Abstract P4-12-08: Utilizing next generation sequencing technologies for hereditary breast cancer risk assessments in a private oncology practice
Authors: Hamlington Barbara , Sedlacek Scot , Langer Lucy , Goetsch Brittney , Lemas Katie , Diab Sami 
Published: May 2015

Background: The recent introduction of clinical Next Generation Sequencing (NGS) technologies has transformed the ability of health care providers to provide personalized hereditary breast cancer risk assessments to patients and their family members. However, along with the plethora of data derived from NGS technologies come challenges regarding how to interpret this data in a clinically meaning way to guide medical management decisions.

Methods: A retrospective analysis was performed on a population of 242 patients with a personal or family history of breast and/or ovarian cancer and completed NGS genetic testing between March 2012 and May 2014 at Ambry Genetics. Data points included age, gender, primary diagnosis, type of NGS genetic test and result. Patients with prior genetic testing were not excluded from the analysis.

Results: Of the 242 patients who completed NGS genetic testing 199 (82%) had a personal history of cancer and 43 (18%) had a family history of cancer. Ten (5%) clinically significant deleterious mutations were found in the affected population; 3 MUTYH mutations were consider not clinically significant and excluded from the analysis. Four (40%) were CHEK2 mutations, 2(20%) BRCA1 mutations, 1(10%) NBN mutation, 1(10%) ATM mutation, 1(10%) MSH6 mutation and 1(10%) PTEN mutation. One patient with a history of ovarian cancer had two deleterious mutations in the BRCA1 and NBN genes, and three affected patients had a deleterious mutation in addition to a variant of uncertain significance (VUS); a patient with synchronous breast and ovarian cancers had a MSH6 mutation and a BRCA2 VUS, a patient with breast cancer had a CHEK2 mutation and a CHEK2 VUS, and a patient with breast cancer had a CHEK2 mutation and a MSH6 VUS. A total of 37 (19%) VUS were found in the affected population, including one patient with a history of breast cancer and a VUS in both ATM and MRE11A. A single (2%) clinically significant BRCA1 deleterious mutation and 6(14%) VUS were detected in the unaffected population.

Conclusions: NGS technologies allow for health care providers to complete more comprehensive hereditary breast cancer risk assessments for patients and their families. However, the high VUS rate (14-19%) and the possibility for multiple mutations and/or variants in a single patient create unique challenges when interpreting NGS genetic test results. Furthermore, the paucity of prospective studies and consensus guidelines limits the ability of the health care provider to interpret NGS genetic test results in a clinically meaningful way to guide patient management. This is highlighted by the case example above regarding the patient with synchronous breast and ovarian cancers who was found to have a MSH6 mutation and a BRCA2 VUS. Given that the patient does not meet Amsterdam criteria, the MSH6 mutations would have been missed had it not been for the NGS technology utilized for this patient. However, challenges still exist about how to interpret this data for both the patient and her family in a clinically meaningful way given that the family does not look like a classic Lynch Syndrome family.

Citation Format: Barbara Hamlington, Scot Sedlacek, Lucy Langer, Brittney Goetsch, Katie Lemas, Sami Diab. Utilizing next generation sequencing technologies for hereditary breast cancer risk assessments in a private oncology practice [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-08.