Radiobiological and Treatment Planning Evidence Supporting Particle Therapy in Aggressive Breast Cancer

Purpose Breast cancer (BC) remains the most commonly diagnosed malignancy among women worldwide with an overall 5-year-survival rate of ∼90%. The prognosis worsens dramatically for patients with metastatic and/or aggressive subtypes. In such cases, particle therapy emerges as a promising approach, offering superior tumor control while limiting the risk of secondary pathologies. Methods and Materials The radiobiological effects of X-rays were compared with those of protons (p), 4 He and 12 C ions, delivered using therapeutically-realistic Spread-Out Bragg Peaks, on 2D- and 3D-models of MDA-MB-231 (Triple-Negative (TN)) and MCF7 (ER-positive) BC cells, whereas 16 O ions were used on the MDA-MB-231 cells. To achieve relevant insights, we evaluated conventional clonogenic survival and spheroid growth dynamics, mimicking tumor architecture, on both cell lines. Cell migration and invasion, tumor‑supernatant–induced angiogenesis and the expression of pro‑angiogenic factors were systematically investigated in the TN-BC subtype to assess the potential therapeutic advantages of ion-irradiation in aggressive BC models. The here-obtained in vitro data served as input for a comparative treatment planning study with p, 4 He and 12 C ions on ten TN-BC cases. Results All ions exhibited superior efficacy compared to X-ray and effectively counteracted the X-ray-induced increase in migration and invasion. 4 He ions indicated a unique balance of advantages, showing greater relative biological effectiveness and inhibition of spheroid growth than p, and a reduction in migration and invasion comparable to 12 C ions. In the planning and NTCP study for TN-BC (α/β=9.4Gy), with similar OAR objectives (α/β=3Gy), p and 4 He ions achieved comparable CTV coverage and OARs sparing, whereas 12 C exhibited reduced coverage mainly due to this large α/β difference. Conclusions These findings suggest particle therapy as a promising strategy for aggressive BC, with p and 4 He ions demonstrating particular potential. Importantly, 4 He ions emerge as a distinctive intermediate option between protons and heavier ions, combining physical precision, biological efficacy, and clinical applicability.