ONCOGENOMICS: PRECISION ONCOLOGY Precision medicine, also known as personalized or individualized medicine, utilizes information gained from a person’s genetic makeup, along with their environment and lifestyle, to guide disease prevention, diagnosis, and/or treatment strategies. [1] Oncogenomics is a form of precision medicine that enables more personalized approaches to cancer diagnosis, treatment, and prognosis. [2] Cancer is often considered a genetic disease, whereby genetic mutations in the DNA of cells lead them to grow uncontrollably and become cancerous. With the increased emphasis on studying DNA and its role in cancer, the next step was to study the genetic characteristics of cancers to develop better treatments.
GENETIC CHARACTERISTICS OF A TUMOR
Oncogenomics was launched in 1998 with the FDA approval of Trastuzumab (Herceptin) for HER2+ breast cancer. It was the first chemotherapy agent developed using genetic analysis of tumors to create a more effective and less toxic treatment that is still used today. [3]. Classified as a “targeted” therapy, it is an antibody that blocks specific receptors called HER2+ that are present in about 20% of breast cancers, and more recently have been found in other types of cancers as well. [4] Since then, more than 150 new therapies targeting specific components of tumors have been approved by the FDA, and just over half of these are considered “precision oncology” drugs targeting specific DNA mutations in tumors. But despite this tremendous progress, most tumors still do not have identifiable mutations that can guide or predict treatment response. [5]
One of the reasons for this is that, while there are some core genetic mutations common across many cancers, each tumor type can also have many variations that vary from individual to individual. This makes the process of identifying and confirming each mutation, as well as matching it to a specific treatment, quite time-consuming and costly.
MATCHING TUMOR GENETICS WITH TREATMENT
Another obstacle is the emerging role of epigenetics in cancer development and growth. Separate from genetic mutations, epigenetics regulates the expression of genes by turning them on and off. Research is revealing epigenetic alterations as yet another layer that contributes to all cancer types. Precision oncogenomics now includes some drugs for cancers that target these epigenetic changes - especially hematologic cancers, as solid tumors appear to be more challenging. [6].
As technological advances enable us to do this faster and easier, we will continue to accelerate progress toward a vision of truly personalized approaches to treating cancer. The pharmaceutical companies are investing heavily in the efforts to come up with personalized drugs. It’s big business to do this, in addition to improving patient care. OncoType DX is a great example of the impact of this approach. Assessing the estrogen receptor and HER2 characteristics of breast tumors has resulted in more precise treatment, as well as better prediction of recurrence risk.
GENETICS OF THE PERSON INFLUENCE TREATMENT
Even in the era of precision oncology, conventional chemotherapies still play a major role in treatment, either by themselves or in conjunction with these newer precision drugs. These drugs are often toxic to the person as well as to the tumor, causing side effects.
One of the contributors to recurrence can be linked to how well people tolerate chemotherapy – as well as how they respond. Vastly underutilized is the role of pharmacogenomics, which looks at how a person’s genes influence how they process medications. This includes effectiveness as well as risk of adverse effects. Despite research showing that 99% of people carry at least one genetic alteration that affects their response to medications [7], and the FDA has approved genetic associations for more than 250 medications [8], it is still rarely utilized when selecting chemotherapy drugs and doses.
L-Image source: Rendell T, Barnett J, Wright D. How community pharmacy pharmacogenomics testing services around the world can inform their design and delivery in the UK. 2021 The Pharmaceutical Journal.
PREVENTING CANCER RECURRENCE: THE HOLY GRAIL
Allopathic medicine doesn't typically focus on prevention. Rather, it is primarily concerned with diagnosing and treating diseases – including cancer. Clearly, we want to do everything we can to try and really get precise about what each person’s cancer is about so we can treat it most effectively.
