The Journal - December 2019
Tex Med. 2019;115(12):e1.
S. Ross*, MD, PhD; Sara M. Pirzadeh-Miller, MS, CGC; Sayoni Lahiri,
MS, CGC; Amber P. Gemmell, MS, CGC
Department of Internal Medicine and Simmons Comprehensive Cancer Center, UT Southwestern Medical Center
*Corresponding Author: Theodora S. Ross, MD, PhD, 5323 Harry Hines Blvd, Dallas, TX 75390, Ph.214-648-4076 (Theo.Ross@UTSouthwestern.edu)
In 2016, the UT Southwestern Medical Center’s Cancer Genetics Program was awarded a grant (PP160103) by the Cancer Prevention and Research Institute of Texas (CPRIT) to increase awareness of hereditary cancer syndromes, particularly Lynch syndrome (LS), and implement a population-based genetic screening program to identify those at high genetic risk for cancer. LS is associated with increased risks for colorectal and other cancers, and published risk-management guidelines can significantly decrease these cancer risks. Despite being the most common hereditary cancer syndrome, and the potential for reducing cancer incidence, LS is grossly underdiagnosed. This population-based screening program, “Detecting Unaffected Individuals with Lynch syndrome” (DUAL), aims to increase detection of LS by screening patients at UT Southwestern Medical Center and affiliated hospitals for increased risk for hereditary cancer based on family history. High-risk patients are then navigated to genetic counseling and testing services, and provided with risk management recommendations. The program also emphasizes education and outreach about hereditary cancer to healthcare providers and to the public throughout the state. In the first 2 years of the program, a total of 1,455 healthcare providers and 187,431 members of the public across 59 counties in Texas have been reached via awareness campaigns and educational events, and 93,531 patients have been screened for hereditary cancer. This program is expected to reduce the incidence of cancer in Texas, reduce unnecessary screening and surgery, and ease the burden on healthcare funds.
Lynch syndrome (LS), the most prevalent hereditary cancer syndrome, often goes undiagnosed due to issues of testing criteria, inadequate reporting of family history by patients, and lack of recognition by medical providers. Population-level screening for LS has been postulated as a method to improve the rate of diagnosis. Persons who have a diagnosis of LS have a high lifetime risk for colorectal cancer (CRC) and endometrial cancer. The risk for CRC can be as high as 80%, and the risk for endometrial cancer can be up to 60%. LS is also associated with increased risks for ovarian, stomach, small intestine, bladder, pancreatic, and central nervous system cancers (Figure 1).
Persons with LS can significantly reduce their risk for CRC by complying with national LS risk management guidelines that recommend earlier and more frequent colonoscopies. Furthermore, they can reduce their risk for gynecologic cancers by undergoing prophylactic hysterectomy and bilateral salpingo-oophorectomy. Surveillance for the other LS cancers can often lead to earlier detection and treatment with the goal of reducing mortality. Receiving a diagnosis of LS not only changes a person’s medical management, but also significantly impacts his or her family members who have similarly inherited a gene mutation associated with LS.
In the health care setting, use of genetics-based risks to prevent cancer is low hanging fruit, and can help eliminate the physical, emotional, and financial burdens associated with a cancer diagnosis. Through the Human Genome Project, completed in 2003, we began uncovering surprising secrets held between the strands of the double helix. These discoveries now have clinical use, where variations in a person’s genetic information can be used to find the underlying etiology of certain diseases, predict risk for developing or passing down diseases, and in some cases, predict response to various treatments. A need for experts who are able to uncover these secrets and apply them medically has led to rapid growth of various health care fields, including genetic counseling. Trained in medical genetics and psychosocial counseling, genetic counselors perform risk assessment and help patients understand the health implications of their family histories and genetic test results across various specialties including prenatal, pediatrics, cardiac, and cancer genetics.
LS, also referred to as hereditary non-polyposis colorectal cancer syndrome, is the most common hereditary cancer syndrome. These terms were used interchangeably to describe families with a higher prevalence of CRC, often across multiple generations, compared with the general population. One in three hundred people in the general population carries a mutation that causes this syndrome.1 The link between family history of CRC and heredity was first described in the 1960s by Henry Lynch, MD, and his team at Creighton University. In the subsequent decades and with advances in molecular biology, mutations in the MLH1, MSH2, MSH6, PMS2, and EPCAM genes, collectively known as the mismatch repair genes due to their involvement in correcting mismatched base pairs within the strands of DNA, were found to be the cause of LS.
