Narratives on Collaboration

Managing the Care of Patients With
HER2-Positive Breast Cancer

A Collaborative Practice Model

Interviews and Reporting by Christine Wilson

In this interactive digital supplement to the Journal of the Advanced Practitioner in Oncology, or JADPRO, we review the treatment and management of patients with HER2-positive breast cancer and discuss a treatment model in which the physician and nurse practitioner work together to efficiently care for the patient. To add depth and perspective, we have included comments and discussion from people involved in different parts of the breast cancer experience: Angela DeMichele, MD, a breast cancer specialist at the Abramson Cancer Center of the University of Pennsylvania; Jennie Greco Lattimer, NP, who has worked closely with Dr. DeMichele for 15 years; and Rachel F., a patient who was diagnosed with metastatic HER2-positive breast cancer at age 38 in July 2015. To gain additional perspectives, read the print version of this supplement which was mailed out to subscribers with the Nov/Dec JADPRO 2016 issue.

B

reast cancer is a complex group of diseases. New understanding of its biology and genetics has shown that breast cancer is characterized by multiple subtypes, which all have significant impact on treatment decisions and prognosis.

Human epidermal growth factor receptor 2 (HER2)–positive breast cancer has been recognized as a distinct subtype since the early 1980s when researchers discovered a link between high levels of HER2 and the ability of cancer cells to grow rapidly (Kumar & Badve, 2008). HER2 receptors can signal to the nucleus when bound to their ligand or heregulin, or simply through homodimerization (due to the high density of receptors on the cell surface) or heterodimerization between HER2 and its partners, HER1, HER3, and HER4. This discovery led to the development of trastuzumab (Herceptin)–a monoclonal antibody that targets HER2 overamplification—and has transformed HER2-positive breast cancer from a disease with a poor prognosis to one that can be treated effectively, especially in its early stages (National Cancer Institute [NCI], 2016a).

However, both de novo and acquired resistance to trastuzumab exists. Activity of members of the HER family, including HER1, 3 and rarely, 4, coexist with HER2 overexpression, often heterodimerizing with HER2, which can be an escape mechanism when HER2 homodimerization is blocked. The HER3 mutation may play a particularly important role in tumor resistance to HER2 blockades (NCI, 2016b; Harbeck et al. 2013).

Survey 1
How many patients with HER2-positive breast cancer do you see in your practice each week?

Today, receptor profiling of breast cancer is standard and essential to determining optimal therapy. Approximately 25% of breast cancer patients test positive for HER2 overexpression or amplification (Breastcancer.org, 2016). Patients with stage I–III HER2-positive disease typically undergo either adjuvant or neoadjuvant treatment in addition to surgery and radiation therapy. This approach produces high rates of complete response to neoadjuvant therapy and long-term survival (Glaberman, Dayao, & Royce, 2014).

Patients diagnosed with metastatic (i.e., stage IV) HER2-positive breast cancer or whose disease recurs following primary treatment have a number of treatment options, including several targeted therapies and chemotherapeutic agents, often given in combination. Although these treatments have significantly prolonged overall survival and quality of life for patients with HER2-positive advanced disease, the vast majority of these patients still die of their breast cancer (Cancer.Net, 2014). This results from the ability of HER2-positive tumors to become resistant to therapy as well as from their heterogeneity. For this reason, additional HER2-directed therapies have been developed that can circumvent resistance and/or take advantage of the ability of HER2 to bind ligand.

Four targeted therapies have been approved for treating HER2-positive breast cancer, as well as a number of chemotherapeutic agents with known activity in treating this type of breast cancer. In addition, research has shown that HER2 mutations, as well as others in the HER family, play a significant role in the growth of a number of other cancers, including gastric and potentially lung and pancreatic tumors (Subbiah & Gonzalez-Angulo, 2014).

“Today, it is so important that nurse practitioners and our advanced practice colleagues understand the science of treating breast cancers. The treatments are really based on understanding the biology of the tumor. Many patients want to know how the drugs work. It's complex and it's critical that I am able to explain the treatment to my patients in a language they can understand.”