But the next question beyond this is how to reduce the risk or even prevent recurrence. Recurrence typically happens for three reasons:
1. Treatment did not remove or kill all of the cancer cells.
2. Reactivation of dormant cells.
3. Not addressing all of the underlying factors that contributed to the cancer developing in the first place.
You’ve likely heard that ‘we all have cancer cells somewhere in our bodies’. It is a normal part of our biology to have damage or errors like mutations happen to our DNA. We also have built-in ways to detect and fix these or destroy those cells so they never become cancerous. This then leads to the question of why some people develop cancer, and other people don't – and this includes recurrence. Answering this question is the directive of where I believe we should be when it comes to research and genetic testing of cancer patients. For this, we need to dig deeper into our genetics, epigenetics, and our biology.
Cancers are designed to evade the immune system, and this is one way they can grow beyond single cells or resist treatment. As an example, research has demonstrated the ability of breast cancer cells to “hide” these receptors, only to have them reappear later. It's a dynamic process because tumors are living things that respond to their environment in ways that help them survive. [9] This is one reason it is challenging to not only fully treat cancers, but to also prevent their recurrence.
Strategically speaking, the focus on the complexity of the genetic and epigenetic makeup of cancers is part of the challenge as to why we keep missing this ‘Holy Grail’ of curing cancer. I feel that having reviewed enough testing paradigms, the community is neglecting the DNA and epigenetics of the person who developed the tumor in the first place.
Image source: Vignoli, A., Risi, E., McCartney, A., et al (2021). Precision Oncology via NMR-Based Metabolomics: A Review on Breast Cancer. International Journal of Molecular Sciences, 22(9), 4687. https://doi.org/10.3390/ijms22094687
MULTIPLE INTERACTIONS: A WHOLE ECOSYSTEM
It is now possible to find out more information about this person that might help us fill in some missing pieces, including their own DNA and epigenetics. Genetic, genomic, and epigenetic testing can provide insights into their predispositions for altered functioning and predisposition to many diseases, including cancer. This helps give us a more precise map for that individual so that we can actually identify their vulnerabilities and create personalized strategies to address these. Addressing hidden factors that may have contributed to developing cancer in the first place may help to decrease the recurrence of the cancer.
Estrogen-sensitive breast cancer is one of the most studied in terms of genetics and risk of recurrence. With standard treatment of surgery and 5 years of endocrine therapy, one of the first and most successful precision medicine stories, the risk of 20-year recurrence is still as high as 50%. Research has thus far discovered genetic alterations in the tumor that can explain about 40% of relapses, indicating there is still much more to learn. New research is giving insights into the mechanisms by which dormant cancer cells adapt to endocrine therapies, including altering genetic expression through epigenetics. [9
Image source: [Barozzi I, et al. Cancer Discov (2024) 14 (9): 1612–1630].
These epigenetic changes result from the interaction of the tumor cells and the environment of the tumor – called the microenvironment. The microenvironment is regulated by the person’s DNA and epigenetics, which are, in turn, interacting with that person’s total biology - influenced by their diet, lifestyle, exercise, stress and trauma, toxin exposures, medications, and more.
Alterations in a person’s DNA can alter gene expression and how their biology is functions, thus influencing potential development of cancer. BRCA1 and BRCA2 mutations are some of the most well-known mutations that can predispose to cancer. But there are also smaller genetic alterations called SNPs that can also affect a person’s cancer risk. Although these SNPs create more subtle influences than mutations, each of these can interact with each other and a person’s environment to increase or decrease a person’s cancer risk. [10]
LINK TO THE LYNCH SYNDROME/NEW HOPE FOR GENETIC DISEASES ARTICLE. Epigenetics adds yet another layer to the complex biological processes that can lead to cancer development and growth, and modify genetic risk. [11]
FIGHTING RECURRENCE: THE MAGIC TRIO
With all of the advances in oncogenomics, as well as analyzing a person’s DNA and epigenetics, we have some powerful tools to fight recurrence. But we need to use them.
The first is to choose the most effective treatment – for the person and the cancer. This involves the latest advances in precision oncology as well as other approaches to treatment.
