Jose Landa was looking for a change. He and his wife came to the U.S. from their home in Venezuela in 2001 because they wanted a safe place to raise their children. An attorney by training, Landa had spent more than 20 years practicing business law, but he and his wife, Jacqueline, decided to do something they found more rewarding. In 2003 they started a small blackberry farm outside Spartanburg, South Carolina, called Double J Farms (named for Jose and Jacqueline). They own 75 acres, and today Double J is one of the largest blackberry farms in South Carolina.
But in 2012 a persistent pain in Landa’s left side threatened his pastoral endeavor. For months he waited for the right diagnosis. Eventually, the pain grew so intolerable that Landa could hardly bear it. Doctors at a hospital near his home in Spartanburg tested Landa for heart conditions, liver problems, and “everything except for the colon,” he says. Finally Landa told his family doctor that the pain had become unbearable. The doctor saw an obstruction on an X-ray and referred him to a gastrointestinal specialist who immediately suspected colon cancer.
In January 2013, after a colonoscopy, Landa received a diagnosis of stage 4 colon cancer. He was 45 years old. He first had surgery to remove the tumor, part of his colon, and the surrounding lymph nodes. Then he started FOLFOX (folinic acid, fluorouracil, and oxaliplatin), the standard chemotherapy for colorectal cancer. The side effects were awful. His eyes became inflamed, blurring his vision. He also had nausea, a bad taste in his mouth, and neuropathy.
“You name it, I had it,” he says. The neuropathy was the worst. Eventually the pain and numbness in his hands and feet were so bad that he couldn’t walk or type on a keyboard. But Landa pressed on. “My doctor said the only chance I had was to keep going. I chose to fight the cancer,” he recalls. “It was really horrible, but I thought, I will get over it.”
One year later, in 2014, the pain returned with a vengeance to the original spot in his side. Every bowel movement was agony. Emergency surgery showed the cancer had returned near where it started. Genetic tests on Landa’s tumors revealed that he had Lynch syndrome. Also around this time, Landa’s sister was being treated for colorectal cancer; she also tested positive for Lynch mutations.
Landa faced a second round of chemotherapy that included FOLFIRI (folinic acid, fluorouracil, and irinotecan hydrochloride), but the treatment didn’t work. A local doctor recommended radiation, but Landa sought a second opinion at MD Anderson Cancer Center in Houston. Doctors there said that radiation would be painful and risky. He chose not to have the radiation, reasoning he would rather die than burden his family.
A short time later, a doctor from MD Anderson called and offered Landa the last spot in an immunotherapy clinical trial; he took it. From May to December 2015, Landa flew from South Carolina to Houston every three weeks for the combination treatment of Opdivo (nivolumab) and Yervoy (ipilimumab). The side effects weren’t too bad — just a lot of itching, which Landa addressed with creams. Eventually he asked the doctors to transfer his treatment from MD Anderson in Houston to Duke University in North Carolina, because the airfare and two-night hotel stays were taking a financial toll. By then, Landa was just taking Opdivo, a drug he continues on today.
The early stages of colorectal cancer (CRC) can be subtle. Symptoms include bleeding, but the amounts may be so small that a patient won’t notice until screening. If too much blood is lost from the tumor, the patient may experience anemia and fatigue. The U.S. Preventive Task Force (USPTF) recommends that screening begin at age 50 and continue through age 75 for people who are not at high risk of CRC. For screening, the USPTF recommends fecal occult blood tests yearly and colonoscopies every 10 years. For people at high risk, doctors may recommend more frequent screening. “People with Lynch or one of the other hereditary colorectal cancers typically will be followed more frequently, with colonoscopies every year, starting in their 20s,” says Sapna Syngal, director of the GI Cancer Genetics and Prevention Program at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School.
People have many choices for at-home screening:
- The oldest of these tests is the fecal occult blood test, which uses a chemical reaction to find hemoglobin in one’s feces. This test has a high rate of false positives: Certain foods and medications can interfere with the results; blood can reach the stool from dental work; and the test may not be able to detect advanced adenomas, a type of colon cancer. “The fecal occult blood test is not perfect, but it’s a lot better than nothing,” says Bert Vogelstein of the Johns Hopkins Kimmel Cancer Center.
