June 17, 2016
11 min read

Genetic Testing in Colorectal Cancer A Roadmap for Treatment

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With just a simple blood draw, genetic testing for inherited colorectal cancer syndromes provides highly reliable results and, when positive, guides medical and surgical management. At-risk patients and their families find genetic counseling to play an important role in navigating this complex maze.

“Patients who develop diseases or cancers strongly associated with known genetic abnormalities are often referred to genetic testing to confirm or exclude these abnormalities,” Douglas G. Adler, MD, a professor of medicine at University of Utah School of Medicine, Salt Lake City, and Healio Gastroenterology board member, said in an interview. “Patients are also often referred for genetic testing even if they have no symptoms or signs of illness, but have multiple family members with certain gastrointestinal cancers or cancer syndromes or are closely related to individuals with a history of genetic abnormalities.”

Adler said genetic testing can help identify other family members at risk for GI or other cancers, as well as “give peace of mind if testing is negative.” But if testing is positive, “patients can work with doctors and genetic counselors to understand the implications and plan accordingly.”

Douglas G. Adler, MD

Douglas G. Adler

With the advent of personalized cancer medicine, “tissue or blood samples can be genetically analyzed to help predict clinical outcomes and/or response to specific medications or to help select medications, such as chemotherapy agents, for treatment of specific cancers,” Adler said.

Adler cited a 2015 study comprising 186 stage II colon cancer patients, for which clinical outcomes correlated with genetic testing. “The authors found that certain mutations were associated with different clinical outcomes and affected overall disease-free survival,” he said. For patients not treated with adjuvant chemotherapy, a worse overall survival was found for BRAF mutation, as well as for KRAS and microsatellite-instability (MSI) status.

AGA Guidelines

The most common hereditary CRC is Lynch syndrome, affecting as many as one out of 440 people and accounting for roughly 2% to 3% of all CRCs, according to Uri Ladabaum, MD, MS, a professor of medicine at Stanford University School of Medicine.

Guidelines from the American Gastroenterological Association recommend the people without CRC or another cancer, but with a family history that suggests Lynch syndrome, “have risk assessment, which can include use of the available risk prediction models, and then consider genetic testing in appropriate patients,” Ladabaum, who was a member of the technical review for the AGA guidelines, said. Furthermore, in patients who present with colorectal cancer, “centers should consider some form of tumor screening for Lynch syndrome,” he said. This can include immunohistochemistry (IHC) or MSI testing.

For patients diagnosed with Lynch syndrome, surveillance colonoscopy is advised, according to the guidelines. “I believe that the appropriate interval in most patients is 1 to 2 years,” Ladabaum said. “But in those patients who are believed to be at higher risk, based on the specific gene mutation or family history, I schedule a yearly colonoscopy screening, generally starting when the patient is in his or her mid-20s.”

Uri Ladabaum, MD, MS

Uri Ladabaum

The most controversial area for risk reduction is the role of aspirin. “The AGA suggests that aspirin should be offered for cancer prevention in patients with Lynch syndrome,” Ladabaum said. “However, this is a conditional recommendation, based on evidence from only one randomized controlled trial.”

Ladabaum’s personal preference is to arrive at shared decision-making with patients after discussing the state of knowledge, the gaps in knowledge and the potential risks and benefits of taking aspirin long-term. “One of the challenges is that we do not know the minimum dose of aspirin that is effective,” Ladabaum said. “The dose that has been studied, 600 mg per day, is reasonably high and can have side effects.”

The treatment for colon cancer could change if the patient has Lynch syndrome, according to Ladabaum, with chemotherapy choices guided by tumor MSI status. Also, patients must make a choice regarding surgical intervention.

“If someone has a colon cancer that is resectable and they do not have Lynch syndrome, one almost never considers taking out the entire colon,” Ladabaum said. But in patients with Lynch syndrome, that option should be discussed with the patient. Most patients of Ladabaum’s choose removal of just part of the colon and continue with close surveillance of the remaining colon.


“While the highest cancer risk in Lynch syndrome is colorectal cancer, women with Lynch syndrome have a very high risk of endometrial cancer and also an elevated risk of ovarian cancer,” Ladabaum said. In addition, both men and women with Lynch syndrome are at risk for other cancers, including gastric cancer and urologic cancers. Moreover, if there are certain families with patterns of cancer consistent with Lynch syndrome, “that should raise the suspicion for Lynch syndrome, even if there are not a lot of colorectal cancer cases in the family,” he said.

Underdiagnosed Syndrome

According to Swati G. Patel, MD, an assistant professor of medicine at University of Colorado Anschutz Medical Center, Aurora, patients with Lynch syndrome carry a 50% to 80% lifetime risk for developing CRC. “Unfortunately, though, Lynch syndrome is woefully underdiagnosed, with less than 10% of Lynch syndrome families in the United States aware of their diagnosis,” she said.

