Management of Early-Stage HER2-Positive Breast Cancer

Sara Hurvitz, MD

As part of our coverage of the Miami Breast Cancer Conference, held March 8–11 in Miami Beach, Florida, we spoke with Sara Hurvitz, MD, about the management of patients diagnosed with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which she discussed during a talk at the meeting. Dr. Hurvitz is a medical oncologist who specializes in the treatment of breast cancer at the University of California, Los Angeles, Jonsson Comprehensive Cancer Center. 

-Interviewed by Anna Azvolinsky

Cancer Network: First, is there anything distinct about the biology of HER2-positive early-stage breast cancer compared with other types of early-stage breast cancer, or in terms of how this disease presents?

Dr. Hurvitz: HER2-positive breast cancer is known to behave more aggressively than HER2-negative disease, and this holds true even for early-stage breast cancer. There are a couple of studies looking retrospectively at the 5-year disease-free survival rates for patients with stage I breast cancers less than 1 cm in size and comparing these rates based on whether the patient’s tumor was HER2-positive or -negative. These studies, one from MD Anderson and the other from the National Comprehensive Cancer Network, both indicated that for patients with early-stage breast cancer, the risk of recurrence was significantly higher if the tumor was HER2-positive, compared with the risk in HER2-normal patients. Based on these results, we no longer reserve HER2-targeted therapy and chemotherapy only for HER2-positive patients with lymph node–positive cancer or larger tumors; we will generally use systemic therapy to target HER2, usually with chemotherapy and even for stage I disease.

Cancer Network: What are all of the current options for women diagnosed with HER2-positive early stage disease? Have there been any recent approvals or new treatment approaches that have been recently adopted in the clinic?

Dr. Hurvitz: The standard of care to treat curable HER2-positive breast cancer has been to give chemotherapy with the HER2-targeted monoclonal antibody trastuzumab, which was the first drug approved for HER2-positive disease. In the United States, one commonly used regimen is ACTH (doxorubicin and cyclophosphamide for four cycles) followed by a taxane, with trastuzumab given concurrently with the taxane; then trastuzumab is continued for a full year. The other regimen, and some studies indicated that it is the most commonly used now, is docetaxel and carboplatin plus trastuzumab, or the TCH regimen, where the chemotherapy is given every 3 weeks for six cycles concurrently with trastuzumab and then trastuzumab is continued for a full year. Right now, the benefit of TCH over ACTH is less toxicity to the heart and a lower risk of leukemia and myeloid dysplasia. The BCIRG006 study indicates that the ACTG and TCH have similar efficacy. These two regimens remain the standards of therapy for HER2-positive breast cancer.

In the last year or so, two new HER2-targeted therapies have been approved in the adjuvant setting. The first is neratinib, an oral tyrosine kinase inhibitor that, similar to lapatinib, hits both HER1 and HER2, but is more potent. The US Food and Drug Administration has approved 1 year of treatment with neratinib for patients who have completed their year of treatment with trastuzumab. There is a fairly significant risk of diarrhea with neratinib, so measures need to be taken to help patients deal with that, including use of drugs like loperamide and possibly colestipol. Interestingly, this drug has been shown to reduce the risk of breast cancer recurrence after 4 years by about 3.5%. It appears to be most effective for patients with estrogen receptor co-expression on the tumor, and certainly the risk reduction imparted by its use will be biggest in high-risk patients, for example those with lymph node–positive disease. The other drug approved in the adjuvant setting is pertuzumab. Approval was based on the APHINITY study, in which patients received chemotherapy with trastuzumab or chemotherapy with trastuzumab plus pertuzumab, where the pertuzumab was given for a full year alongside trastuzumab. The study demonstrated a statistically significant 1.7% absolute improvement in disease-free survival at 4 years. While this outcome led to the FDA approval of pertuzumab, but this small survival improvement [was restricted to] patients with higher-risk, lymph node–positive breast cancer.

In terms of patients with very early stage HER2-positive breast cancer-meaning lymph node–negative, stage I, smaller tumors, one strategy gaining popularity is the de-escalation of therapy, so patients [are not subjected to] so much treatment and all of the toxicities that go along with that treatment. A couple of regimens like this have been studied in single-arm trials. One is paclitaxel given weekly for 12 weeks in conjunction with trastuzumab, so that is limiting the number of chemotherapies given and the duration of therapy. This regimen was shown by Sara Tolaney, MD, and colleagues at Dana Farber Cancer Institute to yield an excellent 7-year disease-free survival rate of around 93%. Another study looked at four cycles of treatment with docetaxel, cyclophosphamide, trastuzumab; similarly, it showed very good rates of disease-free survival, especially in patients with lymph-node negative breast cancer. The disease free-survival rate exceeded 97%. So, those are some options. There have not been new agents specifically approved such as T-DM1 (ado-trastuzumab emtansine), although my hope is that studies will be ongoing in the future, such as the ATEMPT study looking at T-DM1 in patients with lower-risk disease. If that study is positive, then we might be able to use a novel therapy to replace standard systemic chemotherapy in lower-risk disease.

Cancer Network: You mentioned studies of early-stage patients with both lower-risk and higher-risk disease. Do you make decisions regarding initial therapy with HER2-targeting agents for early-stage disease based on the patient’s risk category and individual characteristics, along with considerations of potential therapy options in the setting of early-stage disease that also target HER2 for women with later-stage disease?

Dr. Hurvitz: We use the most effective therapies for management of early-stage disease. We don’t hold off on therapy in order to, for example, “save” it until patients develop metastatic breast cancer. HER2-positive breast cancer is highly curable because of the availability of these HER2-targeted therapies, so we treat patients fairly aggressively upfront to reduce the risk of them experiencing a stage IV recurrence. We consider factors such as hormone receptor co-expression, lymph node status, grade of the tumor, comorbidities, how healthy and functional an individual patient is, and whether the patient has pre-existing heart disease or any risk of heart disease. All of these factors are [part of the decision regarding] which regimen to recommend for a patient who is sitting before us with curable early-stage breast cancer.