The role of radiogenomics in breast radiotherapy

Introduction

Radiotherapy is the mainstay in the treatment of a number of cancers, including breast cancer. It is typically administered as primary treatment or as a part of combination treatment. The process involves the use of ionising radiation targeted at cancer cells with the aim of killing the cells and prevent any further invasion or spread. It has been suggested that radiation therapy may be warranted in up to 50% of breast cancer patients (1), and is essential for patients who have had breast conserving surgery (BCS). The indications for radiotherapy in post-mastectomy patients include the involvement of four or more axillary lymph nodes, T4 disease, tumour size of more than 5 cm, or positive surgical margins. The traditional method of administering radiation is through external beam radiotherapy (EBRT), which irradiates the whole breast. Radiotherapy has been shown to reduce the 10-year risk of any recurrence following BCS by roughly 50% and the 15-year risk of death by 15% (2).

In recent years, the advent of accelerated partial breast irradiation (APBI) has emerged, which involves the irradiation of a specific area of the breast during BCS. The rationale behind this technique is the evidence that local recurrence of breast cancer tend to arise from the tissue around the site of the original surgery, hence irradiating the cavity after lumpectomy can reduce local recurrence and will avoid irradiation of healthy breast tissue. One of the methods of APBI is intraoperative radiotherapy (IORT) which delivers a single dose of radiation to the cavity bed after lumpectomy at the time of surgery. The American Society for Radiation Oncology (ASTRO) concluded in a Consensus Statement in 2016 that in properly selected low-risk patients, APBI provides outcomes similar to whole breast irradiation (3). The use of IORT eliminates the need for patients to continuously visit the hospital for sessions of EBRT, which is a positive factor when patients’ convenience is considered.

While most patients tolerate radiotherapy without complications, a proportion of patients undergoing radiotherapy will develop an adverse reaction. These adverse reactions are categorised into either early or late effects. Early effects are defined as adverse events that arise during or right after therapy or have not healed after 90 days following therapy. Late effects arise in a span of months to years following the cessation of therapy and are more permanent and chronic in their effect resulting in pain, poor cosmesis, or loss of organ function (4).

In the breast, the skin is most commonly affected due to the high turnover rate of the skin cells. Early effects of radiation on the breast can range from mild erythema to necrosis or ulceration, all of which are considered as acute skin toxicity, whereas late effects include telangiectasia, atrophy or subcutaneous fibrosis. Telangiectasia was seen to have a higher risk of developing when there was prior acute skin toxicity (5). An association between genetic variants and the risk of developing radiotherapy-induced acute skin adverse events have also been reported (6). In addition, there have been several risk factors that have been suggested to increase the risk of developing adverse effects related to radiotherapy post-breast surgery. Women with larger breast size are more likely to develop late effects of radiation possibly due to greater dose variation (7). Other risk factors for radiotherapy toxicity include higher body mass, more advanced disease, hormone receptor negative disease and conventionally fractionated treatment regimens (8).

Given that DNA damage caused by ionising radiation is typically repaired by the DNA repair pathway, it has been suggested that individuals with an inherited variant in the DNA repair pathway may have a reduced ability to repair damage caused by ionising radiation and therefore, may be more susceptible to adverse effects of radiation. Indeed, a number of studies have reported a candidate gene approach to examine the association between variants in known DNA repair genes, such as XRCC1 and ATM, with radiosensitivity (9,10).

Scoring systems for the adverse effects of radiation have been established, for example, the American College of Radiology developed a staging system for radiation-associated acute and late changes, known as the Radiation Therapy Oncology Group (RTOG) Morbidity Scheme, which grades adverse effects on a scale from 0 to 4 (11). The Common Toxicity Criteria (CTC) is a scoring system developed by the National Institutes of Health (NIH) to grade acute toxicity effects (12). Another scoring system that is widely used for late changes is the LENT-SOMA scale (13,14) (Table 1). The existence of these different scoring systems leads to the question of which one is better at grading toxicities of radiotherapy, particularly the late effects.

Objectives

The objective of this literature review is twofold.

Firstly, we plan to determine the strength of the association between genetic variants in DNA repair genes with adverse reactions to radiotherapy, in breast cancer patients.

Secondly, we sought to review and compare the current scoring systems of late radiation-induced changes across different types of cancers, using the RTOG Morbidity Scheme, CTC, and the LENT-SOMA scale as reference. We chose to focus on grading the late adverse effects of radiotherapy as these effects are more permanent and disabling compared to more acute adverse effects.

Methodology

A literature search on PubMed was done using a combination of the keywords: “radiation”, “radiotherapy”, “breast cancer”, “genetic”, “gene”, and “toxicity”.

A separate search on PubMed was done for comparing scoring systems, using the combination of keywords: “radiation”, “toxicity”, “scoring”, “grading”, “comparison”. The latest search was carried out on 30 October 2019.

