching it to an antibody that seeks out those cells. This targeted approach aims to maximize damage to the cancer while minimizing side effects for the patient. The review notes that some of these ADCs will likely soon become a standard part of the treatment arsenal.

For the small subset of patients with ER-positive metastatic breast cancer who also have an inherited germline BRCA mutation, PARP inhibitors like olaparib or talazoparib are an important treatment option. The best sequence of using PARP inhibitors versus CDK 4/6 inhibitors is still unknown, but given the overall survival benefit seen with CDK 4/6 inhibitors, they are generally recommended first.

Conclusion and Key Takeaways

The treatment landscape for hormone receptor-positive, HER2-negative metastatic breast cancer has been revolutionized by the introduction of CDK 4/6 inhibitors combined with endocrine therapy. This approach is the standard first-line treatment for most patients, offering significant delays in disease progression and, for some drugs, an improvement in overall survival.

Treatment decisions are personalized based on a patient's menopausal status, prior treatments, and overall health. While extensive research is underway to find biomarkers that can predict response, none are yet used routinely to select therapy. The future is bright, with several new drug classes, particularly antibody-drug conjugates, showing great promise for treating the disease after it becomes resistant to current standard therapies.

Source Information

Original Article Title: How I treat endocrine-dependent metastatic breast cancer
Authors: A. Gombos, A. Goncalves, G. Curigliano, R. Bartsch, J. A. Kyte, M. Ignatiadis, A. Awada
Publication: ESMO Open, Volume 8, Issue 2, 2023
This patient-friendly article is based on peer-reviewed research and aims to comprehensively translate the original scientific content for an educated patient audience, preserving all key data, findings, and clinical context.