In the United States, approximately 150,000 CRC cases per year result in 50,000 deaths.2 Each year, of the more than $14 billion spent nationally on CRC treatment, more than $3.7 billion (26%) are spent in Texas alone.3,4,5,6 Approximately 50% of CRCs in Texas are diagnosed at later stages, for which annual care costs total $1.8 billion.3 With an estimated incidence of 1:300, approximately 1,090,666 people in the United States have a diagnosis of LS, with an estimated 95,666 cases in Texas alone. However, only 2% to 3% of persons with LS are aware of their diagnosis and the associated elevated cancer risks. Only 9% of genetic testing for LS has been performed on persons without a personal history of cancer.7-10
Because of various barriers (economic, transportation, time off work, childcare), persons in underserved communities have lower access to health care, and therefore have a higher risk for poor CRC outcomes, and are more likely to present with advanced stage CRC, with worse stage-specific survival than other groups.11-14 Underserved persons are even less likely to have genetic testing and be diagnosed with LS because of their restricted access to genetic counseling services.11, 15-18
Although a diagnosis of LS can open the door for new treatment options such as immunotherapies for someone with advanced cancer, the biggest impact can be made by identifying LS in his/her at-risk relatives who have not previously been diagnosed with cancer.19 The risks for CRC and LS-associated gynecologic cancers (endometrial and ovarian) can be reduced significantly through appropriate CRC surveillance and prophylactic gynecologic surgeries, respectively. Multiple studies have shown that compliance with recommended CRC screening for LS can reduce one’s lifetime risk for colorectal cancer by 60% and extend disease-free lifespan by 24 years through.20 General population CRC screening guidelines often fail to identify and prevent LS-associated CRC, which is usually diagnosed at younger ages (average age 45 years but reported as early as 20 years).7, 21-24 Identification of LS through genetic testing can lead to cancer prevention in other ways as well. It can often serve as motivation for at-risk persons to engage in cancer prevention habits at younger ages, such as increasing physical activity, changing dietary habits, and smoking cessation.25-27
LS is largely underdiagnosed, in part, due to strict testing criteria that focused historically on people with an existing cancer diagnosis and striking family histories of LS-associated cancers, as well as lack of LS recognition by many medical providers.7-10 Since most persons with LS are currently unaffected by cancer, the low level of genetic analysis in this population is a missed opportunity for cancer prevention.
Population-based screening for LS has been proposed to increase LS identification in persons who have not received a cancer diagnosis. In fact, LS screening satisfies the criteria used by the World Health Organization and the Centers for Disease Control and Prevention to recommend population screening for genetic predisposition to disease. These criteria include the following: the disease imposes a public health burden on the target population; the risk of disease due to mutation in the screened genes is known; and effective interventions exist to reduce morbidity and mortality in mutation carriers.28 Implementation of these population screening recommendations is the next step, and the UT Southwestern Medical Center’s Cancer Genetics Program is one of the leaders in this effort.
In 2016, the Cancer Genetics Program received a Cancer Prevention and Research Institute of Texas (CPRIT) grant (PP160103), titled “Detecting Unaffected Individuals with Lynch syndrome” (DUAL). The goal of this grant is to implement a program to screen persons unaffected by cancer who, on the basis of their family history, are at risk for LS. In addition to this population screening program, we have also focused on increasing awareness of LS through outreach to the public and medical providers.
DUAL is a CPRIT-funded project that seeks to identify unaffected persons with LS, specifically in the Dallas–Fort Worth (DFW) metroplex. Family history screening questions are used to identify patients at increased risk for LS, who are then navigated to genetic counseling and testing services. Those undergoing screening are patients at UT Southwestern Medical Center and affiliated hospitals. The overarching goals of DUAL are: 1) increased awareness and diagnosis of LS, particularly in persons without a cancer diagnosis, through dissemination of information about LS to both clinical providers and the public; and 2) cancer prevention through increased colon surveillance and prophylactic surgeries to reduce the burden of colon and uterine cancers in this high-risk cohort. A multi-pronged approach has been used to achieve these goals, and partnerships with other institutions have been instrumental in extending our reach within Texas (Figure 2).
DUAL emphasizes the underserved population because of the additional barriers that hinder its access to care. The UT Southwestern Medical Center Cancer Genetics Program’s clinics serve an area of more than 4.5 million people and partner with two safety net hospital systems in DFW, which collectively serve more than 70% of the uninsured cancer patient population in Dallas and Tarrant Counties.29 To address other access-related barriers in the underserved population, delivery of genetic counseling and testing were adapted to patient needs. Telephone-based genetic counseling is available to patients, and a saliva test kit that assesses up to 47 genes associated with hereditary cancer is then mailed to each patient’s home. Written instructions for various portions of the testing process are provided to patients either by mail or electronically, and patient navigators and genetic counselors are available by telephone to address patient questions related to any issues. These measures are concerted efforts to address such barriers to care as lack of transportation, taking time off work, and access to childcare services.
