What is the next line of treatment for a 58-year-old patient with metastatic estrogen receptor (ER) positive, human epidermal growth factor receptor 2 (HER2) negative breast cancer, who has progressed on all available endocrine agents, with rapid liver progression, elevated total bilirubin (T bill), significantly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and an Eastern Cooperative Oncology Group (ECOG) performance status of 1?

From the Guidelines

For a 58-year-old patient with metastatic ER-positive, HER2-negative breast cancer who has progressed on all available endocrine therapies and now has rapid liver progression with significant hepatic dysfunction, I would recommend single-agent chemotherapy with a taxane, such as paclitaxel, at a reduced dose due to the patient's liver dysfunction. Given the patient's condition, with elevated liver enzymes (T bili 12, AST 500, ALT 345) and no cytopenias or renal dysfunction, the goal is to balance disease control with minimizing toxicity [ 1 ].

Key Considerations:

• The patient's ECOG PS of 1 indicates a relatively good performance status, suggesting they can tolerate some level of chemotherapy [ 1 ].
• The absence of cytopenias and normal renal function are favorable factors for chemotherapy tolerance.
• The significant liver dysfunction necessitates a cautious approach to chemotherapy dosing to avoid exacerbating liver injury.
• The patient's preference to avoid hospice care and pursue active treatment guides the decision towards a therapeutic approach that offers a chance of disease control and symptom improvement.

Treatment Approach:

• Single-agent weekly paclitaxel at a reduced dose of 60-80 mg/m² on days 1,8, and 15 of a 28-day cycle is a reasonable choice, considering the need to balance efficacy with the risk of toxicity in a patient with compromised liver function [ 1 ].
• Premedications including dexamethasone 10mg IV, diphenhydramine 25-50mg IV, and famotidine 20mg IV should be administered to prevent hypersensitivity reactions.
• Close monitoring of liver function tests weekly for the first cycle is crucial, with dose adjustments based on tolerance.
• If the patient responds with improved liver function, doses can be gradually increased to optimize disease control while minimizing toxicity.

This approach is guided by the principles outlined in the American Society of Clinical Oncology clinical practice guideline for chemotherapy and targeted therapy in women with human epidermal growth factor receptor 2-negative advanced breast cancer [ 1 ], emphasizing the importance of tailoring treatment to the individual patient's condition, previous therapies, and preferences.

From the FDA Drug Label

The efficacy of gemcitabine was evaluated in a multinational, randomized, open-label trial (Study 2) conducted in women receiving initial treatment for metastatic breast cancer who have received prior adjuvant/neoadjuvant anthracycline chemotherapy unless clinically contraindicated Patients were randomized to receive either gemcitabine 1250 mg/m 2on Days 1 and 8 of a 21-day cycle and paclitaxel 175 mg/m 2administered on Day 1 before gemcitabine administration (n=267) or paclitaxel 175 mg/m 2on Day 1 of each 21-day cycle (n=262)

The next line of treatment for the 58-year-old patient with metastatic ER-positive, HER2-negative breast cancer who has progressed on all available endocrine agents could be chemotherapy.

• Gemcitabine in combination with paclitaxel has shown statistically significant improvement in time to documented disease progression and overall response rate compared to paclitaxel alone in patients with metastatic breast cancer who have received prior adjuvant/neoadjuvant anthracycline chemotherapy 2.
• However, the patient's current clinical status, including rapid progression in the liver and elevated liver enzymes, should be carefully considered when making treatment decisions.
• Given the patient's ECOG PS 1 and lack of cytopenias or renal dysfunction, they may be a candidate for chemotherapy.
• The decision to proceed with chemotherapy should be made on a case-by-case basis, taking into account the patient's individual circumstances and preferences.

From the Research

Treatment Options for Metastatic ER Positive HER2 Negative Breast Cancer

• The patient has progressed on all available endocrine agents and is now experiencing rapid progression in the liver, with elevated liver enzymes (T bill of 12, AST 500, ALT 345) 3.
• Given the patient's condition, chemotherapy is a viable option, with capecitabine being a potential choice due to its efficacy in endocrine-resistant breast cancer 3, 4, 5.
• Capecitabine has been shown to have a moderate progression-free survival (PFS) benefit in hormone receptor-positive metastatic breast cancer, particularly in patients who have not previously received a CDK4/6 inhibitor 3.
• The patient's ECOG PS of 1 indicates that they are still relatively active and able to tolerate treatment, making chemotherapy a feasible option 3.

Considerations for Elacestrant

• Elacestrant is a novel oral selective estrogen receptor degrader (SERD) that has demonstrated efficacy in patients with HR-positive, HER2-negative advanced breast cancer, including those with ESR1 mutations 6.
• However, elacestrant is typically considered for patients who have not yet progressed on all available endocrine agents, and its use in this patient population may be limited 6.

Chemotherapy as a Next-Line Treatment

• Given the patient's rapid progression and lack of response to endocrine therapy, chemotherapy with capecitabine may be a suitable next-line treatment option 3, 4, 5.
• The patient's normal renal function and lack of cytopenias also make chemotherapy a viable option 3.