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, 4He and 12C ions, delivered using therapeutically realistic spread-out Bragg peaks, on 2- and 3-dimensional models of MDA-MB-231 (triple-negative [TN]) and MCF7 (estrogen receptor-positive) BC cells, whereas 16O ions were used on 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 proangiogenic factors were systematically investigated in the TN-BC subtype to assess the potential therapeutic advantages of ion irradiation in aggressive BC models. These in vitro data served as input for a comparative treatment planning study with protons, 4He, and 12C ions in 10 TN-BC cases. Results: All ions exhibited superior efficacy compared with x-ray and effectively counteracted the x-ray-induced increase in migration and invasion. 4He ions displayed a unique balance of advantages, showing greater relative biological effectiveness and inhibition of spheroid growth than protons and a reduction in migration and invasion comparable to that of 12C ions. In the planning and normal tissue complication probability study for TN-BC (α/β = 9.4 Gy), with similar organ-at-risk objectives (α/β = 3 Gy), protons and 4He ions achieved comparable CTV coverage and organ-at-risk sparing, whereas 12C ions 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 protons and 4He ions demonstrating good potential. Importantly, 4He ions emerge as a distinctive intermediate option between protons and heavier ions, combining physical precision, biological efficacy, and clinical applicability.