Improved Strategies for Cancer Prevention and Early Detection
The prevention of cancer and the development of more effective strategies to detect cancer precursors and early-stage cancers, when treatment may be most effective, remain critical goals.
The time from initial exposure to a cancer-causing agent—for example, a carcinogen such as ultraviolet light or tobacco smoke, or an infectious agent such as human papillomavirus (HPV)—to the development of cancer typically takes decades. Consequently, it often takes many years before a decrease in exposure results in a reduction in cancer incidence and mortality. However, a decrease in exposure during this long interval can eventually result in substantial long-term dividends, as seen with the reduction in smoking rates that have contributed to the reduction in lung cancer incidence and mortality over the past 10 years.
Many preventive efforts are directed at reducing or eliminating exposures to carcinogens or protecting the body from exposures. Other efforts may involve screening procedures, such as those for cervical and colorectal cancers, which can detect premalignant lesions in individuals without symptoms who can be treated before cancer develops.
Although the pharmaceutical industry regularly funds diagnostic and therapeutically oriented research, the majority of prevention-oriented research is funded by the public sector because many preventive agents and interventions provide minimal or no potential for commercial profit. Nevertheless, prevention has the potential, in the long run, to save more lives from cancer than treatment—as is already true for tobacco use and lung cancer—which underlines the importance of strong support for this research area. Prevention can also preclude the potential physical and psychological morbidity of diagnosis and treatment.
Preventing Cancers Caused by Viral Infections
Identifying an infectious agent as a cause of cancer provides several paths to the possibility of prevention, including reducing or eliminating exposure to the agent, developing a vaccine that prevents infection, or treating the infection before cancer develops. The identification of hepatitis B virus (HBV) in the 1960s, and the recognition that chronic HBV infection is an important cause of serious liver disease, including liver cancer, led to development in the 1980s of the first vaccine that can prevent cancer. Recent developments with three oncogenic viruses—human papillomavirus (HPV), Epstein-Barr virus (EBV), and hepatitis C virus (HCV)—illustrate how research advances have the potential to substantially reduce cancers attributable to these respective agents.
HPV infection causes virtually all cases of cervical cancer and a substantial proportion of several other cancers. In the United States, the number of noncervical cancers attributable to HPV infection is similar to that of cervical cancers. Pap smear-based cervical cancer screening and treatment of identified premalignant lesions has contributed to an approximately 75 percent reduction in the incidence of and mortality from this cancer since the early 1950s.
On the other hand, there have been substantial increases in HPV-associated anal and oropharyngeal cancers, two diseases for which validated population-based screening has not been developed. The vast majority of anal cancers are caused by HPV infection, and anal cancer incidence and mortality increased by 26 percent and 33 percent, respectively, from 2003 through 2012. The incidence of HPV-positive oropharyngeal cancer increased more than threefold during a recent 25-year period, and it is estimated that by 2020, the number of HPV-positive oropharyngeal cancers in the United States will be greater than the number of cases of cervical cancer.
A safe and effective vaccine against HPV types 16 and 18, two oncogenic types of HPV that cause approximately 70 percent of cervical cancers, was approved by the FDA in 2006, followed in 2009 by the approval of a second vaccine that targets the same oncogenic HPV types. In 2014, a third vaccine that targets HPV types 16, 18, 31, 33, 45, 52, and 58 was approved by the FDA. If administered prior to HPV exposure, this third vaccine should, in principle, prevent up to 90 percent of cases of cervical cancer. Theoretically, all three vaccines should also help reduce the incidence of noncervical cancers attributable to HPV infection.
Research is already having a major impact on reducing the incidence of high-grade cervical dysplasia in young women in Australia, where there has been high vaccine uptake. However, these vaccines are underused in the United States, where only about 60 percent of teens have been vaccinated and a much smaller percentage have received the recommended three doses.
In most low- and middle-income countries, where cervical cancer is frequently the most common cancer among women, HPV vaccine program implementation has thus far been limited. As the President’s Cancer Panel noted in a recent report, the underuse of HPV vaccines is a serious threat to progress against cancer but one that can be addressed.
Recent research strongly suggests that two doses, and perhaps even a single dose, of the current vaccines may be sufficient to induce long-term protection in young adolescents. A randomized trial of two versus three doses of one of the FDA-approved vaccines is now underway, and the feasibility of a trial of one versus two doses is being explored. If confirmed to provide long-term protection, reducing the number of doses could make vaccination logistically easier and less expensive.
