Adjuvant Endocrine Therapy in Postmenopausal Women with Breast Cancer

Background Information

 

Approximately three quarters of all invasive breast tumours are oestrogen or progesterone receptor positive, including at least half of all breast cancers in premenopausal women.  This means that the cancer cells express receptors for these hormones on their surface.1 Adjuvant endocrine therapy describes the treatment of these cancers with additional hormone drugs, after surgery to remove the tumour, in order to help stop the disease coming back and increase the chance of cure.

Adjuvant therapy may include chemotherapy, radiation therapy or endocrine (hormone) therapy. There are different types of adjuvant endocrine therapy, all of which work in slightly different ways to prevent breast cancer recurrence.2


When is adjuvant endocrine therapy given?

Adjuvant endocrine therapy is usually given after surgery and radiotherapy for breast cancer, where intervention with hormone therapy has been proven to reduce the risk of recurrence.2,3 Women with breast cancer may also be treated with adjuvant endocrine therapy prior, or subsequent to, chemotherapy.2 In general, women remain on adjuvant endocrine therapy for five years, however, new evidence has emerged showing the value of extending the treatment duration.4


Which women will receive hormonal therapy?

Adjuvant endocrine therapy is recommended for all women with tumours that have been assessed as responsive to hormone treatment, also known as Ôhormone-responsiveÕ breast cancer.4 To determine if the breast cancer will respond to hormones, an oestrogen/progesterone receptor test is carried out on the tumour.5 If positive, the patient will normally be prescribed adjuvant endocrine therapy after their operation.5

 

How does adjuvant endocrine therapy work?

Hormones are secretory substances that control the growth and activity of normal cells.3 Although they do not usually affect cancer cells, in breast cancer, the situation is different and both the female hormones, oestrogen and progesterone, have been shown to have a growth-promoting impact on certain breast cancer cells.3 Depending on the particular type of hormone treatment used, adjuvant endocrine therapy exerts its effects either through the blockade of oestrogen production or by preventing oestrogen from reaching its target receptors on cancer cells.6

 

Types of adjuvant endocrine therapy

Anti-oestrogens – tamoxifen (Nolvadex¨)

Tamoxifen is the oldest and most commonly used adjuvant endocrine therapy.3,7,8 It is an anti-oestrogen drug which works by preventing the hormone from attaching to breast cancer cells and encouraging them to grow.8 Tamoxifen can reduce the risk of recurrence by about 30% and, on average, has been shown to decrease the risk of developing a second breast cancer by around 50%.8 It is taken once daily in tablet form, usually for a period of five years.7 Common side effects associated with tamoxifen include menopausal symptoms, such as hot flushes and weight gain.  Tamoxifen is also associated with an increased risk of thrombosis and endometrial cancer.3,8

 

Aromatase inhibitors – anastrozole (Arimidex¨), exemestane (Aromasin¨), letrozole (Femara¨)

Aromatase inhibitors, the next generation of endocrine therapy, block the small amount of oestrogen that is produced by the adrenal glands which lie just above the kidneys.9 They work by inhibiting the activity of the enzyme, aromatase, which is needed to convert androgen hormones into oestrogen.9 These drugs are used in post-menopausal women whose ovaries have shut down and where the only remaining source of oestrogen production is via the adrenal route.9 Aromatase inhibitors are used to treat post-menopausal women with early breast cancer in order to reduce risk of recurrence and there is growing evidence to demonstrate the superiority of these agents in comparison to tamoxifen. 3,10,11  Aromatase inhibitors may be used as an alternative or subsequent therapy to tamoxifen.  There is evidence that risk of recurrence can be reduced further by switching to exemestane or anastrozole after two to three years of tamoxifen.3, 12, 13 Risk of recurrence can be further reduced by treatment with letrozole after five years of tamoxifen.3, 4 Aromatase inhibitors are taken once daily for a period of several months or years.9 Like tamoxifen, side effects include menopausal symptoms such as hot flushes, vaginal dryness and tiredness however these agents are not associated with the side effects of thrombosis and endometrial cancer.9 Other potential adverse effects include increased osteopenia, nausea, headaches, diarrhea and muscle pain.9

