Background: Germline mutations in CHEK2, a cell-cycle checkpoint kinase, are associated with increased susceptibility to breast, colon, and other cancers. The clinical characteristics and cancer risks of patients with CHEK2 mutations is under investigation.

Methods: Patients identified with a pathogenic germline CHEK2 mutation between September 2013 and April 2017 were evaluated. Clinical multigene panel testing using next generation sequencing technologies was utilized. All patients received comprehensive pre- and post-test genetic counseling. Genetic testing results, demographics, tumor characteristics and outcomes were analyzed.

Results: A total of 107 CHEK2 mutation carriers were identified, of whom 88 (82%) were females. The vast majority were Caucasian (99%), and of those, 17 (16%) had Ashkenazi Jewish ancestry. The median age at time of genetic testing was 52 (range: 22-89). The most common mutations identified were: I157T (28%), c.1100delC (27%), p.S428F (15%) and c.1427C>T (9%). Seven of these patients (7%) were found to carry a second pathogenic cancer risk mutation: BRCA, ATM, NBN, NF1, and MUTYH. One patient was found to carry 3 pathogenic mutations (1100delC, ATM, and BRCA). Sixty-three (59%) patients had a prior diagnosis of malignancy, with a mean age of diagnosis of 53. Of the 88 females, the most common type of malignancy was breast cancer (55%), with a mean age of diagnosis of 52 (range: 35-79). Of the 19 males, breast cancer was seen in 4 patients. The most common known histopathology was invasive ductal carcinoma (72%), followed by DCIS (15%), invasive lobular carcinoma (9%), and papillary carcinoma (4%). Majority of the patients had breast tumors with low or moderate grade (62%), less than two centimeters (61%), node negative (70%), and estrogen/progesterone receptor positive/HER2neu negative (96%). Two patients had triple negative breast cancers. Of the 48 female mutation carriers with breast cancer, 38% underwent bilateral mastectomy. The 1- and 5-year survival was 100% with a median follow up of 57 months. Five of the 48 females developed a contralateral breast cancer, with a median time to contralateral recurrence of 6 years (range: 3-17). Two patients developed in-breast tumor recurrence at 9 and 19 years, respectively. Other cancers observed were papillary thyroid cancer (3 patients), melanoma (2 patients), and prostate (2 patients). One patient developed angiosarcoma of the chest wall two years after radiation therapy.

Conclusion: Our study describes the unique clinical characteristics of CHEK2 mutation carriers in a US-based clinic at Beaumont Health. Majority of breast cancers were early stage, hormone receptor positive and demonstrated excellent outcomes. Despite the early stage, a significant proportion of patients underwent bilateral mastectomy. Additional pathogenic mutations were identified in 10% of patients; validating the importance of panel testing in assessing cancer risk. Future studies are needed to better define the clinical presentation, cancer risks, mutational spectrum, and outcomes of CHEK2 mutation carriers in order to provide tailored screening and management guidelines for this emerging population.

Citation Format: Blankenship LM, Yadav S, Yumpo Cardenas P, Zakalik D. Characteristics of CHEK2 mutation carriers in a large academic health center in Michigan [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-03.