In a recent study published in American Journal of Gastroenterology, Patel and colleagues found only 31% of patients at risk for Lynch syndrome were advised to undergo genetic counseling and that a mere 7% had actually been tested for the syndrome. Further, only 26% of patients thought they should schedule a colonoscopy every 1 to 2 years, based on their family history, despite being specifically counseled to do so as part of the study.

“This study confirms that Lynch syndrome is under-recognized, that high-risk family members are infrequently referred for genetic counseling and that they have a poor level of understanding of screening recommendations based on their family history,” Patel said. “Endoscopists also frequently fail to recognize individuals who have a high familial risk of colorectal cancer and often provide incorrect screening recommendations based on family history.”

Swati G. Patel, MD

Swati G. Patel

Patel said interventions that target members of high-risk families without also involving their providers “are unlikely to improve rates of genetic testing or colonoscopic screening in families at high risk for Lynch syndrome.” She also noted that current medical record systems are not designed to organize complete family histories or output them in the form of useful clinical reminders. Despite these obstacles, “it is critical for patients to undergo appropriate genetic counseling before genetic testing is performed,” Patel said.

Regarding the differences in perspective of genetic testing between a gastroenterologist and an oncologist, “it may not be as much about the individual discipline, but rather the location and the scope of practice,” said Dale R. Shepard, MD, PhD, FACP, a medical oncologist and director of the Phase I program for early drug development to treat cancer at Cleveland Clinic. For example, oncologists at academic centers who are more involved with only treating CRC “are going to be much more in tune about genetic testing for planning therapies than their community colleagues who see a variety of tumors, for which genetic testing may not be front of mind.” Similarly, colorectal surgeons and gastroenterologists at an academic setting “may study genetic testing as a research activity,” Shepard said.

At academic centers, it is much more likely that genetic testing and counseling will be rapidly available and family members screened, according to Shepard. “Although I think genetic testing provides benefit to patients, the key is selecting the right patients in many cases,” he said. “The biggest concern in my mind is who is getting tested and why.”

Shepard believes genetic testing provides a “tremendous benefit” to people who have an early diagnosis of a colon cancer or have multiple cancers or who have a family history of a genetic abnormality. If someone is known to have a genetic predisposition to colon cancer, “then their relative might have a significant increase in risk,” Shepard said. “That might lead to screening opportunities that we would otherwise miss.”

Dale R. Shepard, MD, PhD, FACP

Dale R. Shepard

However, Shepard frowns upon companies that have commercialized expensive genetic testing to the mainstream population through direct-to-consumer marketing.
“Seventy-five percent of colon cancers are sporadic. There is no family history and there is no genetic component,” he said. “Only 5% to 10% of colon cancers have a known genetic cause for those cancers.”

As a result, many consumers will not follow through with screening because they do not feel they are at risk. “Genetic testing should either be from a physician or genetic counselor,” Shepard said.

Finding a particular mutation for Lynch syndrome, for instance, “lets us know whether the patient is at risk for other cancers like ovarian cancer, uterine cancer and breast cancer,” Shepard said. Likewise, RAS gene mutation testing of the tumor itself and known abnormalities “can lead to changes in chemotherapy.” However, Shepard does not feel it makes good sense to screen unaffected family members of patients who do not have a genetic mutation themselves.

Genetic Counseling

Shepard highly values the help of his practice’s genetic counselors at being able to “put the whole picture together in terms of the actual risks of developing cancer in any particular family members, then setting upon plans of expectations.” Often, people simply need to screen earlier and more frequently. “The risk of developing colon cancer is usually four times as likely with a genetic change,” Shepard said. Conveying these odds to family members can ease their mind that they will not necessarily acquire the disease.


Brandie S. Leach, a licensed genetic counselor at the Cleveland Clinic who counsels patients of Shepard, said that genetic counselors typically meet with patients in person, “although there are companies that offer telephone and web-based genetic counseling.” During a visit, the genetic counselor collects information about a patient’s personal and family history; assesses the information to determine if there are any red flags for an inherited cancer condition; and provides education about the genetic condition and the genetic testing process, including insurance coverage, costs, potential test outcomes, turnaround time and protections against insurance discrimination.

“We also provide emotional support to the patient and family through this process, and order genetic testing when appropriate,” Leach said. “We inform the patient of the results and help the patient and family to understand what preventative cancer screening or surgeries are needed, as well as who else in the family might need genetic testing. The purpose of working with a genetic counselor is to understand the cancer risks based on the cancers seen in the family and, when indicated, the implications and limitations of genetic testing.”

