Is abemaciclib (CDK4/6 inhibitor) and tamoxifen (estrogen receptor antagonist) indicated for treatment of metastatic breast cancer with liver metastases (liver mets) in patients with hormone receptor-positive and HER2-negative status?

Abemaciclib Plus Tamoxifen for Metastatic Breast Cancer with Liver Metastases

Yes, abemaciclib combined with endocrine therapy is indicated for hormone receptor-positive, HER2-negative metastatic breast cancer with liver metastases, but tamoxifen is not the preferred endocrine partner—fulvestrant or an aromatase inhibitor should be used instead. 1

First-Line Treatment Recommendations

CDK4/6 inhibitors (including abemaciclib) combined with endocrine therapy represent the standard-of-care for HR-positive, HER2-negative metastatic breast cancer, regardless of visceral involvement including liver metastases. 1

• For postmenopausal women or premenopausal women receiving ovarian suppression, the preferred first-line regimen is abemaciclib plus an aromatase inhibitor (letrozole or anastrozole), which demonstrated improved progression-free survival with a hazard ratio of 0.54 (95% CI 0.41-0.72) compared to aromatase inhibitor alone 1

• This combination is effective even in patients with visceral metastases, which were present in approximately 50% of patients in the MONARCH trials 2

• Liver metastases specifically were present in 33.7% of real-world patients treated with abemaciclib, confirming its use in this population 2

Why Not Tamoxifen?

Tamoxifen is not the preferred endocrine partner with abemaciclib for metastatic disease. 3

• The nextMONARCH trial specifically evaluated abemaciclib 150 mg plus tamoxifen 20 mg versus abemaciclib monotherapy in heavily pretreated patients and found no significant improvement in progression-free survival (9.1 months vs 7.4 months; HR 0.815; P=0.293) 3

• The objective response rate with abemaciclib plus tamoxifen was 34.6%, which was not superior to abemaciclib monotherapy at 32.5% 3

• Current guidelines list tamoxifen as an option for postmenopausal patients but prioritize aromatase inhibitors or fulvestrant when combined with CDK4/6 inhibitors 1

Optimal Endocrine Partner Selection

For first-line therapy, abemaciclib should be combined with an aromatase inhibitor (letrozole or anastrozole). 1

For second-line therapy after progression on an aromatase inhibitor, abemaciclib should be combined with fulvestrant. 1, 4

• Fulvestrant plus a CDK4/6 inhibitor is category 1 evidence for patients who have progressed on prior endocrine therapy 4

• The MONALEESA-3 study demonstrated progression-free survival of 21 months versus 13 months with fulvestrant alone (HR 0.59) in patients who progressed on aromatase inhibitor therapy 4

Special Considerations for Liver Metastases

Patients with liver metastases require careful monitoring for hepatotoxicity when using abemaciclib. 5

• Abemaciclib-induced liver injury occurred in 29% of patients in one retrospective analysis 5

• Concomitant use of an aromatase inhibitor was identified as an independent risk factor for liver injury (OR 10.23,95% CI 2.02-51.91, P=0.005) 5

• This suggests that in patients with pre-existing liver metastases, fulvestrant may be a safer endocrine partner than an aromatase inhibitor when combined with abemaciclib 5

Premenopausal Patient Management

Premenopausal women must receive ovarian suppression or ablation with an LHRH agonist before being treated with the same regimens as postmenopausal women. 1, 4

• Bilateral oophorectomy may be preferable if rapid response is necessary, as it provides faster estrogen suppression than LHRH agonists 4

When to Avoid CDK4/6 Inhibitors

CDK4/6 inhibitors should be avoided in patients with imminent organ failure requiring rapid response—these patients should receive chemotherapy first. 1

• Primary endocrine resistance (relapse during first 2 years of adjuvant endocrine therapy or progression within 6 months of first-line endocrine therapy for metastatic disease) may warrant chemotherapy over endocrine-based therapy 1

Practical Algorithm

1. Confirm HR-positive, HER2-negative status and assess for visceral crisis 1
2. If no visceral crisis and postmenopausal (or premenopausal with ovarian suppression):
   • First-line: Abemaciclib + aromatase inhibitor (letrozole or anastrozole) 1
   • Monitor closely for hepatotoxicity given liver metastases 5
3. If progression on first-line aromatase inhibitor:
   • Second-line: Abemaciclib + fulvestrant (preferred over aromatase inhibitor to reduce hepatotoxicity risk) 4, 5
4. Avoid tamoxifen as the endocrine partner with abemaciclib 3

Key Toxicity Management

Diarrhea occurs in 81-90% of patients taking abemaciclib and is the most common side effect. 6

• Grade 3 diarrhea occurs in approximately 9-10% of patients 6

• Despite high incidence, 83.8% of cases are effectively managed with dose modifications and antidiarrheal medications 6

• Hepatotoxicity monitoring is essential, particularly in patients with liver metastases receiving concomitant aromatase inhibitors 5