Introduction

Over 100 genes have been associated with cancer and a new genetic mutation has been discovered yearly since 1990 [1]. Penetrance describes the percentage of patients with a mutation in a gene who will develop cancer [2]. While family history and young age at cancer diagnosis are commonly used to determine who requires genetic counseling and testing for high penetrant mutations, the broad utilization of genetic panel screening has led to the diagnosis of more individuals with genetic mutations with limited clinical information. The recommendations for high penetrant mutations are clear; however, moderate penetrant mutations and variants of uncertain significance (VUS) have limited validation and therefore limited evidence upon which screening and other recommendations can be made. Therefore, a multidisciplinary team approach involving counseling and long-term surveillance, while developing interventional plans, is needed when dealing with patients carrying these mutations. This is especially important in the setting of commonly encountered breast and ovarian potentiating mutations, but perhaps more applicable with the limited availability of clinical recommendations with moderate penetrant mutations and variants of uncertain significance (VUS).

In those patients who are carriers of genetic mutations, frequent clinic visits within multiple specialties are required to determine a plan of care. Patients require genetic counseling and testing, surgical evaluation from varying surgical disciplines, including general or oncologic surgery, plastic surgery and gynecologic oncology for prophylactic interventions. They may also require screening or diagnostic imaging, oncology for discussion of medical interventions, and a primary physician to manage and coordinate the complex network of care required. For this reason, we developed a High Risk Genetic Clinic (HRC). We sought to determine if a single visit multidisciplinary approach using our HRC for the management of patients with any high/moderate risk genetic mutation found on a hereditary cancer panel test is feasible and beneficial to patient care.

Methods

Patients were referred to the HRC after being evaluated by the Geneticist and undergoing indicated genetic testing through the High/Moderate Risk Panel, 23 Gene Panel, (GeneDx Laboratory, Maryland, USA). Indications for testing were in accordance with the National Comprehensive Cancer Network (NCCN) recommendations. The institutional Genetics department created the custom panel testing for genetic mutations associated with a spectrum of malignancies. Recruitment of patients occurred from October 2015 to January 2017. Patients with a pathogenic high/moderate gene mutation were referred to the HRC for multidisciplinary chart review and evaluation.

Retrospective data collected included patient demographics, personal and family history of cancer, gene involved, and dates from genetic mutation diagnosis to HRC visit. We also looked at specialists seen at the multidisciplinary visit, surgical interventions, surveillance imaging and psychosocial factors. Data from time of identification of a mutation on the gene panel to time of HRC visit only included patients diagnosed after the initiation of the HRC. All statistics were performed using IBM SPSS Statistical Software, Version 24. Means were compared using a paired samples T-test, with statistical significance considered for a p-value ≤0.05.

Results

A total of 35 patients were referred to the HRC and 28 (80%) of those patients were seen in clinic. Four patients declined to come to the HRC and three patients accepted the HRC visit, but did not show to clinic. Mean age at first clinic visit was 40.3 years, while the mean age at genetic mutation diagnosis was 39.3 years of age. The mean age of those patients who did not come to the HRC was significantly younger than those who did come to the HRC at 19.3 versus 39.6 years of age, respectively (p = 0.014).

The majority, 34 of 35 (97.1%), of the patients referred to our HRC were female. Most patients were Hispanic, 22 of 35 (62.9%), followed by white non-Hispanic, 10 of 35 (28.6%), Asian, 2 of 35 (5.7%), and Pacific Islander, 1 of 35 (2.9%). A family history of cancer was seen in 33 of 35 (94.3%) patients and 21 of 35 (60%) had a known family history of a genetic mutation. At the time of testing, 12 of 35 (34.3%) patients had a current diagnosis of cancer (Table 1). Mutations were mostly seen in the BRCA1 gene in 10 of 35 patients (28.6%). The individuals with hereditary cancer mutations that were seen in HRC, along with all genes on the panel, are listed in Table 2. During the study period, the average time from genetic mutation diagnosis to being seen in the HRC clinic was 41.9 ± 26.1 days.

Table 1 Demographic and patient characteristics
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Table 2 Breakdown of genes and cancers seen at the high-risk clinic
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At the HRC visit, patients were seen by a multidisciplinary team with subspecialties relevant to the intervention plan related to the involved gene. The patients all saw genetic providers and the majority saw a social worker (25 of 28 patients, 88.9%). A majority of the patients underwent consultation with the breast surgeon, 25 of 28 (89.3%), and the gynecologic oncologist, 21 of 28 (75%). Other patients were counseled by colorectal surgery, plastic and reconstructive surgery, gastroenterology, and medical oncology (Table 3).

Table 3 Multidisciplinary teams visited during high-risk clinic
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Of the patients seen in the HRC, further imaging to screen for cancer was recommended in 28 of 28 (100%) of patients, however this was only completed in 19 of 28 (67.9%) of patients. Prophylactic surgery was recommended and then performed in 4 of 28 (14.3%) patients to date. Of those patients undergoing prophylactic surgery, they all underwent bilateral mastectomy, one choosing immediate reconstruction, and one with a concurrent bilateral salpingo-oophorectomy.

