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Precision Medicine and Targeted Cancer Therapy

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The days of science fiction meeting reality are here.


Individualized therapy for cancer and chronic disease based on an individual’s genomics, lifestyle, and environmental factors are now part of clinical medicine. The Human Genome Project, completed in 2003, decoded the entire human genome composed of 3 billion DNA base pairs and identified the exome that contains approximately 23,000 genes. The exome is only 2% of the entire DNA content of the entire genome but is where proteins are encoded. The majority of disease causing mutations occur in the exome.1

In 2015, the US Precision Medicine Initiative placed cancer research and treatment at the forefront of medical priorities in the country. Precision medicine incorporates the use of genomic information to guide medical decision making.2 Targeted therapy is a type of cancer treatment that blocks cancer cell growth by interfering with targeted molecules involved with development of cancer.3

One targeted therapy that has been used in early and late stage breast cancer treatment is Herceptin. Herceptin acts on the receptor site for human epidermal growth factor receptor 2 (Her-2). The Her-2 pathway promotes growth and cell division when it is functioning normally but when the Her-2 protein is overexpressed on cell membranes there is unregulated cell growth and tumor formation. Herceptin blocks the Her-2 receptor function and in turn prevents cancer cell proliferation. Targeted breast cancer drugs may work when conventional chemotherapy does not work and may work in concert with other treatments.4 Her-2 chemotherapy medications are similar to other adjuvant chemotherapy agents used for advanced breast cancer. They may cause cardiotoxicity especially if used with anthracycline chemotherapy agents.5

Immunotherapy - Check Point Inhibitors

Immunotherapy is actually not a new therapeutic modality but has not been particularly beneficial in cancer treatment in the past. However, expanded knowledge about immunology and better understanding about the molecular behavior of cancer cells have led to the creation of new forms of cancer treatment like immunotherapy that can potentially extend and improve the lives of patients living with cancer.

Immunotherapy uses the body’s immune system to fight cancer. The immune system is efficient at identifying and destroying tumors even after early malignant transformation. However, the malignant clones are able to evade the immune system’s surveillance through a complex process called immunoediting.

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One of the ways that cancer avoids the immune system’s surveillance is to either reduce the antigenic proteins on the cell surface, or create new surface proteins, neoantigens, that are difficult to recognize as foreign. In addition, tumors stimulate upregulation of checkpoint inhibitors to promote T cell exhaustion, and produce an immune tolerant environment via cytokine production. Specific cytokines are able to suppress immune responses and promote growth of the tumor.6

Given the powerful activity against the immune system by tumor cells, researchers have developed a way to block one method of tumor evasion and allow the immune system to carry out its function. Checkpoint inhibitors are drugs that are monoclonal antibodies. The drugs bind check point receptor sites on T lymphocytes which in turn allows the immune system to process and kill tumor cells.

Pembrolizumab, brand name Keytruda, is a monoclonal antibody that binds to PD-1 (programmed cell death 1) receptor on T-lymphocyte and inhibits the PD-1 pathway that depresses the responsiveness of the immune system. The end result is activation of the immune system with T cell proliferation, increased immune mediators, and tumor destruction. This class of drugs has been shown to be effective against other types of cancers including lung, bladder, head and neck, renal cell, and Hodgkin lymphoma.7

Former US president Jimmy Carter is currently receiving Keytruda (pembrolizumab) for metastatic melanoma to the brain. His brain tumor has shrunk and is no longer detectable on imaging studies after use of the medication. Similar responses have been reported in clinical trials with the drug. It is more tolerable than the first checkpoint inhibitor Yervoy (Ipilimumab) that was released 2011. The monthly cost for pembrolizumab at the average dose is around $14,500. Higher doses which are being used in clinical trials cost up to $83,000.7,8

Immunotherapy does not work for all people with the same cancers nor does it work for all types of cancers. Researchers are trying to answer questions about refining patient selection, identifying tumor markers that may be predictive of response to immunotherapy, and determining how tumors develop resistance to drugs.7

Tumors with a high number of genetic mutations seem to be susceptible to checkpoint inhibitor activity. The reason for the success with the genetically mutated cells is that they stimulate the immune system. The proteins produced by the abnormal genes in tumor cells are more numerous and more abnormal which stimulate the immune system to react by binding the foreign proteins. Cancers that are hypermutated result from carcinogen exposure like tobacco and ultraviolet light. Melanoma and lymphoma generate a robust immune response and have shown consistent susceptibility to the action of checkpoint inhibitors.7,8

The era of precision medicine is here and it brings tremendous promise for improvement in mortality and morbidity of cancer. The methods for screening and determining treatment options will be very different than what they are now. Genomic information of both the individual and the tumor itself will be critically important in medical decision making. The use of checkpoint inhibitors will continue to expand as researchers delve into the questions that arise with their continued use.


Notes

1. Mayo Clinic. www.mayoclinic.org/medical-professionals/clinical- updates/digestive-diseases/whole-exome-sequencing-will-be-new- standard-for-genetic- testing.

2. N Engl J Med. 2015 Feb 26;372(9):793-5. doi: 10.1056/ NEJMp1500523. [Epub 2015 Jan 30].

3. National Cancer Institute. Targeted Cancer Therapies. 2017.www. cancer.gov/about-cancer/treatment/types/targeted-therapies/ targeted-therapies-fact-sheet.

4. American Cancer Society. www.cancer.org/cancer/breast-cancer/ treatment/targeted-therapy-for-breast-cancer.html.

5. Principles of cancer immunotherapy. Shoushtari, A. ,MD,Wolchok, J., MD, Hellman,M., MD. Uptodate.com. July 5, 2017.

6. Clinical Cancer Advances 2016 and www.asco.org/research-progress/reports-studies/clinical-cancer-advances.

7. Chustecka, Z. New Immunotherapy Costing $1Million a Year. Med- scape, Jun 01, 2015. [Accessed Dec 11, 2017].

8. Merck Manual of Geriatrics 3rd Edition. Beers, M. and Berkow, R. Published by Merck Research Laboratories. Division of Merck and Co. Inc. Whitehouse Station, New Jersey, 2000.

Reprinted with permission of ON THE RISK, Journal of the Academy of Life Underwriting (www.ontherisk.com).

 

Download "Precision Medicine"

The Author

  • Lisa Duckett, M.D.
    Vice President and
    Medical Director

    RGA Reinsurance Company

Summary

Genomic medicine promises to change the way oncologists assess, treat, and follow patients with cancer. How will advances in targeted drug therapy, including immunotherapeutic agents, influence the mortality and morbidity of certain cancers? RGA's Dr. Lisa Duckett shares insights in ON THE RISK, the Journal of The Academy of Life Underwriting. 

 
Download "Precision Medicine"
  • checkpoint inhibitor
  • Duckett
  • genomics
  • high cost drugs
  • immunoediting
  • immunotherapy
  • Ipilimumab
  • Keytruda
  • Lisa Duckett
  • Pembrolizumab
  • precision medicine
  • specialty drugs
  • targeted drug
  • targeted medicine
  • Yervoy