Pertuzumab, another monoclonal antibody, binds HER2, but at a different extracellular residue, which can block HER2/HER3 heterodimerization, and appears to synergize with trastuzumab. Ado-trastuzumab emtansine (T-DM1) is a drug/antibody conjugate that uses the trastuzumab to bind HER2 for delivery of the chemotherapeutic payload, emtansine. And small molecule inhibitors, such as lapatinib and neratinib, bind the interacellular component of HER2, blocking signaling pathways.

Additional research now focuses not only on developing new HER2-targeted therapies but also on how to optimally use these existing agents. There is also a real need to identify biomarkers to assess which patients are at high risk for recurrence and who will respond to specific treatment approaches.

The side effects that patients on HER2-positive therapy experience depend largely on the agents used. Trastuzumab and other targeted therapies often have relatively few side effects and are well tolerated, with chronic diarrhea, rashes, and fatigue among the most commonly reported problems. Approximately 10% to 12% of patients on trastuzumab develop heart failure or decreased left ventricular ejection fraction that often requires discontinuation of the therapy, although this effect can be reversible with treatment cessation and managed with medical therapy. One current goal of treatment for HER2-positive breast cancer is to obtain optimal outcomes with minimal toxicity by minimizing, where possible, the use of chemotherapy (Morgan, 2016).

The best treatment for patients with HER2-positive breast cancer is team based, with the advanced practitioner playing a key role in managing the disease and providing comprehensive care for the patient. This article describes a model in which the physician has primary responsibility for developing and overseeing the treatment plan, while the nurse practitioner provides the majority of ongoing care, treatment monitoring, and survivorship planning for patients.

In many ways, the treatment of HER2-positive breast cancer exemplifies the extraordinary progress that has been made in understanding and treating cancer in the past 3 decades. These advances have resulted from a deepening knowledge of the biology of cancer cells and the development of therapies targeted to the differences between normal and malignant cells. There is both great promise for the future and a great need for additional research to ensure that every patient benefits from available therapies. For patients, the challenges of living with a diagnosis of HER2-positive breast cancer, at every stage, are significant and require a comprehensive care plan implemented by both a physician and an advanced practitioner.

What is HER2?

The History

In the early 1980s, cancer researchers first discovered that a mutated gene could stimulate the growth of cancer cells. Additional laboratory research identified that gene as the human epidermal growth factor receptor 2, or the HER2 gene. Led by Dennis Slamon, MD, and his colleagues at the University of California, Los Angeles, medical researchers recognized the potential importance of this mutation and worked to understand the links between HER2 and various types of cancer. They found very high levels of HER2 in about 25% of breast cancers and that this was associated with rapidly increased rates of cancer cell growth. Other investigators determined that the presence of HER2 in breast cancer cells also correlated with a higher risk of recurrence, metastasis, and lower overall survival rates. HER2-positive breast cancer, as it came to be known, was identified as a specific subtype of the disease, noted for its aggressive behavior and poor prognosis (NCI, 2016a).

Slamon and his group collaborated with researchers from the University of Texas and others to develop an agent that could block the activity of the HER2 gene and thus slow the growth of the cancer. This was among the first efforts to target a known difference between normal and cancer cells as a therapy. In 1998, following a series of clinical trials, the US Food and Drug Administration (FDA) approved the HER2-specific monoclonal antibody trastuzumab for use in treating patients with metastatic HER2-positive breast cancer. A phase III trial comparing trastuzumab and chemotherapy with chemotherapy alone demonstrated significant improvements in time to disease progression (7.6 vs. 4.6 months). More impressively, twice as many patients on the combined therapy were disease-free 12 months after beginning therapy compared with those just on chemotherapy (28% vs. 14%, respectively). Additional trials demonstrated a clear advantage of trastuzumab-based therapy for HER2-positive breast cancer in the adjuvant setting. The introduction of trastuzumab transformed HER2-positive breast cancer from a disease with a poor prognosis to one that can be treated effectively and often cured when it is diagnosed early. Patients with advanced disease benefit from treatment in terms of both longer survival and better quality of life (Baselga et al., 1996).

