Li-Fraumeni syndrome is a hereditary disorder that confers an extremely high likelihood of developing cancer on affected individuals.
Deciding who should be tested for this rare but potentially devastating hereditary syndrome and how to best care for those who test positive can be a challenge. Ongoing research at The University of Texas MD Anderson Cancer Center is helping to clarify the guidelines for Li-Fraumeni syndrome identification and surveillance and to improve the early detection of cancers in people with the disorder.
“Patients with Li-Fraumeni syndrome, and often many of their family members, are very prone to cancer, including recurrences and additional, new cancers,” said Louise Strong, M.D., a professor in the Department of Genetics. “Some individuals with the syndrome have gone on to develop five or more cancers.” The most common cancers in these patients are breast carcinoma, sarcoma of the soft tissue or bone, brain cancer, and adrenal cancer. These cancers tend to occur at a younger age—in children and young adults—in people with Li-Fraumeni syndrome than in the general population. Leukemia, lung cancer, colon cancer, and melanoma are also frequently seen in families with Li-Fraumeni syndrome.
In 1976, Dr. Strong initiated a long-term study that has since created one of the largest data sets of Li-Fraumeni syndrome families and has helped characterize these patients’ cancer risks. More recently, Dr. Strong began MD Anderson’s Li-Fraumeni Education and Early Detection program, or LEAD program, to test a new surveillance strategy for patients with Li-Fraumeni syndrome. Findings from these and similar efforts underscore the importance of recognizing and closely monitoring patients with this syndrome.
Data from Dr. Strong’s long-term study helped determine that Li-Fraumeni syndrome is caused by germline (i.e., hereditary) mutations in the TP53 gene. Missense mutations or other changes to TP53 interfere with the body’s recognition and repair of genetic damage, allowing cancer cells to propagate. These mutations can be identified through a blood test.
Individuals should be tested for Li-Fraumeni syndrome if they meet the criteria defined by the National Comprehensive Cancer Network (NCCN). In general, patients who develop any of the cancers associated with the syndrome at a relatively young age—for example, women who develop breast cancer before age 35 years and do not carry BRCA mutations—should be tested for the syndrome. Patients with certain rare childhood tumors—including sarcomas, brain tumors, and adrenal cortical tumors—should also be tested because such patients are at increased risk of carrying the mutant TP53 gene. In addition, all first-degree relatives of patients with the syndrome should be tested. Characteristics such as having multiple cancers in the Li-Fraumeni syndrome spectrum at any age or having first-degree relatives diagnosed with any cancer at a young age can also warrant genetic testing.
Patients diagnosed with Li-Fraumeni syndrome should undergo frequent surveillance for new cancers at many sites. In accordance with the NCCN guidelines, adult participants in the LEAD program typically undergo a physical examination every 6–12 months that includes whole-body and brain magnetic resonance imaging (MRI), dermatological and neurological evaluations, and blood tests for thyroid and adrenal function and various cancer biomarkers. Colonoscopy and breast cancer screening are begun at an earlier age than in the general population. Other types of cancer screenings at specific sites may be undertaken depending on the individual. The program’s surveillance strategy for children with Li-Fraumeni syndrome varies by age but includes whole-body and brain MRI.
The necessity of such close monitoring was starkly demonstrated in a small Canadian study of patients with Li-Fraumeni syndrome in which one group received comprehensive screening that included rapid whole-body MRI every 6 months and another group declined the systematic screening. MRI, which does not use ionizing radiation, was chosen over modalities such as radiography or computed tomography because patients with Li-Fraumeni syndrome are uniquely vulnerable to new cancers in irradiated regions. During the first 8 years of screening, individuals in both groups developed new cancers. However, all patients who received comprehensive screening were alive after 8 years. In contrast, only 20% of the patients who received no screening were alive after 5 years; the others died of cancer. These results helped shape recent updates to the NCCN guidelines for screening patients with Li-Fraumeni syndrome and the similar screening guidelines used in the LEAD program.
Dr. Strong said that the LEAD program has been under way for only 2 years but has yielded some notable findings. “Over the past year, we have screened 23 asymptomatic individuals whose ages ranged from 18 to 61 years, and 21 of these patients had findings of interest,” Dr. Strong said. Most of these findings were cysts or hemangiomas, and only four of those required followup. In addition, three invasive cancers were identified, including gastric cancer and high-grade breast ductal carcinoma in situ in a 42-year-old patient and metastatic thyroid cancer in an 18-year-old patient. Dr. Strong said that both patients underwent treatment and are doing well. She added, “Our screening program has identified tumors that likely would have been life threatening at a later stage.”
Counseling and educating patients
In addition to testing people for Li-Fraumeni syndrome and screening affected individuals for cancer, a major focus of the LEAD program is educating patients with the disorder and their family members about diagnostic testing, surveillance, and other strategies for managing their condition. The LEAD program group created a video-based decision aid to help families navigate the disorder, and the program offers a wide range of counseling services, including discussion of possible outcomes of genetic testing and the risks and benefits of prophylactic surgeries such as mastectomy.
Thanks to the increased understanding of Li-Fraumeni syndrome and to networking among families whose members have the syndrome and among health care providers who care for these families, attitudes about the disorder have significantly changed in recent years, according to Dr. Strong. “Families affected by Li-Fraumeni syndrome have established organizations, increased advocacy, and used blogs and social media to share their experiences,” she said. “These efforts have removed much of the families’ isolation, fear, and sense of hopelessness and stigmatization. More patients now feel they have gained some control and that there are proactive options available to them.”
For more information, contact Dr. Louise Strong at 713-792-2589.
Physicians and patients can contact the LEAD group at 713-794-5323 or LEADProgram@mdanderson.org.
The NCCN Guidelines for screening and surveillance in patients with Li-Fraumeni syndrome and other hereditary cancer syndromes are available at http://bit.ly/1Nubll0.
OncoLog, January 2016, Volume 61, Issue 1