STATINS LOWER RISK OF COLORECTAL CANCER-START SCREENING AT 45

Statin use may significantly lower the risk of colorectal cancer (CRC) in patients with or without inflammatory bowel disease (IBD), based on a meta-analysis and systematic review.

In more than 15,000 patients with IBD, statin use was associated with a 60% reduced risk of CRC, reported lead author Kevin N. Singh, MD, of NYU Langone Medical Center in New York, and colleagues.

"Statin use has been linked with a risk reduction for cancers including hepatocellular carcinoma, breast, gastric, pancreatic, and biliary tract cancers, but data supporting the use of statins for chemoprevention against CRC is conflicting," Singh said during a virtual presentation at the annual meeting of the American College of Gastroenterology.

He noted a 2014 meta-analysis by Lytras and colleagues that reported a 9% CRC risk reduction in statin users who did not have IBD. In patients with IBD, data are scarce, according to Singh.

To further explore the relationship between statin use and CRC in patients without IBD, the investigators analyzed data from 52 studies, including 8 randomized clinical trials, 17 cohort studies, and 27 case-control studies. Of the 11,459,306 patients involved, approximately 2 million used statins and roughly 9 million did not.

To evaluate the same relationship in patients with IBD, the investigators conducted a separate meta-analysis involving 15,342 patients from 5 observational studies, 1 of which was an unpublished abstract. In the 4 published studies, 1,161 patients used statins while 12,145 did not.

In the non-IBD population, statin use was associated with a 20% reduced risk of CRC (pooled odds ratio, 0.80; 95% confidence interval, 0.73–0.88; P less than .001). In patients with IBD, statin use was associated with a 60% CRC risk reduction (pooled OR, 0.40; 95% CI, 0.19–0.86, P = .019).

Singh noted "significant heterogeneity" in both analyses (I2 greater than 75), most prominently in the IBD populations, which he ascribed to "differences in demographic features, ethnic groups, and risk factors for CRC."

While publication bias was absent from the non-IBD analysis, it was detected in the IBD portion of the study. Singh said that selection bias may also have been present in the IBD analysis, due to exclusive use of observational studies.

"Prospective trials are needed to confirm the risk reduction of CRC in the IBD population, including whether the effects of statins differ between ulcerative colitis and Crohn's disease patients," Singh said.

Additional analyses are underway, he added, including one that will account for the potentially confounding effect of aspirin use.

According to David E. Kaplan, MD, of the University of Pennsylvania, Philadelphia, "The finding that statins are associated with reduced CRC in IBD provides additional support for the clinical importance of the antineoplastic effects of statins. This effect has been strongly observed in liver cancer, and is pending prospective validation."

Kaplan also offered some mechanistic insight into why statins have an anticancer effect, pointing to "the centrality of cholesterol biosynthesis for development and/or progression of malignancy."

The investigators and Kaplan reported no relevant conflicts of interest.

American College of Gastroenterology (ACG) 2020 Annual Scientific Meeting.

This article originally appeared on MDEdge.com.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube

It's not ready for the clinic, but new research suggests that angiotensin receptor II blockers (ARBs) widely used to treat hypertension may improve responses to cancer immunotherapy agents targeted against the programmed death-1/ligand-1 (PD-1/PD-L1) pathway.

That conclusion comes from an observational study of 597 patients with more than 3 dozen different cancer types treated in clinical trials at the US National Institutes of Health. Investigators found that both objective response rates (ORR) and 3-year overall survival (OS) rates were significantly higher for patients treated with a PD-1/PD-L1 inhibitor who were on ARBs compared with patients who weren't taking the antihypertensive agents.

An association was also seen between higher ORR and OS rates for patients taking angiotensin converting enzyme (ACE) inhibitors — but it was not statistically significant, reported Julius Strauss, MD, from the Center for Cancer Research at the National Cancer Institute (NCI) in Bethesda, Maryland.

