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Combination Hormonal Therapy Seems More Effective for Men With Hormone-Receptor-Positive Breast Cancer

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The combination of either tamoxifen or an aromatase inhibitor plus a gonadotropin-releasing hormone analogue (GnRHa) reduced levels of estradiol, a form of estrogen, more than tamoxifen alone in men diagnosed with hormone-receptor-positive breast cancer, according to a small study.

Still, the men reported that the combination hormonal therapy affected their quality of life and sexual function.

The research was published online on Feb. 4, 2021, by JAMA Oncology. Read “Efficacy of Endocrine Therapy for the Treatment of Breast Cancer in Men: Results from the MALE Phase 2 Randomized Clinical Trial.”

About male breast cancer
Hormonal therapy and GnRHa medicines
About the study
What this means for you

About male breast cancer

While breast cancer in men is rare, it does happen. Fewer than 1% of all breast cancers are diagnosed in men. In 2021, about 2,670 new cases of invasive breast cancer will be diagnosed in men. For men, the lifetime risk of getting breast cancer is about 1 in 833.

Like breast cancer in women, breast cancer in men can be hormone-receptor-positive or hormone-receptor-negative, as well as HER2-positive or HER2-negative.

Because the number of cases of breast cancer in men is relatively small compared to the number of cases in women, there is a lack of information on male breast cancer in general, and there have been few studies focused specifically on treatments for male breast cancer.

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Hormonal therapy and GnRHa medicines

Estradiol is one of three estrogen hormones produced by the body. In men, about 15% to 25% of estradiol is produced by the testicles. The rest is made by the enzyme aromatase converting testosterone to estradiol.

Healthy estradiol levels in men help with bone maintenance and brain function, as well as controlling libido and erectile function. Men have naturally lower levels of estradiol than women.

Hormonal therapy medicines treat hormone-receptor-positive breast cancer in two ways:

  • by lowering the amount of estrogen in the body
  • by blocking the action of estrogen on breast cancer cells

There are several types of hormonal therapy medicines. Tamoxifen, a selective estrogen receptor modulator (SERM), is one of the most well-known. Tamoxifen can be used to treat premenopausal and postmenopausal women, as well as men. Tamoxifen is taken orally as a pill or a liquid.

Aromatase inhibitors are another type of hormonal therapy. They include:

  • Arimidex (chemical name: anastrozole)
  • Aromasin (chemical name: exemestane)
  • Femara (chemical name: letrozole)

Aromatase inhibitors have been shown to be more effective at reducing the risk of recurrence (the cancer coming back) in postmenopausal women and are now used more often than tamoxifen to treat women who’ve gone through menopause.

GnRHa medicines lower the amount of sex hormones in the body. In women, they stop the ovaries from making estrogen and progesterone. In men, they stop the testicles from making testosterone. Lupron (chemical name: leuprolide), Trelstar (chemical name: triptorelin), and Zoladex (chemical name: goserelin) are all GnRHa medicines.

Because male breast cancer is so rare, it’s not clear which hormonal therapy medicine is the most effective for hormone-receptor-positive male breast cancer.

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About the study

The researchers wanted to do the study because it’s unknown how standard hormonal therapy treatment changes estradiol levels in men diagnosed with hormone-receptor-positive breast cancer. It’s also not clear how changing estradiol levels affects a man’s sexual function and quality of life.

Done in Germany, the study included 56 men diagnosed with hormone-receptor-positive breast cancer between October 2012 and May 2017:

  • the men’s ages ranged from 37 to 83 years
  • none of the men had been diagnosed with prostate cancer
  • 86.5% of the cancers were HER2-negative
  • 52% of the cancers were node-negative, meaning no cancer was found in the lymph nodes

The men were randomly assigned to get one of three hormonal therapy treatments for 6 months:

  • 18 men were treated with tamoxifen
  • 19 men were treated with tamoxifen plus a GnRHa medicine
  • 19 men were treated with Aromasin plus a GnRHa medicine

The researchers did not specify which GnRHa medicine the men were given.

The hormonal therapy treatment was given either before surgery, after surgery, or for metastatic disease.

