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Vol. 09 Issue 2, Spring 2004

Research Commentary: Are Antibiotics Linked to Breast Cancer?
The Ribbon 

Barbour S Warren, PhD and Carol M. Devine, PhD

Recently the popular press was flooded with reports of another potential breast cancer risk factor: antibiotic use. The study which prompted all this attention was published in the mid-February issue of the Journal of the American Medical Association (JAMA)1. This report found that antibiotic use was associated with more than a two-fold increase in breast cancer risk for women with the highest number of prescriptions of antibiotics, relative to women who were never prescribed antibiotics. Following the resulting barrage in the press, undoubtedly many women came to wonder, what is the meaning of this? They were not alone, as this question was the title of an editorial that accompanied the report in JAMA2, a journal published primarily for physicians and researchers. The following discussion will address the meaning of this study and the potential for high antibiotic use to be an actual risk factor for breast cancer.

The Bottom Line.

A good deal more study is needed before this relationship is established. Only two studies have addressed this question1, 3. Both studies reported an association between breast cancer and antibiotic use. However, these two studies do not provide a body of evidence which is strong enough to make a definitive conclusion about this association. Nonetheless these results are important. Antibiotics are prescribed commonly and, if this association does prove to be solid, their contribution to breast cancer incidence could be significant. This study should also be welcomed as a reflection of breast cancer as an active area of research in which potential risk factors are being pursued.

Studies That Have Examined This Possible Relationship.

The first of the two studies that examined antibiotic use and breast cancer risk was a cohort study published in 2000.3 This study tracked women from 12 cities in Finland and evaluated those who had ever used antibiotics for urinary tract infections. From the 157 breast cancer cases that arose in this group of 9,461 women, a significant positive association between antibiotic use for urinary tract infections and breast cancer risk was found. This association only existed for women less than 50 years old; no association was seen for older women. In these studies, the under 50 group of women treated with antibiotics had a breast cancer risk which was 1.74 times that of the women who had not been treated for urinary tract infections. This was a preliminary study. It was small in size, looked at only one type of antibiotic treatment and did not carry out any detailed analyses.

The 2004 JAMA study was larger and more comprehensive and used a different study design. It was a case control study of women in a large non-profit health plan in Washington State. The health plan’s pharmacy records were used to determine antibiotic use for any condition for 2,266 women with existing breast cancer and 7,953 women without breast cancer. This study reported a 2.3 fold increase in breast cancer risk among women of all ages who had received the largest number of antibiotic prescriptions (more than 51 prescriptions over the period of up to 24 years). This result was statistically significant and was found for both premenopausal and postmenopausal women (risk values were not given for either of these groups individually). The results were further strengthened by the finding that breast cancer risk increased with prescription number in an exposure dependent manner (i.e. women with fewer prescriptions had lower risk and women with more prescriptions had higher risk). In addition, these investigators looked at the six different classes of antibiotics and found an exposure dependent increase in risk associated with all of them.

But this study was not without its flaws. These investigators did not report results which took into account the differences in the levels of established breast cancer risk factors which existed between the groups of women used for the comparison. They stated that such an analysis was conducted but they chose only to report the results which accounted for age differences in their calculation of relative breast cancer risk. Concern has been expressed about this shortcoming especially since the groups examined did differ in the presence of several important breast cancer risk factors2.

Is more evidence needed to establish this potential connection between antibiotic use and breast cancer risk?

An earlier article in The Ribbon discussed the five types of evidence needed to establish a cause-effect relationship between an exposure and occurrence of a disease (see The Ribbon, Volume 7 Number 4, 2002). The five types of evidence were: consistency of results; a reasonably high risk associated with the exposure; a dose relationship between level of exposure and disease; a biologically plausible relationship to cause; and finally a reasonable time between exposure and breast cancer occurrence. The evidence from these reports is evaluated in this light.

Currently there is consistency of results but in only two studies. These results could well be incorrect and their conclusions should still be considered preliminary. The results need to be verified in more studies. Such examinations will undoubtedly be conducted in the near future as existing cohort studies are likely to have information on antibiotic use by the members of their studies.

These studies reported about a doubling of risk. This would not be considered a very large increase in risk but could potentially affect many women. In response to this level of risk, some investigators have suggested that antibiotics may not be acting directly, but rather that antibiotic use is a measure of the women’s immune function, as women with weaker immune systems would be likely to be prescribed more antibiotics. This is a very reasonable criticism as decreased immune function is related to cancer occurrence.

The JAMA study did examine and demonstrate a dose relationship between breast cancer risk and the level of exposure to antibiotics – risk progressively increased for groups of women with more prescriptions or days of antibiotic use. This provides an important piece of evidence, but here again these results need to be confirmed in other studies.

The results also need to be biologically plausible. There is ample evidence for biological plausibility. Studies have shown that antibiotics could increase breast cancer risk by several mechanisms, such as effects on the immune system, changes in the growth of cells and decreases in the absorption of beneficial chemicals from plants. But in addition, there are studies which also support the ability of antibiotics to decrease breast cancer risk; antibiotics can increase estrogen elimination from the body, decrease the formation of estrogen, and have protective effects on cell growth.

Finally, the time of exposure has to be appropriate for cancer formation. The JAMA study also reported a sub-analysis of the women who had been in the program between 17 and 24 years, an appropriate time for cancer formation to be affected. They did not convey the actual risk values for this analysis but stated that an increase in risk was still observed. However, the level of risk was decreased and statistical significance was lost. Considerably more study is needed for each of the above types of evidence.

Should a woman’s approach to antibiotic use change because of this report?

This is an emerging area of research and it is currently unclear if even the reported association will remain true. It is also uncertain if a relationship might be due to the antibiotics themselves or to medical conditions which would call for antibiotic treatment. At this point there is insufficient evidence to recommend changes in antibiotic use.

References

1. Velicer CM, Heckbert SR, Lampe JW, Potter JD, Robertson CA, Taplin SH. Antibiotic use in relation to the risk of breast cancer. Journal of the American Medical Association. 2004;291(7):827-835.

2. Ness RB, Cauley JA, Velicer CM, et al. Antibiotics and breast cancer--what's the meaning of this? Antibiotic use in relation to the risk of breast cancer. Journal of the American Medical Association. 2004;291(7):880-881.

3. Knekt P, Adlercreutz H, Rissanen H, et al. Does antibacterial treatment for urinary tract infection contribute to the risk of breast cancer? British Journal of Cancer. 2000;82(5):1107-1110.

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Last Update 05.25.04