by Dr. C.H. Weaver M.D. updated 5/1/2019
Herceptin® (trastuzumab) was initially approved by the U.S. Food and Drug Administration (FDA) for use in the post-surgery treatment of early-stage breast cancer (ESBC) that is HER2-positive in 2006. The approval initially specified that Herceptin be given in combination with the chemotherapy drugs doxorubicin, cyclophosphamide, and paclitaxel and was based on the results of two clinical trials published in the New
England Journal of Medicine.
Breast cancer is diagnosed in over 200,000 women annually in the US alone. Early breast cancer refers to cancer that has not spread outside the breast and regional lymph nodes. Standard treatment for early breast cancer often includes the surgical removal of the cancer, followed by chemotherapy and radiation.
Long-term outcomes are promising overall for patients with early breast cancer who are treated with standard therapy. However, a significant portion of patients may experience a potentially fatal cancer recurrence.
The HER2 pathway is associated with growth and replication of cancer cells. Cancer cells that over-express HER2 are referred to as HER2-positive. Herceptin is a monoclonal antibody that is targeted against the HER2 pathway. Herceptin binds to distinct components of HER2-positive cells and disrupts cellular replication.
The addition of Herceptin to chemotherapy has demonstrated improved outcomes, including survival, in patients with HER2-positive metastatic breast cancer.
Herceptin is currently approved for treatment as a single agent in patients with HER2-positive metastatic breast cancer that has progressed or recurred following prior therapy; it is also approved in combination with the chemotherapy agent paclitaxel (Taxol®) in patients with HER2-positive metastatic breast cancer who have not received prior therapy. Several ongoing clinical trials are evaluating Herceptin in different stages of breast cancer, including its use as neoadjuvant treatment for the disease.
The first trial reported in the New England Journal of Medicine was an international, multi-center trial called the HERA trial. It included nearly 5,100 women with early-stage, HER2-positive breast cancer who had completed surgery with or without radiation therapy and chemotherapy. Patients then received either one year of treatment with Herceptin, two years of treatment with Herceptin, or no further treatment (observation). Published results included patients treated with one year of Herceptin and those under observation.
Herceptin significantly improved outcomes in these patients at a median follow-up of one year:
- Patients treated with Herceptin had a 46% reduced risk of death, a cancer recurrence, cancer in the other breast, or cancer other than breast cancer.
- At two years, cancer-free survival was improved by 8.4% overall in the patients treated with Herceptin.
- Severe side effects affecting the heart (cardiotoxicity) occurred in 0.5% of patients treated with Herceptin.
The second clinical trial reported in the New England Journal of Medicine was a combined analysis of two separate clinical trials; they include the National Surgical Adjuvant Breast and Bowel Project trial (B-31) and the North Central Cancer Treatment Group trial (N9831). Both trials included women with early breast cancer who received surgery with or without radiation therapy, followed by chemotherapy (including doxorubicin and cyclophosphamide), followed by paclitaxel. Approximately half of the women were treated with Herceptin while being treated with paclitaxel.
At three years follow-up, the addition of Herceptin significantly improved survival among these women:
- Patients treated with Herceptin had an approximate 50% reduced risk of a cancer recurrence, a second cancer, or death.
- Patients treated with Herceptin had a 33% reduced risk of death compared to those treated with chemotherapy only.
- Rates of severe cardiotoxicity occurred in approximately 4% of patients treated with Herceptin in the B-31 trial and approximately 3% of patients treated with Herceptin on the N9831 trial.
The researchers concluded that the addition of Herceptin to chemotherapy significantly improves outcomes compared to chemotherapy alone in women with early-stage, HER2-positive breast cancer. It appears that treatment with Herceptin during chemotherapy (versus following chemotherapy) may provide superior results in this group of patients. Women with early breast cancer should speak with their physician regarding testing for HER2, as well as their individual risks and benefits of treatment with Herceptin.
How long should Herceptin be administered?
