Tamoxifen is a critical drug in the fight against breast cancer. As an estrogen-blocker, it has a dual role as a treatment drug and as a prophylactic (preventive medicine) for estrogen receptor-positive (ER+) forms of breast cancer.
For women who have already been diagnosed with ER+ breast cancer, tamoxifen is typically prescribed as adjuvant therapy after surgery or chemo to reduce the risk of recurrence. Further, doctors may also prescribe it as a preventive medicine for women who are at a high risk of getting breast cancer due to genetics and family history.
Approved by the FDA in 1977, the drug’s effectiveness has been well-established over the decades. Studies indicate that tamoxifen can reduce the risk of invasive breast cancer in healthy women from high-risk categories by up to 49%. It can also reduce the risk of recurrence by at least 30% in women who have already received treatment for cancer.
While those numbers are pretty good, they also indicate that up to 50% of women do not respond positively to tamoxifen as a preventive drug for breast cancer. The reason, according to researchers at the University of California Irvine, could be the composition of bacteria in our gut biomes.
The Pharmacodynamics of Tamoxifen Inside the Body
Tamoxifen is typically taken orally in a pill form, ranging from 10mg to 20mg. Most patients are recommended a single daily dose of the drug. For breast cancer prevention, women in high-risk categories are prescribed tamoxifen for at least 5 years, if not more.
Estrogen is a sex hormone that has various effects on the human body, including cell growth. Tissues in the breast and uterus are particularly sensitive to estrogen-induced growth effects. The hormone can trigger uncontrolled growth in genetically damaged or mutated cells, leading to the rise of cancerous tumors. Recent studies reveal that it can even directly alter cellular DNA and cause cancer.
ER+ breast cancer cells often rely on estrogen for tumor growth and proliferation. These cells have special receptors that can bind to estrogen. Tamoxifen has the ability to bind to these receptors, denying cells access to estrogen molecules in the process. This can help prevent, slow down, or stop the progression of breast cancer tumors.
To become biologically active inside the body, tamoxifen must first enter the bloodstream through the intestines. The blood carries the drug molecules to the liver, where it is metabolized into various highly active molecules like N-desmethyltamoxifen and 4-hydroxy-tamoxifen.
Out of the different metabolites, 4-hydroxy-tamoxifen is most effective at binding to estrogen receptors. The liver enzymes CYP26D, CYP3A4, and CYP3A5 all play an important role in processing tamoxifen. Impaired liver function can affect your ability to get the full therapeutic benefits of the drug.
A Quick Overview of the Lab Experiments Conducted by the UC Irvine Team
The intestine plays a vital role in ensuring that tamoxifen is sent to the liver for metabolization. The human gut is also home to trillions of bacteria, whose composition is highly variable between different individuals. The researchers wanted to see if changes in the gut biome could have an impact on tamoxifen absorption rates.
First, they created two groups of mice – one with no gut biome, and a second group with a microbiome borrowed from a human. When tamoxifen was administered to both groups, the mice with a gut biome had a larger concentration of the drug in the blood.
Next, they compared biome samples from different individuals to see if they could isolate the specific bacteria or enzyme responsible for boosting tamoxifen absorption in the intestines. The findings pointed to a specific species called Bacteroides fragilis, a common occupant of the human gut biome.
How Bacteroides fragilis Affects Tamoxifen Absorption
The liver plays a key role in processing sugar and regulating blood glucose levels. During the metabolization of tamoxifen in the liver, sugar molecules often get attached to the drug as a result of certain enzymes, through a process called glucuronidation.
The addition of sugar molecules makes tamoxifen and its metabolites more water soluble, increasing its chances of getting excreted via the kidneys. Gut bacteria like B. fragilis can digest the sugar molecules, thanks to an enzyme they produce called beta-glucuronidase.
When patients have higher levels of this enzyme in their gut biome, they are more likely to receive a stronger response from tamoxifen, as lesser quantities of the drug are wasted/excreted due to glucuronidation.
According to the study’s authors, an overwhelming 75% of ingested tamoxifen and its metabolites are glucuronidated on average. This implies that the presence of B. fragilis and the associated beta-glucuronidase enzyme can make a sizable impact on the availability of tamoxifen metabolites in breast tissue.
Future Implications of this Breakthrough
At present, doctors have no reliable way of predicting if tamoxifen will work as intended in a particular patient. The UC Irvine study could help us overcome this. With further research, we might be able to develop simple lab tests to see if tamoxifen will work well for individual patients.
A stool sample analysis can tell us if the patient’s gut biome has the desirable bacterial species. Armed with this knowledge, doctors will be able to decide if they should give tamoxifen or some other drug for the desirable therapeutic outcome.
Further, the researchers also noted subtle changes in the gut biome when the body is exposed to tamoxifen. These changes can vary from person to person, indicating that factors ranging from diet to lifestyle could all influence how a patient’s body reacts to tamoxifen.
The human gut biome is home to at least 300 different species of bacteria. B. fragilis is probably not the only bacterium of significance from a metabolizing perspective for drugs like tamoxifen.
With further study, we may even discover ways to improve drug absorption levels in patients by altering the gut biome through methods like probiotics/prebiotics, fecal transplantation, antibiotics, and even some dietary changes.
Women in the US have a one in eight chance of developing breast cancer throughout their lifetimes. Improving the effectiveness of drugs like tamoxifen, even by a few percentage points, could save or improve tens of thousands of lives each year, if not more.
