What is the next treatment option for a 65-year-old woman with a BRCA2 mutation and metastatic estrogen receptor (ER) negative, human epidermal growth factor receptor 2 (HER2) low breast cancer, who has previously received doxorubicin (Adriamycin) and cyclophosphamide (AC), docetaxel (Taxotere)/cyclophosphamide (Cytoxan), gemcitabine (Gemzar) and carboplatin (Carboplatin), and has progressed on olaparib (Lynparza)?

From the Guidelines

For a 65-year-old woman with BRCA2 mutation and metastatic ER-negative, HER2-low breast cancer who has progressed on multiple lines of therapy including AC, taxotere/cytoxan, gemcitabine/carboplatin, and most recently olaparib, I would recommend sacituzumab govitecan (Trodelvy) as the next treatment option. The standard dosing is 10 mg/kg administered as an intravenous infusion on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity 1. Prior to administration, premedication with antipyretics, H1 and H2 blockers, and corticosteroids is recommended to prevent infusion reactions. The most common side effects include neutropenia, diarrhea, nausea, fatigue, and alopecia, so regular monitoring of blood counts is essential with potential need for growth factor support. Sacituzumab govitecan is an antibody-drug conjugate that targets Trop-2, which is expressed in many epithelial cancers including breast cancer, and delivers SN-38, a topoisomerase I inhibitor. This agent has shown efficacy in heavily pretreated metastatic breast cancer patients, including those with BRCA mutations who have progressed on PARP inhibitors like olaparib 1.

Some key points to consider in this decision include:

• The patient's history of progression on olaparib, a PARP inhibitor, which suggests that alternative treatments should be considered 1.
• The presence of a BRCA2 mutation, which may influence the choice of treatment, although the optimal sequencing of PARP inhibitors is still undetermined 1.
• The patient's ER-negative, HER2-low status, which may make certain targeted therapies less effective, but sacituzumab govitecan has shown efficacy in this population 1.
• The importance of considering the patient's quality of life and potential toxicities associated with different treatments, as health-related quality of life was better with PARP inhibitors compared with chemotherapy in some studies 1.

Alternative options could include eribulin or clinical trials investigating novel agents, particularly those targeting HER2-low status. However, based on the current evidence, sacituzumab govitecan is the most appropriate next treatment option for this patient 1.

From the FDA Drug Label

12.1 Mechanism of Action Sacituzumab govitecan-hziy is a Trop-2-directed antibody-drug conjugate. Sacituzumab is a humanized antibody that recognizes Trop-2. The small molecule, SN-38, is a topoisomerase I inhibitor, which is covalently attached to the antibody by a linker Pharmacology data suggest that sacituzumab govitecan-hziy binds to Trop-2-expressing cancer cells and is internalized with the subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I-induced single strand breaks. The resulting DNA damage leads to apoptosis and cell death Sacituzumab govitecan-hziy decreased tumor growth in mouse xenograft models of triple-negative breast cancer.

The patient has metastatic ER-negative, HER2-low breast cancer and has previously received multiple lines of therapy, including AC, taxotere/cytoxan, gem carbo, and most recently olaparib. Given the patient's BRCA2 mutation and progression on olaparib, sacituzumab govitecan-hziy may be considered as a next-line treatment option. Key points to consider:

• The patient's age (65 years) and performance status should be taken into account when making treatment decisions.
• The patient's tumor biology (e.g., Trop-2 expression) may also influence the decision to use sacituzumab govitecan-hziy.
• Monitoring for adverse reactions and dose adjustments may be necessary based on the patient's individual response to treatment 2.

From the Research

Treatment Options for Metastatic ER-Negative HER2-Low Breast Cancer

• The patient has a BRCA2 mutation and has previously received AC, taxotere/cytoxan, gem carbo, and most recently progressed on olaparib.
• Considering the patient's history and current condition, sacituzumab govitecan may be a potential treatment option, as it has shown promising anti-cancer activity in patients with metastatic triple-negative breast cancer previously treated with at least two prior lines of systemic therapy 3, 4.
• Sacituzumab govitecan has a manageable side effect profile, with the most common adverse events being nausea, neutropenia, and diarrhea 3, 4.
• The activity of sacituzumab govitecan likely extends beyond TNBC, with promising early efficacy data in many other epithelial cancers, including hormone receptor-positive breast cancer 3.

Considerations for Treatment

• The patient's BRCA2 mutation may impact the effectiveness of certain treatments, such as olaparib, which has been approved for use in patients with advanced ovarian cancer and a BRCA mutation 5, 6.
• However, the patient has already progressed on olaparib, so alternative treatments should be considered.
• Other FDA-approved treatments for TNBC, such as paclitaxel, docetaxel, doxorubicin, and epirubicin, may also be considered, although the patient has already received some of these treatments 7.
• Immunotherapies, such as Keytruda, may also be an option, although their effectiveness in this patient population is still being studied 7.