- A more sensitive at-home test is the Fecal Immuno Test (FIT), which uses antibodies to find blood in the stool. No dietary restrictions are necessary. The FIT test is good at detecting CRC, but is unlikely to replace a colonoscopy. The newest at-home test is the FDA-approved Cologuard, which can detect DNA or blood in the stool. It requires a prescription from a doctor.
- The Pillcam COLON, also called a colon capsule endoscopy, is a tiny capsule that is swallowed. It contains a wireless camera that can take up to 35 pictures per second. This test may be used if a patient can’t tolerate a traditional colonoscopy or anesthesia.
With any of these methods, if something looks suspicious, a colonoscopy is required. Colonoscopies are more invasive but more thorough. They can be done with light anesthesia at an outpatient surgery center. Prep involves fasting and taking a laxative designed to clean the colon. A surgeon searches the villi in the colon with a flexible tube fitted with an eyepiece. The advantage of this procedure is that surgeons can see polyps and remove them immediately.
A less invasive alternative is a virtual colonoscopy (also called computed tomography colonography), which involves the same colon-cleansing prep as a traditional colonoscopy. A small tube is inserted into the colon to blow in air. An inflated colon keeps any polyps from hiding in folds and gives the surgeon a better view. Doctors then look for colon polyps using a CT scan. Virtual colonoscopy may be used for those too frail for a traditional colonoscopy or if a tumor is blocking full access to the colon. If a doctor finds something in this procedure, then the patient will still need a colonoscopy to remove any polyps and will have to start over with the prep.
Colorectal cancer (CRC) is the third most common cancer affecting both men and women in the U.S., and the second most deadly. CRC is expected to claim more than 50,000 people in the U.S. in 2017, while more than 135,000 new cases are expected this year. But thanks to better screening and more effective treatments, over the past two decades more people with CRC are living longer.
CRCs start in the epithelial cells that line the mucosa, the innermost layer of the colon. Cells can divide too much and form polyps. Although not all polyps turn malignant, some can evolve into cancer that can eventually spread if not removed. In 1990, Bert Vogelstein, co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center, showed that colorectal cancer starts with mutations in a “tumor suppressor gene” called APC, which helps prevent cells from growing out of control. This process can take about 10 years.
Some 60 to 80 percent of CRCs are caused by mutations people acquire throughout their lifetimes. This type of CRC is called “sporadic” because the mutations likely occur by chance and are not inherited. About 5 percent of CRCs are caused by mutations that we inherit from our parents. In hereditary colon cancers, these germ-line mutations carry a 40 to 80 percent lifetime risk of the disease. A strong family history puts someone at higher risk of CRC even if he or she doesn’t carry one of the mutations.
The most common inherited types of CRC are Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer), which Landa and his sister have, and familial adenomatous polyposis (FAP). People with FAP have hundreds, even thousands, of polyps in their rectum or colon that start forming in their early teens. People with Lynch syndrome don’t form as many polyps, but they do carry a higher lifetime risk of other cancers, including endometrial, brain, and pancreatic. Other hereditary CRCs, such as MYH-associated polyposis (MAP) and attenuated familial adenomatous polyposis, are rare. MAP patients can also have many hundreds of
If a doctor suspects one of these inherited syndromes, he or she may send the patient to a genetic counselor who can help manage risk. “When you have a genetic syndrome, one of the features is that you present with early onset disease,” says Sapna Syngal, director of the GI Cancer Genetics and Prevention Program at Dana-Farber Cancer Institute and a professor of medicine at Harvard Medical School.
Most colorectal cancer (CRC) is diagnosed in people over 50 years old. Risk factors (outside of having one of the inherited gene mutations, which considerably increase your lifetime risk) include age, family history of colon cancer, or a personal or family history of colon polyps, especially adenomas. Researchers are working on identifying who may be at higher risk so they can make screening recommendations based on genetic susceptibility, lifestyle, and family history.
At the Fred Hutchinson Cancer Research Center, Ulrike Peters and her team in the Cancer Prevention Program are combing through the genome for susceptible places that may interact with known environmental and lifestyle risk factors. They want to know if smoking, excess alcohol, and too much processed meat interact with vulnerable gene variants to increase the risk of developing the disease. In a study published in PLoS Genetics in 2016, the team found that the effect of alcohol was stronger for certain genetic variants.
