Navigating Estrogen Receptor-Positive Breast Cancer: New Advances in Long-Term Management

Table of Contents

• Introduction: Understanding Your Breast Cancer Type
• The Challenge of Late Recurrences: Why Cancer Can Return Years Later
• Extended Endocrine Therapy: Weighing Benefits Against Side Effects
• Additional Treatments to Reduce Recurrence Risk
• Identifying Patients at Risk for Late Recurrence
• Using CDK4/6 Inhibitors in Advanced Breast Cancer
• CDK4/6 Inhibitors in Early-Stage Breast Cancer
• New SERD Treatments: Advances in Targeting Estrogen Receptors
• What This Means for Patients: Practical Implications
• Understanding the Limitations of Current Research
• Future Directions in Breast Cancer Treatment
• Source Information

Introduction: Understanding Your Breast Cancer Type

Estrogen receptor-positive (ER-positive) breast cancer represents the most common form of breast cancer, affecting approximately two-thirds of all patients diagnosed with this disease. This type of cancer, also known as luminal breast cancer, is characterized by cancer cells that have receptors for estrogen, meaning estrogen can fuel their growth.

While effective treatments exist that significantly reduce the risk of early relapse, the single biggest challenge in managing this disease remains late recurrence - cancer that returns many years after initial diagnosis and treatment. This comprehensive review examines the latest advances in understanding and managing this persistent risk, including new medications and treatment strategies that are changing how doctors approach long-term care for ER-positive breast cancer patients.

The Challenge of Late Recurrences: Why Cancer Can Return Years Later

The most concerning aspect of estrogen receptor-positive breast cancer is its pattern of late recurrence. More than half of all disease recurrences occur after 5 years from the initial diagnosis, creating a lifetime trade-off between the relatively limited early recurrence risk and the persistent long-term risk.

Currently, any recurrence happening after 5 years is classified as "late," though most clinical trials only track results for 10 years, with very limited data available beyond 20-30 years after diagnosis. Interestingly, the same factors that predict early recurrence - tumor size and lymph node status - continue to predict late recurrence risk years after treatment.

Researchers believe that breast cancer cells can undergo a process called epithelial-mesenchymal transition, allowing them to escape the original tumor and enter the bloodstream even before diagnosis. Some of these cells can then undergo the reverse process (mesenchymal-epithelial transition) and settle in the bone marrow, particularly in the endosteal niche, where they may remain dormant for years.

The delicate balance of factors in this bone marrow microenvironment likely determines whether these dormant cells eventually die off or reactivate to cause recurrent cancer. The mystery that remains completely unresolved is how these cells "remember" their origin from a large or node-positive tumor, since these classical risk factors continue to predict late relapse risk years later.

Extended Endocrine Therapy: Weighing Benefits Against Side Effects

Since the risk of recurrence persists beyond 5 years, researchers have explored extending endocrine therapy durations. The compelling idea is that if risk persists, treatment should persist accordingly. However, this approach has significant limitations due to cumulative side effects that may outweigh benefits and loss of therapeutic effectiveness over time.

Oral medications called selective estrogen receptor modulators (SERMs), such as tamoxifen, and aromatase inhibitors (AIs) form the mainstay of adjuvant endocrine therapy. Multiple studies have examined extending treatment beyond the standard 5 years:

• ATLAS and aTTom trials: 10 years of tamoxifen decreased recurrence risk but did not unequivocally affect overall mortality, while increasing risks of endometrial cancer and pulmonary embolism
• Postmenopausal women: Adding AIs after 5 years of tamoxifen showed significant improvements in three large clinical trials
• Extension trials: When AIs are already used in the first 5 years, results become more controversial

Based on current evidence, approximately 7 years of adjuvant endocrine treatment appears to yield the optimal benefit-to-harm ratio for most patients with luminal early breast cancer. The cumulative side effects, including bone health impairments that are common with endocrine therapies, must be carefully balanced against potential recurrence risk reduction.

Additional Treatments to Reduce Recurrence Risk

Another approach to reducing long-term recurrence risk involves adding additional medications to standard endocrine therapy. Bone-targeted therapies have shown particular promise in this area:

Adjuvant bisphosphonates have demonstrated ability to reduce recurrences and breast cancer mortality, but only in postmenopausal women. These medications not only improve bone health (which is often compromised by endocrine therapies) but also appear to alter the bone microenvironment in ways that disadvantage reactivation of dormant cancer cells.

