Pathogenic Variants in <i>CHEK2</i> Are Associated With an Adverse Prognosis in Symptomatic Early-Onset Breast Cancer.

Abstract

Checkpoint kinase 2 (<i>CHEK2</i>) is frequently included in multigene panels. We describe the associated outcomes among carriers of <i>CHEK2</i> pathogenic variants in young patients with symptomatic breast cancer. Participants (N = 2,344) in the Prospective Outcomes in Sporadic Versus Hereditary Breast Cancer study had a diagnosis of primary invasive breast cancer at age ≤ 40 years. Summary statistics were used to compare tumor characteristics among <i>CHEK2</i>+ carriers with those who were <i>CHEK2</i>-. Kaplan-Meier curves were used to demonstrate overall survival (OS) and distant disease-free survival. Overall, 53 of the 2,344 participants (2.3%) had a pathogenic <i>CHEK2</i> variant. <i>CHEK2</i>+-associated tumors were significantly more likely to be grade 2, estrogen receptor and progesterone receptor-positive compared with <i>CHEK2</i>- tumors (grade 2, n = 28 of 52 [53.8%] <i>v</i> n = 803 of 2,229 [36.0%]; <i>P</i> = .029). <i>CHEK2</i>-associated tumors were significantly more likely to have nodal involvement (N1, n = 37 of 53 [69.8%] <i>v</i> 1,169 of 2,253 [51.9%]; <i>P</i> = .0098) and demonstrated a trend toward multifocality. A higher proportion of participants with <i>CHEK2</i>+ variants with invasive breast cancer were obese than were those with <i>CHEK2</i>- variant (28.3% <i>v</i> 18.8%; <i>P</i> = .039). Univariate and multivariable analyses revealed that OS and distant disease-free survival were significantly worse in <i>CHEK2</i>+ versus <i>CHEK2</i>- carriers (OS hazard ratio, 1.58; 95% CI, 1.01 to 2.48; <i>P</i> = .043). This work highlights the adverse prognosis associated with breast cancer in carriers of <i>CHEK2</i> pathogenic variants. It also identifies a potential association among obesity, family history, and breast cancer risk in young <i>CHEK2</i> gene carriers.