For the first time, proof of what hormone replacement therapy does to genes involved in breast cancer

New research has found that the type of HRT a woman takes, and the way it is taken, can have a significantly different effect on genes associated with breast cancer. This finding, presented at the World Congress on the Menopause in Cancun, Mexico, opens the way to identify which forms of HRT have minimal effect on breast cancer. It also gives the long-term possibility of personalising HRT according to the genes which a woman expresses.

Since the publication of the Women's Health Initiative report on HRT in 2002, many women have been worried about the effect of HRT on breast cancer. The International Menopause Society states that the increase in breast cancer is small, but that recommends that HRT be individually prescribed, depending on a woman's family and medical history. However, at a deeper level the problem has been; how do we know what HRT actually does to the breast at a genetic level?

What did the researchers do?

For the study, the researchers from the Karolinska Institutet in Sweden, recruited a group of 30 healthy women, and took two samples of breast tissue from each, using a needle biopsy.

Each tissue sample was then tested to measure the activity of 16 genes known to be associated with a greater risk of breast cancer. The women were then divided into two groups, and given HRT for 2 cycles of 28 days.

15 women took oral HRT, using the CEE/MPA (this is a synthetic conjugated equine estrogen, plus medroxyprogesterone acetate, which was used in the WHI trial).

The other 15 were given E2/P, which is estradiol gel plus oral micronised progesterone. Estradiol is a type of estrogen found in the body, so can be considered more natural than the CEE/MPA formulation. The estrogen (E2) was applied to the skin in a gel. The progesterone was micronised (i.e. put into very small particles) and taken orally.

At the end of the HRT cycles, the women then underwent the second breast biopsy.

As lead researcher, Professor Gunnar Soderqvist said: "30 patients is quite a high number of patients for this type of analysis. The assessment of all genes both before and during treatment for the change in gene expression means that each woman was her own control, which adds to the strength of the study."

What did they find?

The researchers used PCR analysis to confirm that the CEE/MPA HRT changed the expression of 8 out of 16 genes (50%), whereas only 4 out of 16 genes (25%) were expressed differently in women taking the E2/P HRT. This difference was shown to be highly statistically significant.

What does this mean?

Professor Gunnar Soderqvist continued: "Until now, it has not been possible to assess breast gene regulation in healthy women in vivo. This is the first study ever describing effects in healthy women during these HRT treatments and shows very important differences mostly in favour of "natural" treatment with the gel containing estradiol/ oral micronised progesterone when compared with "synthetic "oral CEE/MPA.

The study does not show that either HRT formulation "causes cancer," but it does show that the type of HRT and perhaps the route of administration will cause differences in genes associated with breast cancer.

We can conclude by saying that natural treatment with the estrogen gel and oral progesterone affects gene regulation and surrogate markers for breast cancer risk (such as mammographic density and breast cell proliferation) considerably less than the conventional synthetic treatment which stopped the WHI study."

Incoming International Menopause Society President, Professor Rod Baber (Sydney) said: "This very important study show that use of HRT combining a transdermal estradiol preparation with oral micronised progesterone causes significantly less expression of genes associated with breast cell proliferation and breast cancer than the more traditional HRT combination of conjugated estrogens plus medroxyprogesterone.

The basic science from this study supports the evidence we have from clinical trials such as the French E3N trial, which shows that the choice so estrogen and progestogen and the mode of delivery is important in reducing any risk of breast cancer possibly associated with long term HRT"