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Going Statewide 

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GOING STATEWIDE

A cancer research and prevention effort supported by Pelotonia is designed to reduce morbidity and mortality from colorectal cancer in Ohio

By KENDALL POWELL

For the past two years in August, Jenny and Ed Ostendorf have driven an hour and a half from Cincinnati to Columbus to rise early the next day and ride in Pelotonia, an annual cycling event to raise money for cancer research at The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute (OSUCCC – James).

Jenny, a 1982 Ohio State graduate who works in human resources for Proctor & Gamble, and Ed, a residential remodeling subcontractor, are committed to Pelotonia because they know that 100 percent of the money they raise will support cancer research at the OSUCCC – James…and because they enjoy the thrill of cycling among a throng of riders. In 2012, more than 6,200 riders raised almost $17 million.

One of the most far-reaching OSUCCC – James projects funded by Pelotonia is the Ohio Colorectal Cancer Prevention Initiative (OCCPI).
“Pelotonia has been a resounding success,” says Heather Hampel, MS, CGC, genetic counselor and associate director of the Division of Human Genetics, who heads the OCCPI. “Riders from all over Ohio participate, and this study uses some of the money they raise to help everyone in the state by reducing the incidence of colorectal cancer in Ohio.”

Colorectal cancer (CRC), the third most common cancer in the United States, will affect one in 20 Americans. At 51 cases per 100,000 people, the incidence of CRC in Ohio is slightly higher than the national average. This year, 6,370 new CRC cases and 2,456 deaths from the disease are expected in the state.

CRC is one of the most preventable and, when caught early, treatable forms of cancer. The U.S. Centers for Disease Control and Prevention recommends that everyone should be screened for CRC using high-sensitivity fecal occult blood testing, sigmoidoscopy or colonoscopy beginning at age 50 and continuing to age 75.

But, says Hampel, “There is a lack of knowledge in the general public that colonoscopies can prevent CRC by removing polyps in the colon before they become cancerous.” She notes that there is even less awareness that close relatives of CRC patients can be at increased risk of developing cancer. The overall goal of the OCCPI is to reduce CRC morbidity and mortality and to increase awareness of CRC screening in the state of Ohio.

Ohio-Sized Initiative
The OCCPI is working with more than 40 hospitals across Ohio to screen all newly diagnosed CRC patients and their biological relatives for Lynch syndrome (LS), an inherited cancer syndrome that predisposes people to CRC, uterine, ovarian, gastric, kidney and other malignancies.

The ambitious initiative has three arms:

•  Universal CRC Screening for LS: This study will test the tumor tissue from 4,000 newly diagnosed CRC patients at participating hospitals for characteristics of LS. It also will evaluate whether a concerted statewide effort to screen all CRC patients for LS will enhance case identification.

•  Adherence to Colorectal Cancer Screening: This arm will follow the same 4,000 newly diagnosed CRC patients and their first-degree relatives—siblings, parents and children—to learn whether education about the benefits of colonoscopy and receipt of a personalized prescription for colon cancer screening will improve colonoscopy screening rates and prevent future cancers.

•  Molecular Epidemiology of Colorectal Cancer: This arm will build a biorepository of patient samples obtained from participants in both the universal screening and the adherence arms of the project. The repository will include epidemiological data, and blood, tumor and saliva samples. Participating hospitals will have access to samples and data from all 4,000 cases and their relatives. These materials will be studied for novel methods of CRC prevention and treatment. 


HEATHER HAMPEL, MS, CGC, genetic counselor and associate director of the Division of Human Genetics, head of the OCCPI

ALBERT DE LA CHAPELLE, MD, PHD, Distinguished University Professor, the Leonard J. Immke Jr. and Charlotte L. Immke Chair in Cancer Research

Universal CRC Screening
People are diagnosed with LS if they inherit a mutation in one of four DNA-mismatch-repair genes. About 3 percent of newly diagnosed CRC patients carry LS mutations.

“That percentage might sound small, but it represents nearly 4,300 people per year in the United States,” notes Albert de la Chapelle, MD, PhD, a Distinguished University Professor at Ohio State and co-leader of the Molecular Biology and Cancer Genetics Program at the OSUCCC – James, who oversees the genetic-screening arm of the project.

