Risk of primary lung cancer after breast cancer radiotherapy: a systematic review and meta-analysis

Epidemiological studies have shown that the risk of secondary malignancies may increase by radiotherapy. Lung cancer is the most important long-term complication of breast cancer radiotherapy. Major electronic databases including Scopus, Web of Science, and MEDLINE were searched. All cohort studies that investigated the association between radiotherapy for breast cancer and risk of primary lung, bronchus, and trachea cancers conducted until March 2021 were included. The study participants were evaluated regardless of their age and ethnicity. The Newcastle–Ottawa Scale was used to assess the quality of the studies. The designated effects were risk ratio (RR). The random-effects model was used to estimate the average effects. Fifteen studies including 1,640,247 women with primary breast cancer were identified of which 937,151 had not received radiotherapy and 703,096 subjects had received radiotherapy. In general, there was no significant association between breast cancer radiotherapy and lung cancer based on 10 studies (RR = 0.95, 95% CI 0.87–1.02, P = 0.15), There was no association between breast cancer radiotherapy and lung, bronchus, and trachea cancers either based on 5 studies (RR = 0.98, 95% CI 0.93–1.02, P = 0.32). Radiotherapy for breast cancer is not associated with an excess risk of lung cancer. Due to the limited number of studies, lack of data regarding smoking status, and substantial variation in exposure of the lungs in breast cancer radiotherapy worldwide, further investigations based on randomized controlled trials are suggested to address the potential risk of lung cancer after breast cancer radiotherapy.


Introduction
Randomized clinical trial studies have shown that radiotherapy significantly reduces breast cancer recurrence. On average, it can reduce breast cancer mortality by a few percent depending on the characteristics of cancer. The benefits of radiotherapy are greater than the long-term complications for patients with breast cancer [1][2][3][4].
During radiotherapy for the breast and chest wall, the lungs are exposed to radiation, which is unavoidable. This accidental exposure may increase the risk of primary lung cancer, pneumonitis, and pulmonary fibrosis [5]. Because most women with breast cancer are treated in the early stages, survival is important [1,2]. Epidemiological studies have shown that the risks of secondary malignancies may be increased by radiotherapy or systemic therapy [6,7]. Primary lung cancer and heart disease are the most important long-term complications of breast cancer radiotherapy [8,9].
Exposure to radiation in women undergoing radiotherapy may increase the risk of primary lung cancer. A meta-analysis of 75 randomized clinical trials of breast cancer radiotherapy showed that the risk of lung cancer due to radiotherapy increased by 11% (95% confidence interval (CI) 9%, 19%) [10,11].
In this study, the absolute potential risks of primary lung cancer following radiotherapy in women with primary breast cancer were evaluated. Therefore, the study aimed to assess the benefits and harms of breast cancer radiotherapy.

Criteria for including studies
Each of the PICOS elements was defined as follows: the patients were women with primary breast cancer (P), the intervention was radiotherapy after breast cancer (I), the comparison group was patients who did not receive radiotherapy (C), and the outcome was primary lung, bronchus and trachea cancers (O), the studies included cohort studies without language restrictions (S). Risk ratio with 95% confidence interval (95% CI) extracted from the studies. The exclusion criteria included the following: (a) studies that did not have a non-exposed group, (b) studies that did not mention the size of the exposed and non-exposed groups, (c) studies with sample size less than 50, (d) review articles, letters, and case reports.

Search methods
The following terms were searched: (lung malignancy or lung tumor or lung cancer or lung neoplasms) and (breast neoplasms or breast cancer) and (radiation therapy or radiation or radiotherapy) and (second primary). The main databases including MEDLINE, Web of Science, and Scopus were searched until March 2021.

Data extraction
Two authors (BZ and MAR) extracted the data independently. The data file contains the following variables: first author, year of publication, country, outcome (lung, bronchus, and trachea cancers), effect size with its 95% CI, sample size, language, study design, age, and follow-up time.

The methodological quality
The methodological quality assessment of the studies was based on the Newcastle-Ottawa Scale (NOS) [12]. The quality of included studies was considered based on the following classification: low quality: 0 to 6 scores, high quality: 7 to 9 scores [13].

Statistical analyses
Association between breast cancer radiotherapy and risk of lung, bronchus, and trachea cancers was estimated by risk ratio (RR) and 95% confidence interval. The significant level was less than 0.05. The heterogeneity of included studies was measured using the chi-square test and the I 2 statistic. We performed analyses using review manager (version 5.4.1) and Stata software (version 16.0). A random randomeffects model was used to estimate the average effects. Publication bias analysis was evaluated with Begg's and Egger's tests and the Trim and Fill method [14]. This method, which is a rank-based data augmentation technique, formalizes the usage of funnel plots, estimates the potential number and outcomes of missing studies, and adjusts the meta-analysis to include the theoretical missing studies.

Studies characteristics
This meta-analysis consisted of 15 articles; six of them were done in America, five in Europe, and four in Asia. Articles are from 1987 to 2018. In this study, two comparisons were made; in the first comparison, the risk of lung cancer after breast cancer radiotherapy compared with those who did not receive radiotherapy and in the second comparison, the risk of lung, bronchus, and trachea cancers after breast cancer radiotherapy compared with those who did not receive radiotherapy. The comparisons were reported in 10 and 5 studies, respectively. In general, 1,640,247 women with primary breast cancer were enrolled in the studies, of which 937,151 had not received radiotherapy and the remaining 703,096 had received radiotherapy ( Table 1).

The methodological quality
NOS checklist was used for the evaluation of the quality of included studies. All articles were prospective or retrospective cohorts whose data was linked to the surveillance, epidemiology, and results (SEER) cohort. The NOS score for each article was 7-9. Therefore, in general, the quality of articles in this meta-analysis was high.

