Abstract

Human Epidermal Growth Factor Receptor 2 (HER-2) is a growth factor receptor encoded by ERBB2 gene, an avian erythroblastic leukemia viral oncogene homolog 2. The ERBB2 gene is located on the long arm of human chromosome 17 (17q12) and it is also a known proto-oncogene. Over-expression of HER-2 within the ERBB2 gene occurs in approximately 55% of the primary tumors and lymph node metastases (Carlsson, Nordgren, Sjostrom, Wester, Willman, Bengtsson, Ostenstad, Lundqvist, Blomqvist, 2004).  HER-2 over-expression is also associated with increased tumor recurrence and some worst breast cancer prognosis. Over-expression of HER-2 is also linked to ovarian, stomach and aggressive forms of uterine cancer (Carlsson, Nordgren, Sjostrom, Wester, Willman, Bengtsson, Ostenstad, Lundqvist, Blomqvist, 2004). Furthermore, HER2 is co-localized with GRB7 which is a proto-oncogene associated with breast cancer. In light of this, scientific breakthrough shows that a monoclonal antibody trastuzumab (Herceptin) specifically targets and inhibits over-expression of HER-2 (Pruthi, S.2012). Trastuzumab’s downstream binding effect on HER2 increases p27, a protein that halts cell proliferation (Carlsson, Nordgren, Sjostrom, Wester, Willman, Bengtsson, Ostenstad, Lundqvist, Blomqvist, 2004). The need for a better breast cancer treatment which demanded a strong understanding of HER-2 gene expression pathways lead the path to the Herceptin discovery. Therefore, it is very important to understand some of the multi-factorial aspects which drove the successful production of Herceptin. Some of these factors include but not limited to human genomic/personalized medical breakthrough, sufficient financial support, societal need, projected financial profit and the hard work/resilience effort shown by researchers involved in the clinical research.

HER 2: Product Development Factors

The in-depth rational approach of the human genomic gene expression pathways of HER-2 and all other interactions between HER-2 expression relative to tumor formation was one of the breakthroughs in the Herceptin discovery (Ng. 2009).  Many researchers who resiliently worked on Herceptin discovery was also able to generate sufficient scientific data to support the claim that Herceptin will work very well on HER-2 positive breast cancer cells. Despite the fact that HER-2 positive breast cancer affects 20-25% of women with HER-2 mutation, the medical trend towards the idea of personalized medicine made it possible to support the project in view of small market share the drug may cover (Bazell, 1998).

Most FDA regulated drug discovery and approval are a lengthy process that takes up to 10-15 years and cost approximately $1- $1.2 billion in the United states (Whitmore, E. 2004).  Genentech funded the HER-2 research with a lot of money and resources to make sure that the clinical trial and subject recruitment was conducted appropriately (Bazell, 1998). Following the phase I and phase II of the clinical trial it was apparent to Genentech and the researchers that HER-2 was safe, efficacious and most importantly, had minimal side effects due to the precise inhibitory property of Herceptin to HER-2 gene (Bazell, R. 1998). Genentech / researchers promoted the phase III clinical trial shortly after. The result generated in the phase III clinical trial confirmed the previous clinical trial result and established the bases for the FDA approval of Herceptin.
Although the HER-2 type of breast cancer affects 20-25% of women suffering from breast cancer, societal need was one of the powerful tool used in fighting the “War on Cancer”. The US government strongly supports and funds several research on cancer. For instance, in December 23rd 1971, the National Cancer Act of 1971 was signed by president Richard Nixon. At the time, the National Cancer Institute budget for cancer research between 1971 and 1979 increased from $230 million to $940 million (Bazell, 1998). In addition, the Federal grant for cancer research were relatively and readily available to researchers working on cancer drug/therapy.
Another factor that motivated pharmaceutical companies to invest in cancer research is the expected/projected profit that will be harnessed from any block buster candidate drug for breast cancer. Herceptin discovery was no exception to this rule. One of the main focus and business plan of any pharmaceutical industry is to make profit (Bazell, 1998). In some cases were drug discovery is delayed (like in Herceptin discovery), one of the major concern for the delay is mostly associated with the level of market share for the drug. Herceptin which was known to target 20-25% population of women with breast cancer may not have been expected to generate enough profit to cover the research spending over a 20 years period before the patent runs out. Nonetheless, the idea and potential profit expectation in personalized medicine made it possible for the Herceptin project to be move forward.
Furthermore, the tenacity shown by hard working researchers displayed a strong resilient with Herceptin research, was beyond noble. Their efforts went beyond self serving purpose. Their focus were to develop a cure that will benefit a small number women suffering from HER-2 type cancer when all hope was lost for any other alternative cure beside chemotherapy, radiation, surgery or hormonal treatment (Bazell, 1998).  Prior to Herceptin discovery, the aforementioned breast cancer treatment options were not very efficient and often showed re-occurrence of breast tumors. On the other hand, Herceptin was a precisely targeted treatment for breast cancer patients suffering from tumor progression due to mutation in HER-2 gene. Herceptin is so far known as the best breast cancer treatment in the world.

References

Bazel, R. (1998). Her-2: The making of Herceptin, a revolutionary treatment for breast cancer. NY:Publisher

Carlsson, J., Nordgren, H., Sjostrom, J., et.al. (2004). HER2 expression in breast cancer primary tumors and corresponding metastases. Original data and literature review. Br. J Cancer. 2004 ;90 (12):2344-8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15150568.

NG. R. (2009). Drugs: From discovery to approval (2nd ed.). Hoboken, NJ: Wiley-Blackwell.

Pruthi, S. (2012). HER2-positive breast cancer: What is it? Retrieved from http://www.mayoclinic.com/health/breast-cancer/AN00495.

Whitmore, E (2004). Development of FDA-regulated medical products: Prescription drugs, biologics, and medical devices. Milwaukee, WI: ASQ Quality Press.