Hormonal Therapy for Post-menopausal Women with Early Stage Breast Cancer

Breast Cancer
Anna Mazzucco, PhD, Brandel France de Bravo, MPH, Caroline Halsted, Danielle Shapiro, MD, MPH, and Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund

Breast cancer is the most common type of cancer in women around the world, and the second leading cause of cancer deaths among U.S. women. The survival rate for early-stage breast cancer is very high.  For women whose cancer is diagnosed when it is only in the breast, the 5-year survival rate is 99%.  For women whose breast cancer has spread to the lymph nodes, the 5-year survival rate is 85%.

Women who are diagnosed with early-stage breast cancer almost always undergo surgery to remove the cancer (either lumpectomy/partial mastectomy or mastectomy). Most will also choose at least one other treatment in addition to surgery:

1) If they have a lumpectomy, they often undergo radiation to either shrink the tumor before surgery or to kill any cancer cells in the breast that were missed during surgery.

2) If their cancer is estrogen receptor positive (about 84% of breast cancers), many women will try to take hormonal therapy for at least five years after surgery to lower the chance of cancer coming back in either breast the future. For pre-menopausal women, the standard treatment is tamoxifen. For women who have completed menopause (post-menopausal breast cancer), tamoxifen and/or an aromatase inhibitor can be used.[1]

Types of Hormonal Therapies for Early-Stage Breast Cancers

Hormonal therapy (also called endocrine therapy or anti-estrogen therapy) is the opposite of the type of hormones women sometimes take to reduce the symptoms of menopause. It lowers your estrogen levels instead of increasing them.[1]

Hormonal therapy is recommended for most women with breast cancer, and sometimes it is taken by women who have not been diagnosed with breast cancer but are at high risk for it based on their genes or family history. When hormonal therapy is used before breast cancer develops, it is called “primary prevention” or “chemoprevention.” Chemoprevention is completely different from the drugs used in chemotherapy to treat breast cancer.[1]  See our article on breast cancer prevention.

Four types of hormonal therapy are FDA-approved for early-stage breast cancer treatment for post-menopausal women: tamoxifen, exemestane, letrozole, and anastrozole.[3]

For post-menopausal women, there are many recommended ways to take hormone therapy, including: [4]

  • Taking tamoxifen for 5 to 10 years
  • Taking an aromatase inhibitor for 5 to 10 years
  • Taking tamoxifen for 5 years, then switching to an aromatase inhibitor for the next 5 years
  • Taking tamoxifen for 2-3 years, then switching to an aromatase inhibitor for the next 5 years

How Does Hormonal Therapy Work?

Tamoxifen:

Tamoxifen is a selective estrogen receptor modulator (SERM), which means it blocks estrogen activity in breast tissue, but promotes estrogen activity in other tissues (such as in bone and the inner lining of the uterus). Tamoxifen is only effective in breast cancers that are estrogen receptor positive.[3,4]

Aromatase inhibitors:

In post-menopausal women, the ovaries slow down the production of estrogen, but the body uses an enzyme called aromatase to make estrogen from other hormones. Aromatase inhibitors block aromatase, which lowers the amount of estrogen in the body. By taking away the supply of estrogen, aromatase inhibitors help to stop the growth of cancer cells.[3,4]

How Effective are the Treatments?

The effectiveness of treatments is often reported in terms of risk or risk reduction. Risk is another word for chance–what is the chance that something will happen, such as cancer returning or the patient dying? Risk can be reported in terms of relative risk or absolute risk. Let’s use simple numbers to show what we mean: In a study 100 women are given a new drug and 100 other women are given an older drug.  What if the study showed that 4 patients (4%) taking the older drug became nauseous compared to only 2 patients (2%) taking the new drug.  The relative risk of patients getting nauseous is 50% lower for patients taking the new drug, and that sounds impressive.  But the absolute difference is only 2% – when you subtract 2% taking the new drug compared to 4% taking the old drug.