Since the DUAL project inception in September 2016, UT Southwestern’s Cancer Genetics Program has made progress in several areas. A total of 1,455 medical providers and 187,431 members of the public across 59 counties (Figure 3) in Texas have been reached via awareness campaigns and educational events to date. Additionally, a unique LS awareness campaign was created in partnership with 24-Hour Fitness, through which a commercial spot advertising LS and DUAL was aired each hour on the 24-Hour Fitness digital TV network, making an estimated 12.6 million impressions for the course of the advertisement (6 months). Over 24 months, 93,531 persons were screened for LS by using population screening tools implemented through DUAL, and 537 persons chose to proceed with genetic testing (Figure 4). Approximately 60% of the patients screened came from underserved populations.
Of the 537 patients who chose to pursue genetic testing, 483 (90%) patients completed sample collection, and results are available for 422 patients. Fifty-one (12%) patients were positive for a cancer gene mutation that increases their cancer risk. Of the patients who tested positive, 21 (41%) tested positive for LS, an additional 14 (28%) patients tested positive for mutations in other cancer genes associated with hereditary CRC, and 16 (31%) patients tested positive for mutations in cancer genes not known to be associated with hereditary CRC (Figure 5). With the exception of 1 patient who tested positive for a heterozygous RECQL4 mutation, which has no known risk for cancer in the monoallelic state, the identification of the remaining 50 genetic mutations affected the follow-up clinical care of patients. Of the 21 patients who tested positive for LS, 14 (67%) had never been diagnosed with cancer; these are the patients in whom the biggest cancer prevention impact can be made. A total of 41 persons underwent cascade testing for familial mutations through DUAL, half of whom tested positive for their family’s mutation. The 20 patients who did test positive are now aware of their increased cancer risks, and can take appropriate steps to reduce these risks. It is also important to note that those who tested negative for their respective familial mutations no longer require drastic risk-reducing surgery or surveillance, thus easing the burden on healthcare funds.
Although the goal of DUAL is to identify patients at risk for LS, we have also identified a number of unaffected persons with negative genetic testing results who have a complex and concerning family history of colon or uterine cancer or both. Though surveillance guidelines exist for patients with an LS diagnosis, consensus guidelines do not exist for management of patients who meet LS testing criteria but have negative genetic testing results. Because cancer risk-management recommendations for LS include rigorous screening and preventive surgeries with potential unnecessary cost burden on the health care system and patient risk for procedural complications, starting the national understanding of baseline current practices among genetic counselors for these types of families is critical. While a high level of agreement exists among genetic counselors regarding clinical management for these complex families, additional comparative studies involving non-genetic counseling clinicians will be necessary to establish national guidelines. This is imperative as we continue to expand population screening and identify more complex families without genetic mutations.
Overall, through the DUAL project, we have been able to promote education and awareness of LS and increase access to genetic counseling and testing services using a new service delivery model. The DUAL project has helped to identify and care for patients who do not have cancer, but have elevated cancer risks and otherwise may not have been identified. Our experience confirms that population-based screening for hereditary cancer syndromes can be successfully implemented to reduce cancer incidence and save lives, in addition to saving healthcare dollars.
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- American Cancer Society. Colorectal Cancer Facts & Figures 2014-2016. Available at: http://www.cancer.org/acs/groups/content/documents/document/acspc-042280.pdf. Accessed April 25, 2019.
- Risser DR, Miller EA, Williams MA, et al. County-level socioeconomic status and cancer rates in Texas, 2001-2005. Tex Med. 2010;106(10):e1.
- Office of Disease Prevention and Health Promotion. Healthy People 2020. Available at: http://www.healthypeople.gov/2020/default.aspx. Accessed April 25, 2019.
- Sutphen R, Davila B, Shappell H, et al. Real world experience with cancer genetic counseling via telephone. Familial Cancer. 2010;9(4):681–689. doi:10.1007/s10689-010-9369-y
- National Cancer Institute. Cost of Cancer Care by Phase of Care, All Sits, All Ages Male and Female, in 2010 Dollars. Available at http://jnci.oxfordjournals.org/content/105/4/250.full. Accessed April 25, 2019.
- Hampel H, de la Chapelle A. The search for unaffected individuals with Lynch syndrome: do the ends justify the means? Cancer Prevention Research. 2011;4(1):1-5.
- Vasen HF, Mecklin JP, Khan PM, et al. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum. 1991;34(5):424-425.
- Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer Institute Workshop on Hereditary Nonpolyposis Colorectal Cancer Syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst. 1997;89(23):1758-1762.
- Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999;116(6):1453-1456.
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