Combination Hormonal Therapy with Aromatase Inhibitors for Breast Cancer: What Patients Should Know

Table of Contents

• Key Points
• Why This Research Matters
• Hormone Therapy and Breast Cancer: The Basics
• How the Research Was Conducted
• Key Findings: The Randomized Clinical Trials
• The Drug Interaction Problem
• Newer Drugs: Letrozole Combined with Tamoxifen
• What Laboratory Studies Showed
• What This Means for Patients
• Limitations of This Research Review
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• In 10 randomized trials, combining the older aromatase inhibitor aminoglutethimide with tamoxifen or progestins did not improve outcomes in advanced breast cancer.
• Aminoglutethimide lowered blood levels of tamoxifen by 73% on average and megestrol acetate by 79%, explaining why combinations failed.
• In a 17-patient pilot study, letrozole did not reduce tamoxifen levels and suppressed estradiol by a median 88.5%.
• In mice with human breast cancer cells, tamoxifen plus letrozole appeared less effective than letrozole alone.
• As of 1999, the value of combining newer aromatase inhibitors with other hormonal agents remained unproven, so more research was needed.

Why This Research Matters

Hormonal therapy remains an essential part of treatment for most women with breast cancer. It is used in two main situations: the adjuvant setting (after surgery, to reduce the chance the cancer returns) and the metastatic setting (when the cancer has spread to other parts of the body).

A variety of hormonal agents were already in clinical use in 1999. These included antiestrogens, progestins, androgens, estrogens (at high doses), luteinizing hormone-releasing hormone analogs, and aromatase inhibitors.

Yet even with many drugs available, a sizable proportion of tumors do not respond to treatment. Tumors that do respond will, in all likelihood, eventually become resistant. The need for more effective hormone regimens is therefore clear.

Because multiple classes of drugs work by different mechanisms, and because these drugs are generally well tolerated at full doses, researchers became interested in combination therapy. The logic was simple: attacking the cancer's hormone system from several angles at once might work better than a single approach.

Hormone Therapy and Breast Cancer: The Basics

To understand this research, it helps to know the key players in breast cancer hormone therapy:

• Tamoxifen (TAM) — an antiestrogen that blocks the estrogen receptor on breast cancer cells. Instead of letting estrogen attach and fuel growth, it occupies the receptor and acts as a competitive inhibitor.
• Aromatase inhibitors — drugs that block the aromatase enzyme, which converts androgens into estrogen. In postmenopausal women, this conversion is the main source of estrogen in the body.
• Progestins — synthetic hormones similar to progesterone, including megestrol acetate (MA) and medroxyprogesterone acetate (MPA).
• Danazol — a synthetic hormone with progestin-like activity.

The mechanism of aromatase inhibitors is well defined: they reduce circulating estrogens in the body. Notably, aromatase activity also exists within a substantial proportion of breast carcinomas themselves (Lipton et al. 1987), which adds another incentive for studying these drugs.

The idea of combining an aromatase inhibitor with tamoxifen was particularly attractive. The two drugs have different mechanisms of action that could be complementary. The aromatase inhibitor would decrease estrogen levels, allowing tamoxifen to act more effectively as a competitor against whatever estradiol remained.

By 1999, newer aromatase inhibitors had arrived that were more potent, more selective, and better tolerated than the original drug, aminoglutethimide (Goss & Gwyn 1994). This prompted a fresh look at the combination approach.

How the Research Was Conducted

This is a review article, not a single clinical trial. The authors gathered and analyzed all the published randomized trials that tested combination hormonal therapy involving aromatase inhibitors. They also reported their own pilot studies of the newer drug letrozole combined with tamoxifen.

The aromatase inhibitor used in every randomized trial was aminoglutethimide (AG). Because aminoglutethimide also suppresses the adrenal glands, it was always given together with hydrocortisone.

