A Real-World Evidence Study of CDK4/6 Inhibitor Treatment Patterns and Outcomes in Metastatic Breast Cancer by Germline BRCA Mutation Status

Abstract

Introduction: Limited data exist on real-world treatment patterns and the effectiveness of cyclin-dependent kinase (CDK) 4/6 inhibitors in germline BRCA (gBRCA)-mutated breast cancer.

Methods: Adults with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) treated with CDK4/6 inhibitor therapy between 2013 and 2018 were retrospectively selected from the Flatiron Health database. Patients with known gBRCA status were classified as mutated (gBRCAm) or wild type (gBRCAwt). Time-to-first subsequent therapy or death (TFST) and overall survival (OS) were calculated from the earliest line of therapy with a CDK4/6 inhibitor.

Results: Of 2968 patients with HR+/HER2- mBC receiving a CDK4/6 inhibitor, 859 (28.9%) had known gBRCA status, of whom 9.9% were gBRCAm and 90.1% gBRCAwt. Median (95% confidence interval [CI]) TFST was 10 (7-11) months in the gBRCAm group, 10 (9-11) months in the gBRCAwt group, and 11 (10-12) months in the combined gBRCAwt and unknown gBRCA group; median (95% CI) OS was 26 (21-not estimated), 37 (31-51), and 33 (31-35) months, respectively. Cox models indicated the gBRCAm group had shorter TFST (stratified hazard ratio [sHR] 1.24; 95% CI 0.96-1.59) and OS (sHR 1.50; 95% CI 1.06-2.14) than the gBRCAwt group. The gBRCAm group had shorter TFST (sHR 1.38; 95% CI 1.08-1.75) and OS (sHR 1.22; 95% CI 0.88-1.71) than the combined group.

Conclusion: The results of this real-world study suggest that treatment outcomes with CDK4/6 inhibitors may be worse in patients with gBRCAm mBC than in their counterparts with gBRCAwt and unknown gBRCA status, suggesting potential differences in tumor biology. This result highlights the unmet need in patients with gBRCAm requiring optimized treatment selection and sequencing. Future exploration in larger samples of patients who have had biomarker testing is warranted.

Keywords: CDK4/6 inhibitors; Metastatic breast cancer; Survival; Treatment patterns; gBRCA mutation status.

Fig. 1

Study attrition flowchart for the CDK4/6-inhibitor-treated HR+/HER2− mBC cohort. Each box shows the number (n) of patients with percentage (in parentheses) of total number (N). Asterisk indicaes the index date, which is the start date of the first treatment line containing the CDK4/6 inhibitor. CDK4/6 Cyclin-dependent kinases 4 and 6, ER estrogen receptor, HER2 human epidermal growth factor receptor 2, HR+ hormone receptor positive, mBC metastatic breast cancer, PR progesterone receptor

Fig. 2

Time-to-first subsequent therapy by gBRCA status from start of CDK4/6 as first-line therapy (a), from start of CDK4/6 as second-line therapy (b), and from start of CDK4/6 as third-line or higher therapy (c). 95% CIs were calculated using the Brookmeyer–Crowley method. CI Confidence interval, gBRCA germline BRCA, gBRCAm germline BRCA mutation, gBRCAwt germline BRCA wild type, TFST time-to-first subsequent therapy, unk unknown

Fig. 3

Overall survival by gBRCA status from start of CDK4/6 as first-line therapy (a), from start of CDK4/6 as second-line therapy (b), and from start of CDK4/6 as third-line or higher therapy (c). 95% CIs were calculated using the Brookmeyer–Crowley method. NE Not estimated, OS overall survival