On January 30th 2015, President Barack Obama gave the State of the Union Address. He took this opportunity to announce the Precision Medicine Initiative. This revolutionary approach to medical treatment is based on the principle of human individuality – people have different genes, environments, and lifestyles. It only makes sense that people respond to disease differently as well. In order to most effectively improve patient prognosis, treatment should be tailored to the individual. This will improve people’s chances of responding positively to medical intervention [1].
The “precision medicine” approach to treatment sounds like a dream come true. Personally, my grandfather suffered from lung cancer, so I know all too well the difficulties families face when they’re told “there’s nothing more medicine can do.” That’s why I’m so interested in pushing the boundaries of treatment and using science to improve the quality and duration of people’s lives. So when I first heard the words precision medicine, I was curious. How exactly were scientists developing this genre of treatment?
To narrow the scope of such a broad question, I decided to focus on precision treatment with respect to cancer. As leaders in cancer research, scientists at Memorial Sloan Kettering have already started clinical trials based on the principle of targeted therapy, a subset of precision medicine [2].
Cancer begins with DNA mutations. These mutations could either be inherited (termed germline mutations) or acquired. Often, individuals with cancer have different combinations of mutations that have contributed to their conditions. However, there are common mutations that may be observed in many individuals with cancer.
One such common mutation is the infamous BRCA1. BRCA1 is a tumor suppressor gene, and mutations in this gene predispose people to breast and ovarian cancers [3]. BRCA1 has made headlines in the past several years – for example, Angelina Jolie Pitt opted for a double mastectomy once she learned she possessed a BRCA1 mutation [4]. However, this is only one example of a gene that can be mutated in cancer. Similar to the subset of individuals who have BRCA1 mutations, there are subsets of people who share common genetic mutations.
In the past, cancer treatment has been developed to prevent given mutations from exerting their effects. So knowing which mutations have contributed to an individual’s cancer is priceless information. Armed with this knowledge, clinicians can prescribe treatment that will be most effective for a patient’s genetic pattern. This is one of the key principles of precision medicine, and it gives rise to an extremely important question. How do clinicians know which treatments are effective for which mutations?
Memorial Sloan Kettering’s basket studies attempt to shed light on this issue [5]. These studies gather cancer patients with similar mutations into the same clinical trial, regardless of where cancer has exerted its effects in their bodies. For example, an individual with colon cancer could be in the same clinical trial as an individual with lung cancer, provided these individuals had similar genetic mutations. Then, a drug focused on this particular mutation is given to these individuals. The role of researchers is to determine if the drug is effective in treating cancer patients with the mutation in question. Researchers can also examine whether the drug is more effective in, say, lung cancer patients with that particular mutation as opposed to individuals with cancer in other regions of the body. Essentially, basket studies create a valuable repository of knowledge that clinicians can draw upon when discussing treatment options with patients.
An example of such a study was published in the New England Journal of Medicine in 2015. The study looked at the effects of Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. The study’s goal was to find which tumor types responded positively to Vemurafenib to help determine future avenues of research [6]. While ineffective for colorectal cancer, the drug was found to have preliminary efficacy in BRAF V600 mutation-positive non-small cell lung cancer, Erdheim-Chester disease, and Langerhans’-cell histiocytosis. Response rates to Vemurafenib were 42% and 43% in patients with non-small cell lung cancer and Erdheim-Chester disease, respectively. This rate is a marked improvement to the 7% response rate observed for a standard treatment, docetaxel, in a largely nonspecific group of cancer patients [7]. Establishing mutation-specific drugs increases the rate of the drugs’ success, at least in terms of patient response. Furthermore, uncommon forms of cancer could have genetic mutations that resemble those of more frequently occurring forms, which increases the scope of preexisting drugs.
However, with such specific inclusion criteria, basket studies bring forth an important issue. Due to their nature, they will naturally have fewer patients than more traditional study designs. Fortunately, this has not impeded progress in the past, as the FDA has previously approved a drug whose efficiency was demonstrated solely on the basis of basket studies, Imatinib mesylate [8]. But researchers express concern that findings from small groups of patients may not generalize well. Clinicians must remain cautious when making treatment decisions [6].
In essence, findings from basket studies will continue to improve the quality and duration of patients’ lives. Personalized medicine has the potential to identify a problem and provide a targeted solution. As long as findings from basket studies are examined with full regard to their context, we will be able to apply valuable knowledge while exercising an appropriate level of caution. We must continue to ensure that drugs administered to patients have the potential to make a real impact in fighting their diseases – thus, over-generalization of study findings must be avoided. The improvements we have seen in cancer treatment, and personalized medicine as a whole, would not have been possible without collaborative efforts of clinicians, cell biologists, bioinformaticians, geneticists, and people of numerous other disciplines. There is still a lot of work to be done before mankind can provide patients comprehensive cancer treatment options. But it’s heartening to know that we are mobilizing the resources we need to make such a thing possible.
References:
- “The Precision Medicine Initiative.” Whitehouse.gov. <https://www.whitehouse.gov/precision-medicine>.
- Kiesler, Eva. “The Future of Cancer: Five Reasons for Optimism.” Memorial Sloan Kettering Cancer Center, 1 Apr. 2015. <https://www.mskcc.org/blog/future-five-reasons-optimism>.
- Welcsh, PL and King, M. “BRCA1 And BRCA2 And The Genetics Of Breast And Ovarian Cancer”. Human Molecular Genetics 10.7 (2001): 705-713.
- Jolie, Angelina. “My Medical Choice.” The New York Times. The New York Times, 13 May 2013. <http://www.nytimes.com/2013/05/14/opinion/my-medical-choice.html>.
- Stallard, Jim. “Clinical Trial Shows Promise of “Basket Studies” for Cancer Drugs.” Memorial Sloan Kettering Cancer Center, 20 Aug. 2015. <https://www.mskcc.org/blog/clinical-trial-shows-promise-basket-studies-drugs>.
- Hyman, DM. et al. “Vemurafenib In Multiple Nonmelanoma Cancers With BRAF V600 Mutations”. New England Journal of Medicine 373.8 (2015): 726-736.
- Shepherd, FA. et al. “Prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy.” Journal of Clinical Oncology 18.10 (2000): 2095-2103.
- Heinrich, MC. et al. “Phase II, Open-Label Study Evaluating The Activity Of Imatinib In Treating Life-Threatening Malignancies Known To Be Associated With Imatinib-Sensitive Tyrosine Kinases”. Clinical Cancer Research 14.9 (2008): 2717-2725.
Image References:
- https://midhathsblog.files.wordpress.com/2012/04/slide10.gif
Raagini Suresh is currently a senior undergraduate student at Wayne State University. She is interested in cancer genetics, particularly the role of microRNAs in cancer. Her aims are to become a physician who continues to be involved in research, with hopes that she can use research to improve the lives of patients and their families.
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