Based on the statistics, the odds may favor taking the new drug. But if the new drug costs much more or has other side effects, a patient might decide she is willing to take the 2% greater risk of becoming nauseous. We prefer to use the absolute difference in risk as it is more informative for patients than the relative risk.

Tamoxifen

Over decades of clinical trials in hundreds of thousands of women, tamoxifen has been shown to reduce the chances of breast cancer recurrence and breast cancer death. But it is important to consider exactly what the benefits are likely to be for you.

Breast cancer recurrence:

A landmark report showed that about 23% of women aged 55 and older who took tamoxifen for 5 years after their cancer was removed had a breast cancer recurrence within 10 years compared to about 42% of women 55-69 and 44% of women 70 and older who did not take tamoxifen.  In that study, women with early-stage breast cancer included women with Stage 1, Stage 2, and Stage 3A; in other words, it ranges from a very tiny breast cancer to a large cancer that has spread to several lymph nodes. The researchers defined breast cancer recurrence as the first appearance of any breast cancer including, cancer in the same breast, cancer in the opposite breast, or distant spread of cancer.[6]

Breast cancer deaths

Among women who were 55-69 years old at the time of diagnosis, about 90% who did not have a breast cancer recurrence were alive for at least 10 years, regardless of whether they took tamoxifen or not. For women in that age group, about 16% of women who took tamoxifen and had a recurrence died from breast cancer within 10 years of the initial diagnosis, compared to 26% of women who did not take tamoxifen and had a recurrence.[6]

Among women who were 70 years old or more at the time of their diagnosis and did not have a breast cancer recurrence, 80% who took tamoxifen were alive 10 years later, compared to 70% of women who did not take tamoxifen. Importantly, this difference was not statistically significant, meaning it could have happened by chance and is unlikely to be related to tamoxifen therapy.  Among women in this age group who had a breast cancer recurrence, about 20% who took tamoxifen and had a recurrence died from breast cancer within 10 years of the initial diagnosis compared to 37% of women who did not take tamoxifen and had a recurrence. [6]

Living Longer

Most women who are diagnosed with breast cancer do not die from breast cancer.  Of course, eventually they die of something else.  For women who were 55-69 years old at the time of their diagnosis, 5 years of tamoxifen helped women live longer.  More than 90% of women who did not have a breast cancer recurrence were alive 10 years later, regardless of whether they took tamoxifen or not. In contrast, about 76% of women who took tamoxifen and had a breast cancer recurrence were alive 10 years after the initial diagnosis, compared to 67% of women who did not take tamoxifen.[6]

By the time women are over 70, they are likely to have health issues whether or not they are diagnosed with breast cancer. Among those who did not have a breast cancer recurrence, about 80% of women taking tamoxifen and 70% of women not taking tamoxifen were alive 10 years later.  However, this apparent 10% difference was not statistically significant and therefore is probably not related to tamoxifen. In contrast, among women who had a recurrence, about 67% of women who took tamoxifen were alive 10 years later compared to 47% of women who did not take tamoxifen.[6]

As you can see, the benefits of tamoxifen depend on how old and healthy a woman is when she is diagnosed In addition, certain characteristics of early-stage breast cancers, including size of the tumor, types of cancer cells, and how many lymph nodes the cancer had spread to prior to surgery, can help doctors predict the chances of breast cancer recurrence. Therefore, it is important for you to talk with your doctor about these specific issues and which treatment options may be right for you.  Remember that some benefits (such as survival) might be more important to you than others (such as recurrence) – or not!

Aromatase Inhibitors:

Aromatase inhibitors have also been shown to benefit post-menopausal breast cancer patients.  An international breast cancer study showed that about 84% of women taking letrozole were alive and cancer free at 5 years compared to about 81% of women taking tamoxifen. Despite the difference in dying from breast cancer, however, there was no difference in terms of the percentage of women who were alive 5 years after diagnosis.

