The Experience of a Multidisciplinary Clinic in the Management of Early-Stage Breast Cancer Patients Receiving Trastuzumab Therapy: An Observational Study

Background. We established a dedicated cardiac oncology clinic in 2008 for the rapid diagnosis and treatment of cardiotoxicity related to cancer therapy. In this retrospective observational study, we report on clinical outcomes in women with early-stage breast cancer (EBC) referred to this clinic. Methods. Patients with EBC treated with chemotherapy/trastuzumab and referred between October 2008 and December 2010. Data included patient demographics, staging, cancer treatment/completion, dose delays, left ventricular ejection fraction (LVEF) and cardiac treatment. Results. Forty eight patients: median age 55.5 years, stage I/II disease (77%) and HER-2 positive (98%). The majority of women (n = 32) were referred for decreases in LVEF (from baseline). Overall, 37 (77%) patients experienced at least one drop in LVEF while on treatment, of which 22 patients (59%) experienced a ≥10 percentage point drop. The majority of patients (30/37; 81%) experienced declines in LVEF while on trastuzumab. Interventions included trastuzumab delays (n = 16/48; 33%) and cardiac medication (12/48: 25%). A total of 81% of patients completed ≥90% of trastuzumab therapy and 15% of patients discontinued therapy due to cardiotoxicity. Conclusion. The majority of patients referred to our clinic completed therapy. Further studies are needed to determine the impact of this multidisciplinary approach on treatment completion and cardiac outcomes.


Introduction
Breast cancer is the most common malignancy for women in North America [1]. The use of anthracycline-based regimens in the adjuvant setting has been shown to improve overall survival [2], but with an increased risk of cardiotoxicity. Approximately 20% [3] of women with breast cancer overexpress the HER-2 protein, a member of the epidermal growth factor receptor family. Trastuzumab, a monoclonal antibody that targets the HER-2 protein, was initially tested in women with metastatic breast cancer in combination with anthracycline-based chemotherapy. Concurrent administration of anthracycline/trastuzumab led to significant response rates but high rates of congestive heart failure (28%) [4].
In four large randomized control trials (NSABP B31, NCCTG 9831, HERA, BCIRG 006) [5][6][7] of early stage breast cancer, significant improvements in both disease free (HR = 0.60) and overall survival (HR = 0.66) were observed in patients who received chemotherapy and trastuzumab (following anthracyclines) compared with those who received chemotherapy alone [8,9]. This led to the adoption of one year of trastuzumab (every 3 weeks for 18 cycles) as the standard of care for women with early stage HER-2-positive breast cancer. While there was significantly less cardiotoxicity observed with trastuzumab in the adjuvant breast trials (congestive heart failure 2.5%) [10], clinicians have perceived higher rates in clinical practice. In a retrospective singleinstitution study of 105 women with HER-2-positive early stage breast cancer, we reported dose delays of trastuzumab in 30% (n = 32) of patients [11]. In this study, 13% of patients experienced ≥10 percentage point declines in left ventricular ejection fraction (LVEF) to less than 55%, although with appropriate medical management, the majority of patients (89%) were able to complete their targeted treatment. Other case series have reported higher discontinuation rates (20%) [12] for trastuzumab. Early discontinuation of trastuzumab could potentially compromise the clinical benefit of this treatment. Outside the clinical trial setting, there has been no standardized approach to the treatment of women who have sustained cardiac dysfunction while on trastuzumab therapy. In addition, there is little guidance in the literature on who should manage patients that experience cardiotoxicity as a result of their breast cancer treatments.
In March of 2007, a panel of experts from across Canada convened in Toronto to develop a Canadian consensus guideline to assist clinicians in the identification and treatment of women experiencing cardiac dysfunction while on trastuzumab [13]. The panel recommended that women with early stage breast cancer exposed to trastuzumab should be managed in close collaboration with cardiologists. It was clear from this meeting that many medical oncologists did not have the clinical expertise or knowledge necessary to manage the cardiotoxicities experienced by these women. It was also apparent that cardiologists needed a better understanding of the clinical benefit of targeted therapies when making decisions with regards to cardiac management.
In 2008, we established a multidisciplinary cardiac oncology clinic to facilitate the rapid diagnosis and treatment of cardiac complications secondary to cancer therapy. The multidisciplinary team consisted of one medical oncologist, three cardiologists, one pharmacist, and one nurse. While the initial focus of this clinic pertained to women with early stage breast cancer exposed to chemotherapy +/− trastuzumab, the widespread adoption of targeted therapies in oncology has subsequently led to the referral of a much broader patient population. Between October 1, 2008 and December 31, 2010, 188 patients were referred to this clinic, the majority (n = 127; 68%) of whom were breast cancer patients (early and advanced stages).
The purpose of this retrospective observational study is to report on the clinical and cardiac outcomes in women with early stage breast cancer receiving trastuzumab, who were referred to our multidisciplinary cardiac oncology clinic. This study was approved by the Ottawa Hospital Research Ethics Board.