Leach said that genetic counselors are part of a valuable team that includes oncologists, surgeons, gastroenterologists and nurses. “We help to keep the clinicians informed of the latest management guidelines for hereditary cancer syndromes and work with the clinician to ensure the patient receives the most appropriate cancer screening and preventative surgeries, based on the family history and genetic test results,” she said.

Because the costs of genetic testing “are dropping rapidly, we are able to order larger and larger genetic tests at a relatively low cost,” Leach said. “However, there is still a gap in the medical community’s understanding of the health consequences related to some genetic mutations. Genetic counselors will play an important role in investigating these genetic mutations and help patients and clinicians understand this information.”

Surgical Options

For confirmed cases of Lynch syndrome with colon cancer that warrant surgery, the recommended operation is colectomy with an ileorectal anastomosis, according to Jordan J. Karlitz, MD, an associate professor of medicine at Tulane University School of Medicine, New Orleans. “This procedure involves removing a large portion of the colon, because without removal, studies have shown that the rate of developing a second colorectal cancer is very high over the years.” However, tumor testing and ultimately germline genetic testing will play a role in making decisions about how much colon is resected.

The presence of familial adenomatous polyposis (FAP) or MYH-associated polyposis (MAP), two other hereditary syndromes associated with high colorectal cancer rates, can also affect how much colon is removed.

“You try to balance the significant risk of a second cancer with any concerns for functional symptoms after surgery,” Karlitz said. “There is some research showing that patients who undergo subtotal colectomy are more likely to have functional complications. However, in some studies, resection extent has not been shown to differentially impact quality of life.”

Karlitz was lead author of a population-based study conducted at the Louisiana Tumor Registry that appeared last year in the American Journal of Gastroenterology. “We found that for people 50 and younger who are at the highest risk of Lynch syndrome, only 23% of patients were undergoing Lynch syndrome screening by microsatellite instability tumor analysis,” he said. In addition, preoperative tumor testing to help guide selection for germline testing and surgical resection extent was available in only 16.9% of cases.


In a follow-up population-based study in Clinical and Translational Gastroenterology, Karlitz and colleagues found people at risk for Lynch syndrome “rarely underwent extended colonic resection despite the potential for developing a second cancer,” he said. In contrast, people with polyposis were much more likely to undergo this type of surgery.

Karlitz advocates universal testing of Lynch syndrome by either MSI testing or IHC testing in all patients with CRC regardless of age. “If the testing is abnormal, that may prompt germline genetic testing to look for a specific mutation,” he said. “In turn, that can help guide discussions between the patient and physicians regarding colonic resection extent.”

Also, by identifying Lynch syndrome, “you can screen family members, for which half are going to be at risk,” Karlitz said.

Panel Screening

With a dramatic increase in the incidence of colon cancer in those younger than 50 years, Shepard would like to use genetic testing to help find these patients before they are affected. Likewise, although there is a family history link for all age groups, “we have no idea of the cause in the majority of those patients,” he said. “Just like we know about Lynch syndrome and FAP, can we find other genetic components that will trigger us to know who is at risk and what we can do about it?”

Ladabaum, director of the Gastrointestinal Cancer Prevention Program at Stanford, said clinicians are wrestling with the appropriate use of cancer gene panels, comprised of several dozen genes, that allows for screening of Lynch and other genetic syndromes. “In whom should we be doing a panel screen as opposed to more focused testing for a particular syndrome?” he said. “The whole field is moving increasingly toward using panels because the very classic clinical patterns that have been described are proving to be not quite as deterministic as we originally thought.”

Ladabaum speculated that other genes may be discovered and provide a basis for tailored risk-management strategies for the specific affected gene and the specific mutation in the gene.

“With the advances in next-generation gene sequencing, we now have the ability to test for numerous genetic conditions simultaneously,” Patel said. “There is already a paradigm shift in the approach to genetic evaluation with the emergence of this technology.”

Patel believes the shift from targeted testing based on clinical criteria to broad panel-based testing will accelerate. “Studies have already shown that this approach has increased diagnostic yield and we are capturing patients with mutations that the traditional method would have missed,” she said.

Patel cautions, however, that with a multi-gene testing focus, “there is an increased risk of finding genetic changes that are not necessarily clinically significant. Thus, it is increasingly important that patients are appropriately counseled on how to interpret results of genetic testing.

Disclosures: Adler, Karlitz, Patel and Shepard report no relevant financial disclosures. Ladabaum reports being a consultant to Given Imaging and research support from Exact Sciences. Leach reports being on the speakers bureau for Myriad Genetics Laboratory and on an advisory board for Invitae.