Recently, research showed that even relatively short-term adjuvant treatment with denosumab (an anti-RANK ligand antibody) reduces breast cancer recurrence many years after stopping therapy. This suggests that brief interventions during active treatment may have long-lasting protective effects against late recurrence.

CDK4/6 inhibitors represent another class of drugs that can be added to standard endocrine therapies. These medications have been practice-changing in metastatic breast cancer and are now considered standard of care in combination with endocrine therapy for first- or second-line treatment of advanced hormone receptor-positive breast cancer.

Other targeted therapies that inhibit mTOR, PI3CA, and AKT pathways have shown effectiveness in certain patient subgroups with metastatic breast cancer. However, their use in adjuvant settings remains uncertain due to significant side effect profiles.

Identifying Patients at Risk for Late Recurrence

The main challenge in addressing late breast cancer recurrence is identifying which patients are actually at risk. None of the additional interventions come without side effects, and it's unlikely that all relapse-free patients at 10 years would undergo additional treatment for what might be only a 1% annual risk of recurrence at that stage.

Multigene tests have been developed to assess recurrence risk, primarily to assist in deciding whether patients need chemotherapy. Several of these tests have been applied to the late recurrence setting, though for most, this constitutes extrapolation from data focused on the first 5 years after diagnosis.

Currently, only the Breast Cancer Index has demonstrated some utility in predicting benefit from extended treatment durations. More recently, technology has evolved to detect circulating tumor DNA in blood, which may help identify patients who are clinically cured but biologically on the verge of disease recurrence.

However, many questions remain unanswered regarding testing frequency, affordability, and most importantly, what interventions to offer patients identified as high risk. The ethical and communication aspects are significant - once we tell a patient they have increased recurrence risk, we should have meaningful interventions to offer, ideally through clinical trials.

Using CDK4/6 Inhibitors in Advanced Breast Cancer

For patients with advanced breast cancer, adding CDK4/6 inhibition to first-line endocrine therapy has become standard care for the vast majority with ER-positive, HER2-negative disease. All three available CDK4/6 inhibitors (abemaciclib, palbociclib, and ribociclib) show similar effects on progression-free survival and are recommended by treatment guidelines.

Selection between these medications often comes down to physician choice and side effect profiles:

• Abemaciclib: Higher incidence of diarrhea, fatigue, and thromboembolism
• Ribociclib and palbociclib: Higher incidence of bone marrow suppression and neutropenia
• Ribociclib: Higher incidence of nausea and liver function abnormalities, rarely QTc prolongation

Clinical advice generally suggests considering switching between CDK4/6 inhibitors if patients develop side effects characteristic of one particular medication. All three carry a small (1%-2%) risk of pneumonitis, requiring physician vigilance for respiratory symptoms.

Biomarker testing to identify patients who might not benefit from CDK4/6 inhibitors remains limited. Only cancers with specific genetic alterations - RB1 loss mutations/deletions (approximately 2% of treatment-naive breast cancer) or basal-like gene expression profile (approximately 2%) - show clear resistance, but identifying these reliably in clinical practice proves challenging.

CDK4/6 Inhibitors in Early-Stage Breast Cancer

Two years of adjuvant abemaciclib, in addition to aromatase inhibitors with or without ovarian suppression, has become standard therapy for high-risk patients with ER-positive, HER2-negative early breast cancer. The MONARCH-E trial demonstrated significant benefit from this approach:

Initial results showed a hazard ratio of 0.75 (meaning a 25% reduction in recurrence risk) after 15.5 months median follow-up. A recent update after 42 months showed strengthening benefit with invasive disease-free survival at 4 years of 85.5% in the abemaciclib arm versus 78.6% in the control arm (hazard ratio 0.653, meaning a 34.7% risk reduction).

The trial showed clear "carryover benefit" with hazard ratios of 0.674 in years 1-2 (during treatment) and 0.602 after 3+ years (after completing abemaciclib). The 6.9% absolute benefit at 4 years clearly supports offering abemaciclib to high-risk patients meeting trial criteria (four or more positive lymph nodes, or one to three nodes with additional high-risk features).

Interestingly, the adjuvant setting reveals differences between medications. While abemaciclib showed significant benefit, the PALLAS trial found no benefit from 2 years of adjuvant palbociclib (hazard ratio 0.96). This difference may stem from abemaciclib's additional weak inhibition of CDK2, which might enhance activity against endocrine-resistant cancers that dominate early relapses.

