Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair–Related Genes

Abstract

PURPOSE In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair–related genes. PATIENTS AND METHODS We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair–related genes (g BRCA1/2- ATM- CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS Among the total population (n = 217), 15 (6.9%) patients carried g BRCA1/2 (n = 10)- ATM (n = 4)- CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger ( P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group ( P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival ( P = .020) and overall survival ( P = .012). CONCLUSION In this retrospective real-world study, g BRCA1/ 2- ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

Endocrine therapy in metastatic breast cancer-more than just CDK4/6 inhibitors

“…One of the selection criteria of the described studies was a proven germline mutation. However, monotherapy with olaparib also showed positive effects in the presence of a somatic BRCA mutation in a phase II trial by Tung et al [124] . The same study investigated the effect of olaparib in patients with metastatic breast cancer and mutations in homologous recombination-related genes other than BRCA 1/2.…”

The Role of CDK Pathway Dysregulation and Its Therapeutic Potential in Soft Tissue Sarcoma

“…In summary, there are few trials on CDK4 and CDK6 inhibitors in the treatment of STS, most of which are in the preclinical or early clinical stage [ 32 , 58 , 59 , 60 , 61 ].…”

Functions of Breast Cancer Predisposition Genes: Implications for Clinical Management

“…In retrospective real-world data with a total of 217 individuals including 15 patients with BRCA1/2 (n = 10), ATM (n = 4), and CHEK2 (n = 1) GPVs, BRCA1/2-ATM-CHEK2 GPVs were suggested to be associated with poor outcomes in advanced BC treated with CDK4/6 inhibitors; however, there were no randomized controlled trials for CDK4/6 inhibitors in patients with GPVs in the HR genes [83].…”

“…ATM activates Chk2 as a DNA damage sensor, and Chk2 phosphorylates and degrades Cdc25A, a phosphatase that may inhibit the phosphorylation of CDK4/6 [120,121]; therefore, the activation of Cdc25A through a deficiency of ATM-Chk2 signaling may reactivate the CDK4/6 complex. Retrospective data suggested that 15 advanced BC patients with GPVs in HR genes (BRCA1/2-ATM-CHEK2) treated with CDK4/6 inhibitors had poor outcomes [83]; however, this is limited data to suggest CDK4/6 inhibitor resistance in patients with GPVs in the HR genes. CDK4/6 inhibitors plus endocrine therapy would still be recommended as the first-line treatment for ER-positive/HER 2-negative MBC with ATM GPVs.…”