New Treatment Options for Hormone-Positive Metastatic Breast Cancer After Initial Therapy Fails

Table of Contents

• Introduction: Understanding Hormone-Positive Breast Cancer
• CDK4/6 Inhibitors: Current Standard Treatment
• How Resistance to Treatment Develops
• Treatment Strategies After CDK4/6 Inhibitor Progression
• Continuing CDK4/6 Inhibitors Beyond Progression
• Targeting the PI3K/AKT/mTOR Signaling Pathway
• What This Means for Patients
• Study Limitations and Considerations
• Patient Recommendations and Next Steps
• Source Information

Introduction: Understanding Hormone-Positive Breast Cancer

Breast cancer is the most commonly diagnosed cancer globally, accounting for 24.5% of all newly diagnosed malignancies. Mortality rates have significantly decreased due to early detection through mammographic screening and improved treatment options for localized disease.

Approximately 70-80% of all breast cancer cases are positive for the estrogen receptor (ER), and 65% of those cases are also positive for the progesterone receptor (PR). These hormone receptor-positive tumors can be made more sensitive to hormonal manipulation with various drugs that either directly block the ER pathway or suppress estrogen production.

Despite these advances, the development of resistance to endocrine therapy remains a significant challenge for oncologists. The combination of novel endocrine therapies with targeted drugs, particularly CDK4/6 inhibitors, has significantly improved long-term outcomes, changing the treatment approach for metastatic breast cancer.

CDK4/6 Inhibitors: Current Standard Treatment

CDK4/6 inhibitors have revolutionized treatment for hormone receptor-positive, HER2-negative metastatic breast cancer. These medications work as cell cycle blockers by suppressing the downstream effects of the complex formed by CDK4/6 with cyclin D, inducing cell cycle arrest in the G1 phase, thereby preventing entry into S phase and subsequent DNA synthesis.

In major clinical trials including PALOMA-2, MONALEESA-2, MONARCH-3, and MONALEESA-7, all three available CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) combined with endocrine therapy demonstrated consistent improvements in progression-free survival (PFS) as first-line treatments in both postmenopausal and premenopausal women.

Significant overall survival benefits have been reported for ribociclib combined with endocrine therapy in both the MONALEESA-7 and -2 trials. In the MONARCH-3 trial, abemaciclib showed a numerical improvement in median overall survival of 13.1 months, though this was not statistically significant. No significant overall survival benefit was observed with palbociclib as a first-line treatment in the PALOMA-2 trial.

How Resistance to Treatment Develops

Resistance to endocrine therapy develops through several mechanisms. The three main processes involve alterations in the estrogen receptor itself (amplifications, fusions, or mutations in the ESR1 gene which encodes ERα), aberrations in regulators of the ER pathway, and changes in other signaling cascades such as hyper-activation of growth factor receptors.

ESR1 mutations in the ligand-binding domain are among the most frequent genetic events affecting ERα and resulting in endocrine therapy failure. These mutations occur in approximately 5% of ER+/HER2- metastatic breast cancer cases. Additionally, larger chromosomal aberrations involving the ESR1 gene were described in endocrine therapy-resistant breast cancer.

Resistance to CDK4/6 inhibitors develops through different mechanisms including alterations in genes controlling cell cycle regulation, activation of alternative pathways, and changes in transcriptional and epigenetic modifiers. Specific resistance mechanisms include:

• Over-expression or amplification of the CCND1 gene (encoding cyclin D1) found frequently in patients resistant to CDK4/6 inhibitors
• Over-expression of the CCNE1 gene (encoding cyclin E1) linked to limited response to palbociclib
• Activating mutations in critical domains of CDK4/6 themselves
• Inactivating mutations or loss of the RB1 gene (retinoblastoma protein)
• Mutations in AKT1, AURKA, and KRAS genes found in CDK4/6 inhibitor-resistant tumors

Treatment Strategies After CDK4/6 Inhibitor Progression

After progression on CDK4/6 inhibitor therapy, no established sequence for the following lines of systemic therapy exists so far. Reasonable options include switching to another endocrine therapy as a single agent, continuing CDK4/6 inhibitors beyond progression, endocrine therapy associated with everolimus (an mTOR inhibitor), or combination therapy targeting specific genetic alterations.

Considering the five major randomized trials (MONALEESA-2/7, MONARCH-3, and PALOMA-1/2), patients with progression after first-line treatment with CDK4/6 inhibitors received single-agent endocrine therapy in 65% of cases (range 48-83%), chemotherapy in 44% of cases (range 32-73%), CDK4/6 inhibitors in up to 38% of cases (average 18%), and mTOR inhibitors in 17% of cases (range 14-24%).

In current practice, endocrine monotherapy provides a short progression-free survival of less than 3 months, compelling the research of alternative therapeutic approaches that can offer better outcomes for patients who have progressed on initial CDK4/6 inhibitor therapy.

Continuing CDK4/6 Inhibitors Beyond Progression

Continuing CDK4/6 inhibitor treatment beyond initial progression has been investigated as a potential strategy. The randomized phase II MAINTAIN trial reported a significant 2.5-month improvement in progression-free survival when continuing with a CDK4/6 inhibitor (ribociclib) after progression in combination with a different endocrine therapy.

Specifically, the median progression-free survival was 5.29 months versus 2.76 months (hazard ratio 0.59; 95% confidence interval 0.39-0.95, p=0.006) compared to the switched endocrine therapy plus placebo arm. Most patients (83%) had been previously treated with a different CDK4/6 inhibitor (palbociclib).

