How Far We’ve Come: Treating HER2-Positive Breast Cancer With Targeted Therapies

Insight Articles
February 27, 2014
Josh Fernandez, Digital Media Specialist
Reviewed By: 
Nancy U. Lin, MD

Published in the Spring 2014 issue of LBBC's national newsletter, Insight

In February 2004, twenty years after Claudia Feigner, of Westport Wash., was diagnosed with early-stage breast cancer, scans revealed she had metastases in her lung and lymph nodes. Advances in tumor testing since her initial diagnosis showed the cancer was HER2-positive. This meant she could take the medicine trastuzumab (Herceptin), developed specifically to treat the disease.

“It’s like a miracle drug,” Claudia, 63, says. “Scans early on showed improvement in my lung and lymph-node mets, and after 1 year I had no active cancer. If it had not been available when I was diagnosed [with stage IV disease], my outcome could have been a lot different.”

Claudia is among many people worldwide who have been treated with trastuzumab. The medicine changed how doctors think about and treat HER2-positive breast cancer.

History in the Making

About 15 to 20 percent of breast cancers are HER2-positive, meaning the cancer is fueled by over-production of the human epidermal growth factor receptor 2 protein. HER2-positive breast cancers contain excess copies of this gene, leading to dramatically more HER2 protein on the surface of cancer cells. With more HER2 protein producing signals telling the cells to grow, they do so out of control, causing cancer.

To find out if you have HER2-positive breast cancer, doctors use one of two tests. The immunohistochemistry (IHC) test measures levels of HER2 protein on the surface of cancer cells. Another test, fluorescent in-situ hybridization (FISH), detects extra copies of HER2 genes. You should receive these tests if you are newly diagnosed with breast cancer, have a recurrence, or have breast cancer that spread to other parts of your body.

Before the late 1990s, women with HER2-positive breast cancer had poorer survival rates. Today, among those who receive targeted therapy, this is no longer the case. Researchers better understand what fuels HER2-positive breast cancer and the discovery of targeted therapies that interfere with its growth make it a very treatable disease.

Trastuzumab was the first HER2-targeted therapy. The medicine attaches to HER2 receptors on cancer cells, blocking signals that cause growth and alerting the immune system to destroy the cancer. Trastuzumab is given by vein, either once a week or once every 3 weeks.

Studies of trastuzumab showed promising results for treating and improving the survival of those with HER2-positive metastatic breast cancer. Because of this, in 1998 the U.S. Food and Drug Administration approved the medicine as a therapy for advanced disease. Later research led the FDA to approve the medicine for use by those with early-stage and locally-advanced breast cancers in the mid-2000s.

“Even before its approval, trastuzumab demonstrated that HER2-directed treatment could have a dramatic impact on patients with HER2-positive disease,” says Nancy Lin, MD, a breast oncologist at the Dana-Farber Cancer Institute. “This led to a number of subsequent trials showing it improves cure rates in patients who present with early-stage HER2-positive breast cancer.”

Alexis Sulinski, 48, of Derby, Conn., diagnosed in late 2004 with stage III cancer, was one of the first women to benefit from use of the medicine after its approval for early-stage and locally-advanced disease.

“With Herceptin, I could leave the house and go about my everyday life without a problem,” Alexis says, noting the few side effects she had. “This was something I couldn’t do with my other treatments.”

Beyond side effects, Alexis also believes, “the fact that I took this medicine is the reason I did not have a recurrence.”

Since trastuzumab, there has been so much progress in treating HER2-positive breast cancer that in a lecture at the 2013 Breast Cancer Symposium, George Sledge, MD, chief of oncology at Stanford University School of Medicine, predicted we will soon see the end of the “HER2 era” of poorer outcomes for those with the disease.

“We will always have patients relapsing with HER2-positive disease, and this will require novel therapies,” Dr. Sledge commented. “But from a public health standpoint, I believe HER2 is almost over.”

Paving the Way for Other Targeted Therapies

The success of trastuzumab opened the door for the development of other targeted therapies, providing more treatment options. Today, many of these treatments are approved for HER2-positive metastatic breast cancer and are being studied in early-stage disease.

Eva Snitkin, 42, of Minneapolis participated in MARIANNE, an ongoing study assessing the effectiveness of treating HER2-positive metastatic breast cancer with two targeted therapies at the same time: T-DM1 (Kadcyla) and pertuzumab (Perjeta). She began the study in April 2011, a few months after she was diagnosed with metastases to the bone, finishing treatment 2 years later once T-DM1 became FDA-approved.

“The cancer went away at the time of my first follow-up scan, which was 6 weeks after I began taking the drug,” Eva says. “It was like a targeted cancer bomb.”

Targeted HER2 therapies developed after trastuzumab include pertuzumab, lapatinib (Tykerb), and T-DM1.

