Dose-LET Interactions Predict Capsular Contracture After Proton Postmastectomy Radiation Therapy.

PURPOSE: Pencil beam scanning (PBS) proton therapy enables highly conformal dose distributions and is increasingly used for postmastectomy radiation therapy (PMRT) to reduce cardiopulmonary exposure. However, implant-based reconstruction (IBR) in the setting of PMRT remains susceptible to capsular contracture, and the potential contribution of elevated linear energy transfer (LET) in PBS has not been well characterized. This study aimed to investigate the combined effects of dose and dose-averaged linear energy transfer (LETd) on capsular contracture after proton PMRT and to derive preliminary, exploratory volume cutoffs of dose-LET volume constraints (DLVCs). METHODS: We conducted a retrospective case-control study of consecutive breast cancer patients who underwent mastectomy followed by implant-based reconstruction and conventionally fractionated proton PMRT (50 Gy in 25 fractions) between 2015 and 2021. Patients who developed Baker grade III-IV capsular contracture were identified and matched 1:2 with controls using nearest-neighbor matching based on clinical and pathological variables. Dose-LET volume histograms (DLVHs) were calculated for peri-implant tissue (5-mm shell around the implant). Generalized linear mixed-effects regression (GLMER) was employed to identify DLVH indices significantly associated with capsular contracture. Redundant indices were removed using Spearman correlation analysis. DLVCs were derived from receiver operating characteristic (ROC) analysis and evaluated using a support vector machine (SVM)-based normal tissue complication probability (NTCP) model with leave-one-out cross-validation. RESULTS: Among 145 consecutive patients, 8 developed capsular contracture and were matched to 16 controls. Three independent DLVH indices were significantly associated with capsular contracture (p<0.01): V(55.8 Gy[RBE=1.1], 2.2 keV/μm), V(50.3 Gy[RBE=1.1], 5.4 keV/μm), and V(32.8 Gy[RBE=1.1], 0.9 keV/μm). After Benjamini-Hochberg (BH) false discovery rate correction across all 4,096 DLVH indices, all three remained significant (q_BH = 0.052). The corresponding DLVCs were: V(55.8 Gy[RBE=1.1], 2.2 keV/μm) < 0.0017%, V(50.3 Gy[RBE=1.1], 5.4 keV/μm) < 0.0033%, and V(32.8 Gy[RBE=1.1], 0.9 keV/μm) > 96.98%. The SVM-based NTCP model achieved an area under the ROC curve (AUROC) of 0.867, with accuracy of 91.7%, sensitivity of 87.5%, and specificity of 93.8%. CONCLUSION: Capsular contracture following proton PMRT is significantly associated with the combined effects of dose and LETd in peri-implant tissue. The derived DLVCs represent exploratory candidate dosimetric constraints that warrant further investigation and prospective validation in breast cancer patients undergoing proton PMRT with implant-based reconstruction.