Conversely, in the randomized phase II PACE trial, no benefit was observed when continuing palbociclib with fulvestrant beyond progression on a prior CDK4/6 inhibitor in terms of progression-free survival (median 4.6 months vs. 4.8 months, hazard ratio 1.11) or overall survival (median 24.6 months vs. 27.5 months, hazard ratio 1.02).

Similarly, in the PALMIRA trial, re-challenge with the CDK4/6 inhibitor palbociclib plus endocrine therapy did not improve progression-free survival over endocrine therapy alone in patients pretreated with palbociclib. The median progression-free survival was 4.9 months in the treatment group versus 3.6 months in the control group (hazard ratio 0.84; 95% confidence interval 0.66-1.07; p=0.149).

Targeting the PI3K/AKT/mTOR Signaling Pathway

Another strategy is to target other signaling pathways, such as the PI3K/AKT/mTOR signaling system. This pathway is critical for tumor growth, proliferation, and survival, and its activation can promote resistance to endocrine therapy. PIK3CA somatic mutations are relatively early events in breast tumorigenesis and are present in approximately 30-50% of patients with HR+/HER2- metastatic breast cancer.

In the phase III SOLAR-1 trial that investigated the addition of alpelisib (a PI3Kα-specific inhibitor) to fulvestrant, postmenopausal patients resistant to previous endocrine therapy were enrolled. In patients with a mutation in the PIK3CA gene, the combination of alpelisib plus fulvestrant showed a significantly improved progression-free survival in comparison with fulvestrant alone (11.0 vs. 5.7 months; hazard ratio 0.65; 95% confidence interval 0.50-0.85; p=0.00065).

In the final overall survival analysis, although there was no statistically significant improvement (hazard ratio 0.86; 95% confidence interval 0.64-1.15; p=0.15), overall survival was prolonged by 7.9 months for those patients randomized to the alpelisib arm. Only a small percentage (6%) of the population enrolled in the SOLAR-1 trial had been previously treated with a CDK4/6 inhibitor.

The subsequent phase II BYLieve trial confirmed that the addition of alpelisib to endocrine therapy is effective in patients with HR+/HER2- metastatic breast cancer with a PIK3CA mutation who had previously been treated with a combination of CDK4/6 inhibitors and endocrine therapy.

What This Means for Patients

These findings have significant implications for patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have progressed on CDK4/6 inhibitor therapy. The research demonstrates that treatment strategies need to be personalized based on the specific genetic characteristics of each patient's tumor.

Genetic testing of recurrent and/or metastatic lesions through tumor and/or liquid biopsies may predict response or resistance to specific agents, suggesting the best therapeutic strategy for each patient. This could involve targeting the altered ER-dependent pathway with novel oral selective estrogen receptor degraders (SERDs) and a new generation of anti-estrogen agents, or alternative ER-independent signaling pathways.

For patients with PIK3CA mutations, combination therapy with PI3K inhibitors like alpelisib shows promising results. For those with germline BRCA1/2 mutations, PARP inhibitors such as olaparib or talazoparib may be effective options. These agents are being investigated as single molecules and in combination with other targeted therapies, offering promising approaches to overcome or avoid treatment failure.

Study Limitations and Considerations

While these findings are promising, several limitations should be considered. The studies have relatively short follow-up periods for overall survival data, and some trials had small sample sizes for specific patient subgroups. Additionally, the various CDK4/6 inhibitors may have different efficacy profiles, making direct comparisons challenging.

The differential efficacy of various CDK4/6 inhibitors remains unclear and could be due to multiple factors including different pharmacokinetics, variable pharmacodynamics, differences in study populations, missing survival data, or treatment discontinuation due to adverse events. Palbociclib, ribociclib, and abemaciclib showed similar pharmacokinetics but variable pharmacodynamics, with ribociclib and abemaciclib being more selective toward CDK4 over CDK6.

Additionally, the optimal sequence of treatment after CDK4/6 inhibitor progression remains controversial, and more research is needed to establish clear guidelines for clinicians and patients facing this treatment challenge.

Patient Recommendations and Next Steps

For patients with hormone receptor-positive, HER2-negative metastatic breast cancer that has progressed on CDK4/6 inhibitor therapy, several approaches should be considered:

1. Genetic testing: Discuss comprehensive genetic testing of your tumor (through tissue or liquid biopsy) to identify specific mutations that might guide treatment decisions
2. Clinical trials: Consider participation in clinical trials investigating novel combinations and targeted therapies
3. Targeted approaches: If genetic testing reveals specific mutations (PIK3CA, BRCA, etc.), discuss targeted therapy options with your oncologist
4. Continued CDK4/6 inhibition: In some cases, continuing or switching to a different CDK4/6 inhibitor may be beneficial, particularly based on genetic profiling results
5. Combination therapies: Explore combination approaches that target multiple pathways simultaneously

Patients should have open discussions with their healthcare team about the potential benefits and risks of each approach, considering their specific cancer characteristics, previous treatments, overall health status, and personal preferences.

Source Information

Original Article Title: Novel Treatment Strategies for Hormone Receptor (HR)-Positive, HER2-Negative Metastatic Breast Cancer

Authors: Antonella Ferro, Michela Campora, Alessia Caldara, Delia De Lisi, Martina Lorenzi, Sara Monteverdi, Raluca Mihai, Alessandra Bisio, Mariachiara Dipasquale, Orazio Caffo, Yari Ciribilli

Publication: Journal of Clinical Medicine 2024, 13(12), 3611

Note: This patient-friendly article is based on peer-reviewed research and aims to translate complex scientific information into accessible content for educated patients. Always consult with your healthcare team for personalized medical advice.