The review examined several types of comparisons:

• Five trials comparing tamoxifen alone versus tamoxifen plus aminoglutethimide
• One trial testing a three-drug combination of tamoxifen plus aminoglutethimide plus danazol
• Three trials adding aminoglutethimide to a progestin (megestrol acetate or medroxyprogesterone acetate)
• Early pilot pharmacokinetic studies of letrozole combined with tamoxifen
• A laboratory (preclinical) study using human breast cancer cells grown in mice

The researchers looked at several endpoints. Objective response rate is the percentage of patients whose tumors measurably shrank. Time to progression is how long before the cancer grew again. Time to treatment failure includes progression plus stopping treatment for side effects or other reasons. Survival was also recorded when available.

Key Findings: The Randomized Clinical Trials

The results across the trials were remarkably consistent. None of them showed a clear advantage for combining aminoglutethimide with another hormone drug.

The table below summarizes all the randomized trials reviewed in this article:

*Response in the megestrol acetate (MA) group was determined in a total of 122 patients.

The largest trial was that of Rose et al. (1986), which included 179 patients evaluable for time analyses and 166 evaluable for response. There was no indication of a therapeutic advantage, and the toxicity was greater when aminoglutethimide was added to tamoxifen.

The four smaller tamoxifen studies (Corkery 1982, Ingle 1986, Milsted 1985, Alonso-Muñoz 1988) had similar results. Adding aminoglutethimide did not meaningfully improve response rates, time to progression, or survival.

One trial stood apart. Powles et al. (1984) compared tamoxifen alone against tamoxifen plus aminoglutethimide plus danazol. The three-drug combination produced a higher response rate (43% vs 31%, P=0.05), a result right at the edge of statistical significance. That means there is about a 5% chance the difference occurred by random luck.

However, the combination showed no advantage in duration of response. In fact, the response lasted about 17.5 months with the three-drug regimen versus about 22.5 months with tamoxifen alone. The authors themselves concluded the trial did not demonstrate a therapeutic advantage.

The three progestin studies echoed the tamoxifen findings. In the largest one, Russell et al. (1997), researchers studied postmenopausal women with estrogen-receptor-positive tumors who had previously responded to tamoxifen or stayed stable for at least six months. Objective response rates were 6% with megestrol acetate, 24% with aminoglutethimide, and 23% with the combination. There were no significant differences in time to treatment failure or survival.

Wander et al. (1987) found identical response rates of 32% for aminoglutethimide alone and aminoglutethimide plus medroxyprogesterone acetate. Samonis et al. (1994) found no significant advantage for the three-way comparison among medroxyprogesterone acetate, aminoglutethimide, and the combination.

The Drug Interaction Problem: Why Combinations Failed

Why did these combinations fail to help? A 1990 study by Lien and colleagues provided a likely answer: the drugs were interfering with each other inside the body.

Lien et al. (1990) studied six postmenopausal women who had been taking tamoxifen alone for more than six months. Aminoglutethimide was then added at a dose of 250 mg four times a day (in five patients) or three times a day (in one patient). Patients also took cortisone acetate at 50 mg twice a day for two weeks, then 25 mg twice a day afterward.

The results were dramatic. Aminoglutethimide caused a significant decrease in the area under the curve (AUC) for tamoxifen. The AUC is a measure of the total amount of drug the body is exposed to over time. The mean reduction was 73%, with a range of 56% to 80% across patients.

This corresponded to a mean increase in tamoxifen clearance of 222% — meaning the body was eliminating the drug more than three times as fast. The researchers also examined five metabolites (breakdown products) of tamoxifen, including N-desmethyl-tamoxifen and 4-hydroxy-tamoxifen. The AUC for most metabolites was also reduced, with a mean reduction of about 50%.

The authors concluded that aminoglutethimide was most likely inducing tamoxifen metabolism, speeding up its breakdown in the liver. This reduction in tamoxifen and its active metabolites provided a logical explanation for why the combination trials failed to show superiority. The tamoxifen may simply have been less available to fight the cancer when aminoglutethimide was present.

