The Evolution of Metastatic Breast Cancer Treatment: Exploring the Options

Metastatic breast cancer remains an incurable disease despite advances in systemic therapies. However, personalized treatment approaches have significantly improved overall survival (OS) and progression-free survival (PFS) for many patients, which makes  selecting the best treatment for each individual a critical yet complex step.

The evolution of molecular biology, targeted therapies, and combination treatments has revolutionized how oncologists treat different breast cancer subtypes.

“The current way of thinking is still that if there is an endocrine therapy option and the patient is not in imminent crisis in terms of organ function, that targeted therapy and endocrine therapy is still the best option,” Dr. Maryam Lustberg, Chief of Breast Medical Oncology at Yale Cancer Center, tells SurvivorNet Connect. “But there may be a subgroup of patients that maybe didn’t derive much benefit from their last endocrine therapy, targeted therapy option where actually [an] antibody drug conjugate therapy … may be the more appropriate therapy. So still we’re trying to figure these out, but these are discussions to be had on a case by case basis with your oncologist.”

Today, the cornerstone of metastatic breast cancer management lies in tumor subtyping, which allows for precise targeting of therapies.

The three primary subtypes—hormone receptor-positive, HER2-positive, and triple-negative breast cancer—have distinct treatment strategies.

• Hormone Receptor Positive, HER2-Negative Breast Cancer: Accounts for approximately 60% of all breast cancer cases and remains a mainstay in using endocrine therapy (ET)
• HER2-Positive Breast Cancer: Constitutes about 20% of cases and necessitates HER2-targeted therapies
• Triple-Negative Breast Cancer (TNBC): This aggressive form lacks both hormone receptors and HER2 expression, which limits the treatment options mainly to chemotherapy and emerging immunotherapies

Rationale for HER2-Directed Therapy

Targeting the HER2 receptor has become a cornerstone in the treatment of HER2-positive metastatic breast cancer, as HER2 overexpression is a strong predictor of response to HER2-directed therapies.

First-Line Treatment: Trastuzumab, Pertuzumab, and a Taxane

The first-line treatment of HER2-positive metastatic breast cancer typically involves a combination of trastuzumab, pertuzumab, and a taxane (docetaxel or paclitaxel). The CLEOPATRA trial solidified this combination as the standard of care, demonstrating that adding pertuzumab to trastuzumab and docetaxel improved overall survival (OS) and progression-free survival (PFS). The median OS was extended to 57 months, compared with 41 months in patients who did not receive pertuzumab.

In clinical practice, weekly paclitaxel is often preferred over docetaxel due to its favorable toxicity profile, particularly in terms of less febrile neutropenia and mucositis. Nevertheless, either taxane is an appropriate choice in combination with HER2-targeted therapy. Patients receiving this regimen typically remain on treatment until disease progression or unacceptable toxicity.

For patients who are hormone receptor (HR)-positive and HER2-positive, endocrine therapy combined with HER2-directed therapy is another option, especially for those with indolent disease or without significant visceral involvement. This approach reduces the toxicity associated with chemotherapy while maintaining efficacy in carefully selected patients.

Second-Line Treatment: Trastuzumab Deruxtecan (T-DXd)

For patients who progress on first-line therapy, the second-line treatment of choice is trastuzumab deruxtecan (brand name: Enhertu). The phase III DESTINY-Breast03 trial demonstrated a remarkable improvement in PFS for trastuzumab deruxtecan compared to trastuzumab emtansine (brand name: Kadcyla), with a median PFS of 28.8 months versus 6.8 months, respectively. This dramatic benefit has positioned Enhertu as the preferred second-line therapy for HER2-positive metastatic breast cancer.

However, interstitial lung disease is a significant concern with Enhertu, occurring in approximately 15% of patients in the DESTINY-Breast03 trial. Therefore, close monitoring for respiratory symptoms and prompt management of interstitial lung disease is crucial for patients receiving Enhertu.

