Genomics knowledge is in the process of transforming the way cancer is understood, diagnosed and treated. Viewed at the molecular level, cancer is many different diseases. The concept behind precision medicine is that genomic information could guide treatments based on the specific genetic profile of a particular individual’s tumor—not just by where the cancer is found in the body.
In the years since the Human Genome Project was completed in 2004, a flood of genetic data has become available to researchers and clinicians. More efficient, cheaper DNA sequencing, coupled with advances in computing, made genomics a powerful tool for individualizing cancer diagnosis and treatment.
But this is just the beginning. The big picture is more than just the effects of a single gene or gene cluster. It also includes the actions of regulatory gene networks, RNA, and the effects of your lifestyle and environment — even your resident microbes.
Considerable technical and administrative barriers still exist to interpreting, sharing, analyzing these huge and growing datasets. For example, currently federal agencies may have access to up to 200 million medical records, but they still cannot cross-link data sets. Clinical trials are expensive to run. And often physicians don’t have the time and opportunity to talk to patients about studies. http://www.partneringforcures.org/agenda/view/6667
Removing the guesswork: the role of diagnostic tests
Chemotherapy and radiation are relatively crude tools with harsh effects that can kill healthy as well as diseased cells. Precision medicine promises to more selective treatments including better diagnostic markers and targeted drugs. Information gained from genetic testing and tumor profiling could lead to more effective drugs that target cancerous cells and spare the healthy cells of patients.
At this point, matching patients to treatments is still informed guesswork. Certain genetically targeted treatments work for certain patients. For example, about 20% to 25% of patients with Her2 positive breast cancer will respond to Herceptin. The remaining patients have too much human epidermal growth factor receptor 2 protein (EGFR-2), which makes the tumor grow.
Or about half of metastatic melanoma patients have tumors with the BRAF mutation, which is treatable by several targeted drugs including vemurafenib (Zelboraf®), dabrafenib (Tafinlar®), and trametinib (Mekinist®). But these BRAF-targeted drugs are useless in people whose tumors lack this mutation—indeed they can cause bad reactions. (Some patients are instead treated with an immune therapy such as ipilimumab (Yervoy®) which blocks a protein on t-cells called CTLA-4, and is a member of a class of therapies called checkpoint inhibitors.)
Diagnostic tests or biomarkers, can help clarify who will benefit from targeted drugs. Genomic profiling of the molecular makeup of cancers could provide patients with targeted treatments, hopefully save them from treatments that don’t work, and minimize side effects. This can mean combining molecular, clinical and lifestyle information. The goal is to generate tools and information that can help decision-making.
Enrolling in precision medicine focused clinical trials early can make a difference In a vote for enrolling patients in precision medicine-based phase I trials, at this year’s American Society for Clinical Oncology meeting this year, an analysis of over 13,000 patients enrolled in 346 phase I trials over three years showed that in the trials incorporating precision medicine and genetic profiling with biomarkers, refractory patients’ tumor shrinkage rates were 30.6% compared with only 4.9% in those that did not. https://vimeo.com/169381022 According to the lead author of the study, Maria Schwaederle, PharmD, at of the Center for Personalized Cancer Therapy, University of California-San Diego School of Medicine, using patients’ tumor biomarkers can show the likelihood they would benefit from a specific therapy, and often results in good outcomes for patients—an encouragement to enroll patients in precision medicine-based phase I trials even though they are early-stage.
“Cancer is a disease of the genome”
Cancer is essentially a disease of the genome, https://www.cancer.gov/about-cancer/understanding/what-is-cancer caused by alterations to the genes that regulate cell function, growth and division. Cancers can have many different causes, but each type of cancer has its own process of genetic changes; some mutations accumulate as the cancer progresses and different cells within a tumor can have their own alterations.
Precision medicine needs to have clinical utility, that is, to provide doctors with information that is relevant to treating individual patients. So reliable biomarkers that diagnose cancer, and that can point the way to an existing treatment are necessary. Understanding more about individual tumor genetics can open the way to new treatments. In recent years, new tailored treatment strategies have emerged for different cancers, including:
• Immunotherapies -- spur the body’s immune system to selectively destroy cancer cells • Cancer vaccines and gene therapy -- impair or halt the growth of certain cancer cells. • Monoclonal antibodies--bind to cancer cells and deliver toxic treatment molecules to their targets. • Hormone therapies- impede or top the growth of tumors that depend on certain hormones to grow • Signal transduction inhibitors --block cell signaling, to halt the growth of certain cancer cells • Gene expression modulators--change how the proteins that control gene expression work. • Apoptosis inducers—stop new blood vessels forming that can support a tumor.
Targeted therapies are still limited. Some cancer targets do not yet have therapies that work for them. And targeted therapies have their own side effects. Some patients will respond better to certain targeted therapies than others, depending on their genetic makeup.
The first proof that a genetic glitch caused cancer led to a breakthrough therapy
There are many questions about what mutations cause cancers to start and to progress. Chronic myelogenous leukemia (CML) was the first cancer to be effectively treated by a targeted drug because the cancer has a single driver--a translocation in the BCR-ABL fusion gene in which a piece of chromosome 9 and a piece of chromosome 22 exchanged material with each other. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1934583 Known as the Philadelphia Chromosome, it was first described in 1960 by Peter Nowell, a junior faculty member and David Hungerford, a graduate student at the University of Pennsylvania School of Medicine. Nowell and Hungerford noticed an abnormal small chromosome in leukocytes from patients with CML and ended up being the first to document that a genetic abnormality could cause cancer. It was later determined that the gene swap resulting in the BCR-ABL fusion protein was expressed in malignant cells. This led to the development of imatinib (Gleevec) a tyrosine kinase inhibitor, to treat CML -- one of the early success stories in targeted drugs. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1934568 Researchers knew that tyrosine kinases had a role in cell regulation. While CML is a generally slow-growing cancer, it has more lethal stages and multiple subtypes. Second generation tyrosine kinase inhibitors were later developed to deal with the problem of resistance to treatment.
But most cancers are more complex, with multiple drivers.
Issues of resistance
Cancers can develop resistance to targeted therapies either because the tumor mutates so it is no longer sensitive to treatment, or the cancer finds another pathway to growth. Another issue is that tumor cells are heterogeneous and mutate at different rates. So a tissue biopsy will pick up a snapshot in time of certain tumor cells but may not be able to show what all the cells are doing or inform on tissue progression.
That is the problem that genetic biomarker tests are developed to address. Because of resistance, combinations of therapies are often used with each other or with traditional chemotherapy drugs. But to optimize treatment physicians need to know when a particular drug stops working. Being able to “read” a tumor and know when changes take place as early as possible can help more effective treatment.