Similar problems occurred with progestins. Aminoglutethimide was found to reduce mean plasma levels of medroxyprogesterone acetate by 50% (Van Deijk et al. 1985) and mean serum levels by 60% (Lundgren et al. 1990). It reduced serum megestrol acetate levels by a striking 79% (Lundgren et al. 1990).

There was also a biochemical problem with the three-drug danazol combination. Dowsett et al. (1986) demonstrated that aminoglutethimide and danazol have opposing effects on the concentration of free, biologically active estradiol in the blood. Using danazol together with aminoglutethimide would therefore be expected to be counterproductive.

Newer Drugs: Letrozole Combined with Tamoxifen

The arrival of a new generation of aromatase inhibitors raised the question again. The most promising agents were letrozole and anastrozole, both already approved by the US Food and Drug Administration (FDA) by 1999. These newer drugs are orally active, potent, specific, and well tolerated (Dombernowsky et al. 1998; Buzdar et al. 1996).

Based on their prior experience with letrozole (Ingle et al. 1997), the authors chose to study this drug in combination with tamoxifen. They learned from the aminoglutethimide experience: before launching a large phase III trial, they first tested for any pharmacokinetic interaction between tamoxifen and letrozole — that is, whether one drug changed the levels of the other.

In the first pilot study (reported by Ingle and colleagues as unpublished work at the time of this review), patients received tamoxifen at 20 mg daily for six weeks. Then letrozole at 2.5 mg daily was added. Levels of tamoxifen, N-desmethyl-tamoxifen, and 4-hydroxy-tamoxifen were measured at six-week intervals for up to 18 weeks after letrozole was added.

Seventeen patients were assessed at both week 6 (before letrozole) and week 24 (18 weeks after adding letrozole). The results were reassuring: there was no systematic decrease in tamoxifen or its two main metabolites following the addition of letrozole.

The percent change varied substantially from patient to patient, but the median changes were close to zero for most measurements. This was very different from the dramatic drop seen when aminoglutethimide was added to tamoxifen in the Lien study.

Equally important, estrogen suppression by letrozole remained strong even when tamoxifen was given at the same time. All patients experienced a substantial reduction in estradiol after six weeks of letrozole. The median decrease was 88.5%, with a range of 73.7% to 95.2%.

A complementary study by Dowsett et al. (1997a) asked the reverse question: does tamoxifen change letrozole levels? In that study, patients received letrozole 2.5 mg daily for six weeks, followed by the addition of tamoxifen at 20 mg daily. Blood samples were taken one day before tamoxifen was added and again after six weeks of combined treatment.

The results showed that letrozole levels did fall somewhat. The letrozole AUC decreased by a mean of 30.6% (±17.9%). This reduction was seen in 9 of the 10 patients studied. The range of change was from −5% to +59.4%, and the reduction exceeded 30% in seven patients.

The authors noted that these reduced letrozole levels corresponded to estimated daily doses of only 1.5 to 2 mg instead of the intended 2.5 mg. Whether this degree of reduction is clinically important remained unclear, but it was far less severe than the 73% drop seen with aminoglutethimide and tamoxifen.

What Laboratory Studies Showed

Recent preclinical data raised concerns about combining aromatase inhibitors with tamoxifen. Brodie et al. (1998) used MCF-7 cells, a well-known breast cancer cell line, that had been stably modified to carry the aromatase gene. These cells were grown in ovariectomized (surgically sterilized) nude mice, creating a model of postmenopausal breast cancer that produces its own estrogen.

The researchers compared tamoxifen, letrozole, and anastrozole, both alone and in combination. The key finding was sobering: adding tamoxifen to an aromatase inhibitor provided no additional benefit over the aromatase inhibitor alone.

In fact, while the combination of tamoxifen plus letrozole was significantly more effective than tamoxifen alone, letrozole by itself appeared to be superior to the combination of tamoxifen plus letrozole.

