Section 4
Aromatase Inhibitors in Clinical Practice

FIRST-LINE ENDOCRINE THERAPY IN POSTMENOPAUSAL WOMEN

Aromatase inhibitors are far better than tamoxifen, not only in terms of antitumor activity, but also the safety profile, because of the risk of thromboembolic complications with tamoxifen and the agonist effect on the endometrium. Even though there were few such events in the first-line metastastic trials, the risk of vaginal bleeding was almost 50 percent lower with anastrozole compared to tamoxifen. From the individual patient point of view, postmenopausal bleeding starts a domino effect. An ultrasound is required, the gynecologist becomes involved, and the patient may end up having an endometrial biopsy or D&C. And then you find out that this was the effect of tamoxifen. Whereas, if that can be avoided with a drug with better antitumor activity — controlling the disease for a longer period of time — you have a better overall therapeutic index.

—Aman Buzdar, MD

METABOLIC EFFECTS OF ANASTROZOLE VS LETROZOLE

There is published peer-review data showing that anastrozole — even at five to 10 times the recommended package dose — does not blunt the response to ACTH stimulation and does not interfere with other P-450 cytochrome enzymes. However, 2.5 milligrams of letrozole blunts the secretion of aldosterone and cortisone, and this could have clinical implications.

The question is whether this is clinically relevant? Overt adrenal insufficiency has not been reported with letrozole, but it is possible that this may not become manifest under normal circumstances, but only under acute stress — for example, with sepsis or a fracture — where it might play a major role. Many side effects are not reported, because we don’t look for them.

In terms of adrenal insufficiency, a patient may have acute stress — for example sepsis, where you may be pumping antibiotics into the patient, but what is actually required is a little touch of cortisone. Unless we look for these things clinically, we will not see them. I think this may have clinical implications, particularly in the future, if we are treating patients in the adjuvant setting for an extended time period. We don’t have any data on the clinical implications of keeping patients subclinically adrenally suppressed for, say, five years.

—Aman Buzdar, MD

STEROIDAL EFFECTS OF EXEMESTANE

Exemestane is a very active and impressive compound, but I have concerns because it is a steroidal substance with steroidal side effects. In some patients, this agent causes viralization, which may be very subtle. I use exemestane quite frequently as a second- or third-line therapy, and I have seen subtle changes such as deepening of the voice and acne.

Another androgen-related side effect reported with exemestane in the second-line setting is that it causes somewhat more weight gain compared to anastrozole or letrozole. Also, if you look at the risk of thromboembolic complications, both anastrozole and letrozole are inert compounds and do not interfere with coagulation pathways. We don ’t have data on exemestane, and because of its weak androgenic structure, this will need to be evaluated.

—Aman Buzdar, MD

CHOICE OF AROMATASE INHIBITOR

If we did not have the concern about letrozole causing adrenal problems, letrozole and anastrozole would — in my mind — be essentially equivalent. However, anastrozole has an advantage in metabolic selectivity because — even at substantially higher doses than we use clinically — there is no interference with other P-450 cytochrome enzymes. Also, if you look at antitumor activity — and these are indirect comparisons — both in second-line and in first-line settings, the total clinical benefit is slightly in favor of anastrozole compared to letrozole. With exemestane, there is the issue of weak androgenic activity. If you look at it from the selectivity point of view, I think out of the three agents that we now have, anastrozole is the most selective agent.

—Aman Buzdar, MD

Outside of a clinical trial setting,we use either anastrozole or letrozole as our first choice of endocrine therapy for postmenopausal patients with metastatic breast cancer. Both agents are extremely well-tolerated and effective, and I currently consider the two interchangeable for metastatic breast cancer. I will reserve judgment as to whether there is a true clinically relevant difference until direct randomized trial data become available. If you just watch me practice, I usually choose anastrozole — my automatic pilot will write anastrozole — because I have much more experience with it. There is a rationale to currently choose either anastrozole or letrozole as opposed to exemestane, simply because of the magnitude of the available database and clinical experience.

—Gabriel Hortobagyi, MD

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