Sensitivity analysis
There was high heterogeneity across studies investigating the relationship between lung, bronchus, and trachea cancers and breast cancer radiotherapy (I 2 = 87%). Grantzau's study [18] was the source of the heterogeneity. After excluding this study, the heterogeneity reached 48% (Table 2). In lung cancer meta-analysis results, heterogeneity reached 46% after the removal of Huang's article [19].

Publication bias
There was no evidence of publication bias based on the results of the Begg test (P = 0.767). However, there was some evidence of publication bias based on the Egger test (P = 0.038). Based on the Trim and Fill method, the incorrect risk ratio was 0.99 (95% CI 0.83-1.18) and after adding two miss studies, the risk rate was equal to 0.93 (95% CI 0.63-1.37) (Fig. 4).

Discussion
The results of this study showed that there is no significant relationship between the risk of lung cancer as well as lung, bronchus, and trachea cancers and breast cancer radiotherapy.
The answer to the question of whether radiotherapy after breast cancer may increase the risk of lung cancer should be considered in two aspects. In the first step, the fundamental question is to what extent breast cancer alone can increase the risk of primary lung cancer? Therefore, it is necessary to determine the role of common risk factors in lung cancer and breast cancer, regardless of the status of radiotherapy. Then, in the second aspect, we should measure the potential effect of breast cancer radiotherapy on the incidence of lung cancer using the crude and adjusted risk ratio. The first step was not fully investigated by the studies included in this meta-analysis. However, based on evidence from the literature review, patients with prior colorectal, pancreatic, renal, and breast cancer are at significantly higher rates of non-small cell lung cancer specifically adenocarcinoma [30]. Although the reasons are unclear, several factors seem to be effective, such as biology and patient risk factors, including smoking history and hormone replacement therapy during the postmenopausal period [31]. The overall standardized incidence rate of lung cancer after breast cancer is reported to be 4.88 (95% CI 4.70, 5.07) [30].
In general, several risk and protective factors interact with one another to play a role in the occurrence of any disease [32]. Therefore, we examined the known risk factors for lung cancer that interact with radiotherapy. Even this interaction can occur with systemic therapy for breast cancer. One of these risk factors is smoking. Smoking increases the risk of lung cancer by up to 11 times in the general population. The risks of lung cancer after breast cancer radiotherapy are significant for smokers [11]. Smoking cessation has had a significant effect even during radiation therapy [33,34]. According to Taylor et al., in a systematic literature review of lung and heart doses in breast cancer regimens, women who received overvoltage in previous years were at greater risk than other women (RR = 1.57; 95% CI 1.24, 1.99). In this article, the risk of modern radiotherapy for incidence lung cancer after radiotherapy in patients with breast cancer for long-term continuing in smokers and nonsmokers is estimated at 4% and 0.3%, respectively [11]. A meta-analysis conducted by Grantzau et al. included 11 studies involving 113,516 women exposed to radiotherapy and 203,957 women without exposure. They showed no significant increased risk of lung cancer among women who did not receive radiotherapy. Conversely, the risk was higher in women who received radiotherapy [35]. The standardized incidence rate of lung cancer after 5 year exposure was 1.25 (95% CI 1.05, 1.40) after 10 years was 1.58 (95% CI 1.21, 2.05) and after 15 years was 1.91 (95% CI 1.11, 3.29) [35]. The Materials and methods of this study were different from our Materials and methods in many aspects including effect size, study duration, inclusion criteria.
One of the studies that were omitted in the sensitivity analysis is the study by Huang et al. [19]. Cox regression results show that the adjusted hazard ratio was 10.078 times higher in the radiation therapy group than the nonradiation therapy group. The frequency distribution of patients' stages in this study is not known. One specific characteristic of this study was using relatively aggressive computed tomography of the thorax, which is not routinely The results of a meta-analysis conducted by Aznar and et al. showed that lung exposure to breast cancer radiotherapy is very different in different countries and among various regimens. The extent of the irradiated region, using breathing adaptation, and using prone or lateral decubitus patient positioning or proton therapy can be the main determinants of the amount of exposure [28].
The main limitation of the study was the lack of access to predisposing factors such as smoking status of the patients, lack of evidence to adjust for the common risk factors of primary lung and breast cancers, lack of information about the dose of radiotherapy, and lack of information for classification of patients based on their follow-up years, irradiation site, method, and treatment location. Due to these limitations and potential biases, further investigation based on randomized controlled trials is suggested to better understand the effect of breast cancer radiography on the incidence rate of lung cancer.
Besides these limitations, this meta-analysis had several advantages over the previous similar meta-analysis conducted by Grantzau et al. in 2013 [18]. In the current metaanalysis, we updated the previous meta-analysis by adding new evidence to the analysis. We reported a risk ratio, which is clinically more practical, rather than a standardized incidence rate. We also excluded studies without a control group to improve the validity of the results. However, the main advantage of the current meta-analysis over the previous one was that we examined not only the relationship between primary lung cancer and breast cancer radiotherapy but also the relationship between tracheal and bronchial tumors.

Conclusion
Based on the current evidence, radiotherapy for breast cancer is not associated with an excess risk of lung cancer. Because of the small number of studies, lack of data on smoking status, and significant variance in lung exposure in breast cancer radiation throughout the world, further research is needed to address the possible risk of lung cancer following breast cancer radiotherapy.
Funding This work was supported by the Vice-Chancellor of Research and Technology, Hamadan University of Medical Sciences. The supporter had no role in study design, data collection, analysis, interpretation, or writing of the report.