This result suggests that tamoxifen might actually interfere with the benefit of aromatase inhibition, rather than adding to it. One possible explanation is that tamoxifen's weak estrogen-like activity partially counteracts the dramatic estrogen lowering achieved by the aromatase inhibitor.

What This Means for Patients

So what is the bottom line for patients? Based on the evidence available in 1999, combining an aromatase inhibitor with tamoxifen or a progestin did not improve outcomes in advanced breast cancer.

For aminoglutethimide specifically, the evidence was consistent across multiple randomized trials. Combinations were no better than single drugs, and they were sometimes more toxic. Drug interactions — aminoglutethimide lowering levels of tamoxifen by an average of 73%, megestrol acetate by 79%, and medroxyprogesterone acetate by 50% to 60% — likely explain much of the failure.

For the newer aromatase inhibitors, the story was still unfolding. Letrozole did not substantially reduce tamoxifen levels, which was an encouraging difference. Estrogen suppression was powerful even in combination, with a median 88.5% reduction in estradiol. These findings meant a large phase III trial could reasonably be considered.

However, the laboratory data from Brodie et al. (1998) introduced caution. If aromatase inhibitors alone are superior to the combination, then combining them with tamoxifen could actually dilute the benefit for patients.

The authors' final conclusion was direct and measured: the concept of combining aromatase inhibitors with antiestrogens such as tamoxifen remains attractive, but further preclinical and clinical research is necessary. The value of combining aromatase inhibitors with other hormonal agents remains to be established.

Limitations of This Research Review

This review has important limitations that patients should understand:

• Old drug, old era. All the randomized trials used aminoglutethimide, a first-generation aromatase inhibitor that is no longer commonly used. It required hydrocortisone replacement and had significant side effects.
• Small sample sizes. Several trials were quite small. Corkery et al. (1982), for example, studied only 9 to 11 patients per group. Small trials can miss true differences, but they can also produce unreliable results.
• Tiny pharmacokinetic studies. The Lien tamoxifen-among study included just six women. The Dowsett letrozole study included only 10 patients. The Ingle pilot study included 17.
• Unpublished pilot data. The letrozole-plus-tamoxifen pharmacokinetic results from Ingle's group were described as unpublished work at the time, meaning they had not yet undergone full peer review.
• Advanced disease focus. These trials were conducted in women with metastatic or advanced breast cancer. The findings may not translate directly to the adjuvant setting, where women take hormones after surgery to prevent recurrence.
• Specific patient population. The Russell trial required estrogen-receptor-positive tumors and prior benefit from tamoxifen. Results may not apply to hormone-receptor-negative disease or to women who had not previously responded to hormone therapy.
• No phase III data for newer combinations. As of 1999, no large randomized trial had yet established whether letrozole plus tamoxifen was superior to letrozole alone in patients.
• Animal model limitations. The Brodie preclinical findings came from mice implanted with human breast cancer cells. While informative, animal models do not perfectly predict what happens in patients.

Recommendations for Patients

This research belongs to a specific moment in medical history — 1999, when aromatase inhibitors were just entering routine practice. Treatment has evolved considerably since then. Still, several practical lessons from this review remain relevant.

1. Ask about the rationale for any combination. If your oncologist suggests combining two hormone therapies, ask what evidence supports the combination and whether drug interactions have been ruled out.
2. Know your hormone receptor status. Hormone therapy works mainly for tumors that are estrogen-receptor-positive or progesterone-receptor-positive. These trials focused on that group of patients.
3. Do not combine old and new generation drugs. The dramatic drug interactions seen with aminoglutethimide illustrate why combining hormone drugs is not automatically beneficial — sometimes the drugs undermine each other.
4. Understand that single-agent therapy is often the standard. In this review, no combination beat the best single agent. Aromatase inhibitors and tamoxifen each remained effective options on their own.
5. Ask about side effects. In the largest trial reviewed (Rose 1986), adding aminoglutethimide increased toxicity without improving benefit. More drugs can mean more side effects without more effect.
6. Look for clinical trials. The authors emphasized that further research was needed. Ask your oncology team whether any current clinical trials explore newer hormonal combinations relevant to your situation.

