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Progress in treating HER2/neu-positive breast cancers

The past 30 years have seen many advances in the treatment of breast cancer. One of the most important has been the development of drugs that target HER2/neu-positive breast cancers. Before the anti-HER2 drug trastuzumab (Herceptin) was developed, prognosis was poor for HER2/neu-positive breast cancers. Today, trastuzumab and other anti-HER2 drugs have dramatically improved the prognosis of HER2/neu-positive breast cancers.  

What is HER2/neu?

HER2/neu (human epidermal growth factor receptor 2) is a protein that appears on the surface of some breast cancer cells. This protein is an important part of the pathway for cell growth and survival.  

  • HER2/neu-positive breast cancers have a lot of HER2/neu protein. 
  • HER2/neu-negative breast cancers have little or no HER2/neu protein. 

After HER2/neu was discovered in the 1980’s, researchers learned that for HER2/neu-positive breast cancers, blocking the HER2/neu pathway could slow or stop the growth of cancer cells. This led to the development of targeted therapies for HER2/neu-positive breast cancers (anti-HER2 drugs). 

Tumor tissue from all newly diagnosed breast cancers is now tested to see whether the cancer is HER2/neu-positive or HER2/neu-negative. About 15 to 20 percent of breast cancers are HER2/neu-positive.1-2 

What is a targeted therapy?

A targeted therapy is a drug designed to attack a particular molecular agent or pathway involved in the development of cancer. Unlike chemotherapy drugs, targeted therapies kill cancer cells with little harm to healthy cells.  

A targeted therapy will only work on cancers that have the specific marker it was designed to attack. So, anti-HER2 drugs can only be used to treat HER2/neu-positive breast cancers (cancers with a lot of HER2/neu protein). Anti-HER2 drugs do not help in the treatment of HER2/neu-negative breast cancers.   

How do anti-HER2 drugs work and when are they used?

Different anti-HER2 drugs work in different ways. Some are used to treat early, locally advanced and metastatic breast cancers. Others are only used to treat metastatic breast cancers at this time. The anti-HER2 drugs currently used in the standard treatment of breast cancer are discussed below. 

Trastuzumab (Herceptin)

Trastuzumab is a drug that targets HER2/neu-positive cancer cells. It attaches to the HER2/neu protein and slows or stops the growth of the cancer cells. Trastuzumab is the only anti-HER2 drug that is used to treat all stages of HER2/neu-positive breast cancer (early, locally advanced and metastatic breast cancers). It is given through an IV (intravenously).   

Early and locally advanced breast cancer

For women with HER2/neu-positive early breast cancer, chemotherapy plus trastuzumab cuts the risk of breast cancer recurrence in half and lowers the risk of death by about 40 percent compared to chemotherapy alone. 3-6  Learn more about trastuzumab in the treatment of early breast cancer

Metastatic breast cancer

Trastuzumab can shrink tumors and slow the growth of HER2/neu-positive metastatic breast cancer when used alone or combined with chemotherapy.7-10  A large randomized clinical trial showed that trastuzumab increased survival for women with HER2/neu-positive  metastatic breast cancer. After two and a half years, the women treated with chemotherapy plus trastuzumab had a 20 percent lower risk of death than the women treated with chemotherapy alone.7 Learn more about trastuzumab in the treatment of metastatic breast cancer

Trastuzumab emtansine (T-DM1, Kadcyla)

Trastuzumab emtansine (T-DM1) is a new type of targeted therapy that consists of a chemotherapy drug called DM1 attached to the antibody trastuzumab. Combining these drugs allows the targeted delivery of chemotherapy to HER2/neu-positive cancer cells. T-DM1 is given through an IV. 

Metastatic breast cancer

T-DM1 is used to treat HER2/neu-positive metastatic breast cancers that have already been treated with trastuzumab and a taxane-based chemotherapy. A randomized clinical trial showed that T-DM1 increased survival better than lapatinib (see below) plus the chemotherapy drug capecitabine.11 Learn more about T-DM1 in the treatment of metastatic breast cancer

Pertuzumab (Perjeta)

Pertuzumab is an antibody drug that targets HER2/neu-positive cancer cells in a different way than trastuzumab. It is given through an IV.  

Metastatic breast cancer

Pertuzumab in combination with trastuzumab and taxane based chemotherapy is used to treat HER2/neu-positive metastatic breast cancers that have not previously been treated with chemotherapy, trastuzumab or lapatinib. Studies show this combination of drugs may slow the growth of these cancers and increase survival better than trastuzumab and chemotherapy alone.9,12 Learn more about pertuzumab in the treatment of metastatic breast cancer

Neoadjuvant therapy (chemotherapy before surgery)

In some cases, chemotherapy is given before surgery. This neoadjuvant therapy can sometimes shrink a tumor enough that a lumpectomy may be done instead of a mastectomy.  

