Posted on June 12, 2019
by Jennifer K. Loukissas, M.P.P.
Longitudinal studies of families with rare cancer predisposition syndromes have been a keystone of the DCEG research portfolio since its inception. Hundreds of families have participated over the years, either at the NIH Clinical Center or from their homes as part of field cohorts.
Each family study has a principal investigator, some of whom are also clinicians, leading a diverse a team of experts, including epidemiologists, biostatisticians, geneticists, laboratory staff, and pre- and postdoctoral fellows. At the intersection of clinical care and research is a team of staff clinicians in the Clinical Genetics Branch (CGB) assigned to one or more studies: Neelam Giri, M.D., M.B.B.S., Payal P. Khincha, M.B.B.S., M.S.H.S., Jennifer T. Loud, D.N.P., C.R.N.P., Mary Lou McMaster, M.D., Megan Frone, M.S., G.C.G., and Margarita Aryavand, M.S.N., C.F.N.P., who joined the team earlier this year. Together, they are pediatric hematologist-oncologists (Khincha and Giri), an adult nurse-practitioner (Loud), an adult oncologist (McMaster), a genetic counselor (Frone), and a family nurse-practitioner (Aryavand). They are joined by a rotating cadre of trainees—clinical fellows who come for short-term specialty fellowships in disorders so rare, the average physician may come across just one case in their entire career.
CGB was created in 1999 in response to a defined need for focused clinical cancer genetics research within the NCI Intramural Research Program. Built upon the vision of the founding chief, Mark H. Greene, M.D., and under the current leadership of Sharon Savage, M.D., CGB staff support and advance the branch vision: “Saving lives and improving the quality of life in individuals predisposed to cancer.”
Dr. McMaster, a twenty-year veteran of DCEG clinical studies within the Human Genetics Program, has functioned as a clinician and as a clinical, bench, and population scientist. Her diverse experience has made her acutely aware of the “value that collaborators with different backgrounds and training bring to solving important scientific questions raised by familial cancer syndromes. DCEG provides a fertile environment for that kind of cross-disciplinary, team approach.”
Patients and families who participate in CGB clinical studies do not come for treatment, but to contribute their information to scientific investigation and hopefully learn more about their syndromes, each of which predisposes affected individuals to a high risk of cancer. Participants give biological samples like blood, buccal cells, skin biopsy, tumor tissue, or bone marrow to be used for genetic testing and other assays; detailed medical histories to inform the natural history of their syndrome; and personal and family experiences to better understand the unique psycho-social challenges present in the day-to-day lives of individuals at high risk of cancer.
Dr. McMaster described the patient community this way: “Our participants have given us their time and endured countless questions, questionnaires, examinations, and procedures—they have invested us and the NIH with their trust and hope for their children and their children’s children. Without them, there would be no clinical research enterprise.”
In return, CGB clinicians give participants up-to-date information about their syndrome, the latest research advances, and potential implications for their families. The clinical team provides appropriate health education and answers participant questions that often cannot be addressed by their local healthcare team.
The bulk of a staff clinician’s time is spent preparing for, conducting, and following up on clinic visits. (See side-bar for the patient census for each study and clinic schedule.) Preparation for clinic begins with a chart review of the scheduled patients, which often involves reviewing hundreds of pages of complicated medical records. Following clinic, summary letters are developed and sent to the patient and their local healthcare team, often with recommendations for additional screening and/or close follow-up. There is an almost continuous stream of communication between staff clinicians and patients and families, with updated health information and questions.
When not in clinic, there are data to analyze; reports to develop for presentation at scientific meetings; papers to write, review, and publish; protocol development, amendments, monitoring, and IRB notifications; membership in a variety of scientific and regulatory committees at NCI, NIH, and professional and advocacy organizations; and mentorship of fellows and staff.
Staff clinicians typically field several calls per week from physicians or other members of a patient’s local healthcare team, discussing how to manage complex medical conditions, some of which were first described at the NIH. Just as often, clinicians are on the phone with study participants, like a Fanconi anemia patient who joined the NCI study as a toddler and earlier this year—at age 20—received results of a brain scan that suggested a diagnosis of glioblastoma multiforme. The patient came to the NIH where a neuroradiologist, neurosurgeon, and neurologist reviewed and repeated the scans and decided that the lesions were not glioblastoma but possibly inflammatory responses or infection. The patient underwent a biopsy at a near-by hospital, which confirmed the revised diagnosis.