Lapatinib (Tykerb)

Approved in 2007, lapatinib, given along with the chemotherapy medicine Xeloda (capecitabine), treats HER2- and hormone-positive metastatic breast cancers. Lapatinib when given with capecitabine also has been shown to lead to tumor shrinkage and stabilization in the brain.


Pertuzumab was approved in 2012 to treat metastatic breast cancer after clinical trials proved its benefit. It was approved in late 2013 for women with early-stage disease to be given prior to surgery, and is generally considered for treating women at higher risk of the cancer metastasizing. Results of a clinical trial to test its value when given after surgery are pending. The medicine is given by vein, often given alongside trastuzumab and docetaxel (Taxotere) chemotherapy.


T-DM1 is an anti-body drug conjugate, meaning it is a targeted therapy combined with chemotherapy. It delivers medicine directly to the cancer, while sparing healthy cells from damage.

Multiple treatments are in the pipeline, all showing promise in helping to fulfill Dr. Sledge’s prediction of an end to the HER2 era.

They also revealed T-DM1 had fewer harmful side effects than lapatinib and capecitabine combined. Eva took T-DM1 through a clinical trial.

“I experienced very few side effects and for a period of time, T-DM1 kept the cancer away,” Eva says. “All of us who have the disease hope researchers and pharmaceutical companies keep working on new treatments for us.”

Researchers are now studying T-DM1 in early-stage disease.

Side effects

Like all medicines, HER2-targeted treatments can cause side effects. Rarely, these medicines cause heart problems, liver inflammation, diarrhea and skin problems. The risk of heart problems increases when given with certain types of chemotherapy, like anthracyclines.

Studies show people who take HER2-targeted therapies like trastuzumab and T-DM1 generally tolerate the treatments quite well, Dr. Lin emphasizes.

Studies that led to the approval of T-DM1 in 2013 compared the therapy to lapatinib given with capecitabine in HER2-positive metastatic breast cancer. Results showed T-DM1 significantly increased progression-free survival, the time from the start of treatment until the disease grows or worsens.

The Future

Last year, Marcy Futernick, 57, of Valley Stream, N.Y., felt nervous toward the end of her treatment with trastuzumab for early-stage breast cancer. Just when fears of the cancer coming back began to weigh on her mind, Marcy read about the FDA approvals of T-DM1 and pertuzumab.

“I try to put those fears in the back of my mind,” Marcy says. “Knowing more treatment options are available since I was diagnosed in 2012 makes me feel much better.”

Multiple treatments are in the pipeline, all showing promise in helping to fulfill Dr. Sledge’s prediction of an end to the HER2 era.

Recently, Sara M. Tolaney, MD, MPH, of the Dana-Farber Cancer Insitute, presented encouraging findings at the 2013 San Antonio Breast Cancer Symposium. on the effects of combining trastuzumab with a non-anthracycline chemotherapy (weekly taxol in combination with trastuzumab) to treat 406 women with early-stage HER2-positive disease who had smaller tumors. Results revealed more than 98 percent were alive and cancer-free by a follow-up period of about 3.5 years.

By bypassing anthracyclines, there were fewer acute side effects and the small risks of leukemia and cardiac toxicity linked to anthracyclines were eliminated. There is still some low level risk of heart toxicity with trastuzumab.

"For the majority of patients with stage I HER2-positive breast cancer, I think this is a regimen that is going to be adoped pretty widely," says Eric Winer, MD, senior author of the study.

A number of other HER2-targeted-therapies are in development, Dr. Lin shares. These include oral medicines like neratinib, afatinib, and ONT-380, which block signals used by HER2 proteins to trigger cancer growth. Beyond this, experts continue to study the effectiveness of combining more than one HER2-targeted therapy to treat the disease.

Another area of interest is the phosphatidylinositol-3 kinase (PI3K) inhibitor. Lab research has demonstrated that HER2 signals through the PI3K pathway. In addition, about one-quarter of HER2-positive tumors contain a mutation, or error, in the PI3K gene.

“Those with tumors that have the PI3K mutation seem to be somewhat more resistant to standard therapies,” Dr. Winer explains. “We are testing inhibitors that reverse those mutations.”

Experts believe ongoing genomic research based on human tumor tissue samples in the setting of metastatic cancer will also lead to ways to assess risk of recurrence and resistance for HER2-positive disease, as well as ways to better treat brain metastases. This research is devoted to studying a person’s genes and the combination of gene mutations that may cause breast cancer. Claudia too is hopeful that upcoming research will continue to help other women like her.

“I know, in general, HER2-positive metastatic breast cancer is considered to be aggressive,” Claudia says. “But I have survived for 10 years very successfully, and I’m hopeful more progress will be made.”

Additional Related Topics 
Targeted Therapy