Dealing with Hormonal Therapy for Breast Cancer

Hormone therapy (also called hormonal therapy, hormone treatment, or endocrine therapy) slows or stops the growth of hormone-sensitive tumors by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells. Tumors that are hormone insensitive do not have hormone receptors and do not respond to hormone therapy.

 

To determine whether breast cancer cells contain hormone receptors, doctors test samples of tumor tissue that have been removed by surgery. If the tumor cells contain estrogen receptors, the cancer is called estrogen receptor positive (ER positive), estrogen sensitive, or estrogen responsive. Similarly, if the tumor cells contain progesterone receptors, the cancer is called progesterone receptor positive (PR  or PgR positive). Approximately 80% of breast cancers are ER positive (1). Most ER-positive breast cancers are also PR positive. Breast tumors that contain estrogen and/or progesterone receptors are sometimes called hormone receptor positive (HR positive). 

 

Breast cancers that lack estrogen receptors are called estrogen receptor negative (ER negative). These tumors are estrogen insensitive, meaning that they do not use estrogen to grow. Breast tumors that lack progesterone receptors are called progesterone receptor negative (PR  or PgR negative). Breast tumors that lack both estrogen and progesterone receptors are sometimes called hormone receptor negative (HR negative).

 

Hormone therapy for breast cancer should not be confused with menopausal hormone therapy (MHT)—treatment with estrogen alone or in combination with progesterone to help relieve symptoms of menopause. These two types of therapy produce opposite effects: hormone therapy for breast cancer blocks the growth of HR-positive breast cancer, whereas MHT can stimulate the growth of HR-positive breast cancer. For this reason, when a woman taking MHT is diagnosed with HR-positive breast cancer she is usually asked to stop that therapy.

 

Several strategies are used to treat hormone-sensitive breast cancer:

Blocking ovarian function: Because the ovaries are the main source of estrogen in premenopausal women, estrogen levels in these women can be reduced by eliminating or suppressing ovarian function. Blocking ovarian function is called ovarian ablation.

Ovarian ablation can be done surgically in an operation to remove the ovaries (called oophorectomy) or by treatment with radiation. This type of ovarian ablation is usually permanent.

Alternatively, ovarian function can be suppressed temporarily by treatment with drugs called gonadotropin-releasing hormone (GnRH) agonists, which are also known as luteinizing hormone-releasing hormone (LH-RH) agonists. These medicines interfere with signals from the pituitary gland that stimulate the ovaries to produce estrogen.

 

Examples of ovarian suppression drugs that have been approved by the U.S. Food and Drug Administration (FDA) are goserelin (Zoladex®) and leuprolide (Lupron®).

 

Blocking estrogen production: Drugs called aromatase inhibitors are used to block the activity of an enzyme called aromatase, which the body uses to make estrogen in the ovaries and in other tissues. Aromatase inhibitors are used primarily in postmenopausal women because the ovaries in premenopausal women produce too much aromatase for the inhibitors to block effectively. However, these drugs can be used in premenopausal women if they are given together with a drug that suppresses ovarian function.

 

Examples of aromatase inhibitors approved by the FDA are anastrozole (Arimidex®) and letrozole (Femara®), both of which temporarily inactivate aromatase, and exemestane (Aromasin®), which permanently inactivates aromatase.

Blocking estrogen’s effects: Several types of drugs interfere with estrogen’s ability to stimulate the growth of breast cancer cells:

  • Selective estrogen receptor modulators(SERMs) bind to estrogen receptors, preventing estrogen from binding. Examples of SERMs approved by the FDA for treatment of breast cancer are tamoxifen (Nolvadex®) and toremifene (Fareston®). Tamoxifen has been used for more than 30 years to treat hormone receptor–positive breast cancer. Because SERMs bind to estrogen receptors, they can potentially not only block estrogen activity (i.e., serve as estrogen antagonists) but also mimic estrogen effects (i.e., serve as estrogen agonists). SERMs can behave as estrogen antagonists in some tissues and as estrogen agonists in other tissues. For example, tamoxifen blocks the effects of estrogen in breast tissue but acts like estrogen in the uterus and bone.
  • Other antiestrogendrugs, such as fulvestrant (Faslodex®), work in a somewhat different way to block estrogen’s effects. Like SERMs, fulvestrant binds to the estrogen receptor and functions as an estrogen antagonist. However, unlike SERMs, fulvestrant has no estrogen agonist effects. It is a pure antiestrogen. In addition, when fulvestrant binds to the estrogen receptor, the receptor is targeted for destruction.

