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

Abstract

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. The radiobiological effects of X-rays were compared with those of protons (p), ⁴He and ¹²C 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 ¹⁶O 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, ⁴He and ¹²C ions on ten TN-BC cases. All ions exhibited superior efficacy compared to X-ray and effectively counteracted the X-ray-induced increase in migration and invasion. ⁴He 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 ¹²C ions. In the planning and NTCP study for TN-BC (α/β=9.4Gy), with similar OAR objectives (α/β=3Gy), p and ⁴He ions achieved comparable CTV coverage and OARs sparing, whereas ¹²C exhibited reduced coverage mainly due to this large α/β difference. These findings suggest particle therapy as a promising strategy for aggressive BC, with p and ⁴He ions demonstrating particular potential. Importantly, ⁴He ions emerge as a distinctive intermediate option between protons and heavier ions, combining physical precision, biological efficacy, and clinical applicability.