Discussion

With advances in technology and further understanding of the human genome, the implications of genetic variability will lag behind diagnosis. However, limited understanding at present of even high penetrant genetic mutations necessitates further study. As such, recommendations such as those from the NCCN will continue to develop and change in regards to high/moderate penetrant mutations, as will the indications for the use of the genetic screening panels. Given the increasing ease of testing and number of new genetic mutations identified, evidence based recommendations are often not available to practitioners. This complex interplay of limited disease understanding in patients with multifaceted stressors requires a coordinated plan of care such as our HRC.

Coordination of HRC requires interplay of multiple departments necessitating absolute endorsement from leadership. In the early stages of clinic design, we had to overcome many hurdles, which if addressed early, could be eliminated. First and foremost, all members of the team need to have the same vision—we do this for our patients. While self-sacrifice is commonplace for many medical practitioners, the HRC takes away time from clinic, operating room requirements, or administrative time. Our expanding database of patients will eventually be objectively compared to the traditional treatment modalities of these genetic mutation carriers but our initial inclination is to believe that the HRC is more efficient for all parties involved. We have implemented strategies to reduce physician tardiness or absence including alternating family medicine and internal medicine attendance, blocking off the clinic to alleviate call or operative duties, and making all team members a required aspect of HRC. Furthermore, having a centralized conference room with access to a projector, electronic medical records and imaging enables an efficient review of patients and allows for a concrete plan prior to the patient visit. This is exceptionally important as differences of opinion between practitioners can be settled prior to visiting the patient. We have seen the importance of the multidisciplinary team in reference to a number of mutations.

A majority of the patients in HRC have a mutation in the gene BRCA1, where at least 65% of patients will develop breast cancer by the age of 70 making it a high penetrance mutation [3]. Recommendations from the NCCN regarding BRCA1 are clear including annual exams, annual screening mammography and MRI starting at age 30, and discussion of risk-reducing prophylactic mastectomy and salpingo-oophorectomy [4]. However, moderate penetrant genes such as Partner and Localizer of BRCA2 (PALB2) do not have clear recommendations. In a patient with a mutation in the PALB2 gene, the risk of developing breast cancer by the age of 70 ranges from 33 to 58% in those with and without a family history of breast cancer, respectively [5]. The NCCN has clear recommendations for breast cancer screening, as well as the need for discussion of prophylactic mastectomy [4]. A mutation in the PALB2 gene is also observed in conjunction with familial pancreatic cancer [6]. However, the NCCN does not have clear recommendations for screening for pancreatic cancer. Studies utilizing MRI and magnetic resonance cholangiopancreatography (MRCP) have had limited conclusions regarding the value of screening and larger studies are necessary [7]. Currently, two patients in the HRC have a diagnosis of breast cancer and are carriers of a PALB2 gene mutation. The HRC offers time for our practitioners to review patient specific medical records, the literature relevant to the involved mutation, and devise a concrete, individualized plan. The utilization of larger screening panels in the general population will likely lead to an increase in variants of uncertain significance as well as mutations in moderate penetrant genes, further supporting the need for a multidisciplinary approach.

Many genetic cancer panels exist which examine over 100 different genes [8]. Modern genetic screening will therefore identify a large number of patients who will have mutations that are not clinically actionable, highlighted by the NCCN in their recent recommendations [9]. Large, well-designed studies in diverse populations are required to elucidate the risks associated with the mutations and until then, the benefits and limitations of panels should be fully weighed [8]. Furthermore, patients who carry a mutation should have extensive pre and post-test counseling with a practitioner who has a thorough understanding of the breadth of gene penetrance and access to the multiple teams required to manage these patients [2]. A strength of the HRC is the counseling offered to patients in proximity to their genetic mutation diagnosis. With the complex scheduling interplay with the medical practitioners, we have settled on a monthly clinic to see the patients. Enabling the patient to see the genetic counselor and receive actionable interventions such as risk-reductive surgical counseling in the same clinic limits misunderstandings and miscommunications with the patient as well as between providers. This HRC allows for communication and discussion between multiple providers in real time, making the formulated recommendations congruent and based upon the best evidence available.

While the HRC facilitates a long-term individualized plan benefiting the patients, we have found that younger patients do not show for their visits significantly more often than their elders. These young patients, who would likely benefit most from the HRC, are our key target for improvement of our clinic. Objective data is limited to describe the patients who do not attend clinic from other studies as a loss of follow up is typically grounds for exclusion from data analysis for outcomes based research. However, our feeling from interacting with the young patients who do come to clinic is there is a loss of understanding when explaining their risk for developing cancer. Carrying a high/moderate genetic mutation does not mean that a patient will necessarily develop cancer. As such, understanding the need for intervention in the absence of symptoms is a challenge to convey. The young, newly diagnosed carrier of a genetic mutation needs to be counseled early with emphasis on the importance of attending the HRC to have multiple practitioners translate the importance of the diagnosis and plan.

Utilizing the HRC during a single multidisciplinary visit in patients with high/moderate genes is feasible and beneficial both to patients as well as the providers. The HRC promotes discussion and enables formulation of a long-term plan of care in complex patients, which is especially helpful when no clear standard recommendations are available.