There are three main ways that hormone therapy is used to treat hormone-sensitive breast cancer:

Adjuvant therapy for early-stage breast cancer: Research has shown that women who receive at least 5 years of adjuvant therapy with tamoxifen after having surgery for early-stage ER-positive breast cancer have reduced risks of breast cancer recurrence, including a new breast cancer in the other breast, and death at 15 years (2).

 

Tamoxifen is approved by the FDA for adjuvant hormone treatment of premenopausal and postmenopausal women (and men) with ER-positive early-stage breast cancer, and the aromatase inhibitors anastrozole and letrozole are approved for this use in postmenopausal women.

A third aromatase inhibitor, exemestane, is approved for adjuvant treatment of early-stage breast cancer in postmenopausal women who have received tamoxifen previously.

 

Until recently, most women who received adjuvant hormone therapy to reduce the chance of a breast cancer recurrence took tamoxifen every day for 5 years. However, with the introduction of newer hormone therapies, some of which have been compared with tamoxifen in clinical trials, additional approaches to hormone therapy have become common (35). For example, some women may take an aromatase inhibitor every day for 5 years, instead of tamoxifen. Other women may receive additional treatment with an aromatase inhibitor after 5 years of tamoxifen. Finally, some women may switch to an aromatase inhibitor after 2 or 3 years of tamoxifen, for a total of 5 or more years of hormone therapy. Research has shown that for postmenopausal women who have been treated for early-stage breast cancer, adjuvant therapy with an aromatase inhibitor reduces the risk of recurrence and improves overall survival, compared with adjuvant tamoxifen (6).

Decisions about the type and duration of adjuvant hormone therapy must be made on an individual basis. This complicated decision-making process is best carried out by talking with an oncologist, a doctor who specializes in cancer treatment.

Treatment of advanced or metastatic breast cancer: Several types of hormone therapy are approved to treat metastatic or recurrent hormone-sensitive breast cancer. Hormone therapy is also a treatment option for ER-positive breast cancer that has come back in the breast, chest wall, or nearby lymph nodes after treatment (also called a locoregional recurrence).

 

Two SERMs are approved to treat metastatic breast cancer, tamoxifen and toremifene. The antiestrogen fulvestrant is approved for postmenopausal women with metastatic ER-positive breast cancer that has spread after treatment with other antiestrogens (7). It may also be used in premenopausal women who have had ovarian ablation.

 

The aromatase inhibitors anastrozole and letrozole are approved to be given to postmenopausal women as initial therapy for metastatic or locally advanced hormone-sensitive breast cancer (89). These two drugs, as well as the aromatase inhibitor exemestane, are used to treat postmenopausal women with advanced breast cancer whose disease has worsened after treatment with tamoxifen (10).   

Some women with advanced breast cancer are treated with a combination of hormone therapy and a targeted therapy. For example, the targeted therapy drug lapatinib (Tykerb®) is approved to be used in combination with letrozole to treat hormone receptor–positive, HER2-positive metastatic breast cancer in postmenopausal women for whom hormone therapy is indicated.

Another targeted therapy, palbociclib (Ibrance®), has been granted accelerated approval for use in combination with letrozole as initial therapy for the treatment of hormone receptor–positive, HER2-negative advanced breast cancer in postmenopausal women. Palbociclib inhibits two cyclin-dependent kinases (CDK4 and CDK6) that appear to promote the growth of hormone receptor–positive breast cancer cells.

Palbociclib is also approved to be used in combination with fulvestrant for the treatment of women with hormone receptor–positive, HER2-negative advanced or metastatic breast cancer whose cancer has gotten worse after treatment with another hormone therapy. 

Most breast cancers are ER positive, and clinical trials have tested whether hormone therapy can be used to prevent breast cancer in women who are at increased risk of developing the disease.

A large NCI-sponsored randomized clinical trial called the Breast Cancer Prevention Trial found that tamoxifen, taken for 5 years, reduced the risk of developing invasive breast cancer by about 50% in postmenopausal women who were at increased risk (12). Long-term follow-up of another randomized trial, the International Breast Cancer Intervention Study I, found that 5 years of tamoxifen treatment reduces the incidence of breast cancer for at least 20 years (13). A subsequent large randomized trial, the Study of Tamoxifen and Raloxifene, which was also sponsored by NCI, found that 5 years of raloxifene (a SERM) reduces breast cancer risk in such women by about 38% (14).

