An expanded role for radiation therapy in the management of breast cancer has come at the cost of radiation-induced coronary artery disease (RICAD). Compared to non-irradiated patients, patients who underwent chest wall-radiotherapy for breast cancer have a higher absolute risk of cardiac morbidity and death, with the increase in risk being proportional to the radiation dose [1]. Ionizing-radiation induces reactive oxygen species resulting in accelerated atherosclerosis by endothelial damage and the impaired ability to clear free radicals [2], which leads to a chronic inflammatory state [3]. Atherosclerotic lesions in RICAD are more proximal than those in non-irradiated vessels and the plaques are largely composed of fibrous tissue [4]. In left-sided breast cancer, the anterior and apical wall of the heart, and the internal mammary arteries (IMA) can be in the radiation field.

The frequency of IMA graft failure after coronary artery bypass grafting (CABG) is common (8.6%) [5], and the question of whether chest wall irradiation for the treatment of breast cancer leads to IMA damage remains unclear. Despite limited evidence, careful angiographic or radiographic evaluation and inspection of the IMA’s before grafting has been recommended [6, 7, 8]. However, there is a paucity of data demonstrating radiographically that the IMA can be affected by radiation, or if it is inherently protected against atherosclerosis.

The present study aims to assess the utility of radiographic assessment of the IMA’s and its branches by CT scan and mammography.

Ischemic heart disease rates increase with exposure to radiation therapy among breast cancer patients [1, 11, 12]. The effect of radiation on IMA remains uncertain given insufficient radiographic data demonstrating vascular damage. Several studies showed concerns that radiation might increase IMA fragility, leading to early graft failure [6, 8, 13, 14]. On the other hand, IMA’s have been historically recognized to have inherent protection against atherosclerosis compared to other arteries [15, 16, 17]. Using histologic analysis, recent studies reported no restrictions in the use of irradiated IMA’s as grafts [18, 19]. Other studies also used histomorphologic [19], and echocardiographic doppler investigations [20] to demonstrate that the IMA’s are protected from radiation-induced damage [19]. Yet, a SCAI Expert Consensus Statement recommended using CCTA as an assessment tool for IMA’s which could be affected by radiation therapy rendering it unfeasible as a graft [7].

This study showed that none of the patients with CT scans had new IMA calcifications, stenosis, or atresia at least 5 years after initial radiation therapy. The patient cohort represents a relatively intermediate-high risk cohort based on high rates of cardiac risk factors such as advanced age, hypertension, diabetes, dyslipidemia, and smoking history, despite them being of the female gender. As expected, based on this risk factor profile, CAC was seen in 42.4% of the patients. Yet, only 22% of the patients with coronary calcifications post-radiation were considered new calcifications. Given the small number of patients with pre-radiation CT scans, definitive conclusions as to the effect of radiation-induced atherosclerosis of the native coronary arteries in this cohort cannot be made. Nonetheless, the percentage of patients in this cohort with coronary calcification post-radiation is higher than what has been seen in prior studies with similar patient risk-profile [21]. The finding of new CAC on post-radiation CT scan compared to pre-radiation imaging was not observed in the small sub-set of patients without dyslipidemia, highlighting the influence of atherosclerotic risk factors, independent of radiotherapy on the study results. There was no statistically significant association found between CAC and breast calcifications found on mammograms. Finally, chest wall-irradiation was not associated with the development of vascular calcifications of the IMA branches when evaluated by mammography.

Study shortcomings such as inadequate radiation dose to cause IMA injury, insufficient follow-up duration, or less significant atherosclerotic risk profile of the patient cohort were considered as possible reasons for the absence of IMA damage. A cumulative dose of radiation $>$3000 cGy has been considered as the dose associated with a high risk for radiation-induced heart disease [22, 23]. The mode value of the administered radiation dose in this study was 5040 cGy, and is higher compared to that reported in studies by Renner et al. [24] (3600 cGy), and Brown et al. [8] (3000–6000 cGy) which inferred that IMA’s are susceptible to radiation-induced damage. In the studies reported by Gansera et al. [19] and Handa et al. [25] which concluded that there are no restrictions to the use of IMA conduits post-radiotherapy, the total dose reported was similar to the dose in the present study, i.e., 5000–6000 cGy. The mean duration from initial radiation exposure to IMA evaluation in this study was 10.5 years which is similar to that reported by Renner et al. [24] (11 years). The mean duration to the development of RICAD was reported as 9 years [26]. The prevalence of atherosclerotic risk factors in this study is comparable to that reported in a cohort of 25 patients by Brown et al. [8], which concluded that IMA graft patency in patients who received prior radiation therapy is less than expected for an arterial graft, and comparable to venous grafts. Compared to the patients in their study, the patient population in our study had a higher mean age in years (60 vs 56), a higher prevalence of hypertension (63% vs 52%), and diabetes mellitus (26% vs 16%). From this data, it can be inferred that the patients in this study were exposed to a high enough dose of radiation, had an adequate long-term follow-up, and found to have a significant risk factor profile to observe IMA damage from radiation if it were to occur.