The OSUCCC – James has screened all CRC patients for LS since 2006. Based on that experience, de la Chapelle and Hampel calculate that for every patient diagnosed with LS, three more people on average in their family also carry the mutation. “That translates to nearly 13,000 people per year in the U.S.,” says de la Chapelle, who estimates that as many as 95 percent of LS cases are undiagnosed.

Relatives who learn they have LS can increase surveillance to prevent cancers such as CRC, uterine and ovarian from occurring or to catch them early, at more treatable stages. Increased surveillance includes colonoscopies beginning at age 20 to 25 and repeated every one to two years thereafter; women may choose to have a hysterectomy and oophorectomy to eliminate the risk from uterine and ovarian cancer.

“If you know you have LS, you don’t need to die from cancer; but if you don’t know it, you run a pretty big risk of dying from cancer,” de la Chapelle says.

In addition, he notes, “An equal number or more family members will not have the mutation. Knowing this is a great bonus psychologically but also financially, because these individuals require no more surveillance than the average person.”

The Universal CRC Screening arm of the study will test every new CRC patient’s tumor for LS using immunohistochemistry (IHC) and microsatellite instability, genetic markers for possible LS mutations. These screening tests will be compared for effectiveness.

Suspected cases of LS will be confirmed by sequencing 13 genes that include the four LS genes and genes responsible for other cancer syndromes, such as APC, the cause of familial adenomatous polyposis (FAP), and TP53, which causes Li-Fraumeni syndrome.

If LS is confirmed, the results will be conveyed to the collaborating physicians, and genetic counseling will be offered to patients and their relatives about the need for LS testing and cancer surveillance.


The CDC already recommends universal screening for LS, but the practice is not widespread. In a 2010 paper in Genetics in Medicine, Hampel and colleagues showed that universal screening using IHC and sequencing of the four LS genes is cost-effective by U.S. healthcare system standards. They showed that protocol had an incremental cost effectiveness ratio of $22,552 per year of life saved; generally, any intervention below $25,000 is considered cost-effective.

 “It’s not only a question of the value of life, but also of how much money we save when LS patients don’t develop cancer,” de la Chapelle says.

The OCCPI team estimates that the universal screening arm of the study alone will save 390 years of life among the Ohio CRC patients and their relatives, Hampel says. “There is no question that we can help the at-risk LS relatives who are walking around with no idea that they have up to an 85-percent risk of CRC—we can absolutely save their lives.” 

Tackling Compliance

The Adherence to Colorectal Cancer Screening (ACCS) arm of the study examines whether screening interventions increase the rates of appropriate CRC screening.

“Nationally, only probably half of the people who should get a colonoscopy for cancer prevention actually get one,” says Electra Paskett, PhD, MSPH, associate director for population sciences at OSUCCC – James and leader for the ACCS arm. Screening rates in Ohio, especially in the Appalachian region, are even lower, she says. Colonoscopies take time away from work, require unpleasant colon-cleansing preparations and involve sedation, which means someone must drive the patient home. All these factors contribute to poor compliance—a major reason that less than 40 percent of CRCs are caught early, when survival rates are above 90 percent.

“The number one reason that people get screened is because their doctor recommended it, so we’re hoping to help initiate that conversation,” says Paskett. “But what we don’t know is the compliance of people with LS or other increased hereditary risk. Do they seek screening at the appropriate age and frequency? Do they get an exam when they need to, and not get one if they don’t need one? We don’t have data on that.”

In the adherence-to-screening arm of the OCCPI, enrolled relatives are directed to a website to complete a simple five-minute survey. They enter information about themselves such as age and screening and polyp history. Information on the relative with CRC is already in the database. The website then returns a personalized prescription that includes colonoscopy-screening recommendations. Guidelines for lowering CRC risk are provided, and the participant can access a link to find the location of local gastroenterologists.

In addition, half of the participants are randomly assigned a patient navigator who will call them to follow up five days later. The navigator, a trained lay health adviser from the OSUCCC-James, checks to see if the relative understands the prescription and helps the person overcome barriers to making or attending a screening appointment.

Paskett and her team want the website and navigator system to become a model for wider use. “We hope to develop something that can be used by all oncologists and their CRC patients and family members, with the overall goal to decrease mortality from and incidence of CRC.” 

