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expert reaction to study investigating the relationship between fertility treatment, dense breast tissue, and potential breast cancer risk

Breast density is a known risk factor for breast cancer and a paper published in journal Breast Cancer Research has examined an association with infertility. The authors report that in their study women reporting infertility had higher levels of dense breast tissue and that treatment for fertility may also contribute to increased density.

 

Prof. Paul Pharoah, Professor of Cancer Epidemiology, University of Cambridge, said:

“This paper reports the results from a large, well-conducted study investigating the association between infertility and infertility treatment in women and breast density. Breast density refers to the appearance of the breast tissues on a breast mammogram. In this study the measurement of breast density from mammograms was carried out very carefully. Increased breast density is a well-established risk factor for breast cancer.

“The investigators found that infertility and some infertility treatments (controlled ovarian stimulation) were associated with small but significant increases in breast density, even after controlling for other factors associated with breast density such as body mass index and pregnancies. This finding suggests that infertility treatment might be associated with an increased risk of breast cancer.

“However: this study found no direct link between infertility/infertility treatment and breast cancer risk. This is a cross-sectional study – meaning the breast density was measured at the same time as the history of infertility was ascertained. It is not possible to know whether the infertility/treatment resulted in (caused) an increase in breast density or whether women with dense breasts are more likely to have infertility.

“No studies have shown a definite association between infertility/treatment and an increased risk of breast cancer. This is not surprising if the increase in risk is as small as suggested by this study (see numbers below) as such a small increase would be very hard to detect. Even if the breast density increase associated with infertility treatment were a real cause and effect the effect on breast cancer risk would be very small. The numbers below assume that the reported association is cause and effect.

“The authors of the paper report that the observed effect of controlled ovarian stimulation “is similar to reported for vigorous physical activity. This difference has been linked to an approximately 2.5 % increase in relative breast cancer incidence. Of 1000 forty year old women in the UK, 95 are expected to get breast cancer in their lifetime. Of 1000 women undergoing treatment for infertility 97 would be expected to get breast cancer: a difference of only two in a thousand. Women who have undergone treatment for infertility, or who are thinking about having treatment, should not be concerned about any possible small increase in risk of breast cancer.”

 

Prof. Kevin McConway, Emeritus Professor of Applied Statistics, The Open University, said:

“This study adds another piece to a complicated jigsaw, but the picture is still far from complete. It hasn’t established for certain that fertility treatments increase the risk of breast cancer, and as the lead author says in the press release, if there is an increase in risk it is “a modest increase”. A study of this nature can’t be more precise than that, and it’s important to note that the researchers are not proposing any changes in fertility treatments, just “continued monitoring” of women undergoing some treatments.

“The research shows fairly convincingly that women reporting infertility had more dense tissue in their breasts, and that those who had had fertility treatments requiring higher doses of hormones to stimulate ovulation (COS) had denser breasts than those who had not had such treatments. The researchers found that women who had had different types of treatments for infertility differed in several other ways too, and they had to allow for these differences in their statistical modelling. But, rightly, they still do not go further than suggesting that COS treatment might potentially cause increases in breast density, and they certainly don’t conclude that COS treatment definitely increases breast cancer risk.

“First, they can’t (and don’t) say that the higher average breast density in women who had COS treatment is a consequence of the treatment. That’s partly because they could not follow the women over time. The research paper makes it clear that Swedish women would not generally be offered fertility treatment involving COS unless they had certain kinds of infertility, that perhaps had not responded to other treatments. Perhaps these women tended to have denser breasts for some reason to do with their particular type of infertility, and the hormone treatment did not cause the increase. The study can’t tell us because it’s observational and cross-sectional, as the researchers make clear.

“Then this study did not collect data on whether these particular Swedish women actually developed breast cancer or not. Though there’s good evidence from several previous studies that women with more dense breast tissue are at increased risk of breast cancer, in general these other studies wouldn’t have looked at whether women with denser breasts specifically associated with infertility, or with fertility treatment, had increased breast cancer risk. So the researchers in this new study rightly don’t go further than suggesting that infertile women who undergo COS might possibly be a group with higher breast cancer risk. This study can’t say definitely how much higher, and indeed it can’t (and doesn’t) say for certain that there is any increased risk at all.

“The research paper and the press release do mention previous research that found that women with extremely dense breasts had a much higher risk – four to six times as high – of developing breast cancer than women who had the least dense breasts. This looks worrying, given that about 1 in 8 UK women get breast cancer at some time in their lives. But it’s not particularly relevant to this new research. As the press release again makes clear, the average difference in dense breast tissue volume in women who had had COS, compared to those who hadn’t, was actually rather small. It was nowhere near as great as the difference between the lowest and highest density groups in the previous study. If there COS treatment really is linked to an increased risk of breast cancer, and to repeat myself, this study hasn’t established that it definitely is, the increased risk would actually be “modest”, to quote the study’s main author.

 

Prof. Alastair Sutcliffe, Professor of General Paediatrics, UCL, said:

“Breast cancer is a common disorder amongst women affecting 1 in 11 women in the UK. It has undergone massive improvement in treatments and subsequent survival rates are continuing to increase over the past 25 years plus.

“Nonetheless it is relevant to continue to understand its origins and risks. In this study performed in Sweden, a group of 43,313 women had been involved in a study of the controversial test called mammography. One component of mammography is an ability to measure breast tissue density. A simple heuristic is that the more dense the breast tissue, the higher the risk that person will have of getting breast cancer.

“The study reports an increase in the amount of dense breast tissue in women who have a record of infertility and even more so where they had hormone therapies for that infertility. Interestingly the study made no allowance for breast feeding where the women had gone on to have children. This latter natural way of feeding an infant is well known to protect against breast cancer. Nonetheless there is an inference that hormone therapies and infertility per se increase the risk of this higher density breast tissue.

“So what should safely be concluded? First that women with infertility may well be at higher risk of increased amounts of dense breast tissue, furthermore those who have the controlled doses of powerful hormones that are used in fertility treatments may have a still higher risk of this more dense breast tissue. And finally one might consider a higher rate of screening for breast cancer in this group of women via the mammography method.

“However, it is not clear from this report whether this was an ‘a priori hypothesis ‘ driven study or a post hoc analysis, the latter seems more likely. The only real way to demonstrate a true effect of infertility on breast density or furthermore an effect of ART on breast density would be a randomised controlled trial. These findings are plausible but, nonetheless ‘one swallow does not launch a summer’ and it would be irresponsible in the extreme to frighten women who have been sub fertile and had treatment to think that they would be at higher risk of breast cancer.”

 

Association of infertility and fertility treatment with mammographic density in a large screening-based cohort of women: a cross-sectional study’ by Lundberg et al. published in Breast Cancer Research on Wednesday 13th April. 

 

Declared interests

Prof. Paul Pharoah: I have no conflicts of interest to declare

Prof. Kevin McConway: I have no conflicts of interest

Prof. Alastair Sutcliffe:  No conflicts of interest

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