Although trastuzumab represented a major step forward, it was not the end of the story. In the past decade, three additional targeted agents have been approved to treat HER2-positive breast cancer: pertuzumab (Perjeta), Lapatinib (Tykerb), and ado-trastuzumab emtansine (Kadcyla). These drugs all have different mechanisms for targeting HER overamplification, and they are often used in combination with chemotherapy.

The Science

The HER2 gene, located on chromosome 17q21, is found on the cell's outer surface and codes for a protein of the same name: HER2. Normal cells have two copies of the HER2 gene, which encodes a receptor protein that receives signals from the external environment that trigger cell growth and help cells survive. The problem arises when errors in DNA replication create too many copies of the gene and overexpress the HER2 protein (Ruben & Yarden, 2001).

This uncontrolled cell growth is the reason that HER2-positive breast cancer was regarded as one of the most aggressive subtypes with a generally poor prognosis. But HER2 turned out to be a "driver mutation," or "proto-oncogene," for these cancers, meaning that if the signaling is blocked, the protein is not produced and the growth stops. One mechanism for achieving that goal is to use monoclonal antibodies designed to attach to a specific protein and inhibit its growth. Trastuzumab is a HER2-specific monoclonal antibody that is effective in blocking HER2 signaling in both the adjuvant/neoadjuvant and metastatic settings. The monoclonal antibody, in effect, removes or clears the HER2 protein from the surface of the cells.

As with many effective cancer therapies, resistance poses a significant problem. It can either occur de novo, meaning that there is no response to targeted therapy, or after a positive response. Most patients with metastatic disease treated with trastuzumab relapse within 1 year of beginning therapy. Research has shown that the HER2 gene is one of a family of genes–HER1 (also known as epidermal growth factor receptor), HER3, and HER4–that all contribute to cell growth–signaling pathways. HER1, 2, and 3 are known to be involved in the growth of cancer cells, while HER4 is unusual and not believed to be oncogenic. In some instances, HER2 binds to HER3, a phenomenon known as heterodimerization, or to other signaling pathways (Rubin & Yarden, 2001). This crosstalk, as it is called, allows the signaling pathways to reactivate and the cancer cells to begin growing again (Harbeck et al., 2013).

“The HER family genes and proteins are very similar in structure and function. If we shut down HER2, it is not uncommon for HER2 to bind to HER3 and activate that pathway. HER2 may also engage in what we call 'crosstalk' with hormonal pathways. These are the primary modes of resistance for these tumors. We are actively engaged in deepening our understanding of how these pathways work and interact with each other and conducting trials to develop new or modified combinations of agents that shut down or inhibit these signaling cascades and block crosstalk.”

The utilization of a variety of agents with different mechanisms in targeting the HER family signaling pathways is critical to optimizing outcomes for patients with advanced HER2-positive breast cancer:

Diagnosing Her2-Positive Breast Cancer

Establishing the histologic and biologic subtype is critical for every patient diagnosed with invasive breast cancer. For patients with stage I–III disease, testing is done at the time of initial surgical biopsy. Patients diagnosed with stage IV breast cancer or who have recurrent disease should have HER2 testing done at the sites of metastasis, if possible.

The FDA has approved four methods of testing for HER2 status:

HER2 testing can yield clearly positive or negative results or results that are borderline or unclear. Borderline IHC 2+ results should be retested with the more sensitive FISH test, SPoT-Light HER2 CISH test, or INFORM HER2 Dual ISH test to provide more precise information. By the same token, borderline FISH results should be retested with IHC. Evidence suggests there may be benefit in treating patients with low positive HER2 levels, making sensitive, accurate testing crucial to determining treatment. Studies are underway to evaluate the impact of using trastuzumab or T-DM-1 with patients who have IHC 1+ and 2+ and FISH– scores.

Survey 2
Which method of testing for HER2 do you use most often?

HER2 status can change over the course of the disease. A tumor that is initially diagnosed as positive for HER2 can potentially become negative if it metastasizes, or conversely, a HER2-negative tumor can convert to positive when it spreads. For this reason, it is critical to retest tissue from metastatic sites even in patients who have previously been treated with HER2-targeted therapies to confirm HER2 status.