HER2-low

Traditionally, the presence of HER2 has been divided into two groups, either positive or negative, leaving about 50% of patients somewhere in the middle. Recently, however, research have looked to further expand this definition to include patients that have a minimal amount of HER2 expression but do not meet the classic definition for HER2-positive tumors. This group has been called HER2 “low” and is very important as it represents approximately half of all patients with breast cancer.

Recent advances, such as the development of antibody-drug conjugates Enhertu have shown promise in treating HER2-low breast cancer. This has led to the recognition of HER2-low as a distinct clinical entity, with implications for treatment stratification and personalized therapy, particularly in metastatic cases.

HR+, HER2- Metastatic Breast Cancer

Hormone receptor-positive, HER2-negative (HR+, HER2-) is the most common subtype of breast cancer. Endocrine therapy (ET) is the backbone of treatment, but resistance to ET is a challenge, especially in advanced stages. The combination of ET with targeted therapies, particularly CDK4/6 inhibitors, has significantly extended survival.

CDK4/6 inhibitors: Mechanism of Action

CDK4/6 inhibitors target two key proteins — cyclin-dependent kinase 4 and 6 — that are critical in the regulation of the cell cycle. In HR+,HER2- breast cancer, aberrant signaling through the cyclin D-CDK4/6 pathway leads to unchecked cellular proliferation.

CDK4/6 inhibitors arrest the cancer cells in the G1 phase of the cell cycle, preventing progression to S-phase and thereby reducing tumor growth. This mode of action makes CDK4/6 inhibitors particularly effective when used in combination with endocrine therapies, such as aromatase inhibitors or fulvestrant, which target the hormone-driven proliferation pathways in breast cancer cells.

The following CDK4/6 inhibitors are currently approved for breast cancer:

• Palbociclib (brand name: Ibrance): Palbociclib was the first CDK4/6 inhibitor approved and has been extensively studied in the PALOMA trials. In the PALOMA-3 trial, palbociclib combined with fulvestrant demonstrated a significant improvement in PFS (9.5 months compared to 4.6 months for fulvestrant alone)
• Ribociclib (brand name: Kisqali): The MONALEESA trials have demonstrated ribociclib’s efficacy across different patient populations, including premenopausal women. MONALEESA-3 highlighted ribociclib’s ability to improve OS in the metastatic setting when combined with fulvestrant.
• Abemaciclib (brand name: Verzenio): Abemaciclib has a slightly different profile due to its continuous dosing schedule and higher selectivity for CDK4. This difference may contribute to its unique side effect profile, which includes a higher incidence of gastrointestinal toxicities but less bone marrow suppression. The MONARCH trials have shown its benefit in both metastatic and early-stage high-risk breast cancer, particularly in patients with node-positive disease.

PIK3CA Mutation

Resistance to ET is a significant barrier in the long-term management of HR+ metastatic breast cancer. Activation of the PI3K/AKT/mTOR pathway is a well-known mechanism behind this resistance and among HR+/HER2− breast cancer, approximately 40% of patients harbor mutations in the PIK3CA gene.

Identifying these mutations is critical for guiding targeted therapies, particularly with PI3K inhibitors such as alpelisib (brand name: PiqRay).

PiqRay is a highly selective inhibitor of the alpha isoform of PI3K, specifically targeting the PIK3CA mutation. The SOLAR-1 trial demonstrated the efficacy of alpelisib in combination with fulvestrant in patients with PIK3CA-mutated, HR+/HER2− breast cancer.

The final overall survival (OS) analysis showed a numeric improvement of 7.9 months in median OS for patients receiving alpelisib plus fulvestrant (39.3 months vs. 31.4 months; HR 0.86, 95% CI 0.64-1.15). Although this improvement did not meet the pre-specified threshold for statistical significance, it supports the clinical benefit of alpelisib in this population.

Subgroup analyses revealed that patients with lung or liver metastases had a more pronounced OS benefit, with a median OS of 37.2 months for alpelisib versus 22.8 months for placebo (HR 0.68, 95% CI 0.46-1.00).