Hormonal therapy in breast cancer

Risk factors for developing breast cancer include early menarche, late menopause, first pregnancy at a late age, taking the oral contraceptive pill, taking HRT,² having a high body mass index and family history.³ Breast-feeding is protective against breast cancer,4 especially if for a long period of time. Currently in the UK women are screened for breast cancer every three years from the ages of 50-70 years, and this is being extended across the country to 47-73 years.

Hormone therapy is used as part of the multi-modality approach to treating breast cancer. There are many different types of breast cancer, most of which are hormone-driven. Hormone therapy can be used in the neoadjuvant (pre-surgical), adjuvant (post-surgical), metastatic and prophylactic settings to prevent tumour growth, recurrence, spread and occurrence.  There are different types of hormone treatment, with different mechanisms of action and side effect profiles.  Two new areas of research influencing changes in practice include using hormones as a prophylactic measure in high risk patients, and the length of time that hormones are used in the adjuvant setting.

Hormones and breast cancer

Hormones are chemical messengers which travel around the body, often in the bloodstream, and affect the action of cells and tissues. Immunohistochemical analysis of breast cancer biopsies can reveal whether the cancer cells are oestrogen and/or progesterone receptor positive, indicating that the tumours are driven by these hormones. Approximately 75% of breast cancers are oestrogen receptor positive (er+), and of these approximately 65% are progesterone receptor positive (pr+) as well.5 Hormone receptor positivity can be graded from 0-8 (Allred score). Post-menopausal patients are more likely to have hormone receptor positive disease, which has a better prognosis than hormone receptor negative disease, and is responsive to hormone therapy.⁶

Oestrogen and progesterone are produced by the ovaries in pre-menopausal women. Other tissues which produce oestrogen in pre- and post-menopausal women are fat cells, the liver, adrenal glands and skin. Exogenous sources of oestrogen include the oral contraceptive pill and HRT.

Oestrogens cause the development of secondary sexual characteristics in women, and cause womb thickening during the menstrual cycle and support pregnancy. They also promote bone growth, are involved in the lipid and coagulation pathways. Progesterone has a role in regulating the menstrual cycle and is the hormone which supports pregnancy including involvement in the development of the foetus.

Hormone therapy – mechanism of action and side effects

A number of different drugs have been developed to counteract the effect of oestrogen and progesterone on hormone-sensitive breast cancer, and they work in different ways.

Blocking the effects of oestrogen

Tamoxifen (a selective oestrogen receptor modulator) is the oldest drug that has been used to stop the stimulation of er+ breast cancer and has been in use for over 30 years. It works as a competitive antagonist of the oestrogen receptor in breast cancer cells, stopping oestrogen from binding to the receptor and thus halting the promotion of their division and growth. Interestingly, it has partial agonist activity in cells outside the breast, which explains the increased risk of endometrial cancer in patients taking tamoxifen.⁶

In this way it also promotes bone growth by enhancing the oestrogenic effects on inhibiting osteoclast (bone resorbing cells) activity. Its other significant potential effect is its prothrombotic tendency, which increases the risk of deep vein thrombosis and pulmonary emboli and therefore a careful history must be taken from patients before starting the drug.  Tamoxifen is teratogenic (harmful to the developing foetus), and therefore has implications for pre-menopausal women who may wish to start a family.

Other side effects include hot flushes, night sweats, vaginal dryness, weight gain, depression, loss of libido and cataracts.

Care should be taken when co-prescribing antidepressants with tamoxifen. Paroxetine, fluoxetine and sertraline competitively inhibit CYP2D6 and reduce the effectiveness of tamoxifen.7 As many patients with breast cancer are also treated with depression, alternative SSRI antidepressants eg. citalopram, or other drugs should be considered.

Other SERMs include raloxifene, which was originally developed as a drug to treat osteoporosis.

Fulvestrant (Faslodex) is a newer drug developed to block the oestrogen receptor in breast cancer cells. It is an oestrogen receptor down-regulator, which has no agonist effect. It is given as an injection. It can cause nausea/vomiting and diarrhoea in addition to the side effects common with tamoxifen.

Blocking oestrogen production

Oestrogens are produced from cholesterol outside the ovaries in tissues such as fat, liver, skin and adrenals. In post-menopausal women it is possible to block this production and therefore reduce the effect of oestrogen on breast cancer cells. This class of drugs is not effective in pre-menopausal women because these women produce oestrogen directly in the ovaries.

The drugs inhibit the enzyme aromatase, which is part of the pathway in which oestrogen is produced from cholesterol..

