Herceptin- A Revolutionary Tool among Personalized or Customized Medicines

Herceptin (Trastuzumab) as an Antineoplastic Agent

Herceptin is a monoclonal antibody used in the treatment of breast cancer and stomach cancer which are HER2 receptor positive. Axel Ullrich and his coworkers developed clones of human HER2/neu mutant gene at Genetech lab. Later Dennis slamon and his collegues at UCAA showed HER2 over expresson in 20% of patient with aggressive breast cancer. HER2 is an oncogene protein and a member of epidermal growth factor receptor family like EERB (Erythroblastic oncogene B). The over expression of this oncogene has been shown to play an important role in the development and progression of certain aggressive types of breast cancer cells. Normally it is given as an Iv infusion and as a SC injection (Herceptin hylecta). [10] The different treatment patterns Herceptin follows are;

• Used alone to treat breast cancer in its metastatic stage by preventing the growth of cells.
• Used alone to treat early stages of cancer and also to prevent recurrence.
• Used in combination with Pertuzumab and Taxotere before surgery to prevent HER2 progression
• Used along with Pertuzumab to prevent the recurrence after surgery.

Mechanism of Action of Herceptin

As we know genes are the instructing modules of all cells. They give different signals to cells regarding their growth and repair. If the gene goes abnormal it would be sending wrong signals to the cells. Some cells may possess many more copies of a gene. If all these copies become abnormal the cell will receive multiple wrong signals and show abnormal activities like over growth. This situation is called “over expression” of a gene which leads to the formation of cancerous cells. HER2 receptors are such kind of over expressive genes found on the surface of breast cells which make them cancerous. Herceptin has been found to be effective against this particular gene. Herceptin can block the HER 2 receptors from receiving wrong signals there by it can prevent the overgrowth of breast cancer cells [6].

There are 2 methods currently available for the detection of HER2 receptor over expression in breast cells. IHC (Immunohistochemistry) and FISH (Fluorescence in situ hybridization). Among them we prefer IHC as a common detection method over FISH because of it high prize even though it is the most accurate one. Like every chemotherapeutical agents Herceptin also have a lot of side effects. But it shows major Side effects in patients with heart and lung problems. Many biosimilars are also available for Herceptin Eg; Herzuma (trastuzumab- pkrb), Kanjinti (trastuzumab - anns), Ogivri (trastuzumab –dkst),Ontruzant (trastuzumab-dttb), Frazimera ( trastuzumab-9xyp) [7].

Herceptin as A Personalized Medicine

Herceptin (Trastuzumab) was approved by FDA in 1998. Since then it was hitting the markets as a major single drug and as combinations for patients with metastatic breast cancer who had not respond for other chemotherapeutic agents. After the introduction, the sale of this drug was reported as $188 million in U.S and became a best drug among top 20 bestselling biotech drugs with increasing demand year by year. So it is relevant to select Herceptin for researchers to make it as personalized medicine for future applications [6, 7].

Cells with over expressed HER2/neu genes are said to be HER2 positive that means cancerous. Physicians must prescribe Herceptin only to patients with test result HER2 positive. Otherwise it will have harmful effects. In women with HER2 negative or normal HER 2receptor genes Herceptin increases the risk of heart problems. So the regulatory organizations like FDA should be more careful before approving drugs to multiple uses among large population. They should be able to tell the correct patient on which the dug will exert its correct action. Then we can say whole heartedly a drug is successful. The genetic variations and mutation on the HER2/ neu genes will also causes the same situation. Proper detection mechanisms are needed to determine the correct drug response in every patient. Currently available tests like IHC and FISH are not sufficient to provide clear cut genetic information. More sophisticated technologies are needed. And a regular data base should be maintained for each patient as a profile with detailing of drug dosing and consequent drug response. It should be a common accessible data base to all physicians, technicians and researchers. Then only they could analyse the results and make a control over the drug use. But a hidden problem is also there. Since we are providing all personal information about the patient in a common medium accessible to many people. We cannot assure the safety and privacy of those details further. There may be chances of misusing those data. So there are many ethical as well as non-ethical issues to be solved behind each step [7, 8].

Various studies have been conducting to reveal the relation between genotyping and drug dosing. As we said earlier warfarin dosing related to CYP 450 and CYP 2C9 gene polymorphism is quite relevant to be discussed here. A major cause of variability in warfarin response is due to mutations in the genes of these particular enzymes. The development of FDA approved Amplichip R CYP450 test is a mile stone in personalized medicine. This gene test can give a valid result on variations of these 2 metabolic enzymes CYP450 and CYP 2C19. But the adoption of this test to clinical practice is still doubtful due to the lack of evidences about their clinical utility. And it is not applicable for HER2 gene testing for Herceptin like drug [9, 10].

For proving a drug as a personalised medicines various aspects have to be checked like the identification and screening of the candidate gene on which the drug is going to produce a response, possible polymorphisms, correlation of polymorphism with therapeutic targets, prediction of drug response and clinical outcomes, selection of therapeutic dosages on the basis of genotypes etc. A wide array of genomic technologies is also to be included such as high throughput technologies, global gene expression analysis, genome wide functional analysis, gene expression monitoring etc [11, 12, 13].

Pharmacogenomics Approaches on Herceptin

It has been already proven that treatment with Herceptin shows good improvement and overall survival in metastatic cancer. Despite the effectiveness it has also developed some primary and secondary resistance due to reasons such as incomplete HER2 blockage when we use Herceptin alone, hetrero dynamic signalling from other growth factors like HER 3 biomarkers, oncogene mutation in PK12 pathway and loss of HER2 extracellular domain for action. In order to solve these issues Trastuzumab is given as combination with Pertuzumab and Lapatinib. And it is also given as an antibody drug conjugate like Trastuzumab emtansine. In 2012 FDA has approved Trastuzumab and Pertuzumab combination for the first line treatment of breast cancer because they have synergistic activity and reduced side effects on immune genesis and cardiovascular toxicity as combinations. Regardless of the targeted therapy combinations employed based on tumour genomic profile, these 2 drugs will likely to continue to form a backbone of the personalized regimen for HER 2 positive breast cancer [3, 13].

The oncogene mutation in PK12 pathway and over expression of HER3 biomarker receptors can be subject to poor prognosis and lower response to HER2 therapies. So before implementing the therapy these things have to investigate and validated which is possible by pharmacogenomic indulgence. Neoadjuvant trial is also an attractive platform for rapid triage of drug efficacy, biomarker identification and validation. The utilization of neoadjuvant trials in breast clinics can also be used to approve novel drugs, to compare different combinations, to identify predictive markers and also to determine optimal HER2 sequencing. In the current times one size fits to all is increasingly become obsolete. Since the success of Herceptin for HER 2 breast cancer, there have been strides in the development of personalized therapeutics. Allowing Herceptin as a personalized medicine we can claim that when a patient with HER 2 positive breast cancer come to the clinic, the routine use of gene sequencing, chances of gene mutation, identify gene biomarkers and accordingly select patient who will optimally benefit from particular HER 2 blockers and their combinations [10, 14, 15].