Unlike other areas of epidemiology, staff clinicians often know not only the names of study participants, but also intimate details of their personal and family histories. Depending on the protocol, participants may meet a staff clinician once or many times over the course of their lives. Regardless of the number of clinic visits, multiple generations of patients often build lasting relationships with CGB staff over years or even decades. Because these disorders are rare, the communities of patients are relatively small, which facilitates close relationships. Staff clinicians have supported and encouraged the development of patient advocacy groups and attend annual syndrome-specific family camps to give health education seminars. One family invited the clinical team to a large family (> 35 members) reunion to give a family-wide genetic counseling session and provide study enrollment information to extended family members.
A typical clinic visit: IBMFS
Participants in the clinical portion of the Inherited Bone Marrow Failure Syndromes (IBMFS) study or the Pleuropulmonary Blastoma DICER1 Syndrome Study typically come to the NIH Clinical Center just once, near the time of their enrollment. Because of the complexity of IBMFS disorders and their effect on every organ system in the body, participants—both affected and unaffected family members—meet with sub-specialty clinicians in dentistry, ophthalmology, otolaryngology, dermatology, and others to fully describe the disease phenotype, which may include shorter stature, café-au-lait spots, and other features. Participants undergo laboratory tests and diagnostic imaging; those who do not know the gene responsible for their disorder receive genetic counseling and testing. At the end of the week at NIH, they meet with the study team for a summary consultation.
The overall goal of a natural history study of a hereditary cancer syndrome is to describe the progression of the disorder up to the development of cancer, identify the underlying genetic susceptibility, quantify the risk of cancer over the lifetime, and develop guidelines of care for the medical community. Once the primary issue of bone marrow failure is managed, other complications typically arise.
For example, the high morbidity and mortality of lung fibrosis in patients with dyskeratosis congenita (DC), a unique type of an IBMFS, became apparent as the NCI study matured. “We didn’t expect it to happen so rapidly,” said Dr. Giri about a long-time clinic participant whose DC presented in her mid-40s. She developed lung fibrosis which rapidly worsened, resulting in her death last year. Her son—also a participant in the study now in his mid-20s—came to the NIH this May. Newly engaged, his fiancée came with him to receive an introduction to health implications of DC and genetic counseling. Dr. Giri performed lung function studies and a chest CT scan to look for early signs of fibrosis, “so far, his lungs appear normal. He will continue with lung function studies every two-to-three years, along with the other screening recommended for individuals with DC.”
The LFS clinic
Families with Li-Fraumeni Syndrome (LFS) who participate in the LFS cancer screening cohort return for research-based cancer screening for carriers of TP53 variants, which includes annual bloodwork, rapid whole-body MRI, brain MRI, breast MRI (for women over age 20)—all with and without contrast—and quarterly abdominal ultrasounds (for participants ages 3-16 years). Additionally, they undergo colonoscopies every two-to-five years starting at 25 years of age, and mammograms starting at 40 years of age. A typical visit includes parents and children; some know they are carriers of a variant in TP53 while others attend to obtain genetic education and counseling prior to testing.
The week begins with an introductory session with the entire clinical team and family. Clinical staff describe research advances, upcoming projects, and potential clinical trial opportunities within the NCI. The family may report both good news and bad: new babies born, new cancers diagnosed, family members lost to cancer. Questions arise about risk-reducing surgeries or other risk-reducing interventions.h affected family member is scheduled for imaging and physical examination by Dr. Khincha or Dr. Loud and a private session with genetic counselor, Ms. Frone. Dr. Khincha may examine a patient and engage in counseling on private matters that would only come up in a one-on-one conversation: “they might have concerns about themselves, family members, reproductive options, health behaviors, the complexities of day-to-day living with LFS where it affects not only themselves, but potentially multiple family members.”
“Patient management shifts with each stage of life,” said Dr. Loud. “With a 20-something woman, we talk about reproductive options and potential prophylactic mastectomy. In the young adult population, we spend a lot of time talking about whether they are ready for mutation testing. Couples may talk about planning for a family.”
Ms. Frone’s sessions also vary depending on the patient. For a family or individual new to the study, they may start with background information and education. She counsels them about genetics and inheritance, as well as their personal cancer risk, risk-reducing strategies, and the role of cancer surveillance in early detection of cancer. She also emphasizes the importance of creating and updating a family pedigree to identify all the people potentially at risk and eligible for genetic testing.