HER2-positive breast cancers are also assessed for hormone receptor status (estrogen receptor [ER]/progesterone receptor [PR]). Approximately 50% of patients with HER2-positive disease are also hormone receptor positive, and this influences treatment decisions.

EARLY-STAGE HER2-POSITIVE BREAST CANCER

Treatment Options for Early-Stage HER2-Positive Breast Cancer

Every patient with a confirmed diagnosis of HER2-positive breast cancer needs treatment with HER2-targeted agents in combination with chemotherapy or endocrine therapy. Currently, this is true regardless of the size of the tumor and node status. Prior to the introduction of trastuzumab, the majority of women diagnosed with even early-stage HER2-positive breast cancer had higher rates of relapse, recurrence, and metastasis. Today, the disease-free survival (DFS) rate for patients with early-stage HER2-positive breast cancer is over 90% for patients with hormone receptor–positive disease and 84% for those with hormone receptor–negative disease. Overall 5-year survival for both groups is more than 95%. For patients with stage I–III disease, initial treatment includes surgery, radiation therapy where necessary, and either neoadjuvant or adjuvant therapy (Glaberman, Dayao, & Royce, 2014).

The current standard of care for a patient with stage I–III HER2-positive breast cancer is adjuvant chemotherapy (i.e., taxane with or without an anthracycline or a non-anthracycline regimen that includes carboplatin) plus trastuzumab for 12 months. There are a number of chemotherapy regimens that have been shown to be effective. And although all adjuvant and neoadjuvant therapy for HER2-positive breast cancer involves trastuzumab, the choice of chemotherapy depends on the patient's tumor status, overall health, and choice, as well as physician preference.

Taxanes include docetaxel and paclitaxel. Patients who are hormone receptor positive may also receive endocrine therapy typically after the completion of chemotherapy. Anthracyclines have been associated with irreversible cardiac toxicity and may be used less frequently in older patients or those who have preexisting cardiac conditions or risk factors. Research is increasingly focusing on developing a range of therapeutic approaches matched to the individual tumor and situation.

The most commonly used adjuvant regimens for early-stage HER2-positive breast cancer are:

Traditionally, neoadjuvant therapy has been used to shrink locally advanced and large tumors prior to surgery either to improve outcomes or allow for breast-conserving surgery. Researchers are studying this approach for patients with earlier disease as well. Neoadjuvant therapy now frequently includes pertuzumab. The FDA has approved pertuzumab for neoadjuvant therapy but not for adjuvant treatment of HER2-positive breast cancer. Adding pertuzumab does not significantly increase toxicity in a regimen that includes docetaxel, and it appears to have the greatest benefit in patients with stage IIb–III disease and in those who are hormone receptor negative (Sparano, 2016).

“When we first propose neoadjuvant therapy to our patients, some of them are anxious because they are worried about leaving the cancer in place for an extended period of time. We explain to them that this is active treatment for both the breast tumor and any microscopic cells that may have escaped the breast, and that we will be able to monitor their responses very carefully. Once patients understand that, they really buy into the neoadjuvant approach and understand that this is a way of really reducing the chance that their cancer will recur.”

Today, the outcomes of treatment for most patients with early-stage HER2-positive disease are positive. "The bar for new drugs is very high right now," says Dr. DeMichele. "Our goals now are to identify the subset of patients who are at greater risk for recurrence and make sure they get the additional treatment they need, as well as to refine our approaches so that we are getting the best outcome for every patient with the least amount of toxicity."

Managing the Care of Patients With Early-Stage HER2-Positive Breast Cancer

Patients with all stages of HER2-positive breast cancer face a multitude of physical and emotional challenges. Optimal care is best delivered by a team capable of providing a full spectrum of both treatment options and supportive care. The advanced practitioner can play a key role in helping patients understand their diagnosis and treatment, manage side effects, and engage with resources to address issues such as distress, anxiety, nutrition, and exercise.

