Hypothesis: can the abscopal effect explain the impact of adjuvant radiotherapy on breast cancer mortality?

Radiotherapy is an integral component of loco-regional therapy for breast cancer. Randomized controlled trials indicate that increasing the extent of extirpative surgery primarily reduces the risk of local recurrences, while the addition of radiotherapy to surgery can also reduce the risk of distant recurrences, thereby lowering breast cancer-specific mortality. This may suggest an "abscopal" effect beyond the immediate zone of loco-regional irradiation that favorably perturbs the natural history of distant micrometastases. Immunological phenomena such as "immunogenic cell death" provide a plausible mechanistic link between the local and systemic effects of radiation. Radiotherapy treatment can stimulate both pro-immunogenic and immunosuppressive pathways with a potential net beneficial effect on anti-tumor immune activity. Upregulation of programmed cell death ligand (PD-L1) by radiotherapy is an immunosuppressive pathway that could be approached with anti-PD-L1 therapy with potential further improvement in survival. The world overview of randomized trials indicates that the breast cancer mortality reduction from adjuvant radiotherapy is delayed relative to that of adjuvant systemic treatments, and similar delays in the separation of survival curves are evident in the majority of randomized immunotherapy trials demonstrating treatment efficacy. In this article, we hypothesize that an abscopal effect may explain the benefit of radiotherapy in reducing breast cancer mortality, and that It might be possible to harness and augment this effect with systemic agents to reduce the risk of late recurrences.