Aromatase inhibitors are taken in tablet form. Examples include anastrazole (Arimidex) and letrozole (Femara) which are non-steroidal reversible competitive inhibitors of the enzyme. Exemestane is a non-reversible steroidal inhibitor of aromatase.

Aromatase inhibitors cause similar menopausal type symptoms to tamoxifen, although they are often better tolerated. In addition they increase the risk of osteoporosis, and bone mineral density scans and osteoporosis treatment should be carried out as per National Osteoporosis Society/NCRI joint guidelines⁸. They also can increase the risk of cardiovascular disease and hypercholesterolaemia.⁶  Patients on aromatase inhibitors often complain of pain in the small joints, which can be debilitating.

Blocking ovarian function

In pre-menopausal women, the production of oestrogen from the ovaries can be halted permanently or temporarily. Ovarian ablation (permanent) can be effected by surgically removing the ovaries, or ablating them with radiotherapy, the latter of which is rarely carried out today. Oophorectomy can be carried out in patients with BRCA mutations to reduce the risk of ovarian cancer, and this will also reduce the risk of breast cancer in pre-menopausal women.

Ovarian function can be suppressed temporarily by drugs called GNRH analogues (gonadotrophin releasing hormone agonists) which overstimulate the pituitary, causing eventual down-regulation of production of oestrogen by the ovaries. Goserelin (Zoladex) is an example of a GNRH analogue and can be given as an injection in conjunction with other hormone therapies. It can cause osteoporosis and menopausal symptoms as well as increasing the risk of cardiovascular disease.

Indications for hormone therapy in breast cancer

Neoadjuvant

In certain cases, neo-adjuvant treatment is considered if breast conserving treatment is not possible, to try and reduce the tumour size and prevent a mastectomy. It can comprise of chemotherapy or hormonal therapy, the latter of which is particularly indicated in the post-menopausal population, especially as chemotherapy is less successful in er+ tumours. One trial found neo-adjuvant letrozole to have a response rate of 55% compared with 36% in patients taking tamoxifen (p<0.001), and 44% of patients underwent breast conserving surgery compared with 35% on tamoxifen (p=0.022).9 Therefore neo-adjuvant letrozole is an option for post-menopausal women to reduce the tumour bulk enabling breast conserving surgery.

Adjuvant

Breast cancer treatment often incorporates different modalities. The definitive treatment is surgery (breast conserving or mastectomy), followed by adjuvant treatment options to reduce the risk of disease recurrence. The balance of risk of recurrence must be weighed up against the side effects and risks associated with the treatment. Adjuvant treatments include chemotherapy, hormones, radiotherapy and targeted therapy (eg. Herceptin), and these are not all appropriate for each patient.  Hormone therapy is recommended to all patients with er+ disease, although it may be less efficacious in patients with tumours with low levels of the er receptor, pr- disease, her2+ (especially tamoxifen), and in cancers with a high proliferative index.¹⁰

Initially all er+ patients were given five years of adjuvant tamoxifen as it was found that this reduced annual recurrence by 41% and annual mortality by 34% compared with no hormone treatment.¹¹ The addition of ovarian suppression in pre-menopausal patients is debatable. Trial evidence has shown that in patients who would have benefited from CMF chemotherapy but did not have it, tamoxifen for five years plus Zoladex for 2€“3 years has a similar effect on overall survival and was more effective in improving relapse free survival and reducing recurrence at six years, although an older regimen of chemotherapy was used in this trial.¹² The ZIPP trial has shown that tamoxifen (five years) and zoladex (two years) are equally effective in improving survival and reducing recurrence of disease. A statistically significant result was not found for adding the two together. However, NICE guidelines recommend the addition of two years of goserelin to five years of tamoxifen if chemotherapy is indicated but not given.¹³

In post-menopausal women, aromatase inhibitors are now recommended. The ATAC¹⁴ study was a randomised control phase III study randomising 9300 women between five years of tamoxifen and five years of anastrozole. For hormone-receptor-positive patients, the results were significantly in favour of the anastrozole group for disease-free survival (HR 0.86, 95% CI 0.78-0.95; p=0.003). The benefit was found to be greatest in those who were pr-. However, there was no overall survival benefit in the arimidex arm. These results were supported by the BIG-98¹⁵ study which also found an increased five-year disease-free survival when taking letrozole compared with tamoxifen (84% versus 81%). These studies support the use of aromatase inhibitors in the adjuvant setting, however caution should be taken in patients with osteoporosis or with significant heart disease for whom tamoxifen is more appropriate.