Results were limited to English only for all searches. All types of articles were included. Titles that appeared relevant to the research topic were selected. Abstract and full text, if available, were reviewed and selected titles were narrowed down from there.

A total of 21 articles were selected for this literature review. Ten were originally found and through cross-referencing and using the ‘Similar Articles’ feature on PubMed, a further 11 articles were sourced.

Limitations

As radiotherapy side effects are a relatively rare event, most of the studies had a small sample size.

Another limitation is the genetic polymorphisms themselves. The penetrance of the genetic polymorphisms was not defined, although it is believed that the adverse response to radiotherapy can be because of multiple low-penetrance variants.

Whilst each study described the method for assessing the severity of adverse events, this was not standardised across studies, making it difficult to meta-analyse the results. The end-outcome of the studies were not uniformly defined, ranging from vague descriptions such as ‘late changes’ to specific terms such as ‘fibrosis’.

Another limitation is that the meta-analyses/systematic reviews we analysed might include overlapping studies. Some meta-analyses included other non-breast cancers. The dosage of the radiation used is not clearly stated either, which can lead to different effects.

Results

Overview of studies

A total of 17 studies on the effect of genetic polymorphism on radiotherapy toxicity were reviewed (15-31). Seven studies investigated the effect of the ATM genetic polymorphism (15-19,27,29). Eleven studies investigated the effect of the XRCC1 genetic polymorphisms (19-28,30), and 9 studies included other genetic polymorphisms. (18,19,22,24,26-28,30,31) (Table 2).

The most widely researched ATM polymorphism is the SNP rs1801516. Based on all the studies, 4 of the 7 studies on the ATM gene suggested a significant association with adverse effects (15-17,29). Two studies showed an increase risk of acute events (16,29), while another 2 studies showed a significant association with late fibrosis (15,17). One study showed a borderline association with late fibrosis (29).

For the XRCC1 polymorphs, 399Gln, 280His, and 194Trp and T-77C were the commonly analysed variants. Out of the 11 studies on the XRCC1 gene polymorphs, only 3 had a polymorphism that showed significant association with radiosensitivity (20,21,30). In one study (20), 399Gln was showed a borderline significance with overall radiotoxicity while 280His did not. In another study (21), XRCC1 T−77C mutation was shown to have a 2.86-fold increase in acute skin toxicity. Another study (30) also found that XRCC1 T-77C mutation had an increased risk of acute skin toxicity. However, the majority of studies found no significant association of XRCC1 polymorphisms with radiation toxicity.

A total of 5 studies on the scoring system for radiation toxicity were reviewed (32-36) (Table 3). Three studies compared RTOG with LENT-SOMA (34-36), 1 study compared RTOG with CTC (33), and 1 study compared all three scoring systems (34). In the comparison between RTOG and LENT-SOMA, all related articles concluded that LENT-SOMA is a better scoring system for late radiation toxicities (32,34-36). This could be due to the fact that LENT-SOMA is more comprehensive as it covers a wider range of adverse effects (34) LENT SOMA was noted to more accurately reflect the condition of the patient (36).

On the other hand, the LENT-SOMA scoring has its weaknesses as well. It was noted that the LENT-SOMA scoring is more complex and time-consuming than the RTOG scoring, therefore it would not be ideal in a situation that has time constraints (34,35).

In the single comparison between RTOG and CTC, the conclusion was that RTOG had a higher interobserver agreement, however, there was moderate correlation between the two scales in terms of consistency of findings, suggesting that there was not a tangible difference (33).

Discussion

The genetics behind radiosensitivity

After analysing the results of the reviewed articles, there appears to be some correlation between genetic polymorphisms and the presence of radiosensitivity. However, there remain inconsistent results, therefore it cannot be said for certain that there is a genetic link between the two. Several other factors can affect the development of radiation-induced tissue damage, as a study pointed out that different breast volumes affected the predisposition towards injury (7).

Due to the lack of a uniform scoring system for radiotherapy side effects, it is important to consider that the results of some studies may have been over- or under-estimated. Regarding studies that showed a reduced association of the genetic variant with radiosensitivity, they might be considered as anomalies due to the lack of reproducibility when compared to most of the similar studies that prove otherwise. However, each result cannot be discounted, as they all carry their own weight.

There has been a theory that proposes that the phenotype of increased radiosensitivity is a complicated polygenic trait, where multiple gene polymorphisms are involved in bringing out the effect (10). This has been suggested in 4 of the reviewed articles (19,23,24,26). One article showed no increased risk when computing a risk score for multiple alleles (27). The idea is that on their own, these polymorphisms offer low penetrance, but the more polymorphisms an individual has, the combined penetrance will increase the total risk of developing radiosensitivity. More research needs to be done regarding this hypothesis, as there are limited studies on this topic.

