Standard therapies for treating hormone-sensitive metastatic breast cancer (BC) include the blockage of estrogen pathways by using selective estrogen modulator receptors or selective estrogen receptor downregulators and by using aromatase inhibitors to block estrogen production. The addition of nonhormonal targeted therapies, including therapies based on alternative molecular pathways, continues to expand rapidly for advanced or metastatic BC. This article reviews targeted therapy treatment options for patients with metastatic BC, including strategies for administration, side effects, and nursing considerations.
AT A GLANCE
- Targeted therapies for the treatment of metastatic BC are based on inhibition of different molecular pathways and mutations.
- The number of metastatic BC therapies, including oral anticancer agents, that can be self-administered by patients at home are increasing.
- Oncology nurses who are familiar with evolving metastatic BC therapies are best equipped to provide comprehensive patient care and support.
Breast cancer (BC) remains the leading incidence and second-highest cause of cancer mortality in women in the United States, and people who are diagnosed with new or recurrent advanced-stage or metastatic BC have an increasing number of options for treatment (American Cancer Society [ACS], 2018). Metastatic BC treatments focus on systemic therapies that block estrogen and progesterone receptors for hormone receptor (HR)–positive disease and human epidermal growth factor receptor 2 (HER2/neu) receptor sites for HER2/neu-positive disease. Hormonal therapies for HR-positive disease include selective estrogen receptor modulators (e.g., tamoxifen or raloxifene, selective estrogen receptor downregulators (e.g., fulvestrant), or aromatase inhibitors that block estrogen productions (e.g., anastrozole, letrozole, exemestane). Because these hormonal therapies have been reported to have fewer side effects and are better tolerated compared to chemotherapy, they are considered to be a preferred treatment for patients with metastatic BC (Spring, Bardia, & Modi, 2016).
Monoclonal Antibody Therapy
According to ACS (2018), one in five women with HER2/neu-positive metastatic BC will receive treatment that includes monoclonal antibody therapy. Monoclonal antibody therapies include trastuzumab via IV, trastuzumab with hyaluronidase-oysk injection via subcutaneous injection, and pertuzumab administered in conjunction with trastuzumab and chemotherapy via IV (Wilcken et al., 2014). Ado-trastuzumab emtansine is a second-line monoclonal antibody therapy that is administered with another chemotherapy agent to treat HER2/neu-positive metastatic BC (Hamizi et al., 2013). One HER2/neu kinase inhibitor agent that is taken orally for the treatment of metastatic BC is lapatinib, which inhibits the epidermal growth factor pathway (Blackwell et al., 2009).
Side effects of monoclonal antibody targeted therapies can include cardiac dysfunction, diarrhea, fatigue, nausea and vomiting, and rash. Additional side effects specific to lapatinib may include hepatoxicity, pneumonitis, and hand-foot syndrome (Blackwell et al., 2009). Cardiac dysfunction or heart failure are serious adverse events that are associated with this class of drugs, particularly when administered in combination with other cardiotoxic chemotherapy agents, such as anthracyclines, doxorubicin, or epirubicin chemotherapy. Patients receiving these agents require routine cardiac screening to monitor for symptoms (Fiúza, 2009; Valachis, Nearchou, Polyzos, & Lind, 2013). Patients aged 50 years or older with preexisting heart disease who are receiving potentially cardiotoxic therapies are at a greater risk for cardiac-related adverse events (Armenian et al., 2017). Guidelines recommend obtaining an echocardiogram as the preferred screening method for heart function; however, a multigated acquisition scan that uses a radioactive tracer can also be used to evaluate heart pumping function prior to administering treatment. In addition, routine echocardiographic surveillance is also recommended for patients with metastatic BC receiving trastuzumab indefinitely (Armenian et al., 2017).
Cyclin-Dependent Kinase Inhibitors
During the course of treatment, patients with metastatic BC who are HR-positive or HER2/neu-positive may become resistant to hormone- or HER2/neu-blocking therapies (Kwapisz, 2017). Cyclin-dependent kinase (CDK) inhibitors that target CDK retinoblastoma pathways associated with endocrine therapy resistance are additional targeted therapies for HR-positive and HER2/neu-positive metastatic BC (Spring et al., 2016). The mechanism of action for metastatic BC CDK4/6 agents involves cell cycle regulators that control cell division. The U.S. Food and Drug Administration (FDA) has approved the following oral agents for the treatment of metastatic BC: abemacicib, palbociclib, and ribociclib. These CDK4/6 inhibitors are used in combination with selective estrogen modulator receptors, selective estrogen receptor downregulators, or aromatase inhibitors as first-line therapy for metastatic BC. In addition, these agents can be used to treat disease progression following systemic chemotherapy treatments. Common adverse events for CDK inhibitors are hematologic issues, such as neutropenia, diarrhea, nausea and vomiting, and fatigue (Spring et al., 2016). According to Spring et al. (2016), neutropenia is particularly reported by patients receiving palbociclib and ribociclib, and diarrhea is the most commonly reported drug-related adverse event for patients receiving abemacicib.