A further option is to switch from tamoxifen to an aromatase inhibitor at 2-3 years. This is supported by the IES study¹⁶ which found an increased DFS at three years (91.5% versus 86.8%) but again no overall survival benefit.  This approach reduces the long-term effects from either of the drugs as they are each being used for less time.

Metastatic disease

Hormone therapy is a very effective treatment option in patients with er+ metastatic disease. If the patient has bone or soft tissue disease and but no visceral metastases, then hormone therapy is preferable to chemotherapy.

Pre-menopausal patients can be given tamoxifen. If they have had this recently, then ovarian suppression can be considered with goserelin instead. Post-menopausal women can receive an aromatase inhibitor €”arimidex or letrozole.

As second-line treatment, post-menopausal women are offered is  further AI medications (arimidex, letrozole, exemetane) and these are usually tried in sequence, as well as tamoxifen. Once these have failed, then fulvestrant can be considered as an option in post-menopausal women, given as a monthly gluteal intra-muscular injection.¹⁷  Fulvestrant is currently not approved by NICE but is available through the centralised Cancer Drug Fund.

Aromatase inhibitors can be given as second-line treatment in pre-menopausal women as long as they have been given ovarian suppression treatment (eg. Zoladex).

Length of treatment

Traditionally hormones have been used in the adjuvant setting for a total of five years. Extended therapy was addressed in the post-menopausal population, where patients who had taken tamoxifen for five years were then randomised to no further treatment versus five additional years of letrozole (an AI).¹⁸ The interim analysis showed a 43% reduction in recurrence risk in the extended therapy arm, and the trial stopped early so that those on placebo could cross over. The final results showed a significant increase in disease-free survival, and distant disease-free survival in the letrozole group.  In node-positive patients, there was also an overall survival benefit (HR 0.61, p=0.04).

More recent studies have looked at extending the length of tamoxifen therapy. Earlier trials did not show a benefit to extending treatment with tamoxifen for more than five years in patients with early breast cancer.¹⁹ Hence five years of treatment has been standard of care in pre-menopausal patients. However, two recent trials have shown that 10 years of tamoxifen treatment is beneficial to patients. The recently published international phase 3 ATLAS study20 found that in patients with oestrogen receptor positive early stage breast cancer, there was a reduction in recurrence of breast cancer (25.1% versus 21.4% of patients at 15 years) and also a reduction in breast cancer deaths (15% versus 12.2% at 15 years), particularly more than 10 years after diagnosis in patients who had 10 years of tamoxifen rather than five. The increased risk of PE and endometrial cancer was felt to be far outweighed by the benefit of the additional tamoxifen. The data showed an absolute mortality loss of 0.4% (one in 250 women) to endometrial cancer, compared with an absolute mortality gain of 12% (one in eight women) over 15 years.

The data from ATLAS have been supported by another trial which has been presented recently at the American Society of Clinical Oncology conference in Chicago. The aTTom study, a UK-based trial randomising 7000 women to five or 10 years of adjuvant tamoxifen, has shown a 25% reduction in risk of recurrence and a 23% reduction in breast cancer mortality after 10 years of tamoxifen treatment, starting at year 10.

Both ATLAS and aTTom (and the combined data from both trials) recommend extension of treatment with tamoxifen to 10 years. For very low risk patients, the extra side effects and complications may not be worth it, and these patients may choose to stop treatment at five years. There may also be problems with compliance as well as the implications on fertility, as pregnancy is not recommended whilst taking tamoxifen.

For post-menopausal patients, there is no trial comparing 10 years of tamoxifen with five years of tamoxifen and  five years of  letrozole. Therefore recommendations are awaited for this patient group.

Preventative hormone therapy

Currently in the UK, hormone therapy is not used as prophylaxis against developing breast cancer (in the USA there is FDA approval for tamoxifen in high risk pre- and post-menopausal women, and raloxifene is approved for those who are post menopausal). A recently published meta-analysis of nine trials²¹ (including the UK IBIS-1 study) of selective oestrogen receptor modulators (tamoxifen, raloxifene, arzoxifene and lasofoxifene) versus placebo (in one case raloxifene versus tamoxifen) found overall a 38% reduction in breast cancer in the treated group in the first 10 years of follow-up (with the greatest effect in the first five years when they are taking the treatment), needing to treat 42 women to prevent one breast cancer event.  There was a significant increase in thromboembolic events (odds ratio 1.73) but a significant reduction in vertebral fractures (34%). The STAR study,²² which compared tamoxifen and raloxifene as prophylaxis in post-menopausal women, found raloxifene to be less efficacious  (76% as effective as tamoxifen in reducing the risk of invasive breast cancer), but with a better side effect profile – significantly less likely to cause thromboembolic events and endometrial hyperplasia and malignancy. IBIS 2 is a trial currently recruiting comparing tamoxifen and anastrozole in post-menopausal er+ patients in the prophylactic setting.