The team is using these lifestyle results to create a risk assessment test that will help primary care physicians decide who needs more careful screening for sporadic CRC. The test is still a few years away. “We know that people who have a family history tend to go more frequently for screening,” says Peters. “I really hope we can improve screening and adherence through precision prevention and personalized information so [that] those who are at higher risk are more likely to adhere to screening.”
For those diagnosed with CRC, doctors can test colorectal tissue for biomarkers that help guide treatment. The most common are the KRAS and NRAS genes. These genes spur CRC cells to grow and divide. If a test reveals these mutations, the tumor will not respond to certain therapies. Another biomarker is a gene called BRAF, which also tells cancer cells to divide. In CRC, mutations in BRAF point to lower chances of survival.
Michael Morse, a medical oncologist at Duke University, has been trying to find ways to harness the immune system against CRC for the past 20 years. Although the five-year survival for CRC has increased from around 3 percent to 11 percent, it’s difficult to cure all forms of colorectal cancer, both sporadic and familial, that have already spread to other organs. Although the trend is heading in the right direction, Morse calls the number of people cured “still too small.”
Currently there are seven types of immunotherapies in clinical trials, ranging from monoclonal antibodies that act like smart missiles aiming treatment right at cancer cells, to adoptive cell transfer, in which
cancer-killing immune cells are multiplied in the lab and transferred back to patients. Steven Rosenberg, chief of the surgery branch at the National Cancer Institute’s Center for Cancer Research, used adoptive cell therapy to treat a patient with metastatic colon cancer with a mutation in KRAS and whose cancer had spread to the lungs. The team isolated specialized immune cells (T cells) from the tumor that can infiltrate and attack the tumor cells with the mutated KRAS gene, grew them in the lab to expand their numbers, and then put them back in the patient. The lung tumors regressed for nine months.
“The challenge here is you have to get T cells from the patient’s own tumor, so it’s very personalized in the sense that you don’t have a drug off the shelf. But it can be done and is potentially applicable to many different cancer types,” says Vogelstein. “It is promising and certainly worthy of future development.”
One of the most promising areas, says Morse, is a marker called Microsatellite Instability High (MSI-H). The marker is found in about 15 percent of CRC tumors and can signal whether a person might have Lynch syndrome. “If MSI is detected in the tumor, then additional testing is done to determine if a person may have Lynch syndrome,”
Vogelstein’s lab discovered that people with MSI-H colorectal cancer would respond to PD-1 checkpoint inhibitors, like Opdivo, which uncloak the immune proteins that allow cancer to hide from killer immune cells. The Vogelstein team figured out that only MSI-H colorectal tumors respond to PD-1 because MSI-H tumors have so many more mutations than sporadic CRC. “These cancers respond better than any other tumor type, and these are patients in late-stage colorectal cancer,” says Vogelstein. “This is not just immunotherapy; it’s really personalized immunotherapy.”
Researchers are trying to trick the MSI-
stable colorectal tumors that don’t have as many mutations into responding to checkpoint inhibitors, so that the treatment can help more people. “It’s great if you are one of the 2 to 4 percent who respond, but it’s not great if you are one of the 98 percent who are not responding,” says Vogelstein.
In May, the FDA approved another PD-1 inhibitor, Keytruda (pembrolizumab), for any metastatic solid tumor, including colon cancer, that has the MSI-H biomarker. This is the first time the FDA has approved a drug based on a shared biomarker, regardless of where in the body the tumor originated.
In the future, Morse hopes that doctors can sample tumor DNA in real time, determine whether a treatment is working, and extend lives even longer. The median survival used to be 12 to 14 months; now it is 36 to 40 months. So for now, these treatments are turning CRC into more of a chronic disease rather than a curable one, but the treatments themselves are also helping researchers understand more about the biology of this cancer, says Morse. “I’m optimistic we will find better ways to harness the immune response, and in those tumors that don’t have an immune response, to create one. I think hopefully the days of the toxins — the poisons — will be limited. They are still with us for now, but hopefully we will be able to eliminate them in the future.”
