A Story of Discovery: HER2’s Genetic Link to Breast Cancer Spurs Development of New Treatments
- Breast cancers with high levels of human epidermal growth factor receptor 2 (HER2) are more likely to spread and less likely to respond to treatment.
- NCI-supported research helped lead to the key discovery that blocking the action of HER2 could slow the growth of certain types of cancers.
- This discovery paved the way for the development of trastuzumab (Herceptin®), a drug that has improved outcomes and survival rates for women with HER2-positive breast cancer.
- HER2 targeted treatment has helped to change the prognosis for stage 1 to 3 breast cancers from a poor one to a good one.
- NCI continues to support research on how to most effectively use HER2-targeted treatments to destroy cancer cells and how these discoveries can be applied to treatments for a wider range of cancers while reducing harmful side effects and improving survival and quality of life.
Pathway to Discovery
Why do some cancers grow quickly and spread rapidly while others do not? For years, scientists tried to solve this biological puzzle. An important clue was revealed with the discovery that breast cancer cells containing abnormally high levels of a protein called HER2 are more likely to spread to other organs in the body. This critical discovery sparked researchers to look for ways to alter this process.
This led to the development of trastuzumab (Herceptin®), a drug that has improved survival rates for women with stage 1 to 3 HER2-positive breast cancer by more than 30%. This drug, approved by the U.S. Food and Drug Administration (FDA), is the successful end result of decades of cancer research. Today, it is widely used to treat metastatic breast cancer and is being tested in the treatment of other types of cancers.
Researchers find the culprit. The story of trastuzumab’s discovery goes back to the early to mid-1980s when the research community was abuzz with the discovery that a mutated gene could stimulate excessive cell growth and division. Subsequent research identified the growth factor receptor gene, HER2. NCI-funded researcher, Dennis Slamon, M.D., and colleagues recognized the potential importance of this discovery and set out to uncover the genetic link between HER2 and different types of cancers. By investigating HER2 in tumor samples, Dr. Slamon found that HER2 was present at very high levels in about 25 to 30 percent of breast cancer cells—dramatically increasing the rate at which a tumor grew. Building on HER2 as an initial suspect, Dr. Slamon also found that high levels of HER2 were linked to a greater likelihood of metastasis and relapse and an overall decrease in patient survival.
While this work was underway, NCI scientist Stuart Aaronson, M.D., and a team of NCI researchers were among the first to show that HER2 could cause normal cells to behave like aggressive cancer cells by growing uncontrollably. This led researchers to hypothesize that HER2-positive breast cancers could be slowed if the action of HER2 itself could be blocked, paving the way for the development of targeted drug treatments to stop the spread of cancer cells.
Antibodies come to the rescue. One way to block the growth of cancer cells is to use monoclonal antibodies made in the laboratory to attach to a specific protein and halt its growth. With continued NCI support, Dr. Slamon, in collaboration with colleagues from the University of Texas Health Sciences Center, showed that an antibody specific to HER2 could slow the growth of metastatic breast cancer cells and other types of cancer in a laboratory setting.
Building on this exciting breakthrough, researchers at Genentech developed a mouse model that was implanted with HER2-positive human tumors. A collaboration between Genentech and UCLA researchers subsequently showed that antibodies could suppress the growth of HER2-positive tumors in mice.
Researchers at Genentech then developed the HER2-specific antibody trastuzumab, and launched three clinical trials in the mid-1990s for patients with HER2-positive metastatic breast cancer. By 1998, the results of phase III clinical trials showed that patients treated with trastuzumab and chemotherapy had slower progression of breast cancer tumors than patients treated with chemotherapy alone. For patients with the combination treatment, the median time to when the disease progressed was increased from 4.6 months to 7.6 months, a 65 percent increase, to relapse. Also, 28 percent of patients treated with trastuzumab plus chemotherapy had no evidence of tumor progression at 12 months, compared with 14 percent of patients treated with chemotherapy alone. Subsequent clinical trials have also shown positive outcomes among women with early stage HER2-positive breast cancer.
One Discovery, Many Benefits
The story of HER2 doesn’t end with the development of trastuzumab (Herceptin®), a HER2-targeted treatment, or its benefits to patients with metastatic breast cancer. Part of the serendipity of biological research is that understanding can be applied across more than one type of cancer. The fruits of NCI’s discovery linking HER2 to cancer continue to spur new or modified treatments for breast, gastric, and other types of HER2-positive cancers.
New treatments come to light. Because many breast cancer patients do not always benefit from current HER2-targeted treatments or they become resistant after initiating treatment, researchers are continuing to test new or modified drug combinations to improve survival. One antibody being tested is pertuzumab, which blocks HER2 from sending signals to other HER-family proteins that instruct them to grow and replicate. In June 2012, the FDA approved pertuzumab (Perjeta®) as a new treatment for HER2-positive breast cancers. This drug is intended to be used in combination with trastuzumab and docetaxel, a chemotherapy drug. None of this would be possible, however, without NCI’s initial discovery of the HER2’s link to breast cancer.
