Importance of Receptor Status in Long-Term Management of Patients With Breast Cancer

As one of the leading causes of morbidity and mortality in women, every specialty pharmacist should be intimately familiar with breast cancer. In 2017, there are expected to be 318,590 new cases and 40,610 deaths due to breast cancer in the United States.¹ Over the past 4 decades, many new treatments and screening techniques have improved survival and detection of breast cancer.²

The improved screening techniques often assist with early detection of breast cancer during the stages that are most responsive to treatment. Specialty pharmacists are uniquely positioned to help with the treatment of breast cancer. We are specialists in oral oncology agents and offer comprehensive consultations that allow patients to confidently take their medication.

Our thorough understanding of the agents used and their subsequent management enable us to positively impact a patient’s adherence and promote successful use of these therapies. Through our patient interactions, we are able to address potential medication side effects early after initiation of therapy, offsetting the need for dose modification or discontinuation.

This affects results by way of improved outcomes and quality of life. Although we work with a thorough knowledge of chemotherapy agents, many specialty pharmacists do not have the necessary understanding of the pathophysiology behind breast cancer to fully comprehend this disease. We sometimes fall short in considering the long-term implications many of these medications can have on a patient’s life.

The goal in early-stage breast cancer is to obtain complete remission. In this stage, the general treatment regimen consists of surgery and radiation followed by adjuvant chemotherapy as needed. The decisions surrounding route, duration, and type of surgery or chemotherapy are individualized based upon receptor status, lymph node involvement, age, sex, provider, or health system preference, and other extenuating factors.

Even in early breast cancer, the risks of metastasis and recurrence are present. This necessitates the use of adjuvant chemotherapy in certain situations. In metastatic breast cancer, the likelihood of complete remission is low, and the goal of therapy shifts to prolonging survival and improving quality of life.

As new targeted therapies have come to market and improved survival, metastatic breast cancer is becoming a long-term disease in a growing number of patients. Thus, our role in managing these patients has shifted from the management of the immediate impacts of chemotherapy to long-term management of cancer and associated comorbidities.

Hormone Receptor—Positive

Receptor status is an important predictive factor in how a patient’s breast cancer will respond to therapy.² This tool guides an oncologist’s medication choice and treatment decisions. Although receptor status does not predict the likelihood of metastasis or recurrence, it remains important in determining what therapy the tumor will likely respond to.

Both estrogen and progesterone receptors can be present on the surface of breast cancer cells. Immunohistochemistry is used to determine the level of hormone receptors present on the tumor. Higher levels increase the likelihood of responding to endocrine therapy. Between 60% and 75% of patients have tumors that are hormone receptor (HR)-positive at diagnosis.³

In this subset of breast cancer patients, the binding of estrogen causes proliferation and cell growth. A tumor found to be HR-positive has a 60% to 70% likelihood of responding to endocrine therapy and is thus considered to be a good prognostic factor.2 Endocrine therapy works by depriving the tumor of the hormones that cause unregulated cell growth.

This can be done by decreasing circulating hormone levels or blocking the activity of estrogen at the receptor. The most frequently used treatments for endocrine therapy include aromatase inhibitors, selective estrogen receptor modulators (SERMs), luteinizing hormone-releasing hormone agonists, and ovarian suppression.⁴

A patient’s menopausal status guides the choice of which agent will be used. Prior to menopause, the majority of the estrogen circulating throughout the body comes from the ovaries. After menopause, the majority of estrogen is created in the periphery via the enzyme aromatase.²

For this reason, premenopausal women with intact ovaries are not given aromatase inhibitors as adjuvant therapy. This may change as the use of aromatase inhibitors are being investigated in conjunction with ovarian ablation or suppression.⁵

Tamoxifen, a SERM, is currently the gold standard adjuvant endocrine therapy in premenopausal early stage breast cancer. If an aromatase inhibitor is used in this population, a specialty pharmacist must be able to document that the patient is postmenopausal or has gone through ovarian suppression therapy.⁴

It is important to note that amenorrhea does not guarantee that a patient is postmenopausal. Therefore, it may be pertinent for a specialty pharmacist to ask for lab values that point to menopause before dispensing an aromatase inhibitor in monotherapy to this population. Postmenopausal women, on the other hand, can be put on either tamoxifen or an aromatase inhibitor. The duration of treatment for either agent varies based on provider preference, but patients with breast cancer are generally treated for at least 5 years.