Above all, this review highlights a key principle of cancer medicine: more treatment is not always better treatment. Every drug added to a regimen carries the potential for interactions, side effects, and unexpected harm. Decisions about hormone therapy — alone or in combination — should always be individualized, based on your specific tumor characteristics, prior treatments, and overall health.

Frequently Asked Questions

What is hormone therapy for breast cancer, and why did researchers think combining two hormone drugs might work better?

Hormone therapy treats breast cancer by blocking or lowering estrogen, which fuels many tumors. Multiple drug classes work in different ways, so doctors reasoned that attacking estrogen production and estrogen receptors at once might improve results. However, this review found that combining older aromatase inhibitors with tamoxifen or progestins did not improve outcomes.

Did combining an aromatase inhibitor with tamoxifen or a progestin improve breast cancer outcomes in the clinical trials reviewed?

No. Across ten randomized trials using the older drug aminoglutethimide, combinations did not meaningfully improve response rates, time to progression, or survival compared with single drugs. In some trials, the combination caused more side effects. Drug interactions lowered levels of the partner drug, which likely explains why the combinations failed.

Why did aminoglutethimide combined with tamoxifen or progestins fail to help patients?

Aminoglutethimide speeded up the breakdown of tamoxifen and progestins in the body. In one study of six women, it reduced tamoxifen levels by an average of 73%. It also lowered megestrol acetate levels by 79% and medroxyprogesterone acetate by 50% to 60%, so the partner drugs were less available to fight cancer.

Did combining the newer drug letrozole with tamoxifen cause similar drug interactions?

No. In a pilot study of 17 patients, letrozole did not systematically reduce tamoxifen or its main metabolites, and estrogen suppression remained strong. A separate study of 10 patients found letrozole levels fell by about 30% when tamoxifen was added—far less than the 73% drop seen with aminoglutethimide—but whether this matters clinically was unclear.

What did laboratory studies show about combining aromatase inhibitors with tamoxifen?

In mice implanted with aromatase-expressing human breast cancer cells, adding tamoxifen to letrozole or anastrozole provided no extra benefit over the aromatase inhibitor alone. Letrozole by itself appeared superior to the combination, possibly because tamoxifen's weak estrogen-like activity partially counteracts the estrogen-lowering effect of aromatase inhibitors.

What were the limitations of this research review?

All randomized trials used the old drug aminoglutethimide, many trials were small, and pharmacokinetic studies included only 6 to 17 patients. Some pilot data were unpublished. The trials involved advanced breast cancer, not early-stage disease, and results may not apply to hormone-receptor-negative tumors. No large phase III trial of newer combinations had been completed by 1999.

Should I get a second opinion before starting combination hormonal therapy with an aromatase inhibitor and tamoxifen for breast cancer?

Combining an aromatase inhibitor with tamoxifen or a progestin has not been shown to improve outcomes in advanced breast cancer; in some cases, the combination reduced blood levels of the other drug. For newer agents like letrozole, laboratory findings even suggested that adding tamoxifen may reduce the benefit of the aromatase inhibitor alone. Because adding a drug can increase side effects without improving effectiveness, a second opinion can help clarify whether your recommended combination is supported by evidence or whether single-agent hormone therapy is a better choice. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

This patient-friendly article is based on a peer-reviewed scientific publication:

Original title: "Combination hormonal therapy involving aromatase inhibitors in the management of women with breast cancer"

Journal: Endocrine-Related Cancer (1999), volume 6, pages 265–269. Published by the Society for Endocrinology.

This patient-friendly article was created as a translation of the original research for educational purposes. It is not a substitute for individualized medical advice from your oncology care team.