Are estrogens alone really safe for breast in menopausal therapy?

To close off the discussion around the safety of estrogen at ESG, Anne Gompel shared her views on estrogen safety in relation to breast cancer (BC) risk. Data from the WHI RCT estrogen alone arm showed a decreased risk in breast cancer in women on the estrogen only treatment. This was also seen in Anderson et al. Lancet, Oncology, 2012 which demonstrated a significant decrease in breast cancer incidence in women using estrogen and lower deaths from breast cancers and other causes in the treatment arm compared to the placebo group. However this data is the exception not the norm, data from case control and cohort studies between 1996-2005 before the WHI data was published showed there was a significant increase in risk of BC in the estrogen only group, although this risk was still lower than risk increased by combined MHT.

The NURSE study (Sisti et al. Int J Cancer, 2016; 138: 2346-56) showed MHT use increased risk of luminal A and B breast cancer in women who used estrogen (mostly CEE) at long term treatment but not at short term treatment highlighting that length of treatment in WHI was potentially too short to demonstrated increased risk and explain the contradiction in data. New data from the E3N cohort study recently published showed no increased risk of BC in the estrogen only arm either but it is thought this may due to low population density.

So why is the data different between studies? Maybe CEE may act differently on the breast than estradiol. Perhaps it’s due to the population included, the WHI population was older and the prevalence of obesity/ISR was different or maybe the type of BC identified was different. Although it is know that women with a high BMI using MHT are not at a higher risk of BC, the NURSE study showed those with a BMI less than 20 who used MHT had higher BC risk. This may be another reason for inconsistencies in data.

Anne also questioned if oophorectomy could be a cofounding factor? In the WHI estrogen only arm and the NURSE study there was no difference in BC risk observed between those who had a hysterectomy and those who hadn’t only long term use of estrogen resulted in increased risk.

Evidence from epidemiology also confirms the length of estrogen exposure increases the risk of breast cancer, as does age at menarche and age at menopause. Literature shows estrogen can promote or even initiate breast cancer. Preclinical studies show that aromatase inhibitors and antiestrogens can help prevent breast cancer. There are also other estrogen-related risk factors including breast density, plasma E2, age at first live birth and BMI. Data from the collaborative group on hormonal factors in breast cancer have shown that pre-menopausal women have a higher risk than postmenopausal women of the same age.   

The proliferative effects of estrogen

Promotion of estradiol can contribute to maintenance of a proliferative state through genomic and non-genomic pathways through the alpha estrogen receptor and can result in the increased proliferation of breast cancers.  Data from Song et al. shows that E2 is active at much lower concentrations than CEE, but CEE can still activate proliferation even at lower concentrations.  Estrogen can also activate metabolites outside of the alpha receptor including 2-OH, 4-OH and 16 alpha OHE.

The benefit of aromatose inhibitors is that they can stop the conversion of androgens into estrogens, whilst antiestrogens can stop cell proliferation induced mutations that lead to breast cancer. Many studies have demonstrated prevention and indeed protection from breast cancer.  The HOT study looked at use of MHT and Tamoxifen. Data showed that women who had used Tamoxifen with E2 had a significant decrease in the risk of luminal A breast cancer.

The conclusion is not firm, but comparing all the data suggests that for women with a high BMI and high insulin resistance, estrogen could help to decrease BC risk by decreasing insulin resistance.  There may also be a difference on breast impact between E2 and CEE. Anne believes transdermal E2 remains the best option from CVD endpoint perspective but that both options are the same for the breast!