Pancreatic cancer, malignant tumor of pancreas with KRAS mutation
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A multisite study published today in the Clinical Cancer Research, a journal of the American Association for Cancer Research (AACR) shows that a commonly prescribed anxiety drug is linked with worse outcomes in pancreatic cancer patients and shorter progression-free survival (PFS).

The drug, benzodiazepine lorazepam, sold under the trade name Ativan, is commonly prescribed by physicians to treat anxiety during cancer treatment. By contrast, the patients who took a different anxiety medication benzodiazepine alprazolam (Xanax) had a significantly longer progression-free survival than patients who did not.

Benzodiazepines are a class of drugs that suppress the activity of the central nervous system, which helps to treat symptoms of anxiety, insomnia, and seizures. While this class of drugs are commonly prescribed for cancer patients on their treatment journey, Michael Feigin, PhD, associate professor of pharmacology and therapeutics at Roswell Park Comprehensive Cancer Center said that not much is known about how benzodiazepines impact cancer outcomes.

“When we study response to therapy, we think of treatments like chemotherapy or immunotherapy, but patients are also given a lot of medicines for anxiety and pain,” Feigin said. “We wanted to understand the impact of some of these palliative care drugs on the tumor.”

Feigin, senior author of the study, and colleagues first took a census of cancer patients at Roswell Park to see how many of those treated for melanoma, prostate, pancreatic, ovarian, kidney, head and neck, endometrial, colon, breast, or brain cancers had received benzodiazepines. Among all cancers, 30.9% had received  them, with the highest percentage (40.6%) found among pancreatic cancer patients.

Homing in on pancreatic cancer the researchers then looked to find if there were any relationship between benzodiazepine use and survival. After adjusting for age, race, sex, disease stage and progression, and what treatments the patients had received, the data showed that use of any benzodiazepine was associated with a 30% lower risk of pancreatic cancer-related death.

But when the relationship was studied between individual benzodiazepines and outcomes, stark differences emerged. Not including benzodiazepines that are short acting and used during surgical anesthesia, the two most commonly prescribed medications in this class of drugs were lorazepam in 40 patients and alprazolam in 27 patients. Those patients who took alprazolam were discovered to have a 62% lower risk of disease progression or death compared with those who did not take the drug (42 patients).

The story was very different for patients who took lorazepam. Patients taking this drug showed a 3.83-fold higher risk of disease progression and death compared with the 29 patients who did not take it.

Further, when the investigators looked for associations between lorazepam and alprazolam use and patient outcomes in other forms of cancer, they found that alprazolam was rarely associated with significantly different outcomes, while lorazepam use correlated with much worse overall survival in in prostate, ovarian, head and neck, uterine, colon, and breast cancer, as well as melanoma, with effects ranging from a 25% increased risk to a 116% increased risk.

Feigin noted that prior research had studied the effect of benzodiazepines on tumor cell growth, but they had been conducted in models that didn’t not have the dynamics of the tumor microenvironment. “Since the tumor microenvironment plays a big role in pancreatic cancer biology, we wanted to know what the benzodiazepines are doing to the microenvironment,” he said.

First author Abigail Cornwell, a graduate student in the Feigin lab led mechanistic studies that showed lorazepam may activate a protein called GPR68 that is highly expressed in fibroblasts that support the tumor. GPR68 also boosts expression of IL-6 a cytokine that promotes inflammation in the pancreatic tumor microenvironment which produces increased tumor growth.

But not all benzodiazepines activated GPR68. A class of these drugs called n-unsubstituted benzodiazepines (including lorazepam, clonazepam, nordiazepam, and oxazepam) activated the cytokine, while n-substituted benzodiazepines (including alprazolam, diazepam, and temazepam) had no effect on GPR68 activation.

“I think it’s too early to say patients should stop taking one drug or start taking another drug,” Feigin noted, while adding that this research was a correlative analysis. “There’s a lot more to learn in terms of the clinical implications.”

Next steps would be a clinical trial to prospectively evaluate the effects of lorazepam and alprazolam on pancreatic cancer outcomes and the human pancreatic cancer microenvironment.

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