Hormone Therapy for Breast Cancer: History, Advances, and Prevention

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• Early History of Hormone Therapy
• Scientific Breakthroughs in Endocrinology
• Evolution of Surgical Endocrine Therapies
• Development of Anti-Estrogen Drugs
• Endocrine Therapy for Early-Stage Cancer
• Breast Cancer Prevention Therapies
• Full Transcript

Early History of Hormone Therapy

The role of hormones in breast cancer has been observed for centuries. Dr. Marc Lippman, MD, references epidemiology studies from 17th century Verona, Italy. These studies showed a difference in breast cancer incidence between nuns and other women. The first classical endocrine therapy emerged in the late 19th century. Surgeons performed oophorectomy, or ovary removal, on premenopausal women with breast cancer. Dr. Marc Lippman, MD, notes that some women showed enormous objective responses to this ablative surgery.

Scientific Breakthroughs in Endocrinology

The real science of hormone therapy took many years to develop. A major hurdle was the inability to measure hormone levels. Dr. Marc Lippman, MD, explains that this changed in the early 1960s. The invention of radioimmunoassay and radioreceptor assays was a critical breakthrough. These technologies allowed scientists to measure incredibly low concentrations of steroid and peptide hormones. This made endocrinology a true science and clarified hormone feedback loops. It became easy to understand that breast cancer is a hormone-dependent illness.

Dr. Lippman offers a key insight into how estrogen affects growth. He tells Dr. Anton Titov, MD, that giving a man estrogen would cause breast growth. But there are natural limits to this growth. Breast cancer cells, however, forget how to stop growing when stimulated by estrogens. This understanding became clear in the 1940s and paved the way for scientific endocrine therapies.

Evolution of Surgical Endocrine Therapies

Early endocrine therapies focused on surgical ablation of hormone-producing organs. Oophorectomy remained a primary treatment for premenopausal women. Doctors also performed adrenalectomy, or adrenal gland removal. Dr. Marc Lippman, MD, notes that this required glucocorticoid substitution because they are essential for life. The adrenals are an indirect source of estrogens that can stimulate breast cancer growth.

Another major surgical procedure was hypophysectomy, or pituitary gland removal. Dr. Marc Lippman, MD, explains that this surgery, by removing gonadotropins and ACTH, caused hormone levels to fall. This often resulted in regression of breast cancer. These ablative surgeries were popular and very successful for many years before drug therapies were developed.

Development of Anti-Estrogen Drugs

The major advances in the 1970s and 1980s involved moving away from surgery. The goal was to achieve the same endocrine effects without ablative procedures. This led to the development of anti-estrogen drugs. Dr. Marc Lippman, MD, describes several of these drugs that work by interfering with estrogen action. When given to the right women, these anti-estrogens result in breast cancer regression.

This shift to pharmacological therapy was a monumental step forward. It allowed for effective treatment without the risks and morbidity associated with major surgery. The conversation between Dr. Lippman and Dr. Anton Titov, MD, highlights this as a key turning point in oncology.

Endocrine Therapy for Early-Stage Cancer

A critical evolution in treatment was applying endocrine therapy to earlier disease stages. Therapies that worked for metastatic breast cancer were advanced to the adjuvant setting. This means using them after primary treatment like mastectomy or lumpectomy. The goal was to prevent cancer recurrence. Dr. Marc Lippman, MD, states that clinical trials from 30-40 years ago are still being analyzed.

These trials resulted in profound improvements in survival. Dr. Marc Lippman, MD, emphasizes that many women were cured who would have otherwise died. He calls the adroit use of hormone therapy the single greatest advance in breast cancer treatment. This strategy has resulted in extraordinary falls in mortality rates from breast cancer.

Breast Cancer Prevention Therapies

The most recent advance is the use of endocrine therapy for prevention. Dr. Marc Lippman, MD, presents compelling data on its efficacy. Treating women for five years with therapies that interfere with estrogen levels can prevent 60 to 75% of all breast cancers. He describes the data as unequivocal and very compelling.

Despite this powerful evidence, Dr. Marc Lippman, MD, notes a significant problem. These preventive therapies are not as widely used as they should be. This represents a major missed opportunity in public health. Widespread adoption could prevent a vast number of breast cancer diagnoses. Dr. Anton Titov, MD, discusses these important findings with Dr. Lippman to highlight their significance.

