Explaining risk of breast cancer

Schiff: Dr. Sarrel, you said that breast cancer was a major concern of younger postmenopausal women, and Dr. Nachtigall reminded us that the media consistently describe the association of breast cancer and estrogen in a very negative way. We know this fear is the reason that a significant number of women stop using estrogen. It’s a problem we have to deal with whenever we start a woman on HRT.

This is my approach. I tell patients that whether estrogen increases the risk for breast cancer or not is still controversial. I tell them that I myself have serious concerns about long-term use of estrogen but that everyone agrees there’s no increase in risk for the first 5 years of use. I explain that they are at some risk for breast cancer during those 5 years, as all women are, but that estrogen does not increase that risk. If the patient asks me to quantify the risk, I use the following example: if a woman is 57 years old and has been taking estrogen for more than 5 years, her chances of developing breast cancer in the next 12 months are 4 in 1,200. If she has not been taking estrogen her chances are 3 out of 1,200.

In this way, I try to put things into perspective on the issue of breast cancer. I believe telling patients about my concerns helps me obtain their trust.

Dr. Nachtigall, what do you tell your patients?

Nachtigall: The issue of breast cancer is very important because the woman most commonly coming to you for help is the woman with hot flushes, insomnia, or vaginal dryness—real symptoms of the moment. She wants relief, but if she’s frightened of breast cancer she may not get it, and she’s going to suffer. It’s terrible to have to take a drug that you’re afraid of. That alone could have a bad effect on your health.

So my approach is similar to yours, Dr. Schiff. I’m not convinced that estrogen is ever a cause of breast cancer in the normal patient, though I believe it may make the cancer grow if it’s already there. But I definitely agree that short-term use is safe and does not increase a woman’s risk. I explain that to each patient as clearly as I can, and I usually don’t use numbers. I think it’s hard for the average patient to relate her own risk to that of other women. It’s all or none to her. What I usually say is that if she stays on HRT for 10 or 15 years, there may be a very slightly increased risk of breast cancer to her personally but that use for 5 years is perfectly safe.

Schiff: Dr. Berga, do you say something different?

Berga: I do, because I’m not convinced that there is a long-term risk for most women. Certainly survival is better for hormone users than for nonusers when breast cancer does occur. That was demonstrated clearly in a study by O’Meara and co-workers published recently in the Journal of the National Cancer Institute [Figure 2].²⁴ The common view is that estrogen causes breast cell proliferation and that SERMs cause breast cell atrophy, but the story is much more complicated than that. There isn’t much evidence at all for a positive relationship between estrogen and breast cancer. I think the opposite might even be true. Estrogen to some extent stimulates cell differentiation, and differentiation could be protective.

Nachtigall: You’re right that the relationship is very complicated, Dr. Berga. If there is a risk, it’s unlikely to be the same for all women. No two women are alike in their estrogen metabolism, and no two women are alike in their estrogen receptors. Then there are the genetic factors that influence risk—the p53, BRCA1, and BRCA2 genes. You really can’t make simple comparisons.

There’s still a lot to learn about breast cancer and hormones, and it’s a difficult subject to study because it’s hard to control for properly. The Nurses’ Health Study showed a significantly increased risk, but only in a very specific group: women between 60 and 64 currently on estrogen. When you have to fine-tune risk to that extent, you’re not seeing a true risk ratio. Other studies suggesting an increased risk have had the same problem. Dr. Trudy Bush, the principal epidemiologist in both the PEPI [Postmenopausal Estrogen/Progestin Interventions] and HERS [Heart and Estrogen/progestin Replacement Study] trials, questioned these findings in an excellent review published in Obstetrics and Gynecology last year, but of course her analysis didn’t make headlines in the newspapers.²⁵

Sarrel: Since estrogen use is clearly associated with endometrial cancer, people feel it’s logical to assume it induces other cancers. But it’s also true that estrogen protects against colon cancer, so that logic is faulty.^26,27 As Dr. Berga pointed out, estrogen induces not only a growth effect but a differentiating effect on cells, and that is not a characteristic of cancerous growth.

Schiff: Dr. Sarrel, what do you tell your patients about breast cancer?

Sarrel: I tell my patients something very similar to what you described, Dr. Schiff, and I do use numbers. Mine are based on the 1997 reanalysis of 51 studies by the Collaborative Group on Hormonal Factors in Breast Cancer.²⁸ I say that at age 62, an American woman who has never used HRT has a 2-in-100 chance of developing breast cancer the next year. For a woman the same age who has been on HRT for 10 years, the odds are 3 in 100. Like you, Dr. Schiff, I believe there may be a small risk associated with long-term use, and I tell women that. However, I agree with you, Dr. Berga, that there isn’t much evidence to show that estrogen causes breast cancer. I was impressed by Dr. Bush’s conclusion that 50 years of research data do not demonstrate an increased risk of breast cancer in women on estrogen. From my reading of the literature, I would say that if there is an increased risk, it’s a very small risk.

Schiff: There are some who believe even breast cancer survivors can restart HRT, if properly counseled and monitored.

Sarrel: That’s correct. Having managed the menopause program at Yale for over a quarter of a century, I have had a small number of patients who did develop breast cancer while on HRT. What impressed me about these women was their desire to resume hormone therapy after successful treatment of their cancer. They really missed its beneficial effects. That has had a very profound effect on my thinking on this subject.

Schiff: Obviously, this is a controversial area and we have our areas of disagreement, but the common theme that has emerged is that short-term use of estrogen—that is, use for 5 years or less—does not increase the risk of breast cancer. This is very reassuring information we can share with our patients. It does not mean that they have no risk of breast cancer. Women over 50 ought to continue their annual clinical examinations and mammograms, but they can be confident that taking estrogen for relief of hot flushes or vaginal dryness will not increase their risk.

Nachtigall: What I always point out is that the greatest risk for breast cancer is aging: In one large community study, 92% of the women over 50 who got breast cancer had never taken estrogen replacement.²⁹