Balancing the Benefits and Harms of Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Screening

Multiple Endocrine Neoplasia Type 1 (MEN1) is a rare tumor predisposition syndrome caused by germline or sporadic mutations in the MEN1 gene, which codes for the tumor suppressor protein menin. Though it is an autosomal dominant condition, both copies of MEN1 must be inactivated for it to lose its tumor suppressor activity. The inherited or de novo mutation in combination with an acquired somatic mutation (either a point mutation or more commonly a deletion) results in loss of heterozygosity leading to clonal outgrowth and tumor development.

The loss of menin results in the development of endocrine-specific tumors including pancreatic islet tumors (most common), parathyroid, anterior pituitary, and tumors of the adrenal glands and neuroendocrine system (including the stomach, duodenum, bronchus, and thymus). MEN1 is highly penetrant; it is estimated that more than 95 percent of patients with a pathogenic mutation will develop MEN1-related disease in their lifetime, and about two-thirds of patients will die prematurely.

Due to its high penetrance, screening for MEN1-related tumors is extremely important for improving prognosis and preventing mortality. Current screening guidelines recommend clinical, biochemical, and radiological screening for MEN1-related tumors every one-three years starting as young as five years old. Due to the diverse spectrum of tumors, the mental, physical, and financial burden of screening over a lifetime can be overwhelming. Consequently, patients with MEN1 report having poor quality of life and high rates of anxiety and depression.

Screening for MEN-1 related tumors is important, but is it effective enough to warrant the high physical, mental, and financial burden? Due to the rarity of the disease, there is little evidence to support the current screening guidelines, and many physicians have started to question whether MEN1 screening could be approached in a way that is less burdensome for patients, without risking delayed detection of tumors. To address the uncertainties surrounding MEN1 screening, larger studies and new biomarkers that can predict tumor behavior and disease course are needed; in the meantime, employing a joint decision-making approach can help patients feel that they have more control and alleviate some of their anxiety.

Tips for developing a balanced and thoughtful approach to screening for MEN1-related tumors:

1. Consider patient preferences when making decisions about screening frequency and modality. Frequent screening may reduce or increase stress and anxiety depending on the patient. Acknowledge that intensive screening/surveillance may not resolve uncertainty or avoid adverse outcomes. Keeping an open dialogue and involving patients in the decision-making process can give patients a sense of agency and help alleviate anxiety.
    
2. Clinical assessment with thorough investigation of all relevant symptoms should occur regularly. Take time to explore and investigate all symptoms of MEN1-related tumors as manifestations may be easy to overlook.
    
3. In asymptomatic patients, focus on detecting clinically important tumors with a strong case for intervention. Patients with MEN1 are likely to develop multiple tumors over their lifetimes, but not all will be aggressive. Focusing on clinically important tumors can help reduce the number of tests a patient is exposed to.
    
4. Small tumors may not require immediate treatment (such as small nonfunctioning pancreatic neuroendocrine tumors), and follow-up should be aimed at risk stratification to determine whether further testing or immediate treatment is required. Initially, intensive screening may be needed to detect fast growing/high-grade tumors requiring immediate treatment, but if screening shows tumors to be indolent, then less frequent surveillance is warranted. 
    
5. Minimize exposure to harmful/invasive testing and interventions as much as possible, taking into consideration the burden of investigation over the patient's lifetime. Tests that expose patients to radiation can result in a cumulative dose of ionizing radiation that increases the patient’s cancer risk.
    
6. Patient-specific factors, such as sex and family history, may affect the patient’s risk of developing advanced disease and should be taken into consideration when deciding on priorities during testing. As much as possible, tailor the screening approach to the individual.
    
7. Finally, the psychological effect of cancer screening for patients with MEN1 is not trivial, and it should be taken into consideration when deciding on a screening approach. Being aware of how the patient feels about screening may aid in the joint decision-making process. An awareness that patient and/or clinician anxiety can drive screening and treatment choices may help to reduce overscreening and overtreatment. Conversely, recognizing patients who are disengaged from follow-up and discussing their reasons for nonattendance may enable clinicians to come up with a screening plan that addresses the patient’s concerns and reengages them.

Screening for MEN1-related tumors can be overwhelming, but including patients in the decision-making process may help lessen the mental, physical, and financial burden.