Full Transcript

Dr. Anton Titov, MD: Professor Lippman, you created the first model of hormone-dependent human breast cancer, and you've been at the forefront of hormone breast cancer treatment ever since. Could you please give a high-level overview of the history and the presence of breast cancer treatment with hormone therapies?

Dr. Marc Lippman, MD: Sure. It's been appreciated for about 300 years that hormones played some role in breast cancer. There were epidemiology studies in Verona, Italy, in the 17th century. Can you believe it? They showed a difference in the incidence of breast cancer amongst nuns compared to women who weren't in nunneries. The person making this observation correctly attributed this to some sort of use of the breasts.

The first classical way people think of understanding endocrine therapy was done in the late 19th century, when someone first thought that perhaps removing the ovaries might have a beneficial effect on breast cancer. That turned out to be exactly the case in a small series of women who had their ovaries removed. These were obviously premenopausal women. Some of them showed enormous objective responses to removal of ovaries. It was a very gratifying result.

But the real science of this took many, many years to uncover because people didn't know how hormones worked. Not only did they not know how hormones worked, but they weren't able to even measure them. The concentrations of hormones required the invention in the early 1960s of radioimmunoassay and radioreceptor essay. Suddenly, endocrinology became a science.

It became possible to measure incredibly low concentrations of all kinds of steroid and peptide hormones. Hormone feedback loops became clear. And it became very easy to understand that breast cancer was a hormone-dependent illness.

It became appreciated, of course, that at puberty, a girl's estrogen levels rise, and she developed breasts. And it was appreciated shortly after that if you gave a man estrogens, he would grow breasts. The outstanding, though perhaps subtle observation about this is that if I gave you, Dr. Titov, estrogens, you would grow breasts.

But you wouldn't turn into a breast. You would have limits on growth. And that's exactly what happens to women. At puberty, they develop breasts. Their breasts, even though they bathe in estrogens for the next seven or eight decades of their lives, breasts don't particularly change.

Breast cancer remembers that phenotype some of the time. Breast cancer remembers this responsiveness to estrogens. Except when you give a breast cancer estrogens, it has forgotten how to stop growing. So it continues to grow and spread as long as it's stimulated with estrogens.

Therefore, it became clear in the 1940s, originally, that you could scientifically develop endocrine therapies for women involving the removal of ovaries. Of course, as I mentioned, in the adrenal glands, you have to substitute back glucocorticoids because they're essential for life.

But the adrenals are the source indirectly of estrogens which can stimulate the breast. For many years, it was popular and very successful to remove the pituitary. They did hypophysectomy, which also by removing gonadotropins and ACTH would result in falls of hormone levels and regressions of breast cancer.

The major advances in the 70s and 80s were to learn how to do these things without ablative surgery. Drugs such as what was commonly referred to as anti-estrogens were developed. There are several of those drugs, interfering with estrogen action. And when given to the right women, anti-estrogens result in breast cancer regression.

It's also a clear story that for almost all oncology, as things start to work in the more advanced disease settings for women with metastatic cancer, the same therapies can be advanced to earlier stages of cancer. This is exactly what happened with endocrine therapy of breast cancer.

It was first used for patients with metastatic cancer. Then very imaginatively hormones were used to prevent recurrences of the breast cancer, when women had their primary breast cancer treated by mastectomy or lumpectomy. Those clinical trials, which are still being analyzed now 30 and 40 years later, resulted in profound improvements in survival.

In fact, many women were cured who would have otherwise died. The single greatest advance, unquestionably, in the treatment of breast cancer, which has resulted in extraordinary falls in mortality rate, has been the adroit use of either hormone therapy or, in some cases, chemotherapy to treat women at the time of their local therapy.

Then breast cancer has not overtly spread to the rest of the body. More recently, it's become clear that these endocrine therapies can prevent breast cancer. Though these treatments aren't used as widely as they should be, in my opinion.

You can prevent 60 to 75% of all breast cancer in women by treating them for five years with therapies that interfere with their estrogen hormone levels. The data are unequivocal and very compelling.

Dr. Marc Lippman, MD: But unfortunately, these therapies aren't as widely used as they should be.