Presented by: George Fisher, MD, PhD
Associate Professor, Oncology
Uri Ladabaum, MD, MS
Associate Professor, Gastroenterology
Hanlee Ji, MD, PhD
Assistant Professor, Oncology
Samuel Strober, MD
Professor, Immunology and Rheumatology
March 24, 2011
Colorectal cancer (CRC) is the third most common cancer in the United States and is the country’s second leading cause of cancer death (behind lung cancer)
“We are working to raise awareness of the disease and to celebrate the successes we have had with colorectal cancer,” said George Fisher, MD, PhD, an associate professor of oncology, who spoke at a presentation sponsored by the Stanford Cancer Center and the Stanford Health Library. “Our strongest advocates are the people who have been touched by the disease who can help us engage others and build a community dedicated to the elimination of colorectal cancer.”
Colorectal cancer can develop from an atypical growth called a polyp. There are two types of polyps: hyperplastic, which have a very small chance of developing into cancer, and adenomatous, the source of nine out of 10 cases of CRC.
At least half the cases could be prevented with regular screening since early detection is crucial to successful treatment. Colorectal cancer’s mortality rate has declined steadily in recent years, aided by a public awareness of the importance of screening for prevention and early detection, as well as significant improvements in treatment.
“Advances are being made, but until we can create screening systems for all people at risk, we will continue to deal with advanced disease. We are improving our therapies and looking for a cure so that colorectal cancer is gone forever. The challenge can be met if we are able to put all the pieces together,” said Dr. Fisher. “That’s the advantage of an academic medical center like Stanford, where we can combine the multidisciplinary expertise of scientists in different specialties together with clinicians working directly patients.”
Patients benefit from teams made up of surgeons, radiologists, gastroenterologists, and radiation oncologists, he said, as well as experts in peripheral specialties like interventional radiology and genetics, who discuss treatment plans for each individual. “This approach is of enormous value because it allows us to provide care that is both seamless and cutting-edge,” he said. Research is integrated into patient care and includes investigations into cancer stem cells, vaccines, and cancer genomics.
Dr. Fisher also advocated for community involvement to support research in pivotal areas, including investigations to:
- identify biomarkers to aid in early diagnosis and therapy follow-up
- study the genes involved in colon cancer
- refine prevention and therapeutic trials
- educate individuals and families
- encourage lifestyle changes to eliminate avoidable risk factors like smoking and obesity
- promote early screening and develop strategies for early diagnosis
- improve treatments through targeted therapies and genomics
Genetics and Screening
While we do not know the cause of colorectal cancer, it’s most likely related to genetic changes from external influences in our cellular DNA. Risk factors include age (most cases appear in people over age 50), a diet high in red or processed meat, lack of physical activity, obesity, smoking and alcohol use, and health conditions like diabetes.
“Why screen? To find and remove polyps before they can develop into cancer and to identify cancer at an early stage when treatments are most effective,” said Uri Ladabaum, MD, MS, a professor of gastroenterology, who spoke on Screening and the Role of Genetic Evaluation.
The lifetime risk for developing colorectal cancer is one in 18 for men, and one in 20 for women. In most cases, physicians cannot identify a specific risk. In fact, in about 75-85 percent of cases, there is no genetic cause for the disease. Only between 10 and 30 percent of cases are clustered within a family, pointing to a genetic, or hereditary, root.
“When there is a family history of colorectal cancer, the risk is higher based on the number the relatives and the age they had it,” he said. “The younger the age, the greater the risk. But even when older, a first-degree relative (a parent or sibling) can elevate the risk.”
For example, a person with no family history of CRC has a 5 percent chance of developing the disease. The chance is 10 percent for a person with one family member with CRC and three times higher with two family members. Risk is also elevated when a person has an inflammatory bowel disease such as Crohn’s or ulcerative colitis. Irritable bowel is not a risk factor, he said.
Lynch syndrome, or hereditary nonpolyposis colorectal cancer (HNPCC), is a rare inherited condition that increases the risk and early onset of colon cancer. If a parent has the gene mutation for Lynch, each child has a 50 percent greater chance of inheriting the defective gene and an 80 percent chance of developing cancer over their lifetime, said Dr. Ladabaum. However if the gene mutation is identified, colonoscopies can remove polyps before cancer develops and significantly decrease the risk.
Genetic testing for inherited conditions like Lynch syndrome can help identify who is at an elevated risk so screenings can be scheduled more frequently and at a younger age.
“The point of screening is to reduce risk—to find the precursors of cancer and remove them. It’s not just early detection, it’s also prevention,” he said. “We remove the adenomas before symptoms develop, when the condition is most treatable.”
