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Precision Prevention: Predicting and Intercepting Your Cancer

Imagine if we were able to determine an individual’s cancer risk by characterizing their genetic makeup, family history, environmental exposures, and behavioral factors and then tailor personalized prevention approaches based on these factors. To achieve this, we need a comprehensive biological understanding of the causes of cancer and cancer development to develop new interventions that reduce the risk of cancer. This long-term goal—precision prevention—can end cancer as we know it by preventing suffering and death for those at risk and by helping those not at risk avoid unnecessary tests and treatments.

Preventing the enormous burden of cancer means targeting its causes at every level—from promoting behaviors with widespread benefits, like eating a healthy diet and increasing physical activity, to developing precise molecular interventions that prevent premalignant conditions from becoming invasive cancer.

NCI-funded research has enabled prevention strategies that we already know work, including avoiding carcinogens like tobacco, vaccinating against cancer-causing viruses like human papillomavirus (HPV) and hepatitis B, treating H. pylori infections, and using screening and early detection to remove or destroy polyps, dysplasia, and other lesions. Some people at high risk use tamoxifen (Soltamox) and its derivatives to prevent breast cancers and aspirin to prevent colon cancers.

Further investments are needed to gain a deeper understanding of the causes of cancer and to develop additional strategies for targeted prevention interventions. One of the major challenges of cancer prevention is to avoid doing more harm than good, since most people are not at risk of developing life-threatening cancer any time soon and most abnormal cells will not progress to a lethal cancer. To prevent overdiagnosis and overtreatment, abnormal cells that will become aggressive need to be distinguished from those that will remain benign or nonlethal.

Ultimately, preventing cancer requires a multilayered approach. At the core, we need to understand not only the genetics of cancer cells and the biological changes that trigger runaway growth, but we also need to understand the microenvironment that allows tumors to grow in one person and thwarts their growth in another. We need to understand how a person’s immune system, metabolism, and microbiome factor into tumor development and growth. Beyond tissues and the physical organism, we need to understand how people’s behavior and environment affect their cancer risk, and what individual and environmental characteristics predict their ability to adopt and sustain healthy behaviors. Approaches that integrate all of these variables are needed to fully realize the promise of cancer prevention.

With greater investment, NCI will be able to catalyze new discoveries into the biological causes of cancer and support the development of tools and technologies to move personalized prevention strategies forward for all people.

Understanding Which Cells Become Cancer and How to Target Them

Achieving precision prevention requires a more complete understanding of how specific cancers develop. Due to NCI’s long-term investments, researchers now know many of the genes that can cause cells to divide without restraint. Some cancer-causing genetic changes are inherited, but most are not. The same mutations that one person inherits can also arise through infection, exposure to carcinogens, or random chance.

But the link between genetics and cancer is not necessarily straightforward. Many healthy people carry cancer driver mutations but they do not have any sign of cancer. Researchers have come to understand that cancer results from a dynamic interaction between genetic changes in cells and individual susceptibility. Researchers are looking into what keeps cells that carry driver mutations from progressing to cancer as well as the factors that lead to cancer development and progression, including the roles of the tissue microenvironment and immune system. Learn more about NCI’s strategy to develop tumor atlases to predict cancer development and progression.

Ongoing research to understand the early stages of cancer development and the biological mechanisms that protect against cancer can pay off in the form of better prevention and screening approaches. For example, researchers at Boston University and their collaborators showed that it is possible to stratify premalignant lesions in the bronchi of people undergoing lung cancer screening according to the likelihood that the lesions will progress to lung cancer. The researchers identified four distinct subtypes of premalignant lesions based on their molecular features and immune interactions. Their findings also suggested strategies that use the immune system to prevent the more dangerous lesions from progressing to lung cancer.

Leveraging the power of the immune system to prevent cancer is an active area of research. Immense opportunities exist because of decades of NCI investments in understanding the interactions between cancer and the immune system.

Cancer immunoprevention—engaging the immune system to help prevent cancer—for individuals with Lynch syndrome is just one example. People with the syndrome have up to an 80% lifetime risk of developing colorectal cancer and several other types of cancer. Lynch syndrome is an inherited predisposition to cancer caused by mutations in a small number of genes involved in DNA repair. These mutations lead to the production of unusual protein fragments that are not present in normal cells. Researchers had the insight to treat these protein fragments as targets for a vaccine that trains the immune system to kill cells if they express those protein fragments.

