Another worry for breast cancer patients?

Breast cancer is the most common (non-skin) cancer in women, and despite advances in treatment, it is still deeply feared, and with good reason.  But breast cancer is really several different diseases.  Breast cancers can arise from several different cell types, they can occur during the pre- or post-menopausal period, and they can have various cell surface receptors, all of which can change their behavior (and their lethality) significantly.

One of the things common to all cancers is that cells that were formerly normal begin to proliferate inappropriately, and fail to die when they should.  The h0rmone estrogen tells normal breast cells to proliferate, which maintains normal, functional breast tissue.   Estrogen can also tell breast cancer cells to proliferate, which is not a good thing.  One of the great advances in the treatment of breast cancer is the drug tamoxifen, which can block the action of estrogen on breast cells.

When an estrogen molecule enters a breast cell, it binds to a receptor molecule and knocks off a molecular “lock”, allowing two estrogen receptors to bind together.  This “dimer” enters the cell’s nucleus and interacts with DNA, increasing the activity of certain genes which lead to increased cell growth.  Tamoxifen works similarly, but when the tamoxifen-activated dimers interact with DNA, they inhibit cell proliferation.  This is a good thing, and tamoxifen has been shown to save lives in breast cancers that have estrogen receptors.

But when you take a tamoxifen tablet, it’s not the tamoxifen itself that enters the breast cells.  The drug is absorbed by the stomach and eventually transported to the liver where it is converted to a chemical called “endoxifen”.  It is the endoxifen that is the active molecule that helps prevent breast cancer recurrence and reduces mortality.  In order for tamoxifen to become endoxifen, it is processed in the liver by an enzyme called cytochrome P450.  The P450 system serves as a factory for changing chemicals into other chemicals, often in order to help eliminate them from the body; it is essentially a “detoxifying system”.  Cytochrome P450 comes in many different flavors, each one working to transform different chemicals, especially drugs.  Drugs can be transformed in a way that makes it easier to eliminate them, or can be transformed in a way that activates them, as with tamoxifen/endoxifen. The P450 that transforms tamoxifen to endoxifen is called CYP2D6.

P450 is a tricky system.  While one drug may be metabolized by P450, another may inhibit or ramp up the enzyme.  This means that if, for instance, I give a patient tamoxifen, and also give them a drug that inhibits CYP2D6, the tamoxifen may not be turned into endoxifen efficiently.  And this is what apparently  happens with the antidepressant paroxetine (Paxil).

Paroxetine is a very potent inhibitor of CYP2D6.  It’s also a very popular drug.  Depression is very common, especially in breast cancer patients.  Paroxetine is also used to treat hot flashes, a symptoms of both menopause and of tamoxifen treatment.  Given the relatively high chance of a woman being treated with both of these drugs, it would be good to know how significant this drug interaction might be.

A 2010 study published in the British Medical Journal did just that.  It used Canadian health records to look at usage of both drugs and at mortality in post-menopausal women with breast cancer.  What they found was that concomitant use of tamoxifen and paroxetine, but not other similar antidepressants, increased the risk of death.

This is a really, really big deal, but there are some limitations to the study.  First, they did not actually measure endoxifen levels, so that particular link in the causal chain is assumed.  They also did not evaluate patients to see which type of CYP2D6 they had; some people naturally have a more or less functional version, and we don’t know how these patients may have been distributed in the groups.

But the hypothesis is plausible, and the fact that other SSRI antidepressants did not show a significant association with increased mortality should give us pause.  There are many, many inexpensive and reasonably effective choices for the treatment of depression, and after reading this study, as a clinician I would hesitate before prescribing paroxetine to a woman being treated for breast cancer with tamoxifen.

References

Kelly, C., Juurlink, D., Gomes, T., Duong-Hua, M., Pritchard, K., Austin, P., & Paszat, L. (2010). Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study BMJ, 340 (feb08 1) DOI: 10.1136/bmj.c693

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5 Comments

  1. LindaCO

     /  January 5, 2011

    Thank you, this was interesting.

  2. Don’t forget you have to also worry about their CYP2D6 function due to the large amount of polymorphisms too.

  3. Curious – does anyone know if other SSRIs help with hot flashes and other symptoms of menopause/tamoxifen treatment?

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