This has been proven to reduce the risk of breast cancer recurrence by close to 50%.² If there is disease progression while on endocrine therapy, changing to an alternate endocrine medication is an option. This is often done when the patient has had an initial response to endocrine therapy, but disease progression occurred.

Another option for many patients who fail primary endocrine therapy is the use of targeted agents. In particular, targeted therapy is becoming much more prevalent in the advanced and metastatic settings. Inhibitors of mammalian target of rapamycin and cyclin-dependent kinases are currently approved for HR-positive tumors. These agents target downstream signaling in estrogen-dependent tumors. Currently, they must be combined with an aromatase inhibitor or a SERM to provide maximal benefit. It is important to consider that many patients do not fill their aromatase inhibitor or their SERM at a specialty pharmacy.

Therefore, we must counsel our patients on the need to take these medications together, as monotherapy may result in reduced efficacy. As we learn more about the signaling involved in cell replication and regulation in breast cancer cells, we will develop more targets to suppress growth and decrease tumor size. A new class of medications, poly ADP ribose polymerase (PARP) inhibitors, are being evaluated in HR-positive breast cancer with BRCA1/BRCA2 mutations.

Preliminary results of the OLYMPIAD trial, which is evaluating the use of a PARP inhibitor in improving progression-free survival, has been extremely promising. Patients who are unresponsive to endocrine or targeted therapy are often given systemic cytotoxic agents.

Human Epidermal Growth Factor Receptor 2—Positive

Human epidermal growth factor receptor 2 (HER2) is an endothelial tyrosine kinase receptor present on normal healthy breast tissue⁶ that is involved in cell growth and differentiation. The overexpression of HER2 is present in 25% to 30% of patients with breast cancer. In the past, the overexpression correlated with high recurrence rates and a worsened prognosis.⁷

As targeted therapies became available, the survival rate of HER2-positive breast cancer significantly increased. Currently, 3 monoclonal antibodies (trastuzumab, pertuzumab, ado-trastuzumab emtansine) and 1 tyrosine kinase inhibitor (lapatinib) directly target HER2. These targeted agents are used in combination with other adjuvant therapies to induce remission. Anthracyclines and taxanes are commonly used with HER2-targeted monoclonal antibodies.²

With the exception of ado-trastuzumab emtansine, you will rarely see any of these targeted agents used as monotherapy. Furthermore, the combination of lapatinib and capecitabine is generally reserved until there has been disease progression on a trastuzumab-containing regimen.

Triple Negative

Triple negative breast cancer (TNBC) refers to a tumor that is negative for HER2 overexpression and estrogen and progesterone hormone receptors. TNBC accounts for 15% to 20% of all breast cancers.⁸ Currently, the options for these patients include surgery followed by radiation and systemic cytotoxic chemotherapy.⁹

The use of neoadjuvant systemic chemotherapy, often with an anthracycline- or taxane-containing regimen, is being utilized at many treatment centers. Patients who attain a pathological complete response with neoadjuvant therapy have a good prognosis² whereas patients who have residual breast cancer after neoadjuvant therapy have been found to have a high recurrence rate and a worse prognosis.⁸

Developing targeted agents in this population is of great focus right now. Although treatment of HR- and HER2-positive breast cancers has made huge advances over the past 2 decades, outcomes in TNBC have remained relatively static. New combinations of cytotoxic agents are under review, but the prognosis is still poor for patients who do not have an initial positive response to cytotoxic chemotherapy.