The HERA study was a phase III clinical trial that randomly assigned HER2-positive early breast cancer patients to one of three treatment groups following adjuvant chemotherapy: observation, one year of Herceptin, or two years of Herceptin.
Overall survival and cancer-free survival were significantly better in the women randomly assigned to one year of Herceptin compared to the women in the observation group. Risk of death was 34% lower among women treated with one year of Herceptin. Herceptin protected against both distant metastases as well as local recurrence.(8)
Concern of side effects to the heart from Herceptin have led doctors to evaluate shorter courses of Herceptin treatment. The net result of these studies according to Dr. Harold Burstein M.D. a leading authority on the topic is that the optimal duration of Herceptin treatment remains one year for ESBC patients.
For example Mavroudis and colleagues conducted the HORG trial to examine 6 versus 12 months of Herceptin therapy in a cohort of 481 women with early, HER2-positive breast cancer.(9)
The analysis included 240 women in the 6-month group who were followed for 51 months and 241 women in the 12-month group who were followed for 47 months. Disease relapse rates were 11.7% in the 6-month group and 7.1% for the 12-month group. Overall survival was comparable between the two treatment arms, as was cardiac toxicity.8
All five trials that have examined the question of 6 vs. 12 months of Herceptin have similar results.(4-8)
Subcutaneous Herceptin Now an Option
Dr. Jackisch M.D. and colleagues from Germany reported the results of an open-label, multi-center, international clinical trial to compare the effectiveness and safety of subcutaneous and IV Herceptin in patients with HER2-positive ESBC.
A total of 596 individuals were enrolled in the clinical trial between October 19, 2009, and December 1, 2010 and have now been followed for 6 years.
Patients were given 8 cycles of standard chemotherapy and either a fixed-dose of subcutaneous or IV Herceptin for 10 after surgery to complete 1 year of anti-HER2 therapy.
The overall survival and progression free survival were essentially identical for IV and subcutaneous Herceptin. Moreover, the rates of significant cardiac and other serious side effects were similar.
The study suggests that subcutaneous Herceptin is as an effective alternative route of administration for patients with HER2-positive ESBC.(12)
- Slamon D, Eiermann W, Robert N, et al. BCIRG 006: 2nd Interim Analysis Phase III Randomized Trial Comparing Doxorubicin and Cyclophosphamide Followed by Docetaxel (AC-T) with Doxorubicin and Cyclophosphamide Followed by Docetaxel and Trastuzumab (AC-TH) with Docetaxel, Carboplatin and Trastuzumab (TCH) in Her2neu Positive Early Breast Cancer Patients. Proceedings from the 2006 San Antonio Breast Cancer Symposium (SABCS). Oral presentation December 14, 2006. Abstract #52.
- Slamon DJ, et al. N Engl J Med. 2011;doi:10.1056/NEJMoa0910383.
- Metzger Filho O & Burstein HJ. *Ann Oncol.*2018;doi:10.1093/annonc/mdy480.
- Earl HM, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.36.15_suppl.506.
- Hulme C, et al. Ann Oncol. 2018;doi:10.1093/annonc/mdy424.001.
- Pivot X, et al. Cancer Res. 2019;doi:10.1158/1538-7445.SABCS18-GS2-07.
- Joensuu H, et al. JAMA Oncol. 2018;doi:10.1001/jamaoncol.2018.1380.
- Conte P, et al. Ann Oncol. 2018;doi:10.1093/annonc/mdy414.
- Mavroudis D, et al. Ann Oncol. 2015;doi:10.1093/annonc/mdv213.
- Piccart-Gebhart M, Procter M, Leyland-Jones B, et al. Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast Cancer. New England Journal of Medicine. 2005; 353:1659-1672.
- Romond E, Perez E, Bryant J, et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. New England Journal of Medicine. 2005; 353:1673-1684.
- JAMA Oncol. 2019 Apr 18. Epub ahead of print
Copyright © 2018 CancerConnect. All Rights Reserved.