Monthly versus Every Three-Month Ovarian Suppression

DR CARLSON: The data are pretty clear that when we administer the LHRH agonists on an every three-month basis, the ovaries produce breakthrough estrogen. The data are convincing that monthly LHRH-agonist treatment adequately and continually suppresses estrogen production, but the every three-month formulations don’t. They suppress ovarian function for a month or two, but then breakthrough estrogen production occurs.

This is a major problem, particularly for the patient who is being treated with an LHRH agonist and an aromatase inhibitor. The target for the aromatase inhibitors may actually be the intratumoral aromatase enzyme, so it may not be necessary to fully suppress estrogen production in the ovary, but until we know better, the target we can measure easily is circulating estrogen.

If we use an aromatase inhibitor in a premenopausal woman with functioning ovaries, we’re simply not going to adequately suppress estrogen production with the every three-month administration of an LHRH agonist. I agree that if you are going to use an aromatase inhibitor in a woman who is functionally premenopausal, you have to be certain to adequately suppress ovarian function.

We have submitted an abstract to ASCO 2007 updating our experience with an LHRH agonist in combination with an aromatase inhibitor. The trial has completed accrual, and we have 32 women who were treated and can be evaluated.

The most recent update confirms our earlier preliminary data presented at the San Antonio Breast Cancer Symposium. It shows about a 70 to 75 percent clinical benefit for premenopausal women with hormone receptor-positive metastatic breast cancer. The duration of response is good. We have one woman who has been on five-plus years of treatment and has shown a durable complete response.

We measured estradiol levels at baseline, one, three and six months. And for selected patients, but not as specified by the protocol, we recorded follow-up estradiol levels subsequently. We saw rapid and nearly complete suppression of estrogen production by the ovary at one month. This was maintained at three months, and it was maintained in all but one patient at six months. One patient did have breakthrough estrogen production at six months, but subsequent monitoring confirmed that the levels were later suppressed adequately.

It is disturbing that so many people are using a regimen they shouldn’t be using. I believe this is a substantial educational opportunity. We should be using the LHRH agonists on a monthly basis.

Endocrine Therapy After Adjuvant Anastrozole

DR CARLSON: One of the surprising aspects of these responses was the fact that practicing oncologists are not infrequently switching women from anastrozole to letrozole. Twelve percent of practicing oncologists in the 2007 survey said they would change to letrozole after a woman progressed on anastrozole. This is another situation in which we may have an educational opportunity because we have no data that I’m aware of indicating that responses occur with crossovers from one of the nonsteroidal aromatase inhibitors to the other.

I’m not surprised that we see a lot of differences of opinion and practice patterns in the treatment options that either the clinical investigators or the practicing oncologists are selecting. We have little evidence that any one of the hormonal therapies is head and shoulders above or even subtly superior to the others as second-line therapy.

The bottom line from EFECT was that overall rates of response and times to progression were not different for exemestane versus fulvestrant in patients experiencing progression on a nonsteroidal aromatase inhibitor. Among the patients who did achieve a response, a suggestion emerged that fulvestrant might show some superiority in duration of response, but the differences were quite subtle. As we would expect, both of the agents were well tolerated.

In deciding among tamoxifen, fulvestrant and exemestane for a woman whose disease is progressing on a nonsteroidal aromatase inhibitor, I talk with her about whether she prefers an oral agent or an every four-week injection. Some patients express a preference, but many don’t.

To some extent, it’s also a matter of which toxicities the woman is most concerned about. If a woman has a history of osteoporosis or an arthralgia-type syndrome, I might favor tamoxifen or fulvestrant. Those are typical considerations. For a woman whose disease has progressed during therapy with anastrozole, fulvestrant would generally be my first choice.

Whether or not a patient is coming in for a monthly bisphosphonate injection can help to tip the scale. Certainly for women with bone metastases, the use of bisphosphonates is appropriate. In that setting, it is much more convenient for the woman to receive the bisphosphonate and fulvestrant rather than receiving the bisphosphonate and having to remember to take a daily aromatase inhibitor.

Another factor I consider is my belief about how compliant a woman is. A growing body of data suggests that a number of women who walk out of our office with prescriptions for anticancer therapies simply don’t take their medications regularly.

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