Selecting Appropriate Therapy for HER2‐Positive Breast Cancer

Course Director

Kimberly L. Blackwell, MD

Kimberly L. Blackwell, MD
Professor of Medicine
Assistant Professor of Radiation Oncology
Director, Breast Cancer Program
Duke Cancer Institute
Durham, North Carolina


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Part 1 of a 2-part series

Dr. Kimberly L. Blackwell, MD provides expert feedback to the questions submitted by your peers during a recent survey on this topic.

Overview

Breast cancer is increasingly recognized as a heterogenous disorder, characterized by distinct molecular subtypes that affect disease course as well as response to therapy. Identifying these subtypes and tailoring treatment accordingly is fast becoming the standard of care for breast cancer at all stages. The weight of clinical evidence indicates that molecular characteristics may be more important for outcomes than epidemiologic features. In order to ensure optimal patient care, clinicians must accurately identify the molecular subtype, and select the appropriate therapy.


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What are the current best practices for HER2 testing in patients with newly diagnosed breast cancer?

Answer: Today, there are two acceptable ways of testing for HER2 drive in a breast cancer patient: Immunohistochemistry [IHC], which tests for overexpression of the protein; or FISH [fluorescence in situ hybridization] testing, which tests for gene amplification—you're supposed to have two copies of the HER2 gene, whereas many overexpressed or amplified tumors have multiple copies of the HER2 gene (Carlson RW  et al. J Natl Compr Canc Netw. 20064(suppl 3):S1-22; Hammond ME et al. J Clin Oncol. 2010;28:2784-2795. doi:10.1200/JCO.2009.25.6529; Summary of ASCO/CAP HER2 Guideline Recommendations http://www.cap.org/apps/docs/committees/immunohistochemistry/summary_of_recommendations.pdf. Accessed March 28, 2013).

When the test results are quite clear [that] either the HER2 FISH test is amplified or the HER2 immunohistochemistry is overexpressing, then clinical decision-making is relatively easy. We know that both in the early stage and metastatic setting, women who have amplification or overexpression of the HER2 gene benefit from HER2-targeted therapies.

In about 1% to 2% of newly diagnosed breast cancer patients, however, the HER2 testing is equivocal. That means not negative or not positive, but unclear what the benefit of HER2 treatment would be, so many patients and clinicians find themselves in a difficult situation. In that case, we always recommend HER2 FISH testing to try to clarify exactly how HER2-driven the breast cancer is (Wolff AC et al. J Clin Oncol. 2007;25:118-145; College of American Pathologists. HER2 Testing Guidelines and Resources [Updated April 18, 2011]. http://www.goo.gl/96Gnl. Accessed April 12, 2013). A dialogue between you, as a clinician, and your clinical pathologist becomes critical in these situations where the testing is equivocal. And in fact, knowing who the pathologist [is] and even making certain that the sample that they're looking at helps them with the testing is critical in clinical decision-making surrounding HER2-positive newly diagnosed breast cancer.

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With the availability of multiple new agents for HER2-positive breast cancer, what are the best practices for sequential therapy?

Answer: In taking care of patients with HER2-positive metastatic breast cancer, there are now a number of options that target either the HER2 receptor or downstream signaling from the HER2 receptor. In the past two years, pertuzumab, a monoclonal antibody against the HER2 receptor, and now TDM-1, an antibody drug conjugate, have become approved and available in addition to the older agents, lapatinib, as well as trastuzumab.

We know now that there is a survival advantage for adding pertuzumab to trastuzumab in [the] first-line metastatic setting, so at least for most clinicians, pertuzumab remains the go-to first-line treatment in combination with trastuzumab and a taxane for the treatment of first-line, HER2-driven metastatic breast cancer (Swain S et al. 2012 San Antonio Breast Cancer Symposium [SABCS 2012]. Poster P5-18-26; Baselga J et al. N Engl J Med. 2012;366:109-119). What becomes less clear is once patients progress on pertuzumab, what are the best sequences of second-, third- and fourth-line therapy?

The EMILIA study, which is a study of second- and third-line HER2-positive metastatic breast cancer, demonstrated a survival advantage for the use of TDM-1 over the older standard [of] capecitabine and lapatinib for patients who have received prior taxane and trastuzumab-based therapy (Verma S et al. N Engl J Med. 2012;367:1783-1791). And so for most women faced with second-line HER2-positive metastatic breast cancer who have received prior trastuzumab and taxane and progressed on pertuzumab, TDM-1 will become the standard of care, primarily because it offers a survival advantage over the small-molecule inhibitor lapatinib, but also because it has a very favorable side-effect profile, being a first-in-its-class antibody drug conjugate for the treatment of HER2-positive breast cancer. It's a preferred regimen (National Comprehensive Cancer Network [NCCN] Clinical Practice Guidelines: Breast Cancer. V2.2013. www.nccn.org).

The standards past the second-line setting are really trastuzumab-based or lapatinib-based combinations, including the combination of lapatinib and trastuzumab (NCCN Clinical Practice Guidelines: Breast Cancer. V2.2013. www.nccn.org).

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What are options for patients with HER2-positive disease and a history of cardiovascular disease?

Answer: When treating patients with HER2-positive breast cancer—either early-stage or metastatic—who have a history of cardiovascular disease, a number of important clinical discussions need to happen. Probably the major driver of how you incorporate HER2-targeted agents in the treatment of patients with prior cardiovascular disease comes in [the form of] a baseline cardiac assessment. This can either be an echo or multigated assessment [MUGA] of left ventricular ejection fraction [LVEF].

In my practice, for patients who have a normal LVEF and have a high enough risk for either recurrence or are faced with metastatic breast cancer, I will incorporate the use of a HER2-targeted agent with close cardiac monitoring. In the early-stage setting—where we know that the use of HER2-targeted agents such as trastuzumab offers a significant reduction in disease recurrence and a significant improvement in overall survival—the use of these agents in patients with a prior cardiovascular history really needs to depend on a baseline LVEF and a discussion with the patient regarding an increased risk of cardiac side effects versus the benefit with the use of trastuzumab.

Other important considerations when using HER2-targeted agents in either an elderly patient or a patient with a prior history of cardiovascular disease includes the etiology of their prior cardiovascular disease. The exact mechanism of cardiomyopathy caused by trastuzumab is not clear; it does not appear to accelerate cardiovascular disease. So for patients who have a history of coronary artery disease leading to heart problems, I think that the mechanism of trastuzumab-induced cardiomyopathy is quite different. In the setting of a baseline normal LVEF, even with a history of coronary artery disease, I feel comfortable utilizing the HER2-based regimens.

Finally, there is a subpopulation of patients wherein the risk of utilizing trastuzumab probably outweighs any potential benefits. These include patients who have an abnormal LVEF, and in my practice, that's <10% below the lower limits of LVEF normal limits. So for those patients who have a very abnormal LVEF, whether it be due to a history of cardiomyopathy from something else or coronary artery disease, I would not utilize trastuzumab in the treatment of their HER2-positive breast cancer. I frequently get asked—Would I substitute a small-molecule inhibitor in that situation?—and my answer is no, because there is no safety data regarding the use of the small-molecule inhibitors as treatment for HER2-positive breast cancer in the setting of an impaired cardiac function. So unfortunately, for patients who have compromised LVEF, there is no role for either trastuzumab or lapatinib in the early-stage HER2-positive setting (NCCN Clinical Practice Guidelines: Breast Cancer. V2.2013. www.nccn.org).

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