Results are seen in gastric cancer treatment. Results of a major clinical trial showed that trastuzumab, when used in combination with chemotherapy drugs, resulted in longer survival (13.1 months) for advanced HER2-positive gastric and gastroesophageal junction cancers when compared with treatment using chemotherapy drugs alone (11.7 months). As a result, the FDA approved the use of trastuzumab in combination with cisplatin and a fluoropyrimindine to treat patients with HER2-positive gastric or gastroesophageal junction cancers.
Researchers take on resistance and side effects. NCI’s discovery of linking HER2 to aggressive breast cancer continues to be a core building block of today’s cancer research community. In 2013, the FDA approved another drug combination that holds promise for patients who become resistant to trastuzumab treatment using ado-trastuzumab emtansine (Kadcyla®), also known as T-DM1. Studies show the potential of T-DM1 as an effective initial treatment with fewer side effects compared with trastuzumab alone for patients with metastatic breast cancer.
What’s Next for HER2 Research?
Understanding the role of HER2 in promoting cancer cell growth is a strong foundation for more effective breast and gastric cancer treatment in the future. Research at the basic and clinical levels is making important contributions.
A number of clinical trials are trying to determine if using trastuzumab is an effective treatment for breast cancer tumors not classified as being HER2-positive. Serendipitously, researchers discovered that HER2 also works in some HER2 negative tumors. An NCI-funded trial led by Louis Fehrenbacher, M.D., is studying the effect of trastuzumab in women with “HER2-negative/low” tumors to determine whether the treatment can reduce the risk of recurrence and increase overall survival.
Other research is exploring the benefit of trastuzumab and similar HER2-targeted treatments for some ovarian and gastric cancers that have high levels of HER2. In 2014, animal studies showed that the drug combination of trastuzumab and T-DM1 reduced or got rid of HER2-positive ovarian cancer tumors in mice. This holds promise for future studies in humans and continues to build on the early NCI-supported initial discovery.
Researchers are continually seeking treatments, including combination treatments that can effectively destroy cancer cells without causing severe side effects. One potential treatment uses an antibody that recognizes both the HER2 protein on a cancer cell’s surface and a protein on the immune system’s T cells, which fight infection. This allows the patient’s own immune system to attack the cancer by bringing the T cells directly to the cancer cell.
Research to Practice: NCI’s Role
Since the 1980s, NCI has made sustained investments in the study of HER-family proteins and their mechanisms of action. These investments have yielded important scientific discoveries in understanding cancer. Today, the prognosis, survival rates, and outcomes are greatly improved for patients with metastatic breast cancer and other types of HER2-positive cancers. Newer NCI-supported research is looking at how these discoveries can be applied to treatments for a wider range of cancers while reducing harmful side effects and improving survival and quality of life.
Patients with HER2-positive breast cancer show better outcomes and improved survival rates since the development of trastuzumab, a drug that blocks HER2-positive cells from replicating. Researchers are now looking at how this discovery can be applied to treatments for a wider range of cancers while reducing harmful side effects and improving survival and quality of life.
Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9(7):463-475. [PubMed Abstract]
Baselga J, Tripathy D, Mendelsohn J, et al. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol.1996;14(3):737-744. [PubMed Abstract]
Hudis CA. Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med. 2007;357(1):39-51. [PubMed Abstract]
National Cancer Institute. Cancer Drug Information: Pertuzumab (Perjeta). http://www.cancer.gov/about-cancer/treatment/drugs/pertuzumab. Updated July 31, 2014. Accessed August 21, 2014.
National Cancer Institute. Cancer Drug Information: Trastuzumab (Herceptin). http://www.cancer.gov/about-cancer/treatment/drugs/trastuzumab. Updated August 6, 2013. Accessed August 21, 2014.
Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672. [PubMed Abstract]
Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673-1684. [PubMed Abstract]
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast
cancer: correlation of relapse and survival with amplification of the HER-2/neu
oncogene. Science.1987 Jan 9;235(4785):177-82. [PubMed Abstract]
Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [PubMed Central]
Slamon DJ, Romond EH, Perez EA; CME Consultants, Inc. Advances in adjuvant therapy for breast cancer. Clin Adv Hematol Oncol. 2006 Mar;4(3 Suppl7):suppl 1,4-9; discussion suppl 10; quiz 2 p following suppl 10. [PubMed Abstract]
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. 2001;344(11):783-792. [PubMed Abstract]
Yu L, Wang Y, Yao Y, Li W, Lai Q, Li J, Zhou Y, Kang T, Xie Y, Wu Y, Chen X, Yi C, Gou L, Yang J. Eradication of Growth of HER2-Positive Ovarian Cancer With Trastuzumab-DM1, an Antibody-Cytotoxic Drug Conjugate in Mouse Xenograft Model. Int J Gynecol Cancer. 2014 Sep;24(7):1158-1164. [PubMed Abstract]