In September 2013, the FDA approved the use of pertuzumab in combination with trastuzumab and a taxane-based chemotherapy as a neoadjuvant  treatment for HER2/neu-positive locally advanced breast cancers. At this time, however, pertuzumab is not approved for use in the adjuvant setting.  Learn more about pertuzumab as neoadjuvant therapy

Lapatinib (Tykerb)

Unlike trastuzumab and pertuzumab, lapatinib is not an antibody. It is a tyrosine-kinase inhibitor drug. This class of drugs blocks tyrosine kinase enzymes, which are important for cell functions. Unlike other anti-HER2 drugs, it is taken in pill form. 

Neoadjuvant therapy

Lapatinib is under study for use in combination with trastuzumab as a neoadjuvant therapy for HER2/neu-positive locally advanced breast cancers.  

Metastatic breast cancer

Lapatinib is used along with capecitabine (an oral chemotherapy) for HER2/neu-positive metastatic breast cancer that has already been treated with trastuzumab and chemotherapy. A meta-analysis that combined the results from three randomized clinical trials found lapatinib in combination with chemotherapy also improved survival compared to chemotherapy alone.13  

Lapatinib can also be given with hormone therapy (letrozole) for estrogen receptor-positive, HER2/neu-positive metastatic breast cancer. Learn more about lapatinib in the treatment of metastatic breast cancer

Health risks of anti-HER2 drugs

As with most drugs, anti-HER2 therapies have some health risks. For example, in rare cases, trastuzumab can cause heart problems. Patients’ hearts are checked before and during treatment to help ensure there are no problems. Learn more about the possible health risks of trastuzumab and other anti-HER2 targeted drugs. 

Conclusions

The survival benefit from trastuzumab and other anti-HER2 targeted drugs has changed the outlook for people diagnosed with HER2/neu-positive breast cancers. According to Dr. Wendy Chen, medical oncologist at the Dana-Farber Cancer Institute, “The successful target of HER2/neu with therapies such as trastuzumab has dramatically improved the survival for women with HER2/neu-positive cancer and has been one of the major success stories of targeted cancer therapy. The HER2/neu pathway remains a promising area for new drug development." Since the FDA first approved the use of trastuzumab for the treatment of HER2/neu-positive metastatic breast cancers, research has continued to show the benefits of anti-HER2 targeted therapies. The use of trastuzumab and recently pertuzumab, now extend to non-metastatic breast cancers.  

People with HER2/neu-positive breast cancers now have many effective treatment options. These drugs demonstrate the power of targeted therapy for breast cancer and offer the hope of future drug discoveries.  

What is Komen doing?

Since 1982, Komen has invested nearly $59 million in more than 150 grants to support research related to HER2/neu-positive breast cancer. Examples of such research projects include: 

  • Developing and testing new drugs that target HER2/neu, including gene therapy and vaccines 
  • Identifying new drug combinations that are more effective against HER2/neu-positive breast cancer and testing them in clinical trials 
  • Identifying biological markers that can be used to predict which women will respond or become resistant to anti-HER2 therapies 
  • Testing new ways to prevent the development of HER2/neu-positive breast cancer including chemoprevention and dietary approaches such as flaxseed 

For more information on Komen’s research related to HER2/neu-positive breast cancer, see our Research Fast Facts:  HER2.  

References

  1. Carey LA, Perou CM, Livasy CA, et al. Race, breast cancer subtypes, and survival in the Carolina Breast cancer Study. JAMA. 295(21):2492-2502, 2006. 
  2. National Comprehensive Cancer Network. NCCN Guidelines for patients: Breast cancer. Version 2.2011. http://www.nccn.com, 2011. 
  3. Gianni L, Dafni U, Gelber RD, et al. for the Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 12(3):236-244, 2011. 
  4. Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 29(25):3366-73, 2011. 
  5. Slamon D, Eiermann W, Robert N, et al. for the Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 365(14):1273-83, 2011. 
  6. Moja L, Tagliabue L, Balduzzi S, et al. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 4:CD006243, 2012. 
  7. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 344(11):783-92, 2001. 
  8. Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 29(3):264-71, 2011. 
  9. Baselga J, Cortés J, Kim S, et al. for the CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 366(2):109-19, 2012. 
  10. Blackwell KL, Burstein HJ, Storniolo AM, et al. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 30(21):2585-92, 2012. 
  11. Verma S, Miles D, Gianni L, et al. for the EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 367(19):1783-91, 2012. 
  12. Swain SM, Kim SB, Cortés J, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 14(6):461-71, 2013. 
  13. Amir E, Ocaña A, Seruga B, Freedman O, Clemons M. Lapatinib and HER2 status: results of a meta-analysis of randomized phase III trials in metastatic breast cancer. Cancer Treat Rev. 36(5):410-5, 2010. 

Posted December 19, 2013