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Making the Case for Universal Tumor Screening for Lynch Syndrome

Hampel, Heather MS, LGC; Paskett, Electra PhD

doi: 10.1097/01.COT.0000481863.94920.25
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HEATHER HAMPEL, MS, LGC. HEATHER HAMPEL, MS, LGC, is Associate Director, Division of Human Genetics; Associate Director, Biospecimen Research; Professor, Internal Medicine; and Licensed Genetic Counselor,The Ohio State University Comprehensive Cancer Center, Columbus.
ELECTRA PASKETT, PHD. ELECTRA PASKETT, PHD, is Marion N. Rowley Professor of Cancer Research, Division of Cancer Prevention and Control, Department of Internal Medicine, College of Medicine Epidemiology, The Ohio State University College of Public Health.

Several professional organizations have recommended universal tumor screening of all newly diagnosed colorectal cancer (CRC) patients at the time of diagnosis. Reasons for this recommendation are that patients whose tumors have defective mismatch repair (as shown through either microsatellite instability [MSI] testing or immunohistochemistry [IHC] staining for all four mismatch repair proteins):

1) Have a better prognosis,

2) May need to be treated differently, and

3) Are more likely to have Lynch syndrome, which is the most common hereditary cause of colorectal and endometrial cancer and has important implications for patients and their family members.

Barriers to Implementation

A recent study indicates that colorectal cancer patients with microsatellite unstable tumors respond well to immune therapy with agents like anti-PD1 immune checkpoint inhibitors. However, a survey performed in 2012 found that of respondents, only 73 percent of comprehensive cancer centers, 36 percent of College of Surgeons accredited cancer centers, and 15 percent of community cancer hospitals were performing universal tumor screening of all CRC patients (J Clin Oncol. 2012 Apr 1;30(10):1058-63).

There are many possible barriers to the implementation of universal tumor screening for all newly diagnosed patients with CRC, but a major one is that many cancer centers do not have cancer genetics professionals on staff to provide genetic counselling and follow-up genetic testing to the patients whose tumors have defective mismatch repair.

To bridge this gap, we launched the Ohio Colorectal Cancer Prevention Initiative (OCCPI) in 2013, funded completely by philanthropic support from Pelotonia (, an annual cycling event with 100 percent of proceeds going to cancer research at The Ohio State University Comprehensive Cancer Center (OSUCCC).

How OCCPI Works

Fifty-one hospitals throughout the state of Ohio (See table below) are participating in OCCPI. Accrual staff at each of the hospitals enroll newly diagnosed colorectal cancer patients into the study, obtaining informed consent, family history information, medical record release forms, mouthwash, and blood samples. They also request a paraffin-embedded tumor block, and the patients are asked to complete a baseline epidemiologic questionnaire at their convenience via internet or phone interview. All the samples and paperwork are sent to the central study location at OSUCCC so patients do not have to leave their community hospital.

Table: OCCPI
Table: OCCPI:
Participating Hospitals

Tumors are screened using both the MSI and IHC tests and any tumors with defective mismatch repair also are tested for MLH1 promoter hypermethylation. MLH1 promoter hypermethylation is the most common cause of defective mismatch repair and it is generally acquired during a person's lifetime and rarely passed on to their children.

Patients with defective mismatch repair due to MLH1 promoter hypermethylation still have a better prognosis and may benefit from different treatments, but they do not typically have Lynch syndrome.

Patients whose tumors are found to have defective mismatch repair and no MLH1 hypermethylation automatically receive germline genetic testing for a panel colorectal cancer susceptibility genes.

Patients whose tumors have proficient mismatch repair receive germline testing for a panel of cancer susceptibility genes only if they were diagnosed under age 50, have synchronous or metachronous tumors, or if they have a positive family history (a parent, sibling, or child with colorectal or endometrial cancer).

Improving Adherence

In a second component of OCCPI, the focus is on increasing adherence to colorectal cancer surveillance among the colorectal cancer patients enrolled in this study and their first-degree relatives. To that end, they each receive education about the importance of colorectal cancer surveillance and a personalized prescription for when they need to begin colonoscopy and how often they need to repeat the procedure based on the age at diagnosis of the colorectal cancer patient enrolled in OCCPI, and for relatives, their personal history.

Families are then randomized to a patient navigator or no further assistance. In the navigation arm, family members are contacted by phone to ensure they are adherent with their colonoscopy prescription and to help them overcome any barriers to adherence.

Medical records will be obtained 12 months after randomization to determine the effects of each intervention on colorectal cancer surveillance. Families with and without Lynch syndrome are eligible for this part of the study. Relatives of colorectal cancer patients without Lynch syndrome are not at as high a risk for colorectal cancer as those with Lynch syndrome; however, their risk is moderately elevated (two to three times that of the general population depending on their relative's age at diagnosis) and there are many more of them (97% of colorectal cancer patients enrolled in the study will not have Lynch syndrome). As a result, many lives can be saved by this component of the study, in addition to the lives saved in the universal tumor screening arm of the study.

Any patient diagnosed with colorectal cancer in the state of Ohio from January 1, 2013, to December 31, 2016, is eligible for the study. To our knowledge, this is the first statewide effort to institute large-scale screening for defective mismatch repair among all newly diagnosed colorectal cancer patients.

In addition, adherence to colorectal cancer surveillance is being addressed for the entire patient population and their first-degree relatives. It has been estimated that this study will save up to 639 life years among Ohioans and the benefit to the community from live years saved will be around $32 million.

Precision Medicine

This initiative is a real example of precision medicine applied in a cancer prevention setting and implications applied nationwide are profound. The American Cancer Society predicts that there will be 134,490 new cases of colorectal cancer diagnosed in 2016 in the United States. Based on our data, we would estimate that 4,035 of these patients have Lynch syndrome and another 12,105 of their family members also have Lynch syndrome. Intensive cancer surveillance and risk-reducing surgeries can decrease cancer risks and mortality among these individuals16. However, less than 5 percent of colorectal cancer patients with a positive family history have had any Lynch syndrome testing. It is critical that we expand universal tumor screening for Lynch syndrome throughout the United States.

We support efforts to achieve 80 percent compliance with colorectal cancer screening in the general population by 2018, but would like to underscore the fact that individuals with a family history of colorectal cancer need increased surveillance (beginning at an earlier age and repeating on a more frequent interval) over that of the general population, even if they do not have Lynch syndrome. We need to expand efforts to identify and inform these relatives of their risks so they are not under-screened.

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
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