The benefits of aromatase inhibitors continued 10 years after diagnosis, with about 19% of women who took letrozole having any cancer recurrence compared to about 23% of women who took tamoxifen. Breast cancer recurrence included any breast cancer in the same breast, the opposite breast, or distant spread of cancer.[3]

When considering your treatment options, talk with your doctor about your overall health and your heart health, because all women (including women with breast cancer) are more likely to die from heart disease than breast cancer. And some treatments for breast cancer can harm your heart. Read more about heart health and breast cancer in our article.

Treatment Considerations

There are many ways to take hormone therapy, including switching between the types of therapy, and taking the hormone therapy for additional years. The choices can be confusing. Here are some questions to think about: 

What are the benefits of extending therapy? Studies show that extending therapy after an initial 5-year period can lower a woman’s chances of cancer recurrence (including any breast cancer in the same breast, the opposite breast, or distant spread) by a small, but statistically significant 2% to 4%. The study looked at different hormone regimens including “primary” AI (AI for 5 years), “sequential” AI (tamoxifen for 2 years followed by 3 years of AI), and extended AI (5 years of AI after 5 years of tamoxifen). For example, about 7% to 12% of women who took any hormone therapy for 5 years had a recurrence compared to 5% to 8% of women who extended their therapy.[10]

For how long should women extend therapy? A 2018 study found that women adding on 2.5 extra years of letrozole had the same chances of surviving without their breast cancer returning as women adding letrozole for 5 years. However, about 1% of women who took letrozole for an extra 5 years had a new breast cancer develop in the opposite breast compared to 3% in the 2.5 year group. That difference is small but it is a way to lower your already small risk of developing a new cancer in your other breast and making it even smaller.[11,12]

As you consider your treatment options,  it is important to consider the risks as well, as described later in the next section of this article.

Side Effects and Risks of Treatment

Tamoxifen increases the chances of a woman developing endometrial cancer and blood clots in legs and lungs, especially for women over 50 years of age.[3,16] Women taking tamoxifen are also more likely to develop endometrial cancer, although the overall risk is still low; about 2 women out of 1,000 taking tamoxifen will get endometrial cancer each year.[16] In a Danish study, the 5-year risk of developing blood clots was about 1.2% in women with breast cancer taking tamoxifen compared to 0.5% in women with breast cancer who were not taking tamoxifen. Moreover, tamoxifen therapy often causes side effects similar to those experienced in menopause, including hot flashes and irregular periods.[16] In one study, 41% of women taking tamoxifen experienced hot flashes, and 10% experienced abnormal vaginal bleeding.[19]

Aromatase inhibitors increase the risk for osteoporosis compared with tamoxifen or taking no hormonal therapy at all.  Exemestane, a commonly used aromatase inhibitor (brand name Aromasin), also increases the risk for visual disturbances, allergic reaction, or diarrhea.  In one study, about 36% of women experienced joint problems while taking anastrozole, (brand name Arimidex) compared to about 30% of women taking tamoxifen.

The most common complications from hormonal therapy are listed above.  In addition, in very rare cases, other side effects of hormonal therapy can be fatal or can harm a patient’s quality of life.  Close monitoring of women for symptoms, such as abnormal uterine bleeding, is needed, and women taking tamoxifen should receive annual pelvic exams.[3]

Different women respond differently to the various forms of hormonal therapy, which is why it is not uncommon for women to switch to different hormonal treatments after starting.

The Bottom Line

There are many ways to treat early-stage breast cancer in post-menopausal women, in addition to surgery. A woman’s age, tumor characteristics, overall health, and personal wishes/goals may impact her decision. Talk with your doctor about which treatment options may be right for you by asking about the exact benefits of specific treatments on recurrence and overall survival, and considering these specific issues and not just what is best for cancer patients on average.