Patients and Methods
Early stage breast cancer patients receiving trastuzumab who were referred to the cardiac oncology clinic between

Discussion
The evolution of personalized medicine has led to an increasing interest in the development and testing of targeted therapies in oncology. While cancer professionals have been well versed in the identification and treatment of toxicities associated with chemotherapy, there is less understanding of the short-and long-term consequences associated with targeted agents. The widespread adoption of trastuzumab in combination with chemotherapy has led to significant improvements in the clinical outcomes of women with both early-and advanced-stage breast cancer. While congestive heart failure rates (2.5%) [10] in the adjuvant trastuzumab breast trials have been modest, clinicians have observed more subtle signs of cardiotoxicity (e.g., decreases in LVEF) in the nonclinical trial setting, potentially leading to early discontinuation of treatment.
In this retrospective observational study, we report on the clinical outcomes of early stage breast cancer patients treated with chemotherapy and trastuzumab who were referred to a dedicated cardiac oncology clinic. While the majority of patients were referred to the clinic for a decline in LVEF during trastuzumab treatment, many of these women had previous exposure to anthracyclines, thus increasing their risk of experiencing cardiotoxicity. Completion rates for chemotherapy were high for early stage breast cancer patients seen in the cardiac oncology clinic (94%). Although several patients experienced substantial declines in LVEF (≥20 percentage points), 81% completed 16 or more cycles of trastuzumab and only 15% (n = 7) discontinued therapy permanently due to cardiotoxicity. Approximately, 35% of patients experienced short delays in trastuzumab therapy due to cardiotoxicity; however, with appropriate medical management and surveillance, 77% completed treatment.
In summary, the majority of women with early stage breast cancer who were referred to the cardiac oncology clinic completed therapy. The discontinuation rate observed in our study (15%) is higher than reported with the HERA trial (4.3%) [9], but similar to that reported in the NCCTG 9831 study (18.9%) [14]. The lower rates of discontinuation in the HERA trial likely reflect the higher baseline cardiac function Cardiology Research and Practice 5 (LVEF ≥55%) required for study entry compared to the NCCTG trial (LVEF ≥50%). In our study, only one of seven patients who discontinued trastuzumab prematurely had a baseline LVEF <55% and thus, one can speculate that other risk factors for cardiotoxicity were present that were not detected with baseline medical history and cardiac imaging. Better predictors of cardiotoxicity such as cardiac biomarkers and novel imaging techniques are needed for early detection of cardiotoxicity.
In 2010, we established the Canadian Cardiac Oncology Network with the mission of optimizing cardiac care for cancer patients receiving potentially cardiotoxic therapies. Through this multidisciplinary approach, we hope to gain a better understanding of cardiac complications of cancer treatments and develop early detection and intervention strategies to optimize cardiac health in these patients.