Genetic Profiling Transforms the Diagnosis and Treatment of Cancer Diseases
Genome sequencing provides doctors with more information about the causes of cancer diseases and changes the ways of treating tumors. Targeted therapy aimed at oncogenic mutations has brought patients longer survival and better clinical outcomes. Let's take a closer look at the advances and challenges of using genomics in oncology.
Many Faces of One Disease
When Hippocrates first described cancer in ancient Greece, he identified only two forms − ulcerated carcinoma and non-ulcerated carcinos. By the late 19th century, doctors, with the help of microscopes, had discovered that tumors exhibit many cellular appearances.
Our understanding continues to deepen with advancing technology, and today we have at our disposal characteristics of combinations of gene mutations which in a given individual may lead to the onset or aid the progression of cancer disease. For example, lung tumors were predominantly classified as either small-cell or non-small-cell about 10 years ago, but now they are further described by the presence or absence of almost 30 gene mutations.
Therapy Targeted at Genomic Changes
The first intervention targeting a specific mutation came in 1998 with trastuzumab, an inhibitor of the growth-promoting HER2 receptor. Since then, we have a range of drugs targeting specific genomic changes. Currently, there are an estimated 130−140 therapeutically targetable genes in solid tumors. Each newly discovered mutation represents a potential target for developing new drugs.
Genomic Initiatives
Many scientific and clinical institutions focus on whole-genome profiling of oncology patients. The Dutch Cancer Institute profiles all its patients with metastatic disease and started the Drug Rediscovery Protocol study in 2016. In this study, patients who have not responded to standard treatment and have mutations that could respond to targeted therapy are experimentally treated with off-label targeted therapy. This approach provides clinical benefit for approximately one-third of patients.
In the USA, the Cancer Genome Atlas initiative conducts whole-genome sequencing, with a database of more than 20,000 samples of 33 types of primary tumors. Developing analytical tools is essential for understanding and utilizing the massive amount of data. A collective of scientists from 12 research teams and centers across the USA aims to integrate systems biology with oncology so patients in the database can be stratified, for example, by their response to specific treatments.
Personalized Diagnosis and Treatment?
Knowing a patient's genome not only provides information on what caused the disease but also offers insights into how it might develop and respond to treatment in that individual. Some genomic changes can predict the development of resistance to certain therapies.
Other mutations can significantly influence treatment choices, even if the therapy is not directly targeting the mutation. For example, in chronic lymphocytic leukemia, the presence of a mutation in the tumor suppressor gene p53 indicates that the disease may likely not respond well to chemoimmunotherapy and preparing the patient for a bone marrow stem cell transplant might be more appropriate.
Conclusion
Despite the volume of data produced by tumor genomics, its overall benefit in terms of survival for all cancer diseases is still not entirely clear. The number of known tumor-causing mutations still greatly exceeds the number of drugs targeting these mutations. However, considering the survival and quality of life benefits for subsets of patients with mutations that can be targeted by specific therapies, the benefit of genomics is undeniable.
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Source: Nogrady B. How cancer genomics is transforming diagnosis and treatment. Nature 2020; 579 (7800): S10−S11, doi: 10.1038/d41586-020-00845-4.
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