After the 6 months of hormonal therapy were completed, all the men were prescribed tamoxifen alone.

The researchers took blood samples and had the men fill out questionnaires about their quality of life, sexual function, and other side effects three times during the study:

  • before hormonal therapy treatment started
  • 3 months after hormonal therapy treatment started
  • 6 months after hormonal therapy treatment started (the end of the study)

At the beginning of the study, before hormonal therapy treatment started, estradiol levels were similar between the three treatment groups, at about 27 nanograms per liter (ng/L) of blood.

After 3 months of hormonal therapy treatment, estradiol levels were:

  • 45.0 ng/L in the tamoxifen treatment group, an increase of 66.7%
  • 5.0 ng/L in the tamoxifen plus GnRHa group, a decrease of 84.9%
  • 7.5 ng/L in the Aromasin plus GnRHa group, a decrease of 72.2%

At the end of the study, after 6 months of hormonal therapy treatment, estradiol levels were:

  • 38.0 ng/L in the tamoxifen treatment group, an increase of 40.7% from the beginning of the study
  • 13.0 ng/L in the tamoxifen plus GnRHa group, a decrease of 60.6% from the beginning of the study
  • 10.0 ng/L in the Aromasin plus GnRHa group, a decrease of 63.6% from the beginning of the study

When the researchers analyzed the men’s questionnaire responses, they found that men treated with either tamoxifen or Aromasin plus GnRHa reported a decrease in sexual function after 3 and 6 months of treatment.

At the beginning of the study, 18 men reported erectile dysfunction:

  • 5 in the tamoxifen group
  • 6 in the tamoxifen plus GnRHa group
  • 7 in the Aromasin plus GnRHa group

After 3 months of hormonal therapy treatment, 27 men reported erectile dysfunction:

  • 5 in the tamoxifen group
  • 11 in the tamoxifen plus GnRHa group
  • 11 in the Aromasin plus GnRHa group

After 6 months of hormonal therapy treatment, 29 men reported erectile dysfunction:

  • 4 in the tamoxifen group
  • 12 in the tamoxifen plus GnRHa group
  • 13 in the Aromasin plus GnRHa group

These differences in sexual function were statistically significant, which means they were likely due to the difference in treatment and not just because of chance.

When the researchers looked at the men’s quality of life, they found that 59.6% of the men reported decreased quality of life at the beginning of the study. After 3 months of hormonal therapy treatment, 75% of the men reported decreased quality of life, while 67.4% of the men reported decreased quality of life after 6 months of hormonal therapy treatment. These differences were not statistically significant.

“The addition of GnRHa to [an aromatase inhibitor] or tamoxifen leads to a more profound suppression of estradiol, which is known to increase survival in premenopausal women,” the researchers wrote in their conclusion. “It seems that male [breast cancer] can be treated according to premenopausal [breast cancer] due to the comparable observations of increased estradiol suppression. The addition of GnRHa should be therefore reconsidered as a treatment option in high-risk patients and should be weighed against increased adverse effects.”

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What this means for you

If you’re a man who has been diagnosed with hormone-receptor-positive breast cancer, this study offers important information that you and your doctor can discuss when planning your treatment.

While the study is small and more research needs to be done, the results offer good first insights on the differences in the effects of hormonal therapy on male hormone-receptor-positive breast cancer.

Because male breast cancer is so rare, it may be a number of years before a study can enroll enough participants to offer more definitive results.

It’s important that all men be aware of any signs that might indicate breast cancer, including:

  • nipple pain
  • inverted nipple
  • nipple discharge
  • sores on the nipple and/or areola area
  • enlarged lymph nodes under the arm

Because many men don’t consider the possibility that they may develop breast cancer, they may wait a year or longer to talk to their doctor after noticing a breast symptom. This means the cancer is diagnosed at a later stage.

For more information, visit the Breastcancer.org pages on Male Breast Cancer.

If you're a man who has been diagnosed with breast cancer and would like to talk with others, join the Breastcancer.org Discussion Board forum Male Breast Cancer.

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Written by: Jamie DePolo, senior editor

Reviewed by: Brian Wojciechowski, M.D., medical adviser


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