As a result of these trials, both tamoxifen and raloxifene have been approved by the FDA to reduce the risk of developing breast cancer in women at high risk of the disease. Tamoxifen is approved for this use regardless of menopausal status. Raloxifene is approved for use only in postmenopausal women.

Two aromatase inhibitorsexemestane and anastrazole—have also been found to reduce the risk of breast cancer in postmenopausal women at increased risk of the disease. After 3 years of follow-up in a randomized trial, women who took exemestane were 65% less likely than those who took a placebo to develop breast cancer (15). After 7 years of follow-up in another randomized trial, women who took anastrozole were 50% less likely than those who took placebo to develop breast cancer (16). Both exemestane and anastrozole are approved by the FDA for treatment of women with ER-positive breast cancer. Although both are also used for breast cancer prevention, neither is approved for that indication specifically.

 

The side effects of hormone therapy depend largely on the specific drug or the type of treatment (5). The benefits and harms of taking hormone therapy should be carefully weighed for each woman. A common switching strategy used for adjuvant therapy, in which patients take tamoxifen for 2 or 3 years, followed by an aromatase inhibitor for 2 or 3 years, may yield the best balance of benefits and harms of these two types of hormone therapy (17).

 

Hot flashes, night sweats, and vaginal dryness are common side effects of hormone therapy. Hormone therapy also disrupts the menstrual cycle in premenopausal women.

 

Less common but serious side effects of hormone therapy drugs are listed below.

Tamoxifen

Raloxifene

  • Risk of blood clots, especially in the lungs and legs (12)
  • Stroke in certain subgroups (17)

Ovarian suppression

  • Bone loss
  • Mood swings, depression, and loss of libido

Aromatase inhibitors

  • Risk of heart attack, angina, heart failure, and hypercholesterolemia (20)
  • Bone loss
  • Joint pain (2124)
  • Mood swings and depression

Fulvestrant

  • Gastrointestinal symptoms (25)
  • Loss of strength (24)
  • Pain

Exercise to minimize the side-effects of hormonal therapy

 

Because patients will be at a higher risk for osteoporosis, it is essential that a weight-bearing exercise program be included into one’s exercise routine. Weight-bearing exercises force you to work against gravity and include walking, hiking, jogging, climbing stairs, playing tennis, and dancing. Resistance exercises – such as lifting weights – can also strengthen bones. Other exercises such as swimming and bicycling can help build and maintain strong muscles and have excellent cardiovascular benefits, but they are not the best way to exercise your bones.

 

If a patient has had lymph nodes removed or irradiated, the introduction of weights or resistance bands (even holding a yoga pose for for 20-30 seconds) must be slow and gradual. We no longer know what the damaged lymphatic system can ‘handle’ and it is critical to avoid overloading it and risking the onset of lymphedema. Patients should start with range of motion exercises until ‘normal’ range of motion is achieved. Then and only then can they introduce very light resistance and just a few repetitions as tolerated. Both repetitions and resistance can be increased if there is no swelling or pain. It is strongly recommended that patients seek out the expertise of a Cancer Exercise Specialist to customize an individualized program based on surgery, treatment, reconstruction, lymphedema prevention/management, previous fitness level, etc.

 

Mood swings, depression, and pain may all be positively affected by a regular exercise program. According to the Mayo Clinic, research on depression, anxiety and exercise shows that the psychological and physical benefits of exercise can also help improve mood and reduce anxiety. The links between depression, anxiety and exercise aren’t entirely clear — but working out and other forms of physical activity can definitely ease symptoms of depression or anxiety and make you feel better. Exercise may also help keep depression and anxiety from coming back once a patient is feeling better.

Regular exercise may help ease depression and anxiety by:

  • Releasing feel-good endorphins,natural cannabis-like brain chemicals (endogenous cannabinoids) and other natural brain chemicals that can enhance one’s sense of well-being
  • Taking patient’s mind off their worries so they can get away from the cycle of negative thoughts that feed depression and anxiety

Exercise can help to increase mobility, decrease inflammation, increase blood flow, and correct muscle imbalances that lead to joint degeneration and pain.

 

Exercise can also have a profound affect on self-confidence and self-esteem which may have a positive effect on one’s libido.