Side Effects of Treatment for Early-Stage HER2-Positive Breast Cancer

The nature and severity of side effects for patients receiving adjuvant or neoadjuvant therapy for early-stage HER2-positive breast cancer depend largely on the chemotherapy agents that are used and their doses. Targeted therapies, while they do involve some toxicity, are often well tolerated, with some patients reporting mild or no adverse effects. More chemotherapy usually means more side effects of the kind usually associated with cytotoxic drugs. This includes alopecia, which continues to be a major issue for many women being treated for breast cancer.

Cardiac Damage: The most serious potential toxicity from targeted agents, including trastuzumab, pertuzumab, and TDM-1, is congestive heart failure or reduced cardiac function, resulting from heart muscle damage. The overall risk to patients taking trastuzumab is low (2% to 4%), but it is higher in older patients, those who have preexisting heart conditions or hypertension, and those taking anthracyclines. It is essential to monitor ejection fraction with echocardiograms and multigated acquisition (MUGA) scans in any patient taking these agents, usually every 3 months. A decrease in the left ventricular ejection fraction may require taking that patient off the therapy. Although heart damage from anthracyclines is considered permanent, evidence shows that damage from targeted therapies is reversible in most patients. In addition to a treatment break, medication can also be helpful in preserving ejection fraction, even short term while recovery occurs. Patients should be reevaluated after being off therapy for a period of 6 months (Volkova & Russell, 2011).

Infusion Reactions: Some patients experience symptoms following infusion of trastuzumab, including nausea, chills, fever, headache, dizziness, and weakness. These symptoms should usually subside within 24 hours of the infusion. Treatment for an infusion reaction may include stopping the infusion, administering corticosteroids, anti-histamine or anti-adrenergic therapies, and, in rare instances, the need for prolonged monitoring to assure full resolution of symptoms. Treatment for minor reactions can typically be resumed with a decreased infusion rate and corticosteroid pretreatment.

Diarrhea: Chronic diarrhea is the most common side effect in patients who take HER blockers, occurring in as many as 95% of patients. The prevalence and physical impact of having diarrhea is one factor that has led to the recommendation that trastuzumab treatment be discontinued after 1 year. Studies have demonstrated no significant increased benefit from continuing treatment for longer periods, but they have found that shorter treatment spans do compromise outcomes (Bhardwaj, 2014).

Distress Screening and Psychosocial Support

Research has shown that a high percentage of patients with cancer experience some level of distress or anxiety and that those levels are often highest during the period from diagnosis through the first year of treatment. Advanced practitioners can play a key role in assessing these emotional and social issues and assuring that patients have access to appropriate resources. The availability of nurse practitioners and other advanced practitioners to answer questions, listen, and help patients and caregivers find resources is critical in managing these important issues (NCI, 2015).

Survivorship Planning

For many patients, with all types of cancer, the end of active treatment is a difficult time. One key issue is assuring that patients receive high-level medical and psychosocial support as they make the transition and beyond. Every treatment center needs to decide whether to keep patients in the system or refer them back to their primary care doctors.

At the University of Pennsylvania, the survivorship program works to provide each patient with a sense of continuity while not consuming physician time with follow-up visits. They do this by shifting the locus of treatment to the survivorship clinic and to a relationship with nurse practitioners. In addition to follow-up care for the cancer and management of any long-term effects, the survivorship clinic emphasizes preventative care and overall health management.

RECURRENT AND METASTATIC HER2-POSITIVE BREAST CANCER

Living With Metastatic HER2-Positive Breast Cancer: A Patient Profile

In April 2015, 38-year-old Rachel F. developed severe back pain. At the time, she was healthy and the mother of an 8-year-old son and 10-year-old daughter. She was also a successful professional with a demanding career in fundraising and business development for a major nonprofit organization. For 4 months, her pain levels increased until she was unable to walk without support. A magnetic resonance imaging (MRI) scan revealed a compression fracture at the L3 level, and she was referred to an orthopedic surgeon for a procedure to relieve her pain.