The challenge now is to identify which patients are suitably high risk enough to benefit from hormone prophylaxis, and where that benefit outweighs the risks of the treatment (particularly thromboembolic disease and endometrial cancer). NICE issued draft guidance in January 2013 recommending tamoxifen prophylaxis in patients at high risk of developing breast cancer, and the full guidance is awaiting and should be available soon.

Conclusion

In conclusion, hormone therapy is a vital part of the multi-modality approach to treating breast cancer in patients with hormone receptor positive tumours. It can be used in the neo-adjuvant, adjuvant and metastatic setting, and is now being considered in the prophylactic setting too, with NICE guidelines awaited. The length of treatment is an area which is currently under review and change, and adjuvant treatment is likely to be extended to 10 years in the clinic. Various hormone treatments are available with side effects, which need to be carefully considered when discussing treatment options with patients in the clinic.

Conflict of interest: none

References

1.Data were provided by the Office for National Statistics on request, June 2012. Via Cancer Research UK website www.cancerresearchuk.org

2.Beral, V. Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet 2003; 362(9382): 419-27

3.Garcia-Closas M, Brinton LA, Lissowska J, et al. Established breast cancer risk factors by clinically important tumour characteristics. Br J Cancer 2006; 360: 187-95

4.Collaborative Group on Hormonal Factors in Breast Cancer Breast cancer and breastfeeding: collaborative reanalysis of individual data from 47 epidemiological studies in 30 countries, including 50302 women with breast cancer and 96973 women without the disease. Lancet 2002; 360(9328): 187-95

5.Anderson WF, Jatoi I, Devesa SS: Distinct breast cancer incidence and prognostic patterns in the NCs SEER program: Suggesting a possible link between etiology and outcome. Breast Cancer Res Treat 2005; 90: 127-37

6.Lumachi F, Luisetto G, Basso SM, et al. Endocrine therapy of breast cancer. Curr Med Chem 2011;18(4): 513-22

7.Tamoxifen for breast cancer: drug interactions involving CYP2D6, genetic variants, and variability in clinical response. Drug Safety Update 2010; 4(4): A1.

8.Reid DM, Doughty J, Eastell R, Heys SD, et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev 2008; 34: S1-S18

9.Ellis M, Ma C. Letrozole in the neoadjuvant setting: the PO24 trial. Breast Cancer Res Treat 2007; 105(Suppl 1): 33-43.

10.Higgins M, Stearns V, Understanding Resistance to Tamoxifen in Hormone Receptor -Positive Breast Cancer. Clinical Chemistry 2009; 55(8): 1453-55

11.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 randomized trials. Lancet 2011; 378(9793) 771-84

12.Boccardo F, Rubagotti A, Amoroso D, et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. [email protected]. J ClinOncol 2000; 18(14): 2718-27

13.Hackshaw M, Baum M, et al Long-term Effectiveness of Adjuvant Goserelin in Premenopausal Women With Early Breast Cancer JNCI J Natl Cancer Inst 2009; 101 (5): 341-49

14.Howell A, Cuzick J, Baum M, 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

15.Regan M, 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. The Lancet Oncology 2011;  12(12): 1101-08

16.Coombes RC, Hall E, Gibson LJ, et al.: A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 2004; 350(11): 1081-92

17.Howell B, Pippen J, Elledge RM, et al. Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma: a prostpectively planned combined survival analysis of two multicenter trials. Cancer 2005; 104(2); 236-39

18.Goss PE. Preventing relapse beyond 5 years: the MA.17 extended adjuvant trial. Semin Oncol 2006; 33(2 Suppl 7): S8-12

19.Fisher B, Dignam J, Bryant J, Wolmark N. Five Versus More Than Five Years of Tamoxifen for Lymph Node-Negative Breast Cancer: Updated Findings From the National Surgical Adjuvant Breast and Bowel Project B-14 Randomized Trial. JNCI J Natl Cancer Inst 2001; 93 (9): 684-90

20.Davies C, Pan H, et al Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. The Lancet, 2013; 381(9869): 805-16

21.Cuzick J, Sestak I, et al Selective oestrogen receptor modulators in prevention of breast cancer: an updated meta-analysis of individual participant data.Lancet. 2013 May 25;381(9880):1827-34. doi: 10.1016/S0140-6736(13)60140-3. Epub 2013 Apr 30.

22.Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P2 Trial: preventing breast cancer. Cancer Prevention Research 2010; 3(6): 696-706