Breast Cancer Hormone Therapy: Types, Combinations, and Treatment Duration

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• Hormone Therapy Classes
• Choosing the Right Treatment
• CDK4/6 Inhibitors Combination
• Treatment Duration: Metastatic
• Treatment Duration: Adjuvant
• Combination Therapy Rationale
• Full Transcript

Hormone Therapy Classes

Dr. Marc Lippman, MD, identifies the two main sources of estrogen in the body: the ovaries and body fat. He explains the three major classes of hormonal medications used to treat breast cancer. These are LHRH agonists (also called GnRH agonists), selective estrogen receptor modulators (SERMs), and aromatase inhibitors. Dr. Lippman also clarifies that a newer class, selective estrogen receptor degraders (SERDs), is now recognized separately from SERMs. Fulvestrant is the main SERD, with oral versions expected soon.

Choosing the Right Treatment

Dr. Marc Lippman, MD, states that the choice between these breast cancer medications is determined by randomized clinical trials. These trials empirically assess both efficacy and toxicity to identify the most effective drug. For postmenopausal women with metastatic breast cancer, aromatase inhibitors are somewhat more effective than tamoxifen and are usually the first-line treatment. Dr. Anton Titov, MD, facilitates this discussion on treatment selection criteria.

CDK4/6 Inhibitors Combination

Dr. Marc Lippman, MD, highlights the significant advancement of combining endocrine therapy with CDK4/6 inhibitors. These inhibitors block a key pathway of drug resistance. Overwhelming evidence shows that combining a CDK4/6 inhibitor with an aromatase inhibitor dramatically increases response rates and doubles response duration in metastatic breast cancer. This combination is so promising that it has moved into adjuvant clinical trials with very encouraging results. Dr. Lippman suggests single-agent use of tamoxifen or aromatase inhibitors is going out of fashion.

Treatment Duration: Metastatic Setting

The duration of hormone therapy differs between metastatic and adjuvant settings. Dr. Marc Lippman, MD, explains that for metastatic breast cancer, treatment continues until the patient's disease progresses. Toxicity from these therapies is generally minimal and is vastly outweighed by the risks of progressive metastatic disease. He references historical data where patients responded to oophorectomy for over a decade, underscoring that effective endocrine therapy can be given for very long periods.

Treatment Duration: Adjuvant Setting

In the adjuvant setting, treatment duration has been established empirically over decades. Dr. Marc Lippman, MD, recounts how studies proved five years of tamoxifen was superior to one or two years, making it a long-standing standard. However, newer adjuvant trials with CDK4/6 inhibitors use shorter treatment periods. Dr. Marc Lippman, MD, notes this is partly due to the "fiendishly expensive" cost of these drugs, which can be $3,000 to $5,000 per month, calling this an unfortunate circumstance where expense influences efficacy decisions.

Combination Therapy Rationale

Dr. Marc Lippman, MD, provides the rationale for combining different hormone therapies. For premenopausal women, studies show that suppressing ovarian estrogen production with a GnRH agonist (or ovariectomy) and then adding an aromatase inhibitor or tamoxifen is far more effective than tamoxifen alone. This combination is used for poor prognosis or younger women to prevent breast cancer recurrence. These combined treatments are typically administered for about three years, as that is the duration patients are generally willing to tolerate.

Full Transcript

Dr. Anton Titov, MD: How to choose between these medications to reduce estrogen effects in breast cancer?

There are two main sources of estrogen: the ovaries and body fat. There are three major classes of hormonal medications to treat breast cancer: LHRH agonists, or GnRH agonists as they are also called; selective estrogen receptor modulators, SERMs; and aromatase inhibitors.

Your list is incomplete because now people separate drugs like tamoxifen or SERMs, selective estrogen receptor modulators, from a class of drugs called SERDs, selective estrogen receptor degraders. Fulvestrant is the main drug of the SERD class. There will shortly be orally available SERDs over the next couple of months. They are even more active than fulvestrant. Oral SERDs are very exciting.

Dr. Marc Lippman, MD: But the exact answer to your question is randomized clinical trials. These are empiric questions that look at both efficacy and toxicity and try to make statements about the most effective drug.

In metastatic breast cancer for postmenopausal women, aromatase inhibitors are somewhat more effective than tamoxifen. They are usually the first line.

Now there are other well-done randomized clinical trials of another class of drugs, CDK4/6 inhibitors. CDK4/6 inhibitors block one pathway of drug resistance. It has been proven overwhelmingly that, when combined with an aromatase inhibitor, CDK4/6 inhibitors dramatically increase both response rates and double response duration. So that's extremely exciting.

And those drugs have now been promoted to adjuvant clinical trials, where they are also very encouraging. So the single use of tamoxifen or aromatase inhibitors is probably going out of fashion. It seems that combinations of aromatase inhibitors or tamoxifen, at least with the CDK4/6 inhibitors, are vastly more effective.

Dr. Anton Titov, MD: Why are these medications, such as tamoxifen or aromatase inhibitors, LHRH or GnRH agonists, used in combination? What is the rationale for their use together? And perhaps there are some instances when they should not be used in combination?

Dr. Marc Lippman, MD: The best answer to your question is you need to separate whether we are talking about metastatic breast cancer or the adjuvant treatment of breast cancer.

We are giving these drugs to prevent recurrence in the metastatic disease setting unless toxicity intervenes, which is pretty uncommon. The drugs continue till the patient progresses. There's no reason to stop them.

For the most part, as I've already said, the toxicities of these therapies are very minimal, vastly offset by the risks of progressive metastatic disease. So endocrine therapies can be given endlessly until patients progress.

In the old days, breast cancer patients were treated by ovariectomy, oophorectomy. There were certainly patients who responded for more than a decade. So, obviously, you would continue with the current therapy until patients didn't respond to treatment anymore.

In the adjuvant chemotherapy of breast cancer, most of these studies have been done empirically over many decades. When tamoxifen was first used to prevent a recurrence of breast cancer, people gave it for a year. And it worked.

So then people did studies that compared two years to one year. And two years was better. Then people compared five years to two years of tamoxifen. Five years of tamoxifen therapy was better than two years. So five years became something of an established empirical standard for breast cancer treatment.

Some of the new studies of the adjuvant chemotherapy of breast cancer with CDK4/6 inhibitors have been for shorter periods. The reason for that is partly because the CDK4/6 inhibitors are so fiendishly expensive, and no one wants to pay $3,000, $4,000, or $5,000 a month.

So much of this isn't an efficacy issue but an expense issue. And that's, in my opinion, extremely unfortunate that that kind of decision is made under those circumstances.

In terms of combining these therapies, recently a series of studies have proven that in premenopausal women, you can interfere with ovarian estrogen production with a GnRH drug, as you mentioned, or just by ovariectomy. Then, if you give an aromatase inhibitor or tamoxifen, it's far more effective than giving the tamoxifen alone.

So for poor prognosis or younger women, whom we are treating to prevent breast cancer recurrence, the fact is that usually tamoxifen or aromatase inhibitors are combined, when possible, with GnRH agents to suppress the ovary. And those treatments are usually for about three years because that's all people want to tolerate.