Abstract P6-08-25: Surgical decision making and clinical outcomes in breast cancer (BC) patients (pts) with germline alterations in moderate risk BC susceptibility genes (CHEK2, PALB2 and ATM)
Authors: dos Anjos Carlos Henrique , Amoros Kimberly , Pilewskie Melissa , Braunstein Lior , Robson Mark 
Published: March 2020

Abstract
Background: Multigene panel testing is being used increasingly for BC risk assessment. Following a new BC diagnosis, germline testing is primarily used to assess contralateral cancer risk. Presence of a BRCA1/2 mutation indicates a high risk of metachronous contralateral BC, and many women found to carry a BRCA1/2 mutation choose to undergo contralateral prophylactic mastectomy (CPM). There is limited data regarding surgical decisions among women with mutations in other, more moderate risk, susceptibility genes such as ATM, CHEK2, and PALB2. In addition, the contralateral cancer risk in women with these mutations who decline CPM is poorly understood. Here, we describe surgical decision making and outcomes in women with ATM, PALB2 or CHEK2 alterations (pathogenic or variants of uncertain significance (VUS)).Methods: We identified women who underwent peri-diagnostic genetic testing at our institution between 03/2012 and 10/2018. Pts with an early BC diagnosis (Stage 0-3) and an ATM, PALB2 or CHEK2 alteration were included. Records were reviewed to assess genetic testing details, and clinicopathologic variables. Pts surgical decision making, and clinical outcomes were the primary end points of this analysis. We compared the frequency of bilateral mastectomy (BM) and CPM of pts with pathogenic variants and VUS.Results: Of 597 consecutive pts tested, 54 pts were identified with an ATM, PALB2 or CHEK2 alteration. Pathogenic variants were present in 18 pts (3%), and 36 pts (6%) were identified with a VUS in at least one of the three genes. CHEK2 alterations were the most common (11 pathogenic and 17 VUS), followed by PALB2 alterations (3 pathogenic and 17 VUS) and ATM alterations (4 pathogenic and 8 VUS). Five pts were identified with more than one alteration. Median age of population was 43 years, 68% were Caucasians, 70% had an ER+/HER2 negative BC, 78% were pre-menopausal, 80% had pTis/T1, 68% were pN0. 33% received neoadjuvant chemotherapy. Three pts were diagnosed with synchronous bilateral BC. Among the 18 pts with pathogenic variants, 11 (61%) were managed with BM (2 due to synchronous bilateral disease and 9 for prophylaxis), the remaining 7 pts were managed with unilateral mastectomy (4/7) or unilateral lumpectomy (3/7). Among 36 pts with VUS, 8 (22%) underwent BM (1 pt due to synchronous bilateral disease and 7 for prophylaxis). Frequency of BM and CPM was significantly higher in pts with pathogenic variants compared with VUS (p = 0.004 and 0.02, respectively). Rates of BM for pathogenic gene mutations and VUS were, respectively: CHEK2 (9/11 - 82%; 5/17 - 30%), PALB2 (1/3 - 33%; 2/17 - 12%) and ATM (1/4 - 25%; 3/8 - 37%). With a median follow-up of 31.2 months, 4 pts developed a second primary BC (2 pts with pathogenic mutation and 2 pts with VUS), one pt developed local recurrence and one pt developed distant recurrence. No deaths were observed. Conclusion: In this analysis, 54/597 (9%) of tested pts had a germline alteration in ATM, CHEK2, or PALB2. Of those patients 3% had pathogenic variants and 6% had VUS. Frequency of BM and CPM was higher in pts with pathogenic mutations. Longer term follow-up in a larger cohort of patients is necessary to elucidate the true contralateral BC risk among this population.
Citation Format: Carlos Henrique dos Anjos, Kimberly Amoros, Melissa Pilewskie, Lior Braunstein, Mark Robson. Surgical decision making and clinical outcomes in breast cancer (BC) patients (pts) with germline alterations in moderate risk BC susceptibility genes (CHEK2, PALB2 and ATM) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-25.