Updates in combined approaches of radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer

Abstract

Breast cancer is the most prevalent non-skin cancer diagnosed in females and developing novel therapeutic strategies to improve patient outcomes is crucial. The immune system plays an integral role in the body's response to breast cancer and modulating this immune response through immunotherapy is a promising therapeutic option. Although immune checkpoint inhibitors were recently approved for the treatment of breast cancer patients, not all patients respond to immune checkpoint inhibitors as a monotherapy, highlighting the need to better understand the biology underlying patient response. Additionally, as radiotherapy is a critical component of breast cancer treatment, understanding the interplay of radiation and immune checkpoint inhibitors will be vital as recent studies suggest that combined therapies may induce synergistic effects in preclinical models of breast cancer. This review will discuss the mechanisms supporting combined approaches with radiotherapy and immune checkpoint inhibitors for the treatment of breast cancer. Moreover, this review will analyze the current clinical trials examining combined approaches of radiotherapy, immunotherapy, chemotherapy, and targeted therapy. Finally, this review will evaluate data regarding treatment tolerance and potential biomarkers for these emerging therapies aimed at improving breast cancer outcomes.

Keywords: breast cancer; immune checkpoint inhibitors (ICI); immunotherapy; radiation biology; radiotherapy; tumor immunology.

Figure 1

The Cyclic GMP-AMP Synthase-Stimulator of Interferon Genes (cGAS/STING) Pathway Plays a Critical Role in Antitumor Immunity. Following DNA damaging events, DNA fragments enter the cytoplasm of cancer cells. This cytosolic DNA is then recognized by the cytoplasmic sensor cGAS, which can then produce cyclic GMP-AMP (cGAMP). Consequently, cGAMP promotes the recruitment of STING molecules in the endoplasmic reticulum, which leads to TANK-binding kinase 1 (TBK1) phosphorylating interferon regulatory factor 3 (IRF3), and nuclear factor-κB (NF- κB). IRF3 and NF- κB then translocate to the nucleus to promote transcription of type I interferons, which can lead to an antitumor response via the promotion of T cell infiltration into the tumor microenvironment.

Figure 2

Radiotherapy and Immunotherapy Synergistically Promote Antitumor Immune Responses. One potential combined therapeutic approach is to combine radiotherapy with immune checkpoint inhibition. Radiotherapy promotes DNA damage within cancerous cells, which can consequently be recognized by cGAS and lead to activation of the cGAS/STING pathway to promote antitumor immunity through interferon signaling. Likewise, immune checkpoint inhibitors, such as anti-PD-1 monoclonal antibodies, can modulate an augmented antitumor immune response by turning off immune checkpoints. Under normal conditions, these checkpoints result in a decrease in the cytotoxic abilities of T cells; however, when turned off, this enhances the cytotoxic effects of T cells and results in enhanced antitumoral effects. Numerous preclinical and clinical studies suggest synergy exists in combining radiotherapy and immune checkpoint inhibitors in breast cancer patients and studies are currently underway to determine the best ways oncologists can implement these interactions.

Figure 3

Chemotherapy Has Immunomodulatory Effects on the Tumor Microenvironment and May Promote Synergy in Combination with Radiotherapy and Immune Checkpoint Inhibitors. Chemotherapy is a standard of care therapy for the treatment of breast cancer and has significant implications on the immune response. Studies suggest that single-agent chemotherapy can recruit immune cells to the microenvironment of breast cancer tumors. Additionally, in breast cancer patients, response to chemotherapy is dependent upon the presence of tumor-infiltrating lymphocytes. When chemotherapy is combined with radiotherapy, this can induce radiosensitization in preclinical and clinical models, resulting in enhanced cancer cell death. Clinical promise may exist in combining immune checkpoint inhibitors, radiotherapy, and chemotherapy for the treatment of breast cancer. When chemotherapy is combined with immunotherapy, this enhances its efficacy and increases patient survival. Clinical trials are currently underway to ascertain the effects of combined approaches in breast cancer patients.

Figure 4

PARP Inhibitors Prevent DNA Damage Repair and May Synergize with Both Radiotherapy and Immune Checkpoint Inhibition. Mechanistically, PARP proteins are recruited to regions of DNA damage to assist in the repair of single-strand breaks. When PARP proteins are inhibited, this prevents proper DNA repair and promotes the accumulation of double-strand breaks. In patients that express the BRCA1/2 genes, this damage can be repaired; however, in patients with a deleterious BRCA1/2 mutation, this results in synthetic lethality due to the absence of multiple DNA repair pathways. It is well established that radiotherapy induces DNA damage. When radiotherapy is combined with PARP inhibitors, this prevents DNA damage repair in BRCA mutant cancers. Furthermore, the DNA damage induced by radiotherapy that is then not repaired following PARP inhibition can result in the production of cytosolic DNA molecules. As single agents, immune checkpoint inhibitors illicit immune responses by turning off immune checkpoints, resulting in pro-inflammatory, antitumor effects. Studies are currently underway to determine whether combined PARP inhibition, radiotherapy, and immune checkpoint inhibition will promote enhanced antitumor immunity and be efficacious for the treatment of breast cancer patients.