 

Although it is not listed, the majority of patients will experience weight gain. Not only can additional body fat increase the risk of diabetes and heart disease, it can also increase the risk and severity of lymphedema as well as future cancers. Therefore, it is strongly recommended that patients seek out a registered dietician who specializes in oncology, to develop a safe and effective eating strategy to lose fat while maintaining lean muscle mass. Lean muscle will also increase with strength training (weight-bearing exercise) and this will have a positive effect on metabolism. Lastly, aerobic, or cardiovascular exercise (walking, running, biking, dancing, jumping rope, etc.) must also be included in the patient’s exercise program.

*If a patient has vomiting or diarrhea, it is recommended that they do not exercise for 24-36 hours, re-hydrate, REST, and replenish electrolytes.

A Cancer Exercise Specialist can help to determine the proper combination of frequency, intensity, and duration of exercise as well as which exercises are appropriate at any given stage of treatment and recovery.

Become a Cancer Exercise Specialist and help millions in need.

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References

  1. National Cancer Institute, Hormone Therapy for Breast Cancer, https://www.cancer.gov/types/breast/breast-hormone-therapy-fact-sheet#what-is-hormone-therapy
  2. Kohler BA, Sherman RL, Howlader N, et al. Annual Report to the Nation on the Status of Cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. Journal of the National Cancer Institute2015; 107(6):djv048. doi: 1093/jnci/djv048Exit Disclaimer.
  3. 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. Lancet2011; 378(9793)771–784.

 [PubMed Abstract]

  1. Untch M, Thomssen C. Clinical practice decisions in endocrine therapy. Cancer Investigation2010; 28 Suppl 1:4–13.

 [PubMed Abstract]

  1. Regan MM, Neven P, Giobbie-Hurder A, et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1–98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncology2011; 12(12):1101–1108.

 [PubMed Abstract]

  1. Burstein HJ, Griggs JJ. Adjuvant hormonal therapy for early-stage breast cancer. Surgical Oncology Clinics of North America2010; 19(3):639–647.

 [PubMed Abstract]

  1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Dowsett M, Forbes JF, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet2015; 386(10001):1341-1352.

 [PubMed Abstract]

  1. Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer2005; 104(2):236–239.

 [PubMed Abstract]

  1. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncology2010; 11(12):1135–1141.

 [PubMed Abstract]

  1. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. Journal of Clinical Oncology2003; 21(11):2101–2109.

 [PubMed Abstract]

  1. Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. Journal of the National Cancer Institute2006; 98(18):1285–1291.

 [PubMed Abstract]

  1. Chia YH, Ellis MJ, Ma CX. Neoadjuvant endocrine therapy in primary breast cancer: indications and use as a research tool. British Journal of Cancer2010; 103(6):759–764.

 [PubMed Abstract]

  1. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P–2 trial. JAMA2006; 295(23):2727–2741.

 [PubMed Abstract]

  1. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncology2015; 16(1):67-75.

 [PubMed Abstract]

  1. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prevention Research2010; 3(6):696-706.

 [PubMed Abstract]

  1. Goss PE, Ingle JN, Alés-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. New England Journal of Medicine2011; 364(25):2381–2391.

 [PubMed Abstract]

  1. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet2014; 383(9922):1041-1048.

 [PubMed Abstract]

  1. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P–1 Study. Journal of the National Cancer Institute1998; 90(18):1371–1388.

 [PubMed Abstract]

  1. Gorin MB, Day R, Costantino JP, et al. Long-term tamoxifen citrate use and potential ocular toxicity. American Journal of Ophthalmology1998; 125(4):493–501.

 [PubMed Abstract]

  1. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet1998; 351(9114):1451–1467.

 [PubMed Abstract]

  1. Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. Journal of the National Cancer Institute2011; 103(17):1299–1309.

 [PubMed Abstract]

  1. Coates AS, Keshaviah A, Thürlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. Journal of Clinical Oncology2007; 25(5):486–492.

 [PubMed Abstract]

  1. Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncology2008; 9(1):45–53.

 [PubMed Abstract]

  1. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet2007; 369(9561):559–570. Erratum in: Lancet 2007; 369(9565):906.

 [PubMed Abstract]

  1. Boccardo F, Rubagotti A, Guglielmini P, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian Tamoxifen Anastrozole (ITA) Trial. Annals of Oncology2006; 17(Suppl 7):vii10–vii14.

 [PubMed Abstract]

  1. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. Journal of Clinical Oncology2002; 20(16):3386–3395.