All study patients received PD-1/PD-L1 inhibitors and the ORR for patients treated with ARBs was 33.8%, compared with 19.5% for those treated with ACE inhibitors, and 17% for those who took neither drug. The respective complete response (CR) rates were 11.3%, 3.7%, and 3.1%.

Strauss discussed the data during an online briefing prior to his presentation of the findings during the 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics, which is taking place virtually.

Several early studies have also suggested that angiotensin II, in addition to its effect on blood pressure, can also affect cancer growth by leading to downstream production of two proteins: vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-β), he explained.

"Both of these [proteins] have been linked to cancer growth and cancer resistance to immune system attack," Strauss observed.

He also discussed the mechanics of possible effects. Angiotensin II increases VEGF and TGF-β through binding to the AT₁ receptor, but has the opposite effect when it binds to the AT₂ receptor, resulting in a decrease in both of the growth factors, he added.

ACE inhibitors prevent the conversion of angiotensin I to angiotensin II, with the result being that the drugs indirectly block both the AT₁ and AT₂ receptors.

In contrast, ARBs block only the AT₁ receptor and leave the AT₂­ counter-regulatory receptor alone, said Strauss.

More Data, Including on Overall Survival

Strauss and colleagues examined whether ACE inhibitors and/or ARBs could have an effect on the response to PD-1/PD-L1 immune checkpoint inhibitors delivered with or without other immunotherapies, such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibitors, or targeted agents such as tyrosine kinase inhibitors (TKIs).

They pooled data on 597 patients receiving PD-1/PD-L1 inhibitors in clinical trials for various cancers, including 71 receiving concomitant ARBs, 82 receiving an ACE inhibitor, and 444 who were not receiving either class of antihypertensives.

The above-mentioned improvement in ORR with ARBs compared with patients not receiving the drug was statistically significant (P = .001), as was the improvement in CR rates (P = .002). In contrast, neither ORR nor CR were significantly better with patients on ACE inhibitors compared with patients not taking these drugs.

In multiple regression analysis controlling for age, gender, body mass index (BMI), tumor type, and additional therapies given, the superior ORR and CR rates with ARBs remained (P = .039 and .002, respectively), while there continued to be no significant additional benefit with ACE inhibitors.

The median overall survival was 35.2 months for patients on ARBs, 26.2 months for those on ACE inhibitors, and 18.8 months for patients on neither drug. The respective 3-year overall survival rates were 48.1%, 37.2%, and 31.5%, with the difference between the ARB and no-drug groups being significant (P = .0078).

In regression analysis controlling for the factors mentioned before, the OS advantage with ARBs but not ACE inhibitors remained significant (P = .006 for ARBs, and .078 for ACE inhibitors).

Strauss emphasized that further study is needed to determine if AT₁ blockade can improve outcomes when combined anti-PD-1/PD-L1-based therapy.

It might be reasonable for patients who are taking ACE inhibitors to control blood pressure and are also receiving immunotherapy with a PD-1/PD-L1 inhibitor to be switched to an ARB if it is deemed safe and if further research bears it out, said Strauss in response to a question from Medscape Medical News.

Hypothesis-Generating Study

Meeting co-chair Emiliano Calvo, MD, PhD, from Hospital de Madrid Norte Sanchinarro in Madrid, Spain, who attended the media briefing but was not involved in the study, commented that hypothesis-generating research using drugs already on the market for other indications adds important value to cancer therapy.

James Gulley, MD, PhD, from the Center for Cancer Research at the NCI, also a meeting co-chair, agreed with Calvo.

"Thinking about utilizing the data that already exists to really get hypothesis-generating questions, it also opens up the possibility for real-world data, real-world evidence from these big datasets from [electronic medical records] that we could really interrogate and understand what we might see and get these hypothesis-generating findings that we could then prospectively evaluate," Gulley said.

The research was funded by the National Cancer Institute. Strauss and Gulley are NCI employees. Calvo disclosed no relevant financial relationships.

32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics: Abstract 7. Presented in a briefing October 20 and in a plenary session October 25, 2020.