Concurrent Versus Sequential Postoperative Radiotherapy and CDK4/6 Inhibitors in Breast Cancer with Positive Regional Nodes: A Multi-Center Safety and Toxicity Study.

PURPOSE: Our purpose was to compare the safety and toxicity profiles of concurrent versus sequential administration of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and postoperative radiotherapy (RT) in patients with Positive regional nodes, operable, hormone receptor-positive (HR+), HER2-negative breast cancer (HER2-).

METHODS

We conducted a real-world, multicenter retrospective cohort study enrolling 364 patients with node-positive, operable HR+/HER2- breast cancer who received postoperative radiotherapy combined with CDK4/6 inhibitors between January 2019 and December 2024. Propensity score matching (PSM) was performed to balance baseline covariates between the two arms, yielding 87 patients in each matched group. The primary endpoint was permanent CDK4/6i discontinuation, and secondary endpoints included dose reduction, drug substitution, grade ≥3 toxicities, and symptomatic radiation-induced lung injury (sRILI).

RESULTS

No significant intergroup differences were observed in CDK4/6i discontinuation rates before or after PSM (unmatched: 10.4% vs. 8.4%, P=0.536; PSM-matched: 10.3% vs. 9.2%, P=0.798). Similar non-significant findings were identified for dose reduction and drug substitution across unmatched and matched cohorts. For severe toxicities, univariate analysis of the unmatched cohort revealed a significantly higher rate of grade ≥3 drug eruption in the concurrent arm (4.3% vs. 0.4%, unadjusted P=0.013), while this association attenuated to borderline statistical significance after covariate balancing via PSM (4.6% vs. 0.0%, unadjusted P=0.059). No significant between-group differences were detected in sRILI, interstitial pneumonia, grade ≥3 radiation dermatitis, grade ≥3 diarrhea, or hematologic toxicities pre- and post-matching. All grade ≥3 drug eruptions occurred outside radiation fields and presented as diffuse maculopapular rashes involving the trunk and extremities, consistent with CDK4/6i-related hypersensitivity.

CONCLUSIONS

Concurrent CDK4/6 inhibitor therapy and postoperative RT demonstrate a manageable safety and tolerance profile. Given that treatment discontinuation due to ≥G 3 toxicities was observed in both groups, close toxicity monitoring and comprehensive management throughout the treatment course should be implemented when combining RT with CDK4/6i.