The recognition of HPV as a cause of several cancers is having an impact on research and clinical practice beyond vaccines, including the prevention of cancer after persistent HPV infection has occurred. HPV-based testing, which is more sensitive than traditional Pap testing for both forms of cervical cancer (squamous cell carcinomas and adenocarcinomas), has been approved by the FDA for use in cervical cancer screening, initially only in conjunction with the Pap test, and, in 2014, as a primary screening method. This screening approach has the potential to further reduce the incidence of and mortality from this cancer.
To reduce the incidence of anal cancer, NCI has initiated a large screening trial to determine whether the treatment of high-grade anal dysplasia identified by screening high-risk patients can reduce their likelihood of developing invasive anal cancer.
EBV is an oncogenic herpesvirus that infects more than 90 percent of the world’s population before they reach adulthood. Infection with EBV has been associated with several types of cancer, including Burkitt lymphoma (82 percent of cases), gastric carcinoma (9 percent of cases), Hodgkin lymphoma (46 percent of cases), and nasopharyngeal carcinoma (98 percent of cases), as well as with infectious mononucleosis and other serious medical conditions. EBV infection is thought to account for more than 200,000 new cases of cancer each year worldwide. Therefore, developing a prophylactic vaccine against EBV infection is a public health priority.
Several different approaches are being explored in developing an EBV vaccine. In one approach, NCI-supported researchers have prepared virus-like particles that contain a glycoprotein called gp350/220, which is found on the surface of infectious EBV particles and the surface of EBV- infected cells. EBV uses gp350/220 to bind to cells and infect them.
The virus-like particles are similar to EBV in shape and size, and they contain dense arrays of gp350/220 on their surface. When tested in mice, they induced strong, long-lasting antibody responses, marked by the production of antibodies that are able to block EBV infection in vitro. Currently, these virus-like particles are being optimized and tested in additional animal models.
Hepatitis C Virus
HCV infection is a major cause of liver cancer in the United States and throughout the world. Much of the 26-percent increase in liver cancer mortality in the United States from 2003 through 2012 is believed to be attributable to infection with this virus. The recognition that HCV is frequently transmitted by blood products led to effective screening methods that have dramatically reduced the incidence of transfusion-related HCV infection.
Although efforts to develop a preventive HCV vaccine have thus far been unsuccessful, there has been enormous progress in developing effective antiviral drugs for the treatment of chronic HCV infection. Several of these drugs, which induce sustained virologic responses (i.e., elininate detectable HCV in the blood), have been licensed by the FDA since 2011. Long-term follow-up of treated patients will be needed to verify that treatment with these drugs has reduced their risk of liver cancer and other serious liver disease.
These advances in treatment contributed to the 2013 United States Preventive Services Task Force recommendation that all individuals born between 1945 and 1965, a group at high risk of acquiring HCV from contaminated blood products, be screened once for HCV infection. Further research is needed to determine whether additional age groups would benefit from screening for HCV infection.
Preventing Cancers with Drugs
NCI has investigated many natural and synthetic compounds to see if they have chemopreventive properties—properties that help reduce the risk of various types of cancer. The two most notable successes arising from this research are the approvals by the FDA of the drugs tamoxifen (Nolvadex®) and raloxifene (Evista®) to reduce the risk of breast cancer in women at increased risk of the disease.
Evidence from several studies of people who have taken low-dose aspirin for many years shows a substantial reduction in the incidence of and mortality from several types of cancer, including colorectal and lung cancers. However, the adoption of long-term chemoprevention of cancer with aspirin has been limited by concerns about side effects, such as gastrointestinal bleeding and certain forms of stroke, especially in older individuals. NCI is collaborating with the National Institute on Aging on a 5-year study of aspirin’s preventive attributes and side effects in 19,000 people over the age of 70 in the United States and Australia (age 65 or older in U.S. African Americans and Hispanics), in hopes of providing information that will better guide the use of aspirin for chemoprevention.
As in cancer treatment, the genomic methods of precision medicine may help identify patients who are more or less likely to reduce their cancer risk by taking aspirin. For example, a recent international retrospective study of regular aspirin and/or nonsteroidal anti-inflammatory drug (NSAID) use, funded largely by NCI, suggested that the risk of colorectal cancer differed among study participants based on genetic variation at two chromosomal locations, one on chromosome 12 and the other on chromosome 15. Participants who had specific genetic variants at the chromosome 12 location had decreased risks of colorectal cancer with regular aspirin and/or NSAID use, whereas participants with the other possible variants at this location had increased risks of the disease. Similarly, participants who had a specific genetic variant at the chromosome 15 location had decreased risks of colorectal cancer; however, the other possible genetic variants at this location were not associated with risk of the disease.
