Tag: tamoxifen

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Why Does Tamoxifen Work Only for Some Patients but not Others?

On By ModernMedia
Photo by Danilo Alvesd on Unsplash

A new study has shown that variation in the microbiota of the human gut impacts the pharmacokinetics of tamoxifen and thus the effectiveness of the drug. The finding, published in the journal mBio, suggests that in the future, doctors may use a simple stool test to check for certain bacteria in the gut and help predict tamoxifen’s effectiveness for them.

Tamoxifen is a selective oestrogen receptor modulator used to prevent breast cancer. It prevents breast cancer cells from being able to use oestrogen to grow.

“The key takeaway from this study is that while tamoxifen is a common and important treatment for preventing breast cancer recurrence, nearly 50% of patients don’t respond well to it,” said lead study author Yasmine Alam, a PhD candidate in the Department of Biological Chemistry, University of California Irvine. “Since tamoxifen is taken orally and passes through the gut, this difference in how patients respond may be linked to the gut microbiome – the trillions of bacteria in our intestines, which vary greatly from person to person. Our study aims to better understand how these gut bacteria influence the way tamoxifen is absorbed, broken down and recycled in the body, with the goal of improving treatment outcomes for breast cancer patients.”

In the new study, the researchers set out to define the role that gut microbes play in how tamoxifen is processed (ie, absorption, distribution, metabolism and excretion), given its significant variable efficacy across patients. The researchers provided tamoxifen to mice that had no gut microbiome and to mice with a human microbiome (introduced to the mice by a human faecal sample). They found that mice with gut bacteria had higher amounts of tamoxifen in their bloodstream. The scientists then went on to explore what part of the gut microbiome was responsible for controlling the level of drug in the bloodstream. By examining the faecal samples from people, they linked a specific enzyme in bacteria, beta-glucuronidase, as a key factor that allows the drug to enter the bloodstream.

Tamoxifen is absorbed into the bloodstream from the intestine. Tamoxifen is carried by the bloodstream to the liver, where it is converted to its cancer-fighting form. Sometimes a sugar molecule can get attached to it, which signals the body to dump the cancer-fighting form of the drug back into the intestine. This drug can only get out of the intestine by taking the sugar off the molecule – and the researchers found that beta-glucuronidase in gut bacteria can eat the sugar off the drug so it can go on to fight breast cancer.

“Specifically, we found that certain enzymes produced by gut bacteria, called β-glucuronidase, play a role in how tamoxifen is broken down. These enzymes help recycle tamoxifen back into the bloodstream, which can make the drug more effective,” Alam said. “We discovered that a particular type of bacteria, Bacteroides fragilis, was strongly linked to the ability of these enzymes to affect tamoxifen levels in the blood in a positive way. This suggests that the gut microbiome plays an important role in how tamoxifen works in the body.”

The long-term goal of the study is to pave the way for more tailored and effective therapeutic interventions in the prevention of breast cancer recurrence.

Source: American Society for Microbiology

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Tamoxifen Found to be Ineffective in Fungal Meningitis Trial

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Photomicrograph of a sample extracted from a lesion that revealed the presence of Cryptococcus neoformans. Credit: CDC

In a disappointing outcome, a clinical trial has shown that tamoxifen, a promising candidate to improve survival for a deadly form of fungal meningitis, is ineffective. The trial was conducted by University of Oxford researchers and published in eLife.

The study finds that adding tamoxifen, a breast cancer drug, to standard antifungal treatment was no faster in clearing fungal infection from the spinal fluid of people with meningitis. More patients who received tamoxifen had evidence of heart conduction disturbances, rates of severe side effects were similar.

Cryptococcal meningitis is a leading cause of death in people with HIV, but also affects those without HIV, regardless of whether they are immunocompromised. Most infections are caused by a fungus called Cryptococcus neoformans (C. neoformans) and occur in low-income tropical settings. The gold-standard treatment is a combination of three drugs: flucytosine and amphotericin B initially, followed by fluconazole. Yet, even on this gold-standard therapy, a third of patients die within 10 weeks of being diagnosed. Moreover, the drug flucytosine is severely restricted by availability and cost, meaning it is rarely used where the disease burden is highest.

Co-first author Nguyen Thi Thuy Ngan, Clinician at the Oxford University Clinical Research Unit (OUCRU): ‘Tamoxifen has shown antifungal activity against various yeasts in the lab; we subsequently showed that it acts synergistically with amphotericin against two-thirds of clinical Cryptococcus isolates from our archive. As a well-understood, off-patent, cheap and widely available medicine, it was a promising candidate for treating cryptococcal meningitis.’

Co-first author Nhat Thanh Hoang Le, Biostatistician at OUCRU, added: ‘We designed a randomised trial to determine whether using these drugs in combination could improve the speed of clearance of Cryptococcus from patients with meningitis with and without HIV.’

The trial involved 50 patients, 40 with HIV. Of the patients, 24 were assigned to receive a standard anti-fungal treatment of amphotericin B and fluconazole plus tamoxifen, and 26 received the standard anti-fungal treatment only. Researchers measured the Early Fungicidal Activity (EFA) for both groups – how quickly C. neoformans amounts declined in a patient’s spinal fluid in the two weeks following treatment.

Based on their prior work, the team were hoping for better EFA for patients receiving tamoxifen, but there was no detectable difference in EFA.

The only observed difference was increased heart toxicity in the tamoxifen group. Lab studies had shown that a tamoxifen dose five to 10 times higher than that used routinely in breast cancer would be needed to have an antifungal effect. However, high doses of tamoxifen cause QT prolongation, which can cause cardiac arrest. While there was one sudden death in the tamoxifen group in this study, this occurred after the period of tamoxifen administration and it was not associated with an abnormal heart rhythm.

Senior author Professor Jeremy Day, Professor of Infectious Diseases, Oxford University, said: “Despite its apparent anti-cryptococcal effect and synergy with other drugs, tamoxifen does not increase the rate of clearance of yeast from spinal fluid in people with meningitis and is unlikely to result in clinical benefit.

“Our results show the importance of small-scale trials such as this for rapidly evaluating repurposable drugs and preventing the time and cost of a larger clinical study that is likely to fail. However, sadly this does mean that we urgently still need new, specific anti-cryptococcal drugs to be developed, and we also need to ensure that existing, available treatments are made accessible and affordable.”

Source: Oxford University