Adults with average risk should start screening at age 50 and repeat the test every 10 years. A person with a relative who developed symptoms after age 60 should start screening at age 40 and return every 10 years; a person with a relative who developed symptoms under age 60 should be screened at age 40, or 10 years before the relative’s onset, and return every five years.
“We’ve progressed from one-size-fits-all screening protocols to the ability to tailor tests for individual risk,” said Dr. Ladabaum. “Intensive screening can dramatically reduce the incidence of CRC and its mortality rate.”
Analyzing Cancer Genomes
Deoxyribonucleic acid (DNA) is the chemical compound that encodes your genetic blueprint—the instructions your cells need to develop and function. A complete set of DNA is called the genome.
Throughout your life, DNA can make mistakes during cell replication. Most of these genetic glitches are harmless, but once in a while a mutation causes damage that pushes a cell to becoming cancerous. Through a process called sequencing, scientists have created vast databases of the genomic mutations found in several cancers, including CRC.
“Through a combination of technology, computational analysis, and DNA sequencing, we know more about the genetic factors of colorectal cancer than any other cancer,” said Hanlee Ji, MD, an assistant professor of medicine (oncology), who discussed Personalized Colon Cancer Medicine through Analyzing Cancer Genomics. “There’s a new era in personalized cancer treatment, based on the analysis of the genes in tumor cells.”
DNA sequencing allows scientists to identify mutations, cellular variations, and other genomic anomalies that contribute to cancer development. They can then home in on likely suspects, and these mutations can then be used to identify targets for therapy and to anticipate how a patient will respond.
Dr. Ji predicts that as technology continues to improve, genomic applications will be more fully integrated into a diagnostic setting. Assessing the genome will allow physicians to determine the risk of developing CRC, track the possibility of metastasis, and predict patient response. This process is accelerated at Stanford by the close proximity of scientists to clinicians who are working together in a back-and-forth dynamic called translational medicine.
“It used to take months to deal with the amount of data contained in a cell genome, and now it’s possible to isolate a tumor and potentially sequence an entire cancer genome in weeks,” he said. “There is no comparison as to what we could do and what we can do now. Next-generation gene sequencing will cause a major change in how we look at genomics. Diagnostic solutions will allow personalized medicine to become a reality.”
“The purpose of cancer vaccines is to elicit a more powerful immunity in the patient,” said Samuel Strober, MD, a professor of immunology and rheumatology. “However, tumor-specific antigens have been hard to find, and many immune agents now in use target healthy cells as well as the cancerous cells.”
Dr. Strober spoke about the challenge of developing ways to attack a tumor without affecting normal cells. One promising option may be the development of a cancer vaccine. Last year the U.S. Food and Drug Administration approved the first anti-cancer vaccine: a patient-specific dendritic-cell vaccine for use against advanced prostate cancer.
There are two fundamental concepts behind vaccines. One is prophylactic—to prevent the disease from occurring. The Human Papillomavirus vaccine (HPV) works by causing the body to make antibodies that recognize and fight the virus cells before they develop. HPV is a cause of cervical cancer and genital warts.
The other type of vaccine is therapeutic— stimulating the immune system response to home in on existing cancer cells.
Current cancer treatments—radiation and chemotherapy—are non-specific: They destroy healthy as well as malignant cells and can cause severe side-effects. Dr. Strober has been looking at ways to harness the immune system to develop precisely targeted therapies that home in on just the tumor cells.
His research involves using T-cells, a type of white blood cell that protects the body from infection by responding to antigens presented to T-cells by dendritic cells. Antigens stimulate the T-cells to produce proteins that can kill or slow the growth of a foreign invader or a tumor.
Dr. Strober’s laboratory has been developing ways to stimulate immunity to tumors in animal models of primary and metastatic tumors that involve three steps:
- The primary tumor is treated with focused, high doses of radiation to kill the cancer cells. The few cells remaining are made more apparent to the immune system as foreign. The scientists take dendritic cells and insert them into the tumor to activate a T-cell response. The T-cells, which have now been trained to recognize tumor antigens, are collected and stored.
- Animals are treated with additional irradiation and/or chemotherapy to kill metastatic tumor cells and to promote expansion of T-cells that will be injected.
- The T-cells are injected into the blood. Because they have been conditioned to recognize the cancer antigen, they go straight to the tumor and destroy remaining tumor cells.
All three steps are required for the system to work, said Dr. Strober. Using all three steps resulted in a cure in eight of 11 animals, and when a second tumor was introduced, the immune system prevented its growth. “The animal was immunized,” he said, “and 80 percent survived more than six months.”
The process showed that advanced tumors can be treated with the three-step strategy, and Dr. Strober and his team are working with clinicians to develop protocols for human clinical trials. “We hope to have trials in place by the end of 2011,” he said.
For More Information:
Stanford Cancer Center
National Cancer Institute