Footnotes:

  1. American Cancer Society. Cancer Treatment and Survivorship: Facts and Figures 2016-2017. Available online: https://www.cancer.org
  2. Burstein HJ. et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. Journal of Clinical Oncology. 2017;34(14): 1689-1701. Doi: 1200/JCO.2015.65.9573
  3. National Cancer Institute. Breast Cancer Treatment (PDQ). (Nov. 2017). Available online: https://www.cancer.gov/types/breast/patient/breast-treatment-pdq#section/_125
  4. Adjuvant Therapy for Breast Cancer. (Aug. 2017). Available online: https://emedicine.medscape.com/article/1946040-overview#showall
  5. Colleoni M. et al. Annual Hazard Rates of Recurrence for Breast Cancer During 24 Years of Follow-Up: Results From the International Breast Cancer Study Group Trials I to V. J Clin Oncol. 2016;34(9): 927-935. doi: 1200/JCO.2015.62.3504
  6. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378(9793): 771-784. doi:1016/S0140-6736(11)60993-8
  7. Gierach GL, Curtis RE, Pfeiffer RM, et al. Association of Adjuvant Tamoxifen and Aromatase Inhibitor Therapy With Contralateral Breast Cancer Risk Among US Women With Breast Cancer in a General Community Setting. JAMA Oncol. 2017;3(2): 186–193. doi:1001/jamaoncol.2016.3340
  8. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001): 1341 – 1352. doi: http://dx.doi.org/10.1016/S0140-6736(15)61074-1
  9. Pohlmann PR and Isaacs C. Extended Adjuvant Endocrine Therapy for Postmenopausal Women: Treating Many to Benefit a Few, JNCI: Journal of the National Cancer Institute. 2018;110(1): djx142, doi: https://doi.org/10.1093/jnci/djx142
  10. Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer. Journal of Clinical Oncology. 2010;28(23):3784-3796. doi:10.1200/JCO.2009.26.3756.
  11. Blok EJ, et al. Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05). JNCI: Journal of the National Cancer Institute. 2018; 110(1): djx134, https://doi.org/10.1093/jnci/djx134
  12. Van de Velde, C.J.H. et al. Optimal duration of extended letrozole treatment after 5 years of adjuvant endocrine therapy; results of the randomized phase III IDEAL trial (BOOG 2006–05). European Journal of Cancer. 2017;72(Supp1):S9. doi: http://dx.doi.org/10.1016/S0959-8049(17)30108-9
  13. Gianni L. et al. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncology. 2011;12(3): 236-44. doi: https://doi.org/10.1016/S1470-2045(11)70033-X
  14. Cameron D. et al. 11 years’ follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 2017;389(10075): 1195-1205. doi: https://doi.org/10.1016/S0140-6736(16)32616-2
  15. Stenger M. ASCO Post: 11-Year Follow-up of Adjuvant Trastuzumab in the HERA Trial. (March 2017). Available online: http://www.ascopost.com/News/48405
  16. Gogas H, Markopoulos C, Blamey R. Should women be advised to take prophylactic endocrine treatment outside of a clinical trial setting? Ann Oncol. 2005;16:1861-1866. Available online: https://watermark.silverchair.com
  17. Fisher B, et al. J Natl Cancer Inst. 1994; 86:527-537.
  18. Bonneterre, et al. J Clin Oncol. 2000; 18:3748-3757.
  19. Howell A, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet. 2005;365(9453): 60-2. doi: 1016/S0140-6736(04)17666-6
  20. Bliss JM. et al. Disease-Related Outcomes With Long-Term Follow-Up: An Updated Analysis of the Intergroup Exemestane Study. Journal of Clinical Oncology. 2012;30(7): 709-717. doi: 1200/JCO.2010.33.7899
  21. Drugs and Diseases: Gosarelin. Available online: https://reference.medscape.com/drug/zoladex-la-goserelin-342129
  22. Drugs and Diseases: Trastuzumab. Available online: https://reference.medscape.com/drug/herceptin-ogivri-trastuzumab-342231#5