Several reasons may explain why none of the IMA’s showed atherosclerotic disease on CT scan, (a) CT scans are insensitive to detecting radiation-induced IMA damage as an imaging modality, (b) IMA’s are inherently protected against radiation-induced atherosclerosis, (c) Standard chest wall radiation does not result in sufficient IMA dose to produce detectable injury, (d) Longer follow up duration may be required. Although the diameter of the IMA’s is smaller than that of the coronary arteries [27], multidetector CT angiograms have been studied to be adequate for the anatomical evaluation of the IMA’s [27, 28]. The latest published SCCT Appropriate Use Criteria [29] recommends cardiac CT to localize bypass grafts and other retrosternal anatomy before re-operative cardiothoracic surgery, and with the evolution of improved scanner technology, CT scan as a means to noninvasively assess the IMA’s is being pursued [30]. However, there remains a paucity of data in the published literature regarding the utility of CT scan to evaluate for IMA calcification and stenosis.

There is conflicting data in the current literature as to whether the IMA’s are inherently protected from the effects of radiation therapy [6, 13, 14, 19, 20, 24]. Histomorphological analysis performed by Gansera et al. [19] studied 133 irradiated IMA’s and compared them with a control group of 133 non-irradiated IMA’s. Histomorphologic investigations did not identify severe fibrosis or radiation-induced damage of the IMA grafts. Nasso et al. [20] compared two groups of patients undergoing elective CABG with the use of IMA. There was no significant difference in intraoperative IMA flow when assessed by transthoracic echocardiography doppler between irradiated and non-irradiated individuals. Similarly, a retrospective clinical review by Handa et al. [25] of 47 patients undergoing CABG after mediastinal radiation therapy observed good early post-operative results without IMA graft failure. On the other hand, some studies suggest a higher risk of IMA graft failure after CABG in patients with prior radiation therapy [6, 8, 13]. The failure of IMA as a graft may be related to increased vessel friability and/or extensive mediastinal fibrosis resulting in intraoperative injury rather than radiation induced atherosclerosis [14, 18, 24]. This could explain the poor outcomes after CABG despite the absence of stenosis/calcification in IMA’s.

The prevalence of calcifications identified on mammograms in the present patient population was 16%. This is similar to the data published by Gunhan-Bilgen et al. [31], who observed a similar prevalence of breast calcification in post-radiation surveillance mammograms in breast cancer survivors. The prevalence of breast arterial calcification by mammogram in the general population ranges from 9 % to 17 % in women aged between 50–65 years and has been noted to be as high as up to 50% in older women [9]. As expected, the prevalence of calcifications on mammogram in the sub-set of patients without dyslipidemia is lower at 10% in comparison to the 16% observed in the entire cohort.

The clinical significance of calcifications seen on mammograms remains unclear. A statistically significant association between CAC and breast calcification was not observed. This is probably due to the small number of patients with CAC in our study. Breast artery calcification is known to be associated with the presence and even severity of CAC [32, 33, 34], but its diagnostic accuracy in predicting obstructive coronary artery disease is poor [33].

The precise anatomical site of breast calcification observed on mammograms can be difficult to localize. The compression of the breast tissue during the study itself can make it difficult to discern between the branches of IMA and other vasculature such as branches of the lateral mammary artery. There is also the possibility of macroscopic dystrophic/extravascular calcium deposition in the breast tissue which is not uncommon on screening mammograms [35]. Despite the calcifications seen on mammograms, no calcification of the IMA’s was observed on the CT scans. The IMA branches may have different histological features compared to the IMA’s, making them more susceptible to radiation-induced endothelial damage. In contrast to the IMA branches which run a more superficial course making them vulnerable to radiation, the IMA’s run a relatively posterior course, perhaps shielded by the intercostal muscles and fascia.

This study provides a novel outlook in evaluating the radiographic assessment of IMA’s with CT scans and mammograms in breast cancer patients exposed to chest wall-radiation. To our knowledge, this is the first study to date to examine the utility of CT scans and mammograms in detecting IMA damage post-radiation therapy. Our study has some limitations. While this is a retrospective study conducted at a single center with small sample size, the strength of this analysis stems from the prospective, blinded examination of CT scans and mammograms by two independent radiologists. Our study included breast cancer patients only; this cohort was selected intentionally so that the effects of standardized radiation protocols could be compared. These findings, therefore, may not apply to other malignancies such as Hodgkin’s Lymphoma that require a different dose and technique of radiation. The negative controls used were not healthy controls but rather the contralateral, non-irradiated sides. Although, this allows for equal baseline characteristics between the negative control and study sample, the absence of difference in calcifications between irradiated and non-irradiated sides in mammogram could have been potentially due to radiation scatter to the non-irradiated side. Our study however is hypothesis-generating and future prospective studies with standardized imaging protocols (both chest CT and mammograms) should be entertained.

Concept and Design—WM, VN, SB, DG, AV; Research and Data Analysis—VN, WM, MA, MK, DBW, SB, AP, DG, DJH, AV; Manuscript PreAPration/Edit—VN, WM, MA, MK, DBW, SB, AP, DG, DJH, AV; Critical Revision Manuscript—VN, WM, SB, DJH, AV.

Our study received the proper ethical oversight through our institutional IRB (SFH-18-110).

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.