3MO Analysis of germline BRCA1/2 mutations and uncommon somatic alterations from patients with HR+, HER2-, node-positive, high-risk early breast cancer enrolled in monarchE

In monarchE (NCT03155997), 2 years of adjuvant abemaciclib + endocrine therapy (ET) resulted in sustained improvement in invasive disease-free survival (IDFS; HR=0.680, 7.6% absolute benefit at 5 years) in patients (pts) with HR+, HER2-, node-positive, high-risk early breast cancer (EBC). Considering multiple adjuvant options are available for EBC pts with germline BRCA1/2 mutations, we are reporting the exploratory results of pathogenic germline BRCA1/2 mutations (gBRCA1/2) as well as uncommon (incidence between ≥3% and <9%) somatic alterations from monarchE. The whole exome sequencing (WES) biomarker sub-cohort (n=1173, 21% of ITT population) included a stratified random sample of pts from the ITT population plus all pts with IDFS events at the primary outcome data cut. Blood and tissue samples were evaluated for gBRCA1/2 and uncommon oncogenic alterations. At 54 months median follow up, 992 IDFS events (17.6%) were observed in the ITT population (n=5637) and 292 IDFS events (24.9%) were observed in the WES cohort (n=1173; abemaciclib+ET n=580; ET n=593). In the WES cohort, 3.5% (n=41, abemaciclib+ET n=20; ET n=21) had a gBRCA1/2 (BRCA1 n=6, BRCA2 n=35). In pts with gBRCA1/2, 1 (5%) experienced an IDFS event in the abemaciclib+ET arm, compared to 9 (42.8%) in the ET arm. Uncommon somatic alterations were detected in the following genes: CCNE2 (8.3%), PTEN (8.1%), AKT1 (6.0%), RB1 (5.6%), NF1 (5.5%), and BRCA2 (4.2%) and the IDFS event rates for pts with these alterations are reported in the table.Table: 3MOGermline mutationsTotal biomarker cohort (n=1173)Abemaciclib + ET (n=580)ET Alone (n=593)Altered GeneN (%)NIDFS Events (%)NIDFS Events (%)gBRCA16 (0.5%)30 (0.0%)33 (100.0%)gBRCA235 (3.0%)171 (5.9%)186 (33.3%)gBRCA1/241 (3.5%)201 (5.0%)219 (42.9%)Uncommon somatic alterationsPrevalenceAbemaciclib + ETET AloneAltered GeneN (%)NIDFS Events (%)NIDFS Events (%)CCNE297 (8.3%)4918 (36.7%)4818 (37.5%)PTEN95 (8.1%)4014 (35.0%)5517 (30.9%)AKT170 (6.0%)328 (25.0%)3812 (31.6%)RB166 (5.6%)3412 (35.3%)327 (21.9%)NF165 (5.5%)358 (22.9%)3012 (40.0%)BRCA249 (4.2%)227 (31.8%)278 (29.6%) Open table in a new tab In these exploratory analyses from an IDFS-event-enriched cohort of monarchE, fewer IDFS events occurred in pts with germline BRCA1/2 mutations receiving adjuvant abemaciclib + ET compared to ET alone; however, small pt numbers limit the evaluation of statistical significance for both gBRCA1/2 and uncommon somatic alterations.