Identifying New Biomarkers for Risk and Early Detection of Cancer
For many years, scientists have been seeking to identify biological markers, or biomarkers, that accurately indicate increased risk of cancer or the presence of early-stage disease. The identification of increased risk may provide an opportunity for medical intervention to reduce risk, or heightened surveillance and early intervention as needed. Earlier cancer detection may permit earlier, more effective treatment and increase the chances of long-term survival. Biomarkers may also allow differentiation between cancers, precursor lesions that need to be treated, and precursor lesions that would never cause symptoms or threaten life and, therefore, do not need to be treated.
Biomarkers include genetic mutations, other changes in DNA, and abnormalities in proteins or other biological molecules that indicate the presence of an anomaly. They may be detected in blood, stool, other body fluids, or tissue. We know that inherited mutations in certain genes, such as BRCA1 and BRCA2, which can be detected in blood samples, confer high risks of breast and ovarian cancers, but inherited mutations account for only a small percentage of all cancers that occur.
Although numerous biomarkers of cancer risk or malignant disease have been reported in the scientific literature in recent decades, very few have been validated or shown to be clinically useful. This fact led the Institute of Medicine and other organizations to develop recommendations and frameworks for cancer biomarker development.
These recommendations are crucial and timely because our ever-increasing understanding of the mechanisms of cancer, greatly facilitated by advanced genomic, proteomic, and other molecular technologies, is amplifying opportunities for cancer biomarker discovery and development. Moreover, biomarkers that reflect mechanisms related to cancer development or growth may suggest targeted chemoprevention to inhibit these mechanisms, which could form the basis of precision prevention and treatment.
New Candidate Biomarkers
Many malignant tumors shed entire cells, fragments of cells, and intracellular molecules into their immediate environment early in the disease process. Often these substances are detectable in the blood, other body fluids, or feces, providing the potential for easier, less-invasive screening methods for early cancer detection.
One type of biomarker that has been the focus of much interest lately is tumor cell DNA circulating in the blood, also known as circulating tumor DNA, or ctDNA. This DNA is marked by key mutations or other abnormalities found in the DNA of intact tumor cells.
In an international study involving 640 participants that was reported in 2014, researchers, including members of NCI’s Early Detection Research Network, used state-of-the-art molecular techniques to detect ctDNA in patients with various types of early-stage or late-stage cancer. Among patients with early-stage cancer, detectable ctDNA was found in 47 percent of those with stage I disease and 55 percent of those with stage II disease. Among patients with late-stage cancer, ctDNA was detected in 69 percent of the individuals with stage III disease and 82 percent of the individuals with stage IV disease.
Although these findings are promising, a number of technical challenges, including increasing the sensitivity of ctDNA detection, must be overcome before ctDNA assays can be applied clinically. Another challenge is that, theoretically, ctDNA may be released by a tumor before the tumor can be detected definitively with current imaging technologies, raising questions about how patients with detectable ctDNA but no tumor detectable by imaging would be managed medically.
Exosomes are another type of biomarker currently under investigation. They are extracellular, nano-sized vesicles (tiny membrane-enclosed cell fragments) that contain proteins, DNA, and RNA. All cells, including cancer cells, release exosomes. These tiny vesicles can enter the bloodstream and travel throughout body. Over the past decade, researchers have been exploring the use of exosomes as potential biomarkers for various diseases, including cancer.
In 2015, NCI-supported researchers reported that a protein called glypican 1 (GPC1), which is abundantly expressed on the surface of breast and pancreatic cancer cells, is also found on the surface of most exosomes derived from these cells. The presence of GPC1 on exosomes derived from normal breast and pancreatic cells is rare. The researchers then developed a method for detecting exosomes in blood and examined the blood of 190 patients with pancreatic cancer, 32 patients with breast cancer, and 100 healthy donors. In comparison with the healthy donors, all patients with pancreatic cancer and 75 percent of patients with breast cancer had higher levels of GPC1-containing exosomes in their blood.
Additional preliminary experiments suggest that GPC1 might be a marker for early pancreatic disease. Blood levels of GPC1-containing exosomes were consistently higher among five patients with pancreatic cancer precursor lesions than among healthy donors or 26 patients with benign pancreatic disease, such as chronic pancreatitis. The researchers validated their findings in an independent group of patients that included six with chronic pancreatitis, 56 with pancreatic cancer, and 20 healthy donors.
If these preliminary findings are confirmed, the results raise the possibility that a noninvasive screening test to detect pancreatic cancer early may be possible, opening the door to potentially curative surgery or the development of other new therapeutic interventions for more patients diagnosed with this frequently fatal disease.
The above-described research and applications, both realized and potential, represent only a small fraction of NCI’s efforts to advance cancer prevention and early detection. This work and these intriguing possibilities have been bolstered by our increasing knowledge and understanding of cancer and the advanced technologies that are ushering in the new era of precision medicine.