Advances in Combining Radiation and Immunotherapy in Breast Cancer

Abstract

Breast irradiation has long been utilized in the adjuvant or metastatic setting to eliminate microscopic disease or to palliate existing disease, respectively. However, preclinical data have demonstrated that radiation can also alter the tumor microenvironment and induce antitumor immune responses. As a result, multiple clinical studies have been undertaken and have reported synergy between radiation and immune checkpoint blockade across various cancer types. Given recent clinical successes with immune checkpoint blockade in both early-stage and metastatic breast cancer, there has been substantial interest in combining radiation and immunotherapy to enhance local and systemic immune responses. Herein, we review the preclinical rationale for combining radiotherapy and immunotherapy, the early clinical trials that have adopted this strategy in breast cancer, and the landscape of ongoing relevant clinical trials. Finally, we propose future directions based on promising preclinical studies that integrate radiation, checkpoint blockade, and novel agents for the treatment of breast cancer.

Clinical evidence for synergy between immunotherapy and radiotherapy (SITAR)

“…The FDA has approved neoadjuvant pembrolizumab and palliative atezolizumab for triple-negative breast cancer patients, but data for the use of SITAR in breast cancer are limited. A recent review of the clinical studies using SITAR in breast cancer was conducted by Nguyen et al 61 At present, there are only a few phase 2 studies. 31,33 In one phase 2 study, 17 patients received SABR to a single site with pembrolizumab, of these, three had a complete response, one stable disease and 13 progressed, which is apparently a favourable response rate compared with pembrolizumab alone which has a response rate of about 5%.…”

“…The FDA has approved neoadjuvant pembrolizumab and palliative atezolizumab for triple‐negative breast cancer patients, but data for the use of SITAR in breast cancer are limited. A recent review of the clinical studies using SITAR in breast cancer was conducted by Nguyen et al 61 . At present, there are only a few phase 2 studies 31,33 .…”

“…At present, there are only a few phase 2 studies 31,33 . In one phase 2 study, 17 patients received SABR to a single site with pembrolizumab, of these, three had a complete response, one stable disease and 13 progressed, which is apparently a favourable response rate compared with pembrolizumab alone which has a response rate of about 5% 33,61 . Future studies should focus on triple‐negative breast cancer patients, as these patients are more likely to benefit from immunotherapy.…”

αvβ1 integrin is enriched in extracellular vesicles of metastatic breast cancer cells: A mechanism mediated by galectin‐3

“…It is increasingly accepted that the tumour is a complex conglomerate of cancer cells, stromal cells, EVs, and extracellular matrix, which act in concert for the tumour to metastasise and progress (Lima et al., 2021). Thus, combination/comprehensive strategies targeting multiple aspects of tumour biology are now in progress and in use to treat cancer and these approaches are shifting the therapy paradigm (Johansson, 1997, Nguyen et al., 2021). We hope that our study contributes a valuable piece to solve the bigger puzzle of the tumour microenvironment through understanding the implications of EV‐bound integrin αvβ1 in breast cancer metastasis.…”

Disección mecanística del fracaso loco-regional en cáncer de mama

“…Demostrado el rol central de Enpp1, no resulta sorprendente que los inhibidores de Enpp1 hayan emergido como potentes agentes inmunoestimuladores (198). Los efectos observados derivados de la inhibición de Enpp1 pueden potenciarse mediante su asociación a radioterapia por su efecto inmunoestimulador (250,251). La inhibición de Enpp1 de forma específica en las células tumorales se sitúa como una posible terapia inmunoestimuladora y que puede sinergizar con otros tratamientos como la radioterapia u otros inmunoterápicos mediante el bloqueo de PD-1, PD-L1 o CTLA4 que potencien la respuesta efectora antitumoral.…”