The traditional approach to identifying these gene SNPs have been candidate gene studies, where only selected genes that have been linked to radiosensitivity were researched. The flaw of this technique is that it is unlikely to find more SNPs that can be linked to radiosensitivity. A more recent method has been Genome-Wide Association Studies (GWAS), in which a wider spectrum of SNPs can be discovered (37,38). However, a large sample size, in the thousands, is required for GWAS to be considered reliable, and it may detect many false positive SNPs. It is important for replication studies to be carried out to distinguish the true positive SNPs.

So far, there is no validated genetic biomarker that can be used to predict susceptibility to radiosensitivity. All the studies done have not been conclusive enough to identify a genetic polymorphism that can be used as an indicator. The replicability of data is a major issue, as a lack of consistency in results are detrimental to the overall validity of the proposed hypothesis. Currently, there’s the ongoing REQUITE study that aims to validate genetic biomarkers that can be used in the future to predict radiosensitivity (39).

The effect of different radiotherapy techniques on adverse effects

Over the past two decades, there have been technical advances in adjuvant breast cancer radiation, with the advantage of minimising toxicity to the skin, heart and lungs. Radiation factors such as treatment volume (tangential breast fields only versus three or more fields), whole breast dose as well as the boost to the tumour bed, and dose homogeneity, can affect the cosmetic outcome (40). The shorter “hypofractionated” radiation therapy to the whole breast which takes only 4 weeks has been shown to be equivalent to the longer conventional course of radiotherapy which takes 6 weeks. The shorter course is more convenient for patients and is cheaper (41). Current interest in accelerated partial breast irradiation, where only the area around the tumour is irradiated, has led to the completion of several clinical trials, notable the TARGIT-A randomised controlled trial, which demonstrated that low risk patients with early breast cancer, a single dose of radiotherapy delivered at the time of breast conservation surgery, is equivalent to external beam radiotherapy delivered over several weeks (42). Intensity-modulated radiotherapy (IMRT) and volumetric-arc modulated radiotherapy (VMAT) are new radiation techniques that can improve radiation conformity and homogeneity.

The role of surgical factors on adverse outcomes

Besides radiation technique, surgical factors such as excision of large volumes of tissue, and post-operative wound infection can also lead to poor cosmetic outcomes. Recent advances in oncoplastic techniques in breast conserving surgery with use of local tissue flaps and movement of large volumes of breast tissue has also led to better cosmetic outcomes (43).

Scoring systems dilemma

All the studies used different scoring systems to grade late radiotherapy side effects. Besides a few studies using vague terms to describe tissue injury with no reference to any criteria, the most commonly used scoring systems were the RTOG and LENT-SOMA scale. CTC was only referenced in two studies (32,33).

The consensus is that the LENT-SOMA scale is the most accurate and reliable scoring system. However, it is specific to late toxicities. This result is no surprise, considering the history of the development of the LENT-SOMA scale in which the original creators of the RTOG scoring system helped its development with the aim of improving reporting and establishing a uniform scoring system for late toxicities (13). The scoring of early radiotherapy toxicities is beyond the scope of this review.

The use of multiple scoring systems to judge toxicity brings about an aura of uncertainty. End-outcomes for studies can be inconsistent and involve different outcomes across the board, making it difficult to make a proper judgment regarding the true effect of SNPs on radiosensitivity. This makes it harder to draw comparisons across multiple studies, especially when performing a review.

Conclusions

Radiogenomics is an upcoming field of research with much potential. The prospect of an individual’s genetic profile being linked to radiosensitivity can enable a more personalized approach to radiotherapy, with customization of dosage to minimise the risk of developing radiation-induced damage to the breast.

However, the genetic links that have been researched and reviewed in this article remain inconclusive. Although there is a general correlation seen between genetic polymorphisms and radiosensitivity post-breast surgery, the research done so far is limited and with small sample sizes. There is still no validated genetic marker that can be used to predict radiosensitivity, although there are studies ongoing. To conclusively establish a genetic component to radiosensitivity, a multi-centre prospective study should be carried out to determine the genetic polymorphisms that affect radiosensitivity. With different radiation techniques, surgical and host factors, it is difficult to determine the contribution of each factor in cosmetic outcomes.

The lack of a uniform scoring system to assess the side effects of radiation is an obstacle in the attempt to accurately determine how genetics affect radiosensitivity. While it is common for different institutions to have their own preference regarding which scoring criteria is adopted, this will make it hard for the analysis and coordination of data when their research comes together.

In conclusion, there is likely a genetic link to radiosensitivity. However, this remains inconclusive as there are no valid markers to predict radiosensitivity. As of right now, radiogenomics is an upcoming field of research. In the future, studies may be able to accurately identify specific genetic markers. Until then, radiogenomics remains an ocean of vast potential.

Acknowledgments

Funding: None.

Footnote

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aob.2019.12.01). CHY serves as an unpaid editorial board member of Annals of Breast Surgery from Oct 2019 to Sep 2021. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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