At every visit there is a discussion of the family’s specific genetic variant. Ms. Frone regularly reviews the literature and current scientific data to update variant interpretation and classification. On occasions where new data result in a reclassification of a genetic variant, for example from a variant of unknown significance to pathogenic, Ms. Frone provides additional genetic counseling about how it may affect future medical decision-making.
Unlike some of the other syndromes where the phenotype includes debilitating physiological changes or deformities, LFS study participants coming to the NCI are typically healthy. According to Dr. Loud, “you can’t see their uniquely elevated risk of cancer, which approaches a lifetime risk of 90%.” While many participants report that their cancer risk stays on “the back burner” most of the time, their stress-levels peak in the days preceding an appointment and the subsequent wait for results from screening.
Managing the non-cancer outcomes
Imaging takes the bulk of a day, and the length of time in the scanner casts a long shadow over their visit. The MRI scanner is loud and confining. Patients—many of them young—are required to be still for 90 to 120 minutes per scan. They are anxious with claustrophobia and fear that the MRI might find cancer. Once imaging is completed, participants wait up to two weeks for final results, as each scan is reviewed by two expert radiologists.
Many participants require a low-dose anti-anxiety medication to get through the imaging. In an effort to understand this stress and perhaps address it with an alternative approach, the clinical team has partnered with NIH Clinical Nursing Department in a research project to identify adaptive approaches to manage screening-related anxiety, including breathing exercises and mindfulness. They are also exploring whether an anxiety intervention could be helpful preceding or following the visit. In addition, they are working with NIH Radiology Department collaborators to determine if changes to the protocol may be feasible without reducing the sensitivity and specificity of the screening, for example, shortening the time of MRI scanning or performing the MRI without contrast.
This project is part of a large-scale, highly-collaborative behavioral research program in which the staff clinicians play a multitude of roles. Partnerships within the NCI and NIH, as well as with extramural research groups, have been cemented over decades to understand and address the complex needs of the families, resulting in an impressive body of research on family dynamics, perceptions of risk, and other psychosocial aspects of these specialized patient communities (see Couples coping with screening burden and diagnostic uncertainty in Li-Fraumeni syndrome: Connection versus independence, 2018; Easing the Burden: Describing the Role of Social, Emotional and Spiritual Support in Research Families with Li-Fraumeni Syndrome, 2016).
The genetic causes for dozens of inherited cancer predisposition syndromes have been identified, though some patients’ specific genetic susceptibility is still unknown. Natural history studies like those described above, often spanning decades, have accelerated the identification of patients with these rare disorders and led to better clinical management in the form of screening guidelines, variant curation, and the identification of new research opportunities. As the risk of cancer in a syndrome is defined, the impact of that risk on the psychological well-being of individuals at high genetic risk of cancer and their families is also elucidated.
Across many CGB studies, plans are underway to identify chemoprevention agents that are effective and well-tolerated. The LFS team, with collaborators in the Center for Cancer Research (CCR), is designing a chemoprevention trial of metformin, which has been suggested to reduce cancer risk in people with diabetes and shown to increase cancer-free survival in LFS mouse models, in order to determine its effectiveness in decreasing the occurrence of or slowing the development of malignant tumors in individuals with LFS.
The close communication between the LFS families and their local healthcare teams means that when a biopsy is performed, or a tumor resected, tissue samples can be collected and shared with the CGB team. Tumor and normal cells can be flash-frozen, shipped, and banked in the DCEG biorepository for future studies to identify molecular targets, unique mutation signatures, or other markers that may inform cancer treatment or prevention strategies.
The goal of regular screening in IBMFS patients is early identification of various complications, “to make their lives as normal and comfortable as possible,” said Dr. Giri. “We want to reduce progression to cancer.” To improve these approaches, the study team has an effort underway in collaboration with investigators in CCR and extramural groups to conduct molecular studies of pre-malignant lesions in the mouth (oral leukoplakia) which progress to oral cancer, a common cause of cancer death in this patient population. They seek to identify biomarkers of progression, providing greater opportunity to remove these patches at a time when they are pre-malignant and small, and design chemoprevention trials, thereby reducing cancer morbidity and mortality.
Ultimately, says Dr. McMaster, “these studies aim to identify the role of specific, modifiable, environmental factors that modulate susceptibility to cancer, and to identify subgroups of patients who may benefit from early intervention or cancer prevention strategies.”