No abstract

Tumor genomic profiling (TGP) has the potential to identify germline variants in addition to its primary use of informing cancer treatment based on genetic alterations within the tumor. However, there are no formal consensus guidelines to identify patients who would be eligible for genetic counseling (GC) and germline testing (GT) testing in patients undergoing TGP. The purpose of this study is to describe an institutionally developed Germline Review Protocol (GRP) to evaluate adult cancer patient cases already undergoing TGP to determine GC referral eligibility. We report on our retrospective experience implementing this protocol into practice wherein 172 patients out of 638 patients reviewed (27%) were recommended for a GC referral over a 17-month time period. Of those 172 patients recommended for a GC referral, only 34 patients (20%) completed GC and GT. Among patients who received GT, 15 (44%) were positive for at least one pathogenic or likely pathogenic (P/LP) variant, seven patients (21%) were negative and 12 patients (35%) had at least 1 variant of uncertain significance (VUS). The primary reason GC and GT was not completed was because the patient moved to hospice care or was deceased. This is one of the first studies outlining the process and results of a formalized institutional protocol to facilitate patient referrals for GC and GT based on TGP results.

Objective: To describe a patient who presented with hypercalcemic crisis and severe hyperparathyroidism who had urgent surgery. She was found to have a huge mediastinal atypical parathyroid adenoma (APA). We discuss our case, the difficulty discriminating an APA from parathyroid cancer, and the tools that help differentiate these conditions. Methods: We present the clinical manifestations, laboratory results, radiologic and surgical findings, and management in a patient with hyperparathyroid crisis. Discussion follows. Results: We report a case of a 39-year-old woman who presented with symptoms of severe hypercalcemia. Her intact parathyroid hormone level was found to be markedly elevated, consistent with primary hyperparathyroidism. Imaging revealed an anterior mediastinal mass, suggestive of possible ectopic parathyroid tissue. Urgent surgery and subsequent pathologic study of the excised mass revealed a supernumerary 37.5-g parathyroid gland within the mediastinum surrounded by a rim of thymic tissue. Histologically, the adenoma did not meet the World Health Organization criteria for the diagnosis of parathyroid carcinoma; however, the adenoma had atypical pathologic features given an abnormal mitotic figure. Parafibromin staining was performed and largely negative in the center of the tumor. Germline analysis of the MEN1 and CDC73 genes revealed no pathogenic variants. Her postoperative course was complicated by hypocalcemia but took several days to develop. Conclusion: The distinction between APA and parathyroid carcinoma may be difficult, and parafibromin staining and genetic testing for CDC73 mutations should be considered, as the results have implications for patient follow-up as well as for patients' relatives. (AACE Clinical Case Rep. 2018;4:e224-e227

The incidence of familial acute leukemias (AL) and myelodysplastic syndrome (MDS) in the adult population is not well characterized, though recent estimates report that up to 4% of newly diagnosed individuals have a familial syndrome. Recognizing these syndromes is critical to proper clinical management of patients with an inherited susceptibility, and for genetic screening of family members. Within our tertiary care academic institution, less than 1% of AL/MDS cases are referred to genetic counseling, presenting an opportunity for improvement in practice. With the integration of next generation sequencing into standard clinical practice, we recently initiated a bi-monthly meeting to review these sequencing results, with the intent to detect possible familial AL/MDS syndromes and increase appropriate genetic counseling referrals. Here, we describe the potential value of this approach, through a retrospective analysis of somatic genomic profiling results in AL/MDS patients. We performed a retrospective, single-center analysis of all patients who underwent somatic genomic profiling with FoundationOne Heme for AL and MDS between May 2015 and July 2018. Genomic alterations implicated in familial leukemias or familial cancers and included in the FoundationOne Heme panel were as follows: RUNX1, CEBPA, ETV6, GATA2, TERC/TERT, PAX5, CHEK2, and TP53. We recorded baseline characteristics including age, sex, and diagnosis. The presence of the suspected germline variant and up 6 other genomic alterations were recorded. We described whether a comprehensive family history, defined as whether a family history of bleeding tendency, low blood counts, or cancers, was documented for all patients. All patients with a positive family history had the malignancies and blood disorders reported. Finally, we observed if a genetic counseling referral was placed. A total of 108 patients underwent genomic profiling during the study period. Pathogenic variants implicated in familial AL/MDS or familial cancers were detected in 41 of those patients. The number of patients under the age of 50 was 7. Twenty-nine patients had a diagnosis of AML and 12 patients had MDS. Of the reported relevant pathogenic variants, TP53 was seen in 20 patients, RUNX1 in 14 patients, CEBPA in 4 patients, ETV6 in 4 patients, and GATA2 in 3 patients. There were 5 patients that had 2 pathogenic variants noted on their genetic testing. Among the patients with positive pathogenic variant, 22/41 had a comprehensive family history performed. Family history was positive for malignancy in 26/41 patients. Of those 26, 9 patients had a first degree relative with a history of hematologic malignancy including leukemia. Only 2 patients overall were referred to genetic counseling. In AL/MDS patients who underwent somatic genomic profiling at our institution, nearly half of patients with suspected germline variants for familial AML-MDS syndromes had either a family history of malignancy or development of their malignancy at an earlier age, warranting genetic counseling referral. There also is room to improve comprehensive family history collection. Beginning in March 2018, we initiated a bi-monthly meeting to review somatic genomic profiling results in AL/MDS patients with a licensed geneticist. If a suspected germline variant is discovered, we now issue a statement to the primary oncologist to clarify family history if needed, and recommend a referral for formal genetic counseling in the presence of a suggestive family history or on the basis of age. In future investigations, we plan to study how this changes the rate of genetic counseling referrals, and whether this results in an increase in the detection of familial AL/MDS or familial cancer syndromes among this patient group. Disclosures Atallah: Abbvie: Consultancy; Pfizer: Consultancy; BMS: Consultancy; Jazz: Consultancy; Novartis: Consultancy.

Despite major advances in genetic testing for breast cancer, access to genetic counseling and testing are significantly lower among immigrant and refugee populations. Both patient related barriers and provider-based factors contribute to disparities in genetic referrals and testing. Previous studies addressing genetic referral patterns among the minorities have focused on African Americans, however, there are no reports addressing disparities in genetic referrals and testing in Asian immigrant and refugee populations living in the United States (US). Given the rapid influx of these populations and increasing rates of breast cancer among Asian immigrant populations in the US, this area remains unexplored. This review addresses the current data on familial breast cancer syndromes, describe the various barriers, and attempts to provide suggestions to eliminate the disparities in genetic referral patterns.