Risk of Recurrence
After treatment has finished, doctors measure levels of a protein called CEA to see if the cancer has returned. CEA stands for carcinoembryonic antigen and it’s measured in the blood. A clinical trial published in JAMA in 2014 showed that regular CEA screenings or CT scans boosted the chances that doctors could detect recurrence early enough to treat it successfully. The test can have both false positives and false negatives, says Matthew Yurgelun, a gastrointestinal medical oncologist at Dana-Farber Cancer Institute. Though it’s not perfect, doctors can use the results to decide whether any follow-up imaging is needed. Yurgelun uses CEA testing to follow patients in remission to see whether they need a CT scan. “By itself, it doesn’t prove recurrence,” Yurgelun says.
Clinical Genomics of Bridgewater, New Jersey, recently launched Colvera, a blood test designed to detect circulating tumor DNA in CRC patients who are undergoing diagnostic monitoring for recurrence. The assay doesn’t look for mutations but instead detects epigenetic changes in two genes: BCAT1 and IKZF1. Early in cancer formation, some genes, including BCAT1 and IKZF1, get marked with chemical tags. Such tags are part of normal cell biology, turning genes on or off, but in cancer the process goes into overdrive. The test is designed to be used along with CEA testing. In a paper published in Cancer Medicine in 2016, Clinical Genomics researchers showed that Colvera detected twice as many colon cancers as CEA testing.
Finally, PIK3CA is one of the most frequently mutated genes in CRC. PIK3CA mutation status does not appear to have a significant effect on prognosis by itself; however, a recent meta-analysis supported the idea that regular aspirin use is associated with longer survival in CRC patients with a mutated PIK3CA gene.
“I’m optimistic we will find better ways to harness the immune response, and in those tumors that don’t have an immune response, to create one. I think hopefully the days of the toxins — the poisons — will be limited.”
Path to Recovery
Landa was lucky. His tumor had the MSI-H marker and responded to a combination of the PD-1 checkpoint inhibitor Opdivo and Yervoy, a monoclonal antibody. Today Landa is still on Opdivo. Every few weeks he drives three hours to Duke to see his oncologist and have blood tests. He needs high doses of prednisone every time he has a CT scan because he’s allergic to the intravenous dye. The drugs have increased his appetite so he’s now trying to lose the weight he’s gained.
His recovery has been slow but constant. His cancer has been in remission since April 2016 and his life is gradually getting back to normal. He misses riding horses — something he’s done since childhood — but he still has limited feeling in his feet and the idea of being in a saddle makes him nervous. His illness also took a toll on the blackberry bushes — they suffered from inattention, becoming sick with bacterial infections. With his strength returning he has been able to nurse the shrubs back to health. Landa says he and the blackberries are walking the same path to recovery.
“In my opinion, [after] seeing people die from cancer, what happened with me is awesome. It is amazing, because I was able to get treatment in a clinical trial without pain
Along the five feet of the adult colon live thriving, complex communities of bacteria. Researchers are just beginning to understand the relationship between bacteria in the colon and colorectal cancer (CRC). The entire colon has a mucous layer that helps protect it from bacteria. Bacteria are not normally in contact with cells — they are in contact with the mucous layer, explains Cynthia Sears, program leader at the Bloomberg-Kimmel Institute for Cancer Immunotherapy and a professor of medicine at Johns Hopkins University School of Medicine.
Sears’ team has been looking at cancer geography across the intestinal tract. Her team used tissue collected in screening colonoscopies and found the presence of a biofilm — a thin layer of bacteria that sticks to a surface — in both normal tissue and in tumors. The biofilm changes the biology of the mucosa toward promoting cancer growth. The inner part of the mucous layer is typically sterile, although a rare bug may occasionally break through, says Sears. In work published in PNAS in 2016, she and her group were surprised to find that some samples in the inner mucous layer in the right colon, which is normally sterile, had been invaded by huge numbers of bacteria that were now in direct contact with the epithelial cells and had even invaded the mucosa. “We were able to show that even the biofilm in the healthy person modified the biology in the direction of cancer,” says Sears.
The team has on-going projects designed to figure out why the right colon is more prone to this in cancer patients.