Abemacicib has been approved by the FDA for use following disease progression in patients receiving endocrine therapy. In the MONARCH 3 trial, administering abemacicib with fulvestrant improved median progression-free survival for postmenopausal women with HR-positive BC (Goetz et al., 2017). According to a study by Finn et al. (2016), palbociclib used in combination with letrozole versus letrozole alone improved progression-free survival for postmenopausal patients with metastatic BC. Palbociclib and letrozole also demonstrated efficacy in a 2015 PALOMA 3 trial of patients with metastatic BC who experienced disease progression while being previously treated with endocrine therapy (Turner et al., 2015). In postmenopausal women with HR-positive or HER2-negative advanced BC, ribociclib plus fulvestrant demonstrated better efficacy in improving progression-free survival than treatment with fulvestrant alone (Slamon et al., 2018). Based on the results from the MONALEESA-7 trial, which demonstrated that ribociclib used in combination with an aromatase inhibitor and ovarian suppression led to improved progression-free survival compared to an aromatase inhibitor and ovarian suppression alone, the FDA expanded the use of ribociclib for premenopausal and perimenopausal women (Tripathy et al., 2018).
CDK4/6 inhibitor agents, which are frequently administered with combination therapy, often have unique dosing schedules that require routine dose adjustments and have specific guidelines for administration. Indications, dosages, administration guidelines for these CDK4/6 agents, as well as adverse events and patient considerations, are outlined in Table 1.
Additional therapies that block germline BRCA-mutant triple-negative BCs, also known as estrogen receptor– or progesterone receptor–positive HER2/neu-negative disease, are poly adenosine diphosphate ribose polymerase (PARP) inhibitors (Fong et al., 2009). Triple-negative BC, which is an aggressive type of BC, occurs in as many as 13% of all patients with BC and has a higher prevalence in younger women, as well as African American women. Platinum-based drugs are often used to treat triple-negative BC (Bianchini, Balko, Mayer, Sanders, & Gianni, 2016; Kohler et al., 2015). PARP inhibitors that are administered orally with antitumor activity for germline BRCA mutations found in triple-negative BC include olaparib and talazoparib (Fong et al., 2009; Litton et al., 2018). Common adverse events for PARP inhibitors include fatigue, anemia, nausea and vomiting, neutropenia, headache, thrombocytopenia, alopecia, diarrhea, and decreased appetite (AstraZeneca, 2018; Pfizer, 2018). Serious adverse events that have been reported with the use of PARP agents are myelodysplastic syndrome, acute myeloid leukemia, myelosuppression, and pneumonitis (AstraZeneca, 2018; Pfizer, 2018). Patients with luminal androgen-receptor triple-negative BC are often treated with antiandrogen blockade agents (Bianchini et al., 2016).
Implications for Nursing
Oncology nursing considerations for targeted therapies for patients with metastatic BC include being knowledgeable of drug classes based on indicated molecular targeted pathways and genetic mutations, proper drug administration, educating patients, and monitoring for side effects and adverse events. Patients prescribed oral targeted therapies for metastatic BC require education on drug procurement, proper drug storage, drug dosages and frequency, potential drug interactions, and support strategies, such as medication reminders, actions to take for missed or skipped doses, and how to report side effects to ensure the timely management of symptoms. The Oncology Nursing Society ([ONS], 2016) oral adherence toolkit provides a compilation of tools that can be used with patients with metastatic BC to improve adherence to oral therapies. The toolkit includes a patient assessment checklist, examples of materials to incorporate into patient education, and oral chemotherapy and ordering standards, as well as strategies on how to develop a process for medication tracking, methods to encourage patient adherence, medication reconciliation, and additional resources (ONS, 2016).
Care precautions for patients receiving treatment for metastatic BC include hematologic considerations, such as monitoring for risks for infection (e.g., fevers), fatigue, bleeding, and bruising. In addition, patient education on monitoring for symptoms, such as headache, cough, rash, diarrhea, nausea and vomiting, and hand-foot syndrome, is needed to ensure that proper symptom management interventions are administered. Routine blood work, including complete blood count with differential, electrolytes, and liver function tests, is recommended depending on the type of therapy being used to treat metastatic BC. Nurses can educate patients with metastatic BC who are being treated with kinase inhibitor targeted therapies on the potential for drug interactions involving CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, ritonavir, telithromycin, voriconazole); CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifapentine, phenobarbital, St. John’s wort); and substrates of CYP3A4, CYP2C8, or P-glycoprotein (ABCB1). Educating patients on the importance of avoiding certain foods and drinks while being treated with oral kinase inhibitors is also warranted.
The rapid growth of targeted therapies, including oral agents, continues to expand treatment options for patients with metastatic BC. As more patients with metastatic BC begin self-administering oral agents at home, oncology nurses need to remain updated on these evolving newer therapies. Best practice standards for caring for patients with metastatic BC being treated with oral targeted therapies should include having a team of nurses, oncologists, pharmacists, and social workers who can address drug procurement assistance, proper education, medication administration, monitoring for potential drug–drug interactions, and psychosocial support.
About the Author(s)
Rachel M. Richards, DNP, ANP-BC, is an assistant professor and Elizabeth A. Keating, MS, ANP-BC, is an instructor, both in the Graduate School of Nursing, and Jean E. Boucher, PhD, RN, ANP-BC, AOCNP®, is an associate professor of nursing and medicine in the Graduate School of Nursing and director of the DNP program, all at the University of Massachusetts Medical School in Worcester. The authors take full responsibility for this content and did not receive any honoraria or disclose any relevant financial relationships. Richards can be reached at email@example.com, with copy to CJONEditor@ons.org.
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