Abstract P3-03-01: Clinical utility of finding pathogenic mutations beyond BRCA1/2 in breast cancer patients
Authors: Esplin ED , Michalski S , Yang S , Hampel H , Jeter J , Sweet K , Pilarski R , Pearlman R , Shane K , Brock P , Westman J , Chittenden A , Stopfer J , Schneider K , Sacca R , Stickevers S , Kipnis L , Koeller D , Gaonkar S , Sotelo J , Vaccari E , Cochrane S , Champine M , Espinel W , Lincoln SE , Nussbaum RL 
Published: February 2018

Abstract
Background
The clinical utility of germline genetic testing for BRCA1 and BRCA2 has long been established. However, management recommendations for pathogenic variants in other genes, typically included in multigene panels, have only recently been included in consensus guidelines for HBOC. The clinician actions implemented for findings in these genes, and patient follow-up, are not yet well studied. We report interim results from a multi-site study of clinical actions undertaken in patients presenting with HBOC and carrying a pathogenic germline mutation in cancer risk genes other than BRCA1/2.
Methods
We retrospectively examined a cohort of patients with a personal history of HBOC who had been referred for hereditary cancer multigene testing from three major academic medical centers. For patients with pathogenic findings in a non-BRCA1/2 cancer risk gene, ordering clinicians completed a short case report form describing the clinical actions taken in response to the genetic test result, and patient follow-up. Some patients were lost to follow-up and answers of “unknown” were permitted. Genes with positive findings included CHEK2, PALB2, ATM, MUTYH, RAD51C, TP53, MSH6, RAD50, APC, BARD1, BRIP1, MSH2, NF1, NBN, PMS2, and PTEN. Case report forms were available for 77 patients as of our cut off date, and these data were de-identified and summarized for this interim report. Additional cases continue to accrue in this ongoing study.
Results
In 57% (44/77) of cases, clinicians reported that counseling and/or clinical management recommendations were changed in response to the genetic test findings. Management changes included modification of imaging surveillance (38%), considered or recommended surgical prophylaxis (12%), modified surgical plan for an existing malignancy (5%), and for one patient each: inclusion in a research trial for PARP inhibitors, modification of colonoscopy schedule, and screening for cancers other than existing malignancy. Clinicians indicated that genetic test results changed management in 48% of patients, did not change management in 29%, and had unknown impact for 23%.
Clinicians also reported that counseling and/or management for the patients' family members was changed in 67% (52/77) of cases, including family variant testing. 27% (21/77) of the patient families had cascade genetic testing, and one or more new carriers were identified in 47% (10) of the tested families. In 58% of cases, the impact of management recommendations on family members was unknown as of the case report date.
Conclusions
Pathogenic variants in non-BRCA genes are present in about 3-11% of patients with a history of HBOC. This study suggests that genetic test results in cancer genes beyond BRCA1/2 changed clinical management for a majority of patients and their family members, led to identification of new carriers, and directly impacted treatment decisions. In almost half of these patients, genetic test results impacted their health outcome, including those reported to be disease free after undergoing interventional or prophylactic surgery informed by their genetic variant. More research is needed to improve the implementation of genetic testing based management recommendations for patients and their family members.
Citation Format: Esplin ED, Michalski S, Yang S, Hampel H, Jeter J, Sweet K, Pilarski R, Pearlman R, Shane K, Brock P, Westman J, Chittenden A, Stopfer J, Schneider K, Sacca R, Stickevers S, Kipnis L, Koeller D, Gaonkar S, Sotelo J, Vaccari E, Cochrane S, Champine M, Espinel W, Lincoln SE, Nussbaum RL. Clinical utility of finding pathogenic mutations beyond BRCA1/2 in breast cancer patients [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 P3-03-01.