New SERD Treatments: Advances in Targeting Estrogen Receptors

Targeting the estrogen receptor remains the single most effective way of treating ER-positive breast cancer. A new class of oral selective estrogen receptor degraders (SERDs) is entering clinical practice, with elacestrant now available for patients with advanced ESR1-mutant breast cancer.

These new oral SERDs have demonstrated activity in advanced settings and are rapidly moving to early breast cancer trials. Medications like giredestrant, imlunestrant, elacestrant, and camizestrant appear particularly effective against cancers with ESR1 mutations that typically resist standard endocrine therapy.

Some evidence suggests these new agents might even prevent development of ESR1 mutations, making them promising candidates for future treatment standards. Multiple large clinical trials are currently evaluating these medications in early breast cancer settings, which may significantly change treatment paradigms in coming years.

The development of effective oral alternatives to injectable SERDs like fulvestrant represents a major advancement in patient convenience and quality of life, while potentially offering improved efficacy against resistant forms of ER-positive breast cancer.

What This Means for Patients: Practical Implications

For patients currently navigating treatment decisions for ER-positive breast cancer, several key practical applications emerge from this research:

1. Adjuvant CDK4/6 inhibition with abemaciclib substantially reduces relapse risk and is standard care for high-risk early breast cancer patients
2. Elacestrant provides a new treatment option for patients with advanced breast cancer and ESR1 mutations detected in circulating tumor DNA
3. Oral selective estrogen receptor degraders are being tested in multiple clinical trials and may become future mainstays of endocrine therapy
4. Late relapse remains a key challenge, with over half of recurrences occurring 5 or more years after diagnosis, requiring ongoing vigilance

Patients should discuss their individual recurrence risk with their oncologists, considering tumor characteristics, genetic testing results, and tolerance for extended therapy. The decision to pursue extended endocrine therapy or additional treatments should balance potential recurrence risk reduction against quality of life impacts and treatment side effects.

Understanding the Limitations of Current Research

While significant advances have been made in understanding and treating ER-positive breast cancer, important limitations remain in our current knowledge:

Most clinical trial databases only extend to 10 years, with very limited data on truly long-term outcomes beyond 20-30 years after diagnosis. This gap makes it challenging to understand the complete natural history of ER-positive breast cancer and the ultimate effectiveness of our treatments.

The mixed results from extended endocrine therapy trials highlight that longer treatment isn't always better for every patient. The optimal duration must be individualized based on recurrence risk, treatment tolerance, and patient preferences.

While new biomarkers like circulating tumor DNA show promise for identifying patients at risk for late recurrence, many questions remain about testing frequency, interpretation, and most importantly, what interventions to offer patients who test positive.

Perhaps the biggest limitation is our fundamental lack of understanding about cancer dormancy - how to identify, measure, and address dormant cancer cells that may reactivate years after initial treatment. Only when we decipher these mysteries will we truly be able to prevent and effectively treat late disease recurrence.

Future Directions in Breast Cancer Treatment

The future of ER-positive breast cancer treatment lies in several promising directions currently under investigation:

Researchers are exploring whether continuing CDK4/6 inhibition beyond progression provides benefit. The phase II MAINTAIN trial found improved progression-free survival when switching both the endocrine therapy and CDK4/6 inhibitor after progression, while the PACE study did not show benefit from continuing the same CDK4/6 inhibitor.

The PADA-1 trial demonstrated that switching from an aromatase inhibitor to fulvestrant when ESR1 mutations appear in circulating tumor DNA (before clinical progression) improved outcomes. This approach of treatment adaptation based on molecular rather than clinical progression is being further investigated in the SERENA-6 trial.

For patients who relapse after adjuvant abemaciclib, limited evidence exists to guide treatment. Current clinical practice often involves re-challenging with CDK4/6 inhibition if sufficient time has passed since previous treatment, though this approach lacks robust clinical trial support.

The ultimate goal remains changing our treatment target from proliferating tumor cells to addressing dormancy and quiescence. Only when we can effectively identify, prevent, and treat dormant cancer cells will we truly begin talking about curing ER-positive breast cancer.

Source Information

Original Article Title: Managing a Long and Winding Road: Estrogen Receptor Positive Breast Cancer

Authors: Michael Gnant, MD; Nicholas C. Turner, MD, PhD; Cristina Hernando, MD

Publication: 2023 ASCO Educational Book

DOI: https://doi.org/10.1200/EDBK_390922

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 personal medical advice tailored to your specific situation.