Section 1
Hormone Replacement Therapy in Breast Cancer Survivors

Editor’s Note: When hormone replacement is utilized in a postmenopausal woman with an intact uterus, a combination estrogen-progestin preparation is standard. However, in the past several years, the impact of progestin use on breast cancer risk has become controversial. At the 3rd Annual Lynn Sage Breast Cancer Symposium (October 2001), Malcolm Pike, PhD, of the University of Southern California, opined that the progestin component of combined therapy represents the most preventable cause of breast cancer among women in the United States today, and he estimated that HRT was responsible for causing approximately 10 percent of breast cancers occurring in postmenopausal women.

Below are select, edited excerpts of Dr Pike’s presentation as well as comments from an interview with him shortly after his presentation. Dr Pike summarizes key evidence suggesting that progestins substantially contribute to an increased risk for breast cancer. He also provides alternative strategies to reduce progestin exposure in HRT and addresses other clinical issues commonly raised in medical oncology practice.

ESTROGEN VS ESTROGEN-PROGESTERONE REPLACEMENT THERAPY AND BREAST CANCER RISK

Estrogen-progesterone replacement therapy is the most preventable cause of breast cancer that’s around today. There have been three recent large studies ^1-3, all of which showed a much greater increase in breast cancer risk from estrogen-progesterone replacement therapy than from estrogen replacement therapy alone — maybe three or four times greater (Figure 1).

Dr Hofseth and her colleagues showed that breast cell mitotic rate on continuous combined estrogen-progesterone replacement therapy was more than double that of women on estrogen replacement therapy alone ⁴. So, here was the first bit of real nonepidemiological evidence that this was true. The second set of evidence came from a randomized trial — the PEPI trial — where Dr Greendale and her colleagues ⁵ showed that there was a much greater increase in mammographic densities of women on estrogen-progestin than on estrogen alone (Figure 2).

The Overview ⁶ that was done a few years ago — which reported on all of the epidemiological studies ever done — showed that ERT alone increased breast cancer risk about 2% per year of use. There are arguments about how much longer that increased risk will last after HRT is stopped, and that question remains unanswered. A woman will experience a small increased risk of breast cancer, but if she uses it for just a few years to control hot flashes, then that would be a completely reasonable thing for her to do — hot flashes are pretty awful.

—Malcolm Pike, PhD

Select Publications

APPROACHES TO REDUCING BREAST CANCER PROGESTIN EXPOSURE WITH HRT

One way to manage breast cancer versus endometrial cancer risk is to give progestins less frequently. Bruce Ettinger ¹⁰ in Oakland and Dan Williams ¹¹ at UCLA both showed that if you gave progestins for 12 to 14 days every three months — instead of every month — you got complete control of endometrial hyperplasia. And we showed in an epidemiological study that this was extremely likely to be successful in preventing endometrial cancer, which is the primary reason to give a progestin.

Another option is to use an intrauterine device. ¹² Progestasert® (intrauterine progesterone contraceptive system) has to be removed every 18 months but contains a very low dose of progesterone that does not get into the circulation. The newer IUD containing progestins — Mirena ® (levonorgestrel-releasing intrauterine system) — should last for 10 years. Progesterone can also be delivered intravaginally, which can change the ratio of concentrations in the endometrium relative to the blood by a factor of 50.

—Malcolm Pike, PhD

Select Publications

EVALUATION OF CURRENTLY AVAILABLE HORMONE REPLACEMENT DRUG THERAPIES

Ortho-PREFEST® (estradiol/norgestimate) has just been approved by the FDA. It’s one milligram estradiol and 0.09 milligrams of norgestimate — one of the new progestins, and it is given for three days every six days. This agent is intended to keep estradiol and progesterone at the highest levels, which is potentially a disaster. There’s no requirement of the FDA at the current time to show that new forms of estrogen-progesterone replacement therapy do not increase breast cancer risk. We must insist on that, because this is a major cause of breast cancer in the United States at the moment.

HRT IN WOMEN RECEIVING TAMOXIFEN

The premenopausal woman taking tamoxifen has high levels of circulating estrogen, because tamoxifen is acting as a stimulant to the ovary. And yet tamoxifen still works. In the P-1 study ¹⁴ and in other randomized trials, tamoxifen was very effective in preventing breast cancer as well as contralateral disease in premenopausal women. So, for a postmenopausal woman on an antiestrogen, a small dose of estrogen probably doesn't matter.

—Malcolm Pike, PhD

Select Publications

IBIS II TRIAL OF ANASTROZOLE FOR BREAST CANCER PREVENTION

These trials must take the same sort of approach that we used with SERMs — to look at all the effects including bone and lipids. There’s no real question that if you block all estrogen, you’ll get a tremendous effect on breast cancer risk. Will that effect be as great as tamoxifen? I don’t know, because the effect of tamoxifen is really quite astounding — a 50% reduction in risk, effective instantaneously.

You might get that with an aromatase inhibitor but we don’t know that. In normal women, breast cancer rates increase sharply in premenopausal women and much less after menopause. But between premenopause and postmenopause — in the perimenopausal period — breast cancer rates actually drop temporarily. And that must be because the cells were living in this estrogen-progesterone environment, and now they’re changing to a low-level estrogen environment. Also, in premenopausal women, the drop in breast cancer rates with an oophorectomy is as sharp as with tamoxifen. So, any real drastic change in hormones will do this.

With anastrozole, it will depend on how large the change is and where you think the dose response curve is. A postmenopausal woman has 20 picograms per ml of estradiol, and with anastrozole s h e ’s going to have nothing. But you’re also going to have to look at her bones and lots of other things. It’s the same problem as with SERMs. You’re going to have to prove that all these other things are okay, not just that you’re reducing breast cancer risk, because I’m sure you will.

—Malcolm Pike, PhD

Select Publications

Home · Search