KEY POINTS
- This retrospective cohort included 3,423 women with stage I–III invasive breast cancer who received CT-planned adjuvant radiotherapy at the University Medical Center Groningen between 2005 and 2015. Median age was 59 years, and median follow-up was 7.7 years.
- Effective dose to immune cells was modeled from radiation exposure to circulating blood using contributions from mean heart dose, mean lung dose and estimated dose to large and small blood vessels. Median EDIC was 2.08 Gy (IQR 1.64–2.72); 82% of patients received <3 Gy.
- During follow-up, 710 patients (20.7%) died, including 323 breast cancer deaths (9.4%). Five- and ten-year breast cancer-specific survival in the entire cohort were 93.5% and 86.6%, while locoregional recurrence occurred in 3.9% and distant metastases in 11.6%.
- Higher EDIC was independently associated with breast cancer mortality. Each 1-Gy increase corresponded to an adjusted HR 1.66 (95% CI 1.44–1.91; p<0.001) after accounting for age, T and N stage, grade, molecular subtype, lymphovascular invasion, chemotherapy, RT schedule and cardiovascular risk factors.
- The absolute survival gradients were large. Patients in the lowest EDIC quartile (0–1.63 Gy) had breast cancer-specific survival of 98.4% at 5 years and 94.3% at 10 years, versus 84.6% and 71.5% in the highest quartile (2.72–6.20 Gy).
- The association became particularly pronounced above 3 Gy. Breast cancer-specific survival was 82.2% at 5 years and 66.5% at 10 years with EDIC 3.0–4.5 Gy, falling to 63.2% and 48.1% for 4.5–6.2 Gy. However, patients with high EDIC also had more adverse tumor characteristics and more frequently received chemotherapy, highlighting substantial potential for residual confounding.
- Higher EDIC was also associated with worse overall survival and increased locoregional and distant failure in multivariable analyses. The proposed mechanism is radiation-induced lymphopenia, but lymphocyte counts were not available, so the study could not directly establish this biological pathway or show that intentionally reducing EDIC improves cancer outcomes.
CLINICAL TAKEAWAY
The study adds weight to the concept of the immune system as an organ at risk, particularly when large thoracic volumes are irradiated. But EDIC should not yet become a planning constraint: this is retrospective association from an older predominantly 3D-conformal treatment era, and prospective studies are needed to determine whether reducing immune-cell dose actually improves outcomes.