Environmental risk factors - can we ever know when we're done?

Complexity, confounding, heterogeneity: these are just a few of the issues that can and do play havoc with biomedical research where we attempt to infer causation from observational data. A paper just published in Cancer Research ("Circadian and Melatonin Disruption by Exposure to Light at Night Drives Intrinsic Resistance to Tamoxifen Therapy in Breast Cancer," Dauchy et al.) is a good example of some of the issues.  Reported all over the web, including here by the BBC, the study suggests that low levels of light might inhibit the effectiveness of breast cancer drugs.

Many breast tumor cells have receptors for estrogen on their cell membranes; the hormone binds to the receptors and activates cell growth and proliferation, the signal characteristics of cancer cells.  To inhibit that growth, many women with estrogen-positive breast cancers are treated with an estrogen agonist or antiestrogen such as tamoxifen, the metabolites of which bind to the receptor and slow or halt further growth of the tumor.  However, 30 - 50% of tumors become resistant to tamoxifen over time.

Antiestrogens: National Cancer Institute

Dauchy et al. write:

Resistance to endocrine therapy is a major impediment to successful treatment of breast cancer. Preclinical and clinical evidence links resistance to antiestrogen drugs in breast cancer cells with the overexpression and/or activation of various pro-oncogenic tyrosine kinases. Disruption of circadian rhythms by night shift work or disturbed sleep-wake cycles may lead to an increased risk of breast cancer and other diseases. Moreover, light exposure at night (LEN) suppresses the nocturnal production of melatonin that inhibits breast cancer growth.

Many previous studies have shown a relationship between sleep disturbance and cancer risk, and more specifically, between melatonin and cancer risk, so Dauchy et al. focused their research on the role of melatonin as a mediator between tamoxifen and cancer cell growth.  Human breast tumor xenografts (cross species tissue transplants) were implanted into rats and the animals then spent 12 hours in light and 12 hours in dim light or in total darkness every day, and the progression of the tumors followed. The animals exposed to dim light had lower melatonin levels, and their tumors were larger than the rats in total darkness.  Once the tumor reached a specific size, the animals were treated with tamoxifen, and progression or regression of the tumor was then documented.  Further, supplementing the mice in dim light with melatonin lead to smaller tumors and lower tamoxifen-resistance.  The equivalent of the dim light the rats were exposed to would be, according to the authors, the light entering a room under a door.  They suggest that exposure to light from electronic devices before sleep may also lower melatonin levels.

Senior author Steven Hill was quoted in The Telegraph as saying that because resistance to tamoxifen is an increasing problem, this study could be significant.

“Our data, although they were generated in rats, have potential implications for the large number of patients with breast cancer who are being treated with tamoxifen, because they suggest that night-time exposure to light, even dim light, could cause their tumours to become resistant to the drug by suppressing melatonin production.

How melatonin encourages tamoxifen to inhibit breast cancer growth is not understood, although melatonin may play multiple roles in inhibiting cancer cell growth.  The result, if it is replicable, is important however, and because this is not just an association study but an experiment based on a prior hypothesis it is at least that much more persuasive.  But we know from legions of work on inbred mice that mimicking a human effect in one strain doesn't seal the deal, because the results widely differ among strains when investigators are conscientious enough to test multiple strains -- and sometimes some strains show essentially no effect. Presumably this is for genetic reasons, which could mean that the current rat-based study may apply to some, but not to all women.  That would not make it a bad study nor a dismissible result, but it would temper that result.  

The rats in this study were exposed to complete darkness or dim light consistently, 12 hours every day, so it's impossible to know whether variation in light exposure by phase of the moon, say, or other  kinds of varying light sources would make a significant difference in the amount of melatonin a woman makes, nor in how much melatonin is required for tamoxifen to maintain its effectiveness.  
Often, one doesn't know when study results are important or convincing enough to warrant complex changes in drugs, treatment, or behavior.  In this case, it seems rather benign to ask women in treatment to avoid light at bedtime. But even here, should they be compulsive about it?  Shut the curtains in a full-moon?  Nothing to light their way to the bathroom?  And, the authors caution that women shouldn't begin taking melatonin as a result of this study.  

But this work is interesting in its own right, and clearly worth paying attention to.  It also is a reminder of why it's so hard to study environmental risk factors for disease.  As far as we know, when the benefits of tamoxifen were first shown, there was no a priori reason to suspect that it would lose its effectiveness, at least in part, because of exposure to light at night, or interruption in melatonin cycles.  This is a sobering but important reminder that there is always the potential for unidentified and unexpected interactions between unknown and unexpected risk factors (confounders).

We now know at least that there seems to be an interaction between melatonin and tamoxifen in rats, at least in regard to implanted human tumor cells, but we don't know how much of the tamoxifen resistance in human breast cancers this particular interaction might explain (if any, since these were rats, not humans).  But complexity is a hallmark of diseases like cancers, and there's not going to be a single, simple explanation.