We found that patients who took ARBs in conjunction with SBRT for early stage NSCLC exhibited a doubling in OS and RFS compared to patients who did not take ARBs. No patients on ARBs during treatment developed local or distant recurrence during the follow up period of this study, suggesting that ARB use may improve systemic tumor control. Notably, these effects were not seen with the other antihypertensive or lipid-lowering agents. This work builds on previous findings which show improved survival in late stage NSCLC patients taking ACEi or ARBs while undergoing platinum based chemotherapy.15
A 2019 retrospective study found that patients who had undergone SBRT for early stage NSCLC were at increased risk for major cardiac events, including cardiac death, unstable angina, and myocardial infarction21. This work concluded that cardiac radiation dose is an independent predictor of cardiac events, building on an existing body of literature establishing cardiac events as a major cause of death in lung cancer patients21,22,23. ACEIs , ARBs and statins are all classes of drugs which reduce mortality from cardiovascular causes, yet only ARB use is associated with improved OS and RFS13. There was no difference in age or comorbidities, assessed by Charlson Comorbidity Index, among groups, indicating that the competing risks of death were similar between the ARB and no ARB groups. Furthermore, no local or distant recurrences were observed in patients taking ARBs. The few regional recurrences recorded in the ARB group likely represent untreated occult micrometastatic nodal disease, as SBRT does not include regional fields and no patients received systemic therapy. Together, this suggests that the reduced mortality in this patient population is most likely due to a cancer-specific treatment effect of ARBs and not a reduction in competing causes of death.
The main pro-tumorigenic effects of angiotensin II, including angiogenesis, vascular remodeling, proliferation and inflammation, are mediated through the type 1 angiotensin receptor (AT1R)24. Binding of angiotensin II to AT1R results in increased transcription of TGFB1 mRNA and TGF-β cleavage from binding proteins in the extracellular matrix24–26. Therefore, blockade of angiotensin II signaling through AT1R would be expected to decrease TGF-β levels, leading to increased radiosensitivity and decreased metastatic potential. To this end, there are 17 open studies in the United States listed on clinicaltrials.gov utilizing TGF-β blockade and other therapies to treat NSCLC as of the writing of this manuscript. Although we did not have banked specimens to measure TGF-β in our patient population, our data provide preliminary real world support for the combinatorial use of these agents in prospective early stage NSCLC studies. As previous research in this area has focused on patients undergoing palliative platinum based chemotherapy in late stage NSCLC, this work suggests a novel intervention to target a patient population undergoing SBRT at a much earlier disease stage.15 Both platinum based chemotherapy and radiation rely on DNA damage to exert anti-tumor effect, suggesting a possible shared mechanism between the improved survival with ARBs in this report and Wilop and colleagues’ retrospective study.15
The specificity of the improved outcomes to ARBs suggests that differences in the mechanisms of action between ARBs and ACEIs could provide insight into the mediators of this effect. Both ACEIs and ARBs derive their antihypertensive effects by decreasing the vasoconstrictive activity of angiotensin II, which is mediated by AT1R. Whereas ARBs function as specific inhibitors of the AT1R, ACEIs block the conversion of angiotensin I to angiotensin II, thereby preventing signaling through both the AT1R and type 2 angiotensin receptor (AT2R). Although less is known about the downstream effects of AT2R, activiation of this receptor is thought to counterbalance the effects of AT1R, with ligand binding inducing an anti-inflammatory, anti-fibrotic, anti-proliferative response27. In preclinical lung cancer models, agonists at AT2R or nanoparticle-based AT2R gene therapy attenuated tumor growth27,28. We therefore speculate that unopposed signaling through the AT2R in the context of ARB treatment provides a second potential mechanistic explanation for the improved outcomes associated with ARBs, but not ACEIs. ACEIs were also associated with a survival improvement in patients with advanced NSCLC treated with platinum chemotherapy, leaving open the possibility of either unique mechanisms of action or a cohort-specific phenomenon.15
Several limitations of this work warrant discussion. First, the retrospective design of the study introduces the possibility of unmeasured confounding variables that could contribute to these effects. Indeed, the very same unmeasured factors that led some patients to be prescribed ARBs rather than ACEIs could account for the discrepancy in outcomes. The relatively small sample size, particularly of patients taking ARBs, limit both the reliability and generalizability of our findings. We did not have access to stored samples from our patient population, so neither an association with TGF-β levels nor other biological correlates for these responses could be assessed. Toxicity data were captured from explicit mention radiation oncology visit documentation and radiology reports. Because our institution does not use structured capture of toxicity data, and toxicity documentation is physician-specific, our review likely did not capture all of the grade 1-2 treatment toxicity. Toxicity data were only reviewed up to six months after treatment, so toxicity development outside of that window were not reflected in this paper.