The workup revealed extensive bone lesions consistent with metastatic cancer, as well as a breast mass that proved to be the primary tumor. Rachel was referred to the University of Pennsylvania and diagnosed with HER2+/ER+/PR+ stage IV breast cancer with extensive bony metastases but no organ involvement. She was started on first-line therapy with trastuzumab, pertuzumab, and docetaxel, and she experienced significant nausea and fatigue during her six cycles of chemotherapy as well as diarrhea related to the pertuzumab. One year after her diagnosis, she continues on trastuzumab and pertuzumab with only mild side effects. She also takes tamoxifen and leuprolide.

Rachel's clinical response to treatment has been excellent. Her focus is now on “making her children's lives as normal as possible.” She has stopped working outside the home in order to spend more time with them and to deal with the demands of her treatment schedule. She looks and feels good but is very aware of the uncertainty of her future. “If I have 2 years to live,” she says, “then I want to spend it with my family, but if it's 10, I guess I should get a job. You just don't know though. Even in my most normal moments, I am aware that my future is limited. I am out of the crisis mode and into living with a chronic disease, but it's still really hard, every day.”

Approximately 70% of advanced HER2-positive breast cancer is diagnosed as recurrent disease, with 30% being de novo. The former number has decreased and continues to fall with the use of more effective primary treatment. Although metastatic (stage IV) HER2-positive breast cancer is not considered curable, a number of available treatment options have been shown to extend survival with good quality of life. A small percentage of patients experience long-term responses lasting years or more.

As noted previously, it is important to attempt to biopsy metastatic sites in order to confirm the HER2 status of the disease. HER2-positive tumors can become HER2 negative, and in some cases, the opposite can occur. Knowing the HER2 status is critical to making appropriate treatment decisions.

The most common sites of metastasis for HER2-positive breast cancer are bone, liver, lungs, and brain. Brain metastases are common in HER2-positive disease and require an altered approach to treatment, as most agents do not cross the blood–brain barrier. Patients are typically not screened regularly for brain metastases, but any patient who exhibits symptoms such as headaches, confusion, memory loss, weakness, or numbness should be evaluated. Treatment includes radiation and, in cases of limited (i.e., one to four) metastases, surgery to remove the tumors. Those patients with metastatic disease in other sites should continue to receive anti-HER2 therapy (Kennecke et al., 2010).

Treatment Options for Metastatic and Recurrent HER2-Positive Breast Cancer

Clinical trials have played a critical role in establishing the current arsenal of therapies available to treat both early-stage and metastatic HER2-positive breast cancer. There is still a strong focus on developing new agents, including those that block multiple pathways, TKI inhibitors, and immunotherapy. Many trials aim to uncover the optimal use of therapies both to improve outcomes and minimize toxicity.

First-Line Treatment

Note that the CLEOPATRA study established the benefit of adding pertuzumab to the then standard first-line regimen of trastuzumab and docetaxel. The benefit was seen in overall survival (56.5 vs. 40.8 months) with little difference in the toxicity profile, and there was no increase in cardiac toxicity in the pertuzumab arm. As pertuzumab provides a dual blockade of HER2, it is now considered standard in first-line therapy—as well as neoadjuvant therapy in many patients. Figuring out how to shut off cancer cells’ ability to utilize alternatively signaling pathways is a crucial step forward in the effort to prevent or delay treatment resistance.

Even patients who have relapsed or recurred after receiving trastuzumab can still benefit from it in the metastatic setting when it is combined with pertuzumab or chemotherapy. In first-line therapy for HER2-positive metastatic breast cancer, the chemotherapy is usually given for 4 to 6 months, while the anti-HER2 therapy and endocrine therapy continue indefinitely, when appropriate.

Resistance continues to be a major issue in treating metastatic HER2-positive breast cancer. Most metastatic patients will relapse, often after 18–24 months on first-line treatment (NCI, 2016b).

Survey 3
Which agent do you give to your HER2-positive breast cancer patients most often for second-line therapy?

