Abstract P6-08-02: 21-gene recurrence score results according to germline pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2 and Lynch Syndrome genes
Authors: Kurian Allison W , Abrahamse Paul , Ward Kevin , Hamilton Ann S. , Deapen Dennis , Shak Steven , Katz Steven J. 
Published: March 2020

Abstract
BACKGROUND: Women diagnosed with breast cancer increasingly undergo multiplex sequencing of germline cancer susceptibility genes. Little is known about cancer prognosis and predicted chemotherapy benefit, which are measured from the tumor by the 21-gene recurrence score (21G), according to germline pathogenic variants (PVs) in BRCA1/2 and other commonly sequenced genes.
METHODS: Surveillance Epidemiology and End Results (SEER) data for all women aged 20 years and older, diagnosed with breast cancer in 2013-2016 and reported to Georgia and California statewide SEER registries (N=158,480) by December 1, 2017 were linked to germline genetic testing results from four laboratories that performed nearly all clinical testing. 21G results were obtained from SEER and the testing laboratory. We examined 21G among all patients who were eligible for 21G testing (estrogen receptor (ER) and/or progesterone receptor (PR)-positive, HER2-negative, T stage 1-2, N stage 0-1), N=84,128. We report the median 21G score according to germline testing results, with multivariable modeling adjusting for age, tumor size, grade and lymph node involvement.
RESULTS: 23,508 patients eligible for 21G testing linked to a recurrence score result (27.9%) of whom 6,951 (29.7%) had germline testing. Mean 21G score was slightly higher in women diagnosed at age less than 50 years (18.0, 95% confidence interval (CI) 17.8-18.3) versus at age 50 years and older (17.0, CI 16.9-17.1). 402 women had a PV in BRCA1, BRCA2, CHEK2, ATM, PALB2 or the Lynch Syndrome genes (MLH1, MSH2, MSH6, PMS2). The table shows mean 21G scores by PV, which were highest for BRCA1 (33.6) followed by PALB2 (24.1) and BRCA2 (23.2), compared to women who had a negative germline test (17.3) or no germline test (17.0). The proportion of patients with a high 21G score (26-100, a range for which chemotherapy is indicated) was increased with PVs in BRCA1 (63.2% versus 14.6% with a negative germline test, p&lt;0.001), PALB2 (36.7%, p=0.01), and BRCA2 (35.4%, p&lt;0.001). In a multivariable model controlling for clinical factors, BRCA1 PV (beta coefficient=11.9, CI 7.6-15.5) and PALB2 PV (beta coefficient=4.7, CI 0.6 - 8.9) were independently associated with 21G score.
CONCLUSIONS: BRCA1/2 and PALB2 PVs are associated with higher 21G scores (mean 23-34), while ATM, CHEK2 and Lynch Syndrome gene PVs are not associated with substantially higher 21G scores than in women testing negative or untested (mean 17-18). These results can inform decision-making about 21G testing and chemotherapy use among breast cancer patients who carry PVs in commonly tested cancer susceptibility genes.
Table. 21 gene recurrence (21G) score according to germline genetic testing resultsGermline genetic testing resultsNMean 21G score95% confidence interval21G score 26-100, %P-value, % 21G score 26-100BRCA1 pathogenic variant (PV)5733.629.1-38.163.2%&lt;0.001PALB2 PV3024.120.6-27.736.7%0.001BRCA2 PV16423.221.7-24.835.4%&lt;0.001ATM PV4519.917.5-22.420.0%0.398Lynch Syndrome PV (MLH1, MSH2, MSH6, PMS2)2319.413.9-24.821.7%0.404CHEK2 PV9119.017.5-20.514.3%0.757Variant of uncertain significance in any gene97817.917.2-18.616.6%0.093Negative5,49517.317.1-17.614.6%ReferenceNo germline genetic test16,55717.016.8-17.115.3%0.209
Citation Format: Allison W Kurian, Paul Abrahamse, Kevin Ward, Ann S. Hamilton, Dennis Deapen, Steven Shak, Steven J. Katz. 21-gene recurrence score results according to germline pathogenic variants in BRCA1, BRCA2, PALB2, ATM, CHEK2 and Lynch Syndrome genes [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 P6-08-02.