Unearthing Root Causes

The Molecular Epidemiology of CRC study arm focuses on genetic and environmental factors that increase CRC risk. “This is an opportunity to understand the causes of CRC that affect the general population,” says Peter Shields, MD, deputy director of the OSUCCC – James and leader of the molecular epidemiology portion of the study. “Ultimately, we want to have good blood or saliva tests that will predict who is most at risk for CRC.” 

But first, Shields explains, a CRC research infrastructure is needed that includes a biorepository that can be mined for the molecular causes of this disease. Both the CRC patients identified in the universal screening arm and the relatives in the adherence arm of the study will be asked to participate in the molecular epidemiology arm and contribute samples to the biorepository: CRC patients will provide blood, mouthwash and tumor samples; their relatives will provide a mail-in mouthwash sample, which will contain cells from the oral lining for DNA analysis.

Those samples, combined with the lifestyle and environmental questionnaire completed by participants, plus the tumor and blood samples from the relative with cancer, and pathology from polyps removed during relatives’ colonoscopies, will provide one of the most comprehensive clinical and genetic CRC databases in the world.

“If you take all the CRC risk, about 30 percent is estimated to be due to genetics,” says Amanda Toland, PhD, associate professor of Molecular Virology, Immunology and Medical Genetics. “But we’ve only identified genes responsible for somewhere around five to six percent of cases.”
 
Both Toland and Shields are leading efforts to identify other factors responsible for this “missing heritability.” Shields is investigating the relationship between a specific bacterial infection and CRC, as well as genomewide association studies, to determine which genetic variants, in combination with environmental factors such as diet, exercise, smoking and alcohol use, increase CRC risk.  Toland’s group is investigating parent-of-origin effects, where certain genetic mutations might increase CRC risk only if inherited from a particular parent.
“There’s a lot we don’t know about how CRC develops,” Shields says. “This effort will build the research infrastructure we need to better understand how this disease happens.”

That knowledge should, in turn, improve screening and treatment. In particular, it could lead to faster and cheaper genetic tests that further personalize care by identifying patients who might need colonoscopies at age 40 and those who could safely wait until age 60.
“We hope to identify risk factors for CRC that will enable us to tell patients whether they are at high risk or low risk, and if it is high, what kinds of screening and prevention are needed to keep this person and family from getting CRC,” Shields says.

He acknowledges that the scale of the OCCPI—thousands of participants enrolled from more than 40 hospitals in a year and a half—is ambitious. “To get big answers, you have to do big studies,” he says. “You have to do team science, and this team is composed of a very diverse set of multidisciplinary investigators. And answering questions about cancer risk requires large numbers of patients—we have to go to the whole state.”

The Ostendorfs, in their early 50s, ride in memory of both of their fathers, who died of cancer, and in honor of both of their mothers, who are breast-cancer survivors. Jenny lost her father to colon cancer and says she’s glad to know Pelotonia funds will be increasing awareness about the inherited risks of CRC.

“My family has lived it. My father’s oncologist told my cousins, siblings and me that we really needed to stay on top of that. We get regular screenings—going every five years—and then my cousins and I trade colonoscopy stories!” 

UNIVERSAL SCREENING OF COLORECTAL CANCER CASES FOR LYNCH SYNDROME(LS) COULD SAVE THOUSANDS OF LIVES ANNUALLY

143,000
the number of new CRC cases expected in 2013.
 
4,300
the 3 percent of people with CRC that universal screening would show have LS.
 
12,900
The total number of people with LS who could be identified annually and whose lives could potentially be saved through universal CRC screening followed by genetic counseling and testing to identify affected family members.

Increased surveillance of people with LS can prevent CRC, uterine and ovarian cancer from occurring or can catch them at early, more treatable, stages. Increased surveillance includes colonoscopies beginning at age 20 to 25 and repeated every one to two years.



 
30-Jul-13
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Jeffrey Wacksman M.D.  commented on  Sunday, September 15, 2013  9:44 PM 
I am 67 have had colonoscopy every 4-5 years since age 50. My father had colon cancer as did his mother. I have had no polyps removed. Am I a candidate for genetic testing???


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