Second-Line Treatment

Ado-trastuzumab emtansine: The most promising agent currently available for treating patients with HER2-positive breast cancer who progress on first-line therapy is ado-trastuzumab emtansine (T-DM1). This antibody-drug conjugate incorporates the HER2-targeted antitumor properties of trastuzumab with the cytotoxic agent emtansine (DM1). The combination is a mechanism for delivering the drug intracellularly, potentially improving the response rates and benefits to patients while minimizing damage to normal tissue.

Several studies have established the benefit of T-DM1 as second-line therapy for HER2-positive breast cancer. T-DM1 is usually given as a single agent and has a favorable toxicity profile when compared with regimens that include chemotherapy or lapatinib. The most common adverse effect is thrombocytopenia, while diarrhea, a side effect of other treatments, is less common. A large study, MARIANNE, demonstrated that T-DM1 either as a single agent or in combination with pertuzumab did not yield better results than the current standard, trastuzumab/taxane, for first-line therapy in previously untreated metastatic HER2-positive patients. That study is one indication that there is still much to be learned about the optimal use of these available agents for individual patients at every point in the treatment process (Santa-Maria, Nye, Mutonga, Jain, & Gradishar, 2016).

Lapatinib: Lapatinib is a TKI that is often used in combination with chemotherapy or an aromatase inhibitor in hormone receptor–positive patients who have relapsed on anti-HER2 targeted therapies. Capecitabine is the most common chemotherapy agent combined with lapatinib. The most common side effects of lapatinib are rash and diarrhea.

Chemotherapy: Several drugs have activity against metastatic breast cancer. They include anthracyclines, taxanes, alkylating agents, platinums, antimetabolites, vinca alkaloids, and other drugs such as gemcitabine. Anthracyclines are associated with cardiac toxicity, a risk that is increased when they are used with anti-HER2 agents. As a result, many physicians now prefer to use nonanthracyclines whenever possible in treating HER2-positive breast cancer.

There is little evidence to support giving combination chemotherapy to patients who have progressed on first- and second-line therapies for their advanced disease. Although response rates tend to be higher with the combinations, overall survival does not. The physician and patient together should choose which agents to use in what order and for what duration based on the rate of disease progression, the patient's health status, and life preferences.

Trials are currently underway to reduce the incidence of cardiotoxicity in patients receiving anthracyclines. These include using a cardio protective drug, dexrazoxane, and altering the method of administration for doxorubicin. Patient selection is also important in minimizing cardiotoxicity. Patients who are older and have a history of chest wall irradiation, previous exposure to anthracyclines, hypertension, and underlying heart disease or diabetes are all at increased risk of developing treatment-limiting or life-threatening heart issues (NCI, 2016b).

A number of new HER2-targeted agents are currently in clinical trials, as are new approaches to the treatment of HER2-positive brain metastases. It is important to consider clinical trials as a way to extend treatment options for patients.

Clinician Roles in Managing the Care of Patients With Metastatic and Recurrent HER2-Positive Breast Cancer

Regardless of whether it is de novo or a recurrence, the diagnosis of metastatic breast cancer is a life-altering event. A person moves from being a healthy person to a patient with an incurable disease, finding her worst anxieties confirmed. Many patients are not aware of the meaning of metastatic breast cancer until they learn they have it. For the HER2-positive metastatic population, physicians and advanced practitioners need to:

LOOKING TO THE FUTURE

In 3 decades, HER2-positive breast cancer has been transformed from a disease noted for its aggressive clinical course and poor prognosis to one that is often curable when detected early and treatable in its advanced stages. Today, a great deal of ongoing work is aimed at addressing these issues. Through collaborative practice, clinicians will be able to best support their patients as they journey through this life-altering experience.




Acknowledgments

Grateful thanks to Dr. DeMichele and Ms. Lattimer for sharing their time, expertise, and unique perspectives. Special appreciation goes to Rachel F. for sharing her candid comments, and her unique perspective on this life-altering experience.


Disclosure

Dr. DeMichele has been a consultant for Novartis and Pfizer, and has received grants from Calithera Biosciences, Genentech, Novartis, and Pfizer. Ms. Lattimer has served on a speakers bureau for Genentech.


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Interviews and reporting by Christine Wilson

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