To the best of our knowledge, this was the first study to investigate the potential clinical benefit of ARBs in patients with OSCC receiving surgery. In this 10-year retrospective cohort study, patients who received ARBs for at least 180 days had improved OS and DSS, compared to patients who did not receive ARBs. In addition, patients with locally advanced OSCC experienced the greatest benefit from ARBs.
The RAS consists of several enzymatic and non-enzymatic protein components and is essential for maintenance of vascular homeostasis. Angiotensinogen is produced in the liver and cleaved by the aspartyl protease renin to angiotensin I. Angiotensin I is subsequently cleaved by the angiotensin I-converting enzyme to produce angiotensin II (Ang II). Ang II is a key component of the RAS, which exerts its actions by binding to two G protein-coupled receptors: angiotensin receptor 1 (AT1R) and the lesser known angiotensin receptor 2 14. It is increasingly evident that, in addition to systemic effects on blood pressure and fluid homeostasis, AT1R and Ang II have important roles at the local tissue level. AT1R overexpression has been reported in numerous cancers, including ovarian, breast, and bladder cancer 15,16. Consistent with these findings, ARBs and ACEIs have been reported to reduce tumor growth and vascularization in a wide range of cancers, suggesting a role for Ang II in cancer development and progression 4.
Several clinical studies have suggested a role for the RAS in terms of the effectiveness of anti-cancer therapies 17–19; however, the clinical utilities of ARBs alone have not been reported. Although a nationwide population-based study showed that long-term ARB use was associated with a lower incidence of cancer 9, a meta-analysis of randomized controlled trials found that ARBs were associated with a modest increase in cancer risk 10. The ARB Trialists Collaboration study and a recent meta-analysis concluded that ARB use had no effect on cancer incidence 20,21. Briefly, the varying extent of concurrent ACEI use among the studies may explain the discrepancies. We evaluated patients who had received ARBs only (Table S3).
Head and neck cancer is the sixth most common cancer worldwide 22. The critical role of RAS in head and neck cancer has been shown in various tissues, including the oral mucosa 23. Additionally, the ACEI perindopril has been shown to reduce the growth of head and neck squamous cell carcinoma (HNSCC) in vivo 24, suggesting a role for Ang II in HNSCC. Ang II also has been found to promote HNSCC cell migration and invasion 25. The effects of Ang II on autocrine and paracrine signaling pathways are mediated by AT1R, suggesting that ARBs might provide a clinical benefit in patients with HNSCC. However, no large study has yet shown that ARBs improve the clinical outcomes of patients with head-and-neck cancer.
We found that ARB use for at least 180 days improved the 10-year OS and DSS rates of patients with OSCC (Figs. 2 and 3); the effects were most pronounced for patients with late-stage resectable OSCC (Tables 3 and 4). This was also true of subgroups of patients defined via TN staging; ARB use was associated with increased survival of patients with advanced T (T3 and 4) category (Table S2). As T refers to local tumor containment, the data suggest that ARBs are beneficial for patients with locally advanced OSCC. It remains unclear how ARBs affect OSCC progression and improve survival rates. An prior in vitro study might explain this effect: co-injection of cancer cells with stromal cells increased tumor size and fibrosis; ARB treatment attenuated these effects 26.
Our study had a few limitations. First, medical records were incomplete for some patients. Therefore, some critical clinicopathological characteristics (e.g., surgical margin, extranodal extension, and depth of tumor invasion) could not be analyzed in our study. However, the large cohort size supported the validity of conclusions drawn for the assessed clinicopathological characteristics. Second, although our study included only data from patients treated with ARBs, a considerable proportion of the patients were receiving concurrent treatment with other agents to control hypertension, which might have influenced our findings. Several patients received amlodipine and hydrochlorothiazide (Table S3); however, there is no evidence that these agents suppress cancer development or progression 27 28. Therefore, we presume that treatment with these agents had a minimal influence on our findings. Third, various ARBs were included; therefore, the standardized effective dosage was difficult to calculate and the dose effect could not be measured. On the other hand, the use of propensity score matching (PSM) and the large database were highlights of our study. PSM attempts to reduce the bias due to confounding variables that can arise if the effects of treatment are assessed simply by comparing outcomes between patients that received the treatment versus those that did not. We created a 1:4 propensity-score-matched study group to minimize any confounding effect of non-randomized allocation when comparing the groups.