Breast cancer is the most common cancer in women. Every year in U.K. approximately 50000 women and 340 men are diagnosed with breast cancer1 with poor patient survival. Breast cancer is the most malignancy disease and leading patients death. It can be detected by mammography which uses X-ray images to detect abnormal growths or changes in the breast tissue2.
HER2-positive breast cancer is one of the breast cancer which is caused by either amplication and subsequent over expression of the HER23, 23. Approximately 25% to 30% of primary breast cancers are observed in over-expression of human epidegrermal growth factor receptor 2 (HER2)4, 5, 23. HER2 is a 185kDa transmembrane tyrosine kinase receptor (p185HER2)3, 6, 23 that encoded by the erbB2 ocogene7. It is located on human chromosome 17q217, 8. Lapatinib, pertuzumab, and trastuzumab have been well developed for HER2-positive breast cancer treatment3. The latter case will be focused on this paper.
Herceptin is a generic name of trastuzumab, is a humanised IgG1-class recombinant monoclonal EGFR antibody to HER27, 9, 23. It is a monoclonal antibody that contains more than 90% of human genes and approximately 7% of murine genes10 made up the antigen loops23. Herceptin can also be used as first-line mono therapy for advanced breast cancer11. Before development of herceptin, in patients whose breast cancer has spread, metastatic breast cancer (MBC) median survival was 22 months4, 10. After treatment of herceptin, survival from 22 months to 27 months or a 5 month improvement in survival10. The mechanism of herceptin target HER2 will discuss later in this paper.
The first studied of herceptin was in 199112. In 1975, Georges Köhler and César Milstein discovered to confront disease by using antibodies13. After six years of researching, human HER2 gene was sequenced for the first time ever13. In 1991, herceptin was created and started phase I clinical trials on the following year13. Phase III pivotal trials for herceptin was completed in 199713. According the data in 2008, more than 420,000 women with HER2-positive breast cancer have been treated with herceptin13, 14.
Before herceptin was created, a lots of treatments had been used. Radical Mastectomy, doxorubicin, and tamoxifen were the main previous treatment for breast cancer12. In 1894, William Halsted developed the Halsted radical mastectomy after his published about breast cancer12. He suggested that breast cancer started spreading from the primary tumour to other parts of the body through the surrounding tissue and lymph nodes12. Radical mastectomy is a surgical procedure which removes all amount of the breast tissue, including nipple, lymph nodes in the armpit, and chest muscles under the breast12, 15. However mastectomy did not cure the breast cancer very well. Recurrence of breast cancer after a few years of mastectomy lead to side effects and decreased the quality of life for women12.
Doxorubicin was the first studied of chemotherapy drug in 1974. It is responsible for shrinking the breast tumours cells without removing the full breast. Doxorubicin should be given into the vein but it may leak16. Leaking from the vein during having doxorubicin, it damages the tissue, known as extravasation17. Doxorubicin has serious side effect such as heart problems after being treated, during the treatment, or months to years after the treatment has ended16, 17. Decreasing the number of blood cells in bone marrow is one the severe side effect of doxorubicin16. This may lead to the development of infection or bleeding. High doses of doxorubicin can lead to developing of leukaemia as well16. Liver disease patients should not be given doxorubicin16,17.
Tamoxifen (Novaldex) is a hormonal chemotherapy drug. Treatment with tamoxifen results in significant tumour shrinkage thus it is given for the advanced breast cancer12. It inhibits the activity of oestrogen12. It is agreed that tamoxifen as adjuvant therapy for post-menopausal women following breast cancer surgery12. It is given as a tablet, after treatments to prevent cancer recurrence, before surgery to shrink the tumour cells to avoid mastectomy17.
HER2 dimerisation promotes the mislocalisation and rapidly degrades p2724. P27 is a cyclin-dependent kinase inhibitor24, 25, 27 which interrupts cell cycle progression and promotes cell-cycle arrest and apoptosis24, 25, 27. Herceptin binds to domain IV of the extracellular domain (ECD) of the HER2 receptor24 to inhibit HER2 heterodimerisation or homodimerisation7, 24. Herceptin also inhibits tyrosin kinase activity by targeting receptor erbB24, 23, 26, 28 . As a result, interrupts the downstream signalling pathway such as P13K and ras-Raf-MAPK23, 25, 28 which induce P27 25. Plus, Akt and mTOR are inhibited23, 28 as well. They are downstream effector of p13K28. Consequently, inhibit tumour cells cell cycle. It is believe that herceptin targets HER2 induces breast cancer apoptosis via antibody-dependent cellular cytotoxicity (ADCC) 23, 28. The actual mechanism of herceptin target HER2 is still not well understand28 but some mechanism and effects that stated have been marked in the literature28.
Normally, herceptin is given by intravenous infusion every once three weeks18. Intravenous infusion should be given slowly which takes up to 90 minutes18, 19. Subcutaneous injection18 can also be used for giving herceptin however it only takes two to five minutes18, 19. It is recommended at a does of 4mg/kg then followed by 2mg/kg weekly19. Herceptin not only can treat HER2, it can also be used to treat stomach cancer and oesophagus cancer20.
On the other hand, not all the patients can be treated by herceptin. They suffer the recurrence of breast cancer or they are not response to herceptin23, 28. Activity of transtuzumab is limited by the high level of HER2 over-expression or HER2 gene amplification29. The biggest issues of trastuzumab is an increased occurrence of breast cancer brain metastases due to mAb can not pass through an intact blood brain barrier30. However it can be treated by lapatinib which is able to pass through the blood brain barrier30. Moreover, trastuzumab increases occurrence of congestive heart failure (CHF)30 due to the combination of trastuzumab and doxorubicin treatment30.
Current studies of trastuzumab are developing the integration of lapatinib, trastuzumab, and chemotherapy30. Furthermore, a combination of hormonal treatments with trastuzumab is being studied31. United states and European cooperative groups have been researching the combination of trastuzumab into the adjuvant and neoadjuvant31. Herceptin work well when uses with other drugs. For instance, trastuzumab emtansine21, a combination of trastuzumab and a chemotherapy drug, emtansine. Trastuzumab emtasine binds to the receptors on the HER2 protein cancer cell resulting the blockage of cell cycle of cancer cells21. Trastuzumab emtansine also releases the emtansine directly into the cancer cell22 thus it demolishes the cancer cells from inside21. Herceptin combines with chemotherapy shows the greater increased overall patient survival, progression-free survival, and higher response rate than herceptin treatment alone19.
To conclude, trastuzumab is the current treatment for HER2-positive breast cancer although it has severe side effects. Besides, trastuzumab resistance has been strongly studies recently to treat HER2-positive breast caner31. The actual mechanism of how they work is virtually important therefore can support the studies of trastuzumab resistance. Nevertheless, trastuzumab has been widely used in treating HER2-positive breast cancer.