Introduction
Radiotherapy (RT) is a main component of breast cancer (BC). Acute radiation-induced toxicities (RITs) are usually reported during treatment and mainly resolve 2-3 months after the last RT fraction. In some patients late RITs may continue to impact adversely quality of life (QoL). The parameters that influence rate and severity of these toxicities may be related to RT technique parameters in addition to patient-related characteristics (e.g., age, comorbid conditions) or associated drugs or underlying genetic susceptibility or in particular situations of autoimmune connective tissue disease (CTD). All these issues will be discussed.
Breast radiotherapy and autoimmune disease
Autoimmune CTD has been considered as a relative contraindication to breast conservation and radiation for patients with early-stage BC. Controversies exists however regarding RT indications and its fractionated among patients with CTDs. Early case reports and small case series from the 1960s to the 1980s reported severe RITs among patients with specific diagnoses of SLE, scleroderma, and Sjogren’s syndrome. While these anecdotal reports have highly influenced clinical practice in the past more modern matched-pair analyses evaluating RT effects in patients with CTDs have demonstrated no worse acute toxicity compared with controls; findings with regard to late toxicity have been conflicting. For rheumatoid arthritis (RA), old series demonstrated that among patients with RA, there was actually a much lower rate of late effects and similarly did not find an increase in the rate of acute or late toxicity in the patients with CTD.
Several mechanisms have been suggested to explain RT effect in these populations. It is thought that among these patients, RT may both trigger and augment pathways of immune dysregulation that already exist in CTD patients, ultimately leading to increased damage to tissue and vasculature that exceeds what might be expected from RT alone. A background of overexpressed profibrotic factors, such as transforming growth factor beta and interleukin 1, may also lead to more RITs in patients with active CTD. In addition, comedication with steroids for immunomodulation may enhance the propensity for RT toxicity, possibly through independently mediated glucocorticoid effects on skin healing (ie, reduced proliferation of fibroblasts).
Breast radiotherapy and genetic disorders
Some reports showed radiation hypersensitivity in individuals with genetic disorders, such as ataxia-telangiectasia (AT), Nijmegen breakage syndrome, Fanconi anaemia and DNA ligase IV deficiency. Indeed, deficient DNA double-strand break recognition or repair responsible for genome stability and cell survival, have been proposed as an important underlying etiology of RITs. Accordingly, rare biallelic germline variants in double-strand break repair genes have been linked to radiosensitivity in these recessive genetic disorders. However, in practice the overall risk of complications after breast RT in patients with ATM variants for example does not appear to be higher relative to the risk in patients who do not possess ATM variants. Although increased toxicities have been reported in breast cancer patients with the c5557G>A variant (rs1801516), this risk is not sufficient enough to suggest a change in local management for these patients.
Another concern is RT in of hereditary BC. The data strongly suggest that radiation should not be withheld from germline BRCA1/2 carriers because of toxicity concerns for those who have indications for treatment. Randomized comparisons do not exist for women with germline mutations and are not likely to be conducted given the personal nature of the surgical decision-making process. Acknowledging the limitations of the available data, studies do not suggest increased rates of toxicity in germline BRCA1/2 carriers treated with RT compared with women with sporadic disease. Thus, RT should not be withheld when indicated for optimal cancer management. Further, there are limited data regarding the management of BC in patients with other genetic syndromes or with polymorphisms and other genetic variants. Although BRCA1 and BRCA2 account for the majority of known hereditary breast cancer patients, there are several other genetic conditions that are associated with an increased BC risk. Because many of the genes are involved in both increased BC risk and potentially DNA repair and radiation response, there are potential concerns regarding RT. After the initial association studies of single gene mutations in radiosensitive cancer patients, the last decade saw numerous publications exploring the association of normal tissue radiosensitivity and alleles of single nucleotide polymorphisms (SNP). Two systematic reviews published have summarized the findings of almost 60 studies conducted across a range of candidate genes involved in DNA damage response, oxidative stress response or radiation fibrogenesis many of them reporting statistically significant associations with a variety of clinical end points. Studies into the most frequently investigated candidate genes within each pathway are XRCC1, ATM, Oxidative response genes, TGF beta.