Hormonal Therapy for Pre-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 breast cancer is diagnosed before it has spread, 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 either to 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 in either breast in the future. For pre-menopausal women, the standard treatment is tamoxifen.[1]

Types of Hormonal Therapies for Early Stage Breast Cancer

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.

How Does Hormonal Therapy Work?

Tamoxifen is a selective estrogen receptor modulator (SERM), which means it blocks estrogen in breast tissue, but promotes it 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]

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 focus on the absolute difference in risk as it is more informative for patients than the relative risk.

Tamoxifen therapy after surgery for early-stage breast cancer reduces the chances of breast cancer returning and the chances of dying from breast cancer.  But it is important to consider exactly what the benefits are likely to be for you.

Benefits of 5-Year Therapy

Does tamoxifen prevent breast cancer recurrence?

A landmark report showed that about 26% of women taking tamoxifen for 5 years after their cancer was removed had a breast cancer recurrence within 10 years, compared to about 40% of women not taking tamoxifen.[6] In that study, women with early-stage breast cancer includes 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. However, women who took tamoxifen for 5 years had a 0.6% chance per year of having their breast cancer return in the same breast (this is called local recurrence) compared to a 1.1% chance per year in women who did not take tamoxifen.

Does tamoxifen prevent breast cancer deaths in women with breast cancer recurrence?

Most  women who had a recurrence did not die of breast cancer:  About 17% of women younger than 45 years and 22% of women aged 45-54 years who took tamoxifen died from breast cancer within 10 years of the initial diagnosis, compared to, respectively,  20% and 28% of women those same ages who did not take tamoxifen.[6]

Does tamoxifen save lives?

The benefits of tamoxifen vary depending on  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.  These issues 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!

Preventing Breast Cancer in the Opposite Breast

About 1 in 20 (5%) women diagnosed with breast cancer will develop breast cancer in the opposite breast within the 10 years after first breast cancer diagnosis. A 2017 study in the prestigious medical journal JAMA found that taking tamoxifen can reduce the percentage of those women from developing cancer in the opposite breast within 10 years, from about 5% to  2%.[7] Unfortunately, the study authors did not report on breast cancer deaths or deaths for any other reason. Therefore, we do not know whether tamoxifen’s reduction of cancer in the opposite breast had any impact on the women’s longevity.

Benefits of Extending Therapy

One popular option is to change from tamoxifen to an aromatase inhibitor when menopause is reached (menopause occurs when a woman has not had a menstrual period for a continuous 12 months).  Read more about aromatase inhibitors in our article on post-menopausal early stage breast cancer.

Extending tamoxifen for an additional 5 years can also decrease a woman’s chances of breast cancer recurrence by about 4% in the 10 years after surgery if her cancer had spread to her lymph nodes prior to surgery.[2]  However, women who had early-stage breast cancer that did not spread to their lymph nodes did not benefit from more than 5 years of tamoxifen.[2]

In addition to reducing recurrence, the studies also found that taking tamoxifen for 10 years instead of 5 years reduced the chances of dying from breast cancer within those 10 years from about 15% to about 12%. These differences are small and disappear for women with the earliest stage breast cancers. Even more important, overall survival –how long a woman lives after her initial diagnosis of breast cancer–was not significantly affected by taking tamoxifen for more than 5 years.[2]  In other words, even if a woman taking tamoxifen for 10 years was less likely to die of breast cancer within those 10 years, she was not less likely to die from any cause.

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.

Side Effects and Risks of Treatment

Tamoxifen increases the chances of developing endometrial cancer and blood clots in the legs and lungs.[3,16] In a Danish study, the 5-year risk of developing blood clots was about 1.2% in breast cancer patients taking tamoxifen compared to 0.5% in breast cancer patients who were not taking tamoxifen.[10]  Tamoxifen 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 periods .[19]

The Bottom Line

There are many ways to treat early-stage breast cancer in pre-menopausal women, in addition to surgery. A woman’s age, tumor characteristics, and personal wishes/goals may affect the benefits and risks of different treatments. 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