Mice with the equivalent of Lynch syndrome that have received such a vaccine develop fewer cancers and survive longer, especially when they also receive an anti-inflammatory NSAID medication. A study in people with Lynch syndrome who have a history of cancer showed that this vaccine approach is safe, and additional clinical studies are planned to test the vaccine’s effectiveness in preventing cancer.

The most important risk factor for cancer is age, but the reasons why that’s true are not clear. Some researchers believe that age simply reflects more time for tumors to develop, but older people also undergo physiological changes, such as in the immune system, that we do not fully understand. For example, even though aspirin has been shown to prevent cancer in some cases, a clinical trial funded by NCI and others found that taking low-dose aspirin daily may actually increase the risk for cancer in those over age 65. Aspirin is known to influence molecular processes relating to the initiation, progression, and spread of cancer. Understanding why age makes a difference in this context—and in other contexts—will help improve prevention approaches across the lifespan.

Improving Cancer Prevention through the Promise of Technology

Cancer researchers are confident that precision prevention will become a reality through a deep biological understanding of cancer development coupled with new tools and technologies. These technologies include powerful computational methods, wearable data collection tools, sophisticated but practical screening and diagnostic platforms, and advanced research tools such as human organs on chips.

Better computational tools are needed both to move research forward and to develop more effective interventions. Cancer is incredibly complex, so investments in large-scale computational approaches are needed to integrate data about the biological causes of cancer and to stratify cancer risk. Improvements in technologies that make collecting data less costly and less burdensome, like wearable sensors and telemedicine tools, may help researchers engage larger numbers of people to gather data for research and to deliver interventions.

NCI is supporting numerous lines of research to further incorporate a molecular understanding of cancer into cancer screening. For example, NCI-funded researchers are figuring out how to integrate imaging technologies with biomarker testing to help distinguish lesions that may be life-threatening from those that are not. This type of screening is important to avoid the physical, psychological, and financial costs of overdiagnosing and overtreating lesions that will not be harmful to the patient.

Cancer screening tests can find cancer at early stages, and some tests can also help to prevent cancer by detecting premalignant lesions that can be removed or destroyed before they become cancerous. Current screening tests typically detect one type of cancer or precancer at a time. In the future, early detection and screening approaches using liquid biopsies may detect multiple cancers simultaneously.

A rapidly evolving technology for the early detection of cancer is the liquid biopsy test, which typically relies on a simple blood draw. Researchers are developing tests to detect cancer-related molecules secreted in the blood to screen for multiple types of cancer at once. Highly sensitive and specific tests are needed for this purpose, to reliably detect low levels of circulating DNA or proteins while minimizing the chances that a test incorrectly indicates the presence of cancer.

NCI-funded investigators at Johns Hopkins University recently reported on a multicancer blood test that detected early stages of cancer in women with no prior history of cancer, including cancer types for which no screening tests currently exist. The researchers suggest such screening could become routine to detect cancers earlier and treat them before they become life-threatening. In the study, the screening test led to few unnecessary follow-up tests. With additional support from NCI’s Small Business Innovation Research (SBIR) Program, PapGene, acquired by Thrive Earlier Detection Corp. of Cambridge, Massachusetts, is further developing this technology. More research is needed to assess the balance of risks and benefits of such screening, its cost-effectiveness, and whether the approach improves long-term outcomes for patients.

While liquid biopsy tests are still being developed for early detection, such tests are already used in the clinic to help diagnose cancer, to guide treatment decisions, and to monitor for cancer recurrence. In the future, liquid biopsy tests could be used to detect early changes in the disease development process in order to intervene and prevent invasive cancer.

While early detection is not as desirable as preventing cancer from developing in the first place, tests that detect early stages of cancer are improving quickly and are poised to help people by detecting tumors before they become life-threatening. In addition to detecting early stages of cancer, liquid biopsies could potentially detect biomarkers that indicate a risk for cancer before the disease arises. These screening tests will have to be evaluated to assess whether they truly help improve patient outcomes. NCI is well-suited to evaluate the benefits and harms of such tests.

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