The second is identifying contributing factors that may have contributed to their cancer. Here, the focus is on assessing the person’s genetics, epigenetics, diet, lifestyle, and environment - and then creating personalized strategies to support more optimal functioning of these biological systems – potentially reducing the risk of recurrence.
Image: Rulten, S. L., Grose, R. P., Gatz, S. A., et al (2023). The Future of Precision Oncology. International Journal of Molecular Sciences, 24(16), 12613. https://doi.org/10.3390/ijms241612613
The third is active surveillance for early detection, enabling a higher chance of success if recurrence does happen. This is best done with a combination of lab testing and diagnostic imaging. Lab testing can provide reassurance that strategies are working as intended or guide adjustment, as well as give early clues to abnormalities that may indicate recurrence. Newer epigenetic tests can now look for cancer cells before they are visible by imaging. Regular imaging can evaluate for early signs of local recurrence or metastasis, providing peace of mind that all is well or ensuring that any recurrence is detected early.
THERE IS HOPE
Research continues to build on this foundation, and we are expanding the ways that genetics, genomics, and epigenetics can help us better understand the causes and choose the best treatments for various cancers. But we don’t have to keep waiting for more to take action. We have the knowledge and tools now to give us crucial insights into the biology of cancer, how best to treat it, and ways to reduce the risk or even potentially to prevent recurrence.
References:
1. https://www.genome.gov/genetics-glossary/Precision-Medicine
2. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/precision-medicine
3. Ferreira-Gonzalez, A., & Mardis, E. R. (2019). Precision oncogenomics. Cold Spring Harbor Molecular Case Studies, 5(2). https://doi.org/10.1101/mcs.a004150
4. Maadi, H., Soheilifar, M. H., Choi, S., et al (2021). Trastuzumab Mechanism of Action; 20 Years of Research to Unravel a Dilemma. Cancers, 13(14). https://doi.org/10.3390/cancers13143540
5. Suehnholz ,S. P., Nissan, M. H., Zhang, H. et al. Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer. Cancer Discov (2024) 14 (1): 49–65. https://doi.org/10.1158/2159-8290.CD-23-0467
6. Yu, X., Zhao, H., Wang, R., et al. (2024). Cancer epigenetics: From laboratory studies and clinical trials to precision medicine. Cell Death Discovery, 10(1), 1-12. https://doi.org/10.1038/s41420-024-01803-z
7. Ji, Y,. Skierka, J. M., Blommel, J. H., et al. Preemptive Pharmacogenomic Testing for Precision Medicine: A Comprehensive Analysis of Five Actionable Pharmacogenomic Genes Using Next-Generation DNA Sequencing and a Customized CYP2D6 Genotyping Cascade. J Mol Diagn. 2016 May;18(3):438-445. doi: 10.1016/j.jmoldx.2016.01.003.
8. Pritchard, D., Patel, J. N., Stephens, L. E., & McLeod, H. L. (2022). Comparison of FDA Table of Pharmacogenetic Associations and Clinical Pharmacogenetics Implementation Consortium guidelines. American Journal of Health-System Pharmacy: AJHP, 79(12), 993-1005. https://doi.org/10.1093/ajhp/zxac064
9. Barozzi, I., Slaven, N., Canale, E. et al. A Functional Survey of the Regulatory Landscape of Estrogen Receptor–Positive Breast Cancer Evolution. Cancer Discov (2024) 14 (9): 1612–1630. https://doi.org/10.1158/2159-8290.CD-23-1157
10. Fahed, A.C., Wang, M., Homburger, J.R. et al. Polygenic background modifies penetrance of monogenic variants for tier 1 genomic conditions. Nat Commun 11, 3635 (2020). https://doi.org/10.1038/s41467-020-17374-3
11. Baylin, S. B., & Jones, P. A. (2016). Epigenetic Determinants of Cancer. Cold Spring Harbor Perspectives in Biology, 8(9). https://doi.org/10.1101/cshperspect.a019505
