Abstract: Radiotherapy can increase the cell cycle arrest that promotes apoptosis, reduces the risk of tumor recurrence and has become an irreplaceable component of systematic treatment for patients with breast cancer. Substantial advances in precise radiotherapy unequivocally indicate that the benefits of radiotherapy vary depending on intrinsic subtypes of the disease; luminal A breast cancer has the highest benefit whereas human epidermal growth factor receptor 2 (HER2)-positive and triple negative breast cancer (TNBC) are affected to a lesser extent irrespective of the selection of radiotherapy strategies, such as conventional whole-breast irradiation (CWBI), accelerated partial-breast irradiation (APBI), and hypofractionated whole-breast irradiation (HWBI). The benefit disparity correlates with the differential invasiveness, malignance, and radiosensitivity of the subtypes. A combination of a number of molecular mechanisms leads to the strong radioresistant profile of HER2-positive breast cancer, and sensitization to irradiation can be induced by multiple drugs or compounds in luminal disease and TNBC. In this review, we aimed to summarize the prognostic differences between various subtypes of breast tumors after CWBI, APBI, and HWBI, the potential reasons for drug-enhanced radiosensitivity in luminal breast tumors and TNBC, and the robust radioresistance of HER2-positive cancer.


Keywords: radiotherapy, molecular subtype, breast cancer, molecular mechanism, radiosensitivity


INTRODUCTION

Adjuvant radiotherapy is one of the essential components in the treatment of breast cancer and has been recommended in combination with breast-conservation surgery (BCS) for early-stage breast cancer (ESBC) patients and with mastectomy for high-risk patients.1 Compared with total mastectomy and lumpectomy alone, 50 Gy breast irradiation following lumpectomy dramatically lowers the rate of local recurrence (LR) by 7.5% and 6.1%, respectively.2 Moreover, the distant metastasis (DM) rate is decreased in mammary cancer population with radiosensitive characteristics after receiving radiotherapy.3,4 Reduction in overall mortality in breast cancer produced by radiotherapy is essentially identical to systemic chemotherapy.5,6

Multiple radiotherapy strategies are used to treat women at different tumor stages. For the majority of ESBC patients who are qualified for organ preservation, preoperative radiotherapy is a widely adopted standard intervention, whereas postmastectomy radiotherapy is suitable for patients with advanced breast cancer. Nevertheless, not all patients undergoing radiotherapy benefit from it; a large cohort of the patients inevitably suffer radiation-related adverse effects, including fatigue, telangiectasia, angiosarcoma, skin erythema, and cosmetic damage.7–9

Historically, the implementation of radiotherapy for breast cancer is mainly determined by the following patient-related factors: age, comorbidity, tumor stage, lymphatic vessel invasion, etc. The progress in biological methods in the past two decades has elucidated the heterogeneity of diverse molecular subtypes used to design individualized treatment. According to the expression levels of Ki-67 protein and the status of estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2), breast cancer can be categorized into four subtypes: luminal A, luminal B, HER2-overexpression, and triple negative breast cancer (TNBC),10 which are outlined in Table 1.

Several studies investigated whether the intrinsic molecular subtype of breast cancer can influence the outcome of radiotherapy11–13 due to differential prognosis and feedback between chemotherapy and endocrinotherapy.14–20 The EORTC 22881-10882 boost vs no boost trial prescribed or did not prescribe a boost radiation dose of 16 Gy to patients with stage Ⅰ and stage Ⅱ breast cancer who underwent BCS plus conventional whole-breast irradiation (CWBI) of 50 Gy and found that certain phenotypes of tumors are radioresistant and rarely benefit from extra irradiation dose21 suggesting the existence of the dose-benefit gradient of radiotherapy in breast cancer. Therefore, a number of radiotherapy paradigms with low toxicity have been advocated in clinical studies, such as accelerated partial-breast irradiation (APBI) and hypofractionated whole-breast irradiation (HWBI); however, the clinical utility of these methods across four phenotypes of the disease using the same treatment modality is significantly different, which is attributed to inherent radiosensitive or radioresistant properties of the phenotypes to an extent.

The objective of this review was to summarize the prognostic distinctions of various subtypes of breast tumors treated with different radiotherapy methods and to explain the intrinsic reasons for differential radiosensitivity of the subtypes. The molecular mechanisms of cell death induced by ionizing radiation in the tumor and in surrounding normal stem cells are also discussed.

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