Increased tumor response to neoadjuvant therapy among rectal cancer patients taking angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers

Abstract

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensive medications that have been reported to affect aberrant angiogenesis and the dysregulated inflammatory response. Because of such mechanisms, it was hypothesized that these medications might affect the tumor response to neoadjuvant radiation in patients with rectal cancer. METHODS: One hundred fifteen patients who were treated with neoadjuvant radiation at the University of Wisconsin (UW) between 1999 and 2012 were identified. Univariate analyses were performed with anonymized patient data. In a second independent data set, 186 patients with rectal cancer who were treated with neoadjuvant radiation at the Queen's Medical Center of the University of Hawaii (UH) between 1995 and 2010 were identified. These data were independently analyzed as before. Multivariate analyses were performed with aggregate data. RESULTS: Among patients taking ACEIs/ARBs in the UW data set, a significant 3-fold increase in the rate of pathologic complete response (pCR) to neoadjuvant therapy (52% vs 17%, P 5 .001) was observed. This finding was confirmed in the UH data set, in which a significant 2-fold-increased pCR rate (24% vs 12%, P 5 .03) was observed. Identified patient and treatment characteristics were otherwise balanced between patients taking and not taking ACEIs/ ARBs. No significant effect was observed on pCR rates with other medications, including statins, metformin, and aspirin. Multivariate analyses of aggregate data identified ACEI/ARB use as a strong predictor of pCR (odds ratio, 4.02; 95% confidence interval, 2.06-7.82; P < .001). CONCLUSIONS: The incidental use of ACEIs/ARBs among patients with rectal cancer is associated with a significantly increased rate of pCR after neoadjuvant treatment. Cancer 2016;122:2487-95.

Targeting the renin-angiotensin system to improve cancer treatment: Implications for immunotherapy

“…As discussed earlier, RASi may enhance the efficacy of VEGF-targeted therapies and thereby improve clinical outcome. However, in HCC ( 125 , 126 , 159 , 164 ) and some CRC ( 167 ) and RCC ( 144 ) studies listed in tables S2 and S3, most of the patients were not treated with anti-VEGF treatment, suggesting that anti-VEGF–responsive tumors generally seem to be more sensitive to RASi.…”

“…In some tumor types, the effect of RASi was investigated primarily in either early tumors (such as resected urinary tract cancer) ( 130 , 147 , 150 , 151 ) or advanced stages (such as metastatic NSCLC) ( 142 , 149 ). In RCC and CRC, positive outcomes were reported for both early ( 144 , 167 ) and metastatic diseases ( 137 – 140 , 172 ). Notably, in PDAC, a survival benefit in RASi users was only shown for locally advanced/metastatic diseases treated with CHT ( 168 – 170 ) but not for resected early/locally advanced tumors ( 174 ).…”

Angiotensin II subtype 1a receptor signaling in resident hepatic macrophages induces liver metastasis formation

“…The expression of AT1 is especially enhanced in cancer . In fact, it is reported that ACE inhibitors and angiotensin II receptor blockers inhibit the risk of cancer and cancer‐related death . We have shown that AT1 signaling induces tumor growth and metastasis formation in a lung metastasis model .…”

“…(30)(31)(32) In fact, it is reported that ACE inhibitors and angiotensin II receptor blockers inhibit the risk of cancer and cancer-related death. (33) We have shown that AT1 signaling induces tumor growth and metastasis formation in a lung metastasis model. (9) Neo et al (34) reported that treatment with ACE inhibitors suppressed angiogenesis in a mouse model of CRC liver metastasis.…”

Liver Protective Effects of Renin-Angiotensin System Inhibition Have No Survival Benefits in Hepatocellular Carcinoma Induced By Repetitive Administration of Diethylnitrosamine in Mice

“…Furthermore, other studies revealed that ACEIs or ARBs might decrease the risk of esophageal [ 16 ] and keratinocyte [ 17 ] carcinoma. Their use was also associated with increased response in rectal cancer [ 18 ] and longer OS in patients with renal cell, pancreatic, brain, and lung cancer [ 19 ] [ 20 ]. However, little is known about the impact of RAS inhibition on the OS of HCC on the experimental and clinical sides.…”