 [PubMed Abstract]

 

 
 
 
 
 
 

References

  1. National Cancer Institute, Hormone Therapy for Breast Cancer, https://www.cancer.gov/types/breast/breast-hormone-therapy-fact-sheet#what-is-hormone-therapy
  2. Kohler BA, Sherman RL, Howlader N, et al. Annual Report to the Nation on the Status of Cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. Journal of the National Cancer Institute2015; 107(6):djv048. doi: 1093/jnci/djv048Exit Disclaimer.
  3. 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. Lancet2011; 378(9793)771–784.

 [PubMed Abstract]

  1. Untch M, Thomssen C. Clinical practice decisions in endocrine therapy. Cancer Investigation2010; 28 Suppl 1:4–13.

 [PubMed Abstract]

  1. Regan MM, Neven P, Giobbie-Hurder A, et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1–98 randomised clinical trial at 8.1 years median follow-up. Lancet Oncology2011; 12(12):1101–1108.

 [PubMed Abstract]

  1. Burstein HJ, Griggs JJ. Adjuvant hormonal therapy for early-stage breast cancer. Surgical Oncology Clinics of North America2010; 19(3):639–647.

 [PubMed Abstract]

  1. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG), Dowsett M, Forbes JF, et al. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet2015; 386(10001):1341-1352.

 [PubMed Abstract]

  1. Howell A, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prospectively planned combined survival analysis of two multicenter trials. Cancer2005; 104(2):236–239.

 [PubMed Abstract]

  1. Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncology2010; 11(12):1135–1141.

 [PubMed Abstract]

  1. Mouridsen H, Gershanovich M, Sun Y, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. Journal of Clinical Oncology2003; 21(11):2101–2109.

 [PubMed Abstract]

  1. Mauri D, Pavlidis N, Polyzos NP, Ioannidis JP. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: meta-analysis. Journal of the National Cancer Institute2006; 98(18):1285–1291.

 [PubMed Abstract]

  1. Chia YH, Ellis MJ, Ma CX. Neoadjuvant endocrine therapy in primary breast cancer: indications and use as a research tool. British Journal of Cancer2010; 103(6):759–764.

 [PubMed Abstract]

  1. Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P–2 trial. JAMA2006; 295(23):2727–2741.

 [PubMed Abstract]

  1. Cuzick J, Sestak I, Cawthorn S, et al. Tamoxifen for prevention of breast cancer: extended long-term follow-up of the IBIS-I breast cancer prevention trial. Lancet Oncology2015; 16(1):67-75.

 [PubMed Abstract]

  1. Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prevention Research2010; 3(6):696-706.

 [PubMed Abstract]

  1. Goss PE, Ingle JN, Alés-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. New England Journal of Medicine2011; 364(25):2381–2391.

 [PubMed Abstract]

  1. Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet2014; 383(9922):1041-1048.

 [PubMed Abstract]

  1. Fisher B, Costantino JP, Wickerham DL, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P–1 Study. Journal of the National Cancer Institute1998; 90(18):1371–1388.

 [PubMed Abstract]

  1. Gorin MB, Day R, Costantino JP, et al. Long-term tamoxifen citrate use and potential ocular toxicity. American Journal of Ophthalmology1998; 125(4):493–501.

 [PubMed Abstract]

  1. Tamoxifen for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet1998; 351(9114):1451–1467.

 [PubMed Abstract]

  1. Amir E, Seruga B, Niraula S, Carlsson L, Ocaña A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. Journal of the National Cancer Institute2011; 103(17):1299–1309.

 [PubMed Abstract]

  1. Coates AS, Keshaviah A, Thürlimann B, et al. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1–98. Journal of Clinical Oncology2007; 25(5):486–492.

 [PubMed Abstract]

  1. Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists’ Group. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncology2008; 9(1):45–53.

 [PubMed Abstract]

  1. Coombes RC, Kilburn LS, Snowdon CF, et al. Survival and safety of exemestane versus tamoxifen after 2–3 years’ tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet2007; 369(9561):559–570. Erratum in: Lancet 2007; 369(9565):906.

 [PubMed Abstract]

  1. Boccardo F, Rubagotti A, Guglielmini P, et al. Switching to anastrozole versus continued tamoxifen treatment of early breast cancer. Updated results of the Italian Tamoxifen Anastrozole (ITA) Trial. Annals of Oncology2006; 17(Suppl 7):vii10–vii14.

 [PubMed Abstract]

  1. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. Journal of Clinical Oncology2002; 20(16):3386–3395.

 [PubMed Abstract]