In patients with TNBC with a BRCA1 or BRCA2 genetic mutation, PARP inhibitors are being investigated. In addition, pembrolizumab, a monoclonal antibody targeting programmed death receptor 1, is currently under investigation for use in this population.⁸

Long-Term Management Cardiovascular

As targeted therapies and new screening techniques continue to improve 5-year survival rates for patients breast cancer, the role of specialty pharmacists in managing these patients will continue to grow. Targeted and cytotoxic therapeutic agents have long-term complications that require extensive monitoring and counseling; the cardiovascular effects of breast cancer treatment with trastuzumab and anthracyclines are well documented.

Cardiac dysfunction has been reported in up to 50% of patients treated with an anthracycline, with close to 5% developing clinically significant heart failure.¹⁰ In addition, trastuzumab has caused cardiac dysfunction in 5% to 10% of patients, with 2% to 3% developing heart failure.¹⁰

This risk significantly increased with the concomitant use of trastuzumab and an anthracycline agent.² For patients with HER2-positive or TNBC, this is a risk that many patients must live with. The rationale behind using these treatments is that their immediate benefit outweighs the long-term risk of cardiovascular complications.

Radiation therapy, used frequently in all breast cancer subtypes, can also put patients at risk for cardiovascular events. While many specialty pharmacies may not be directly involved in dispensing these medications, knowing their impact on our patients is important. At some point, we will likely see patients with a history of anthracyclines or trastuzumab put on new targeted agents as they are developed.

Therefore, we must understand how past treatments affect long-term health. To improve patient outcomes, specialty pharmacists should counsel all patients with breast cancer on the importance of blood pressure control, cholesterol management, exercise, and a healthy diet. Education on regular health screenings should also be emphasized to decrease the risk of heart failure and complications.

Depression

The psychological impact of having breast cancer is something that many pharmacists do not address. It is believed that 10% to 25% of patients with cancer have some degree of clinical depression and that this population has a 3 to 4 times higher likelihood of having depression than the general population.¹¹

It is also important to note that depression has been linked to nonadherence to oncology medications, a decreased quality of life, and worsened outcomes during cancer treatment.¹¹ It is extremely important that this be addressed at the beginning of therapy or at the earliest sign of depressive symptoms. Treatment of depression in oncology patients is approached in a similar manner to the general population.³

Patients who are on tamoxifen for adjuvant endocrine therapy must be careful when using fluoxetine or paroxetine due to the impact on CYP2D6, an enzyme involved in the metabolism of antidepressants. Therefore, it is good practice to address depressive symptoms with patients during initial oncology consultation and as needed throughout treatment.

Fertility

Another factor that must be considered is a patient’s desire to have children after treatment. Women of child-bearing years should have a discussion with their oncologist about their intentions to get pregnant,⁴ as the timing of radiation, surgery, and types of agents used will differ in patients who wish to have children. The use of tamoxifen and trastuzumab should be avoided during pregnancy,¹² as should chemotherapy agents during the first trimester, if possible, because this is the time many organ systems are developing in the fetus.¹²

Additionally, there should be a discussion of fertility preservation options with younger patients who opt for surgical oophorectomy or when chemotherapeutic agents increase the likelihood of fertility issues.⁴ The results of a recent retrospective study demonstrate that even though chemotherapy agents may increase the risk of fertility issues, there does not appear to be a higher risk of common pregnancy-related complications in this population.¹³

This is an important counseling point for many pharmacists in our setting. In conclusion, specialty pharmacists are equipped with a unique skill set that positions them to take a more active role in the long-term management of patients with breast cancer.

An understanding of the receptors that are being targeted allows for an assessment of the appropriateness of therapy, which results in improved patient care. This level of knowledge will also lead to improved adherence and increased quality of life for our patients.

About the Author

Adam Furman received his doctor of pharmacy degree from Oregon State University in 2012. He joined Ardon Health as a clinical pharmacist in December 2014 and was promoted to clinical pharmacist lead in 2015. In this position, he has taken an active role in care management, the development of clinical programs, and inventory management. Dr. Furman serves as a member of the Clinical Oversight Body at Ardon Health, preparing and presenting clinical programs and quality improvement measures. Prior to joining Ardon Health, he spent 2 years working as a pharmacist in the community and long-term care settings.