HT and breast cancer risk☆

WHI study 

The WHI study found that breast cancers increased with combined hormone use. The recent report (5) updated results on the number and characteristics of the breast cancers diagnosed, as well as the frequency of abnormal mammograms, in the randomized trial of estrogen plus progestin vs placebo. The breast cancers found in women taking estrogen plus progestin, compared with those in women taking the placebo, were comparable in grade, receptor status, and histology, but were significantly larger and associated more often with positive lymph nodes. These findings directly challenge the concept that cancers resulting from the use of estrogen plus progestin are early stage, have a more favorable prognosis, and are more easily treated.

In the WHI study, study medications could be dispensed only if required annual mammography were performed. Consequently, the reported frequency of mammography use was closely comparable in the two groups. There was about a 4% increase in abnormal mammograms seen after only 1 year of estrogen plus progestin use, which continued throughout the study duration. Women who remained in the study for the 5.6-year median average duration had about a 10% chance of having an otherwise avoidable abnormal mammogram related to the use of estrogen plus progestin. Increased abnormal mammograms were also seen in the 5678 women between ages 52 and 59. This effect of estrogen plus progestin on abnormal mammogram frequency represents a new identified risk of short-term hormone use.

A report on quality of life (QOL) that included information on 2000 women entering the WHI with moderate-to-severe vasomotor symptoms found that symptoms improved after 1 year in about 50% of women on placebo and about 75% of women on hormones (7). Thus, leaving aside questions of chronic disease risk, a woman considering estrogen plus progestin for vasomotor symptom relief must balance the 25% chance of having improved symptoms after 1 year (difference between placebo and hormone groups in the QOL report) with the 4% chance of dealing with an otherwise avoidable abnormal mammogram. These findings represent new issues for incorporation into the informed decision-making process.

In the WHI, while prior menopausal hormone use appeared to increase the breast cancer risk, suggesting a cumulative dose effect, the suggested interaction was not statistically significant. However, the effects of hormone use on mammograms and breast cancer stage suggested that estrogen plus progestin hinders breast cancer diagnosis, thus making the assessment of HRT safety of short-term use problematic—use for a short period might appear to be safe, when in fact breast cancers are being stimulated and masked from diagnosis during therapy. This complex issue is receiving further attention.

With respect to the influence of estrogen alone on breast cancer, a separate randomized trial of CEE alone versus placebo in the WHI continues with Safety and Monitoring Board oversight. The Data and Safety Monitoring Board indicated on May 31, 2002, that no increase in breast cancer had been observed in the CEE trial as of that time.

The emerging information regarding the influence of estrogen plus progestin on breast cancer risk adds further weight to the recommendation against use for chronic disease risk reduction.

Million Women Study 

Additional information confirming and extending many of the major WHI findings regarding the associations of menopausal hormones and breast cancer comes from the Million Women Study (6). This extremely innovative observational study linked UK mammography centers with cancer and death registries, resulting in the remarkable entry of 1,084,110 women aged 50 to 64 years and observation of 9364 breast cancers. Breast cancer risk was associated with the use of estrogen alone but was substantially greater for estrogen plus progestin combinations.

The risk of breast cancer increased the longer a woman used HT. Also, CEE in lower and higher dosage and ethinylestradiol had comparable effects on breast cancer in this observational study. Oral, transdermal, and implanted hormones also were associated with increased breast cancers. For the estrogen plus progestin combinations, similar effects were seen regardless of progestin constituent and regimen (sequential or continuous).

Confirming the larger size and advanced stage reported for breast cancers seen with hormone use in the WHI, the British investigators reported, for the first time, an increased risk of breast cancer mortality associated with HT.

Taken together, the WHI random prospective trial and the large observational Million Women Study provide compelling evidence regarding HT use and the increased risk of developing potentially life-threatening breast cancer. The WHI focuses on the short-term risk of increased frequency of abnormal mammography and potential difficulty in breast cancer diagnosis. The Million Women Study speaks particularly to the likely futility of preventing breast cancer stimulation by changing currently identified hormone constituent agents, doses, or formulations.

Remaining issues 

What issues regarding breast cancer and HT remain?

The duration of exposure required for harm, especially in consideration of short-term use and breast cancer development, remains a difficult question. Neither the WHI nor the Million Women Study can easily disentangle masking of breast cancers and delay in diagnosis from a lack of effect on breast cancer for any given period. In any event, in both the randomized WHI and the Million Women Study, breast cancers developed after shorter than predicted intervals based on most prior observational studies suggesting an early hormonal effect on growth of established breast cancers, narrowing the “window” for breast cancer safety.

What about the use of estrogen alone, especially for women without a uterus?

The WHI estrogen trial continues, monitoring a global index of chronic diseases potentially under estrogen influence. The Million Women Study suggests estrogen alone will increase breast cancer risk, but the risk will be substantially less than that of combined hormone use.

Can the frequency of abnormal mammograms associated with estrogen plus progestin use be avoided? Based on small clinical experiences (8) and in the absence of appropriate prospective randomized trials, some suggest that discontinuation of hormones for relatively brief periods will prevent the problem of abnormal mammograms. This important question requires more extensive evaluation before being promoted to women as a safe means of reducing the risk of abnormal mammograms.

In summary, the emerging information regarding the influence of estrogen plus progestin on breast cancer risk adds further weight to the recommendation against long-term use for chronic disease risk reduction and raises additional questions regarding risks of even short-term use targeting vasomotor symptoms. These issues will be of special relevance to women with mild to severe menopausal symptoms—including hot flashes, sleep disturbances, and vaginal dryness—who are either perimenopausal and considering initiating HT or who have attempted to discontinue HT but have severe recurring symptoms. In such circumstances, a risk–benefit discussion is clearly needed, with an emphasis on the lowest dose and shortest duration of therapy necessary for symptom control. These data strongly relate estrogen plus progestin to breast cancer, raising particular concerns for women with diagnosed breast cancer who are experiencing severe vasomotor symptoms.

It is incumbent for physicians to incorporate these findings into their daily practices.