What are the next steps for a patient with ER (estrogen receptor)-positive, HER2 (human epidermal growth factor receptor 2) 1+, PR (progesterone receptor)-negative advanced breast cancer who is progressing in the liver on ribociclib (Kisqali) (cdk4/6 inhibitor) and fulvestrant (Faslodex) (estrogen receptor antagonist)?

From the Guidelines

For a patient with ER-positive, HER2 1+, PR-negative advanced breast cancer progressing in the liver while on ribociclib and fulvestrant, the recommended next step is to switch to endocrine therapy with an alternative mechanism of action, such as exemestane (25mg daily) combined with everolimus (10mg daily) as suggested by the most recent guidelines 1. This combination provides a different approach by targeting the mTOR pathway, which can help overcome resistance to CDK4/6 inhibition. The choice of this combination is based on the patient's prior treatment with a CDK4/6 inhibitor and the need to switch to a different mechanism of action to regain control of the disease. Alternatively, chemotherapy with capecitabine (1000-1250mg/m² twice daily for 14 days of a 21-day cycle) or weekly paclitaxel (80-90mg/m² on days 1,8, and 15 of a 28-day cycle) could be considered, especially given the liver progression which suggests more aggressive disease. Before initiating new treatment, it's essential to obtain repeat biopsies of progressing lesions to confirm the tumor's receptor status, as this may have changed. Additionally, genomic testing should be performed to identify potential actionable mutations like ESR1, PIK3CA, or BRCA mutations that could guide targeted therapy options. Treatment selection should also consider the patient's performance status, comorbidities, prior toxicities, and preferences regarding quality of life versus aggressive disease control. The rationale for changing therapy is that progression on CDK4/6 inhibition indicates resistance to the current mechanism of action, necessitating a switch to agents with different molecular targets to regain control of the disease. It is also crucial to carefully select candidates for alpelisib treatment, considering comorbidities, especially pre-existing diabetes and baseline glycated haemoglobin (HbA1c) levels, as suggested by the SOLAR-1 phase III randomised, placebo-controlled trial 1. Key considerations in the management of this patient include:

• The patient's tumor biology, including ER, PR, and HER2 status
• Prior treatment history, including response to and toxicity from previous therapies
• Performance status and comorbidities
• Patient preferences regarding quality of life and disease control
• The potential for genomic testing to guide targeted therapy options.

From the FDA Drug Label

The FDA drug label does not answer the question.

From the Research

Next Steps for Patient with ER-Positive, HER2 1+, PR-Negative Advanced Breast Cancer

• The patient is progressing in the liver on ribociclib and fulvestrant, and the next steps should be based on the clinical data and patient selection criteria 2.
• Considering the patient's ER-positive, HER2 1+, and PR-negative status, the combination of ribociclib and fulvestrant has shown significant progression-free survival and overall survival benefits in similar patient populations 3, 4.
• However, the patient's progression in the liver may indicate a need to reassess the treatment strategy, and alternative options such as exemestane may be considered, as seen in a case report where a patient with fulminant hepatitis due to ribociclib was switched to exemestane 5.
• The safety profile of ribociclib plus fulvestrant should also be taken into account, with monitoring for hepatobiliary toxicity, pneumonitis, and QTc prolongation, as these toxicities can occur at a low rate 6.
• Patient selection and special settings, such as cardiac morbidities or other risk factors for QTc prolongation, should be considered when choosing alternative treatments, and different agents like palbociclib or abemaciclib may be used in these cases 2.

Treatment Options

• Exemestane: may be considered as an alternative treatment option for patients who experience toxicity or progression on ribociclib and fulvestrant 5.
• Palbociclib or abemaciclib: may be used as alternative CDK4/6 inhibitors in patients with cardiac morbidities or other risk factors for QTc prolongation 2.
• Other hormonal pathway therapy options: may be explored in patients who experience progression on ribociclib and fulvestrant, considering the patient's ER-positive, HER2 1+, and PR-negative status 6.