Radiation therapy for triple-negative breast cancer: from molecular insights to clinical perspectives

ABSTRACT

Introduction

Triple-negative breast cancer (TNBC) lacks three common receptors, making traditional treatments less effective. This review highlights the importance of radiotherapy and emerging therapeutic strategies to enhance treatment outcomes in TNBC.

Areas covered

We conducted a literature search on PubMed for publications from 2000 to 2023 to discuss the critical role of radiotherapy in managing TNBC, emphasizing its applications from locoregional control to improving survival rates. The review explores molecular mechanisms underlying TNBC’s radiotherapy response, including DNA damage repair and apoptosis, with a focus on BRCA1/2 mutations and Poly (ADP-ribose) polymerase (PARP) inhibition. We summarize preclinical and clinical research on radiosensitization strategies, from gene-targeted therapies to immunotherapy combinations, and the impact of post-mastectomy radiation therapy on locoregional control. The potential of personalized treatment approaches, integrating molecular profiling, targeted radiosensitizers, and the synergistic effects of radiotherapy with immunotherapy, is also discussed.

Expert opinion

Future TNBC treatment strategies should focus on precision medicine, integrating immunotherapy, developing novel radiosensitizers, and targeting biological pathways to overcome radioresistance. The integration of radiomics and artificial intelligence offers promising avenues for enhancing treatment personalization and efficacy, aiming to improve patient outcomes in TNBC.

KEYWORDS:

• Radiotherapy
• TNBC
• preclinical study
• clinical trial
• radiosensitizer
• immunotherapy

Article highlights

• Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 expression, making standard treatments ineffective. TNBC is challenging to manage due to chemotherapy resistance, disease relapse, and diverse molecular characteristics.

• Radiation therapy induces various DNA damage, primarily double-strand breaks (DSBs). Repair of DSBs involves homologous recombination (HR) and non-homologous end-joining pathways. TNBC is often associated with BRCA1/2 mutations, leading to genomic instability and unfavorable prognosis.

• PARP inhibitors show promise in treating TNBC with DNA repair defects. Other genes and pathways, such as RAD51D, MRE11A, and ATM/ATR signaling, contribute to TNBC development and progression.

• TNBC exhibits potential resistance to radiotherapy, linked to gene targets like EGFR, MELK, PARP, and others. Various strategies have been explored to enhance radiosensitivity, including combining radiotherapy with targeted therapies and inhibitors.

• Clinical trials explore the combination of radiotherapy with immunotherapy, chemotherapy, and targeted therapy in TNBC. Pembrolizumab and radiotherapy show promising activity in metastatic TNBC. The TONIC trial examines priming with radiotherapy before immune checkpoint blockade. Stereotactic radiotherapy (SBRT) and virus therapy followed by pembrolizumab demonstrate good tolerability.

• Future research should focus on precision medicine, immunotherapy integration, novel radiosensitizers, and biological pathway targeting. Clinical trial design and implementation should consider optimal treatment sequencing and combinations. Radiomics and artificial intelligence can aid in personalized treatment planning and monitoring.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

Funded in part by the Breast Cancer Research Foundation.