 

Adjuvant endocrine therapy – influence on recurrence risk

Many studies have highlighted that adjuvant endocrine therapy is an essential tool in the fight against breast cancer as it decreases the risk of recurrence by at least one third.7 Analysis of almost 37,000 women with early breast cancer showed that adjuvant tamoxifen treatment (anti-oestrogen therapy) substantially improved the 10-year survival of women with ER-positive tumours and those whose tumours were of unknown ER status.14 Similarly, another analysis of recurrence among ER+ patientsÕ found that use of tamoxifen therapy significantly improved patients outcomes.15 However, even with adjuvant endocrine therapy, more than 20% of node-negative patients had their disease recur within 15 years after diagnosis.15

 

A number of studies have compared tamoxifen with aromatase inhibitors in the early breast cancer setting and have shown that there is significant evidence to support the use of aromatase inhibitors over tamoxifen.10, 11, 16 For example a trial10 incorporating both a head-to-head comparison of letrozole with tamoxifen and a sequencing of both agents to determine the most effective approach to minimise the risk of breast cancer recurrence showed that letrozole:

 

For this reason a number of recent guidelines - including those from St Gallen and the National Comprehensive Cancer Network – have recommended that aromatase inhibitors be used as part of the optimal adjuvant treatment of postmenopausal women with hormone-sensitive breast cancer.17, 18

 

Despite the fact that adjuvant endocrine therapy can reduce recurrence after diagnosis and initial treatment, there is an ongoing risk of recurrence.7 A study that evaluated the risk of breast cancer recurrence following adjuvant endocrine therapy in over 2,400 women with early breast cancer revealed a substantial and continuing risk of recurrence long after completion of five years of standard adjuvant endocrine therapy.10 Another study showed that more than half of all breast cancer recurrences and two-thirds of all breast cancer deaths occur after 5 years of standard tamoxifen therapy.4 Despite the residual risk of recurrence after 5 years of adjuvant endocrine therapy, continued use of tamoxifen after this period has been found to be associated with an increase in serious adverse events without further efficacy benefits.15

 

Therefore, a number of studies have looked at the benefit of using AIs in the extended adjuvant setting.  For example a trial4 looking at the effectiveness of letrozole vs. placebo in women who have received prior standard adjuvant tamoxifen therapy for five years, showed that letrozole:

 

Significantly, the interim data from the study led the investigators to unblind (open the code of the treatment taken) the trial early so that those patients taking placebo could be offered the opportunity to switch to letrozole.  A further analysis of the data showed that the women (n=1655) who opted to take letrozole following a prolonged delay after completing tamoxifen experienced a significant improvement in outcome (disease-free survival, distant disease-free survival, and overall survival) in comparison to those who opted to take no further treatment (n=613).19

– Ends –

References

1.      Winer E. Optimizing endocrine therapy for breast cancer. Journal of Clinical Oncology 2005; 23 (8): 1609-1610.

2.      Cancerbackup. Treating breast cancer with hormonal therapies. March 2006. Available at: http://www.cancerbackup.org.uk/Cancertype/Breast/Treatment/Hormonaltherapies

3.      Cancer Research UK. Types of breast cancer hormone therapy. July 2005. Available at: http://www.cancerhelp.co.uk/help/default.asp?page=3333

4.      Goss PE, Ingle JN et al. Randomised trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005; 97: 1262-1271

5.      Breakthrough Breast Cancer. Hormone treatment. Accessed June 2006. Available at: http://www.breakthrough.org.uk/about_breast_cancer/treatment/drug_therapy/hormone_treatment/index.html

6.      Patient Health International. Treatment options and issues for younger women with early breast cancer. Feature; October 2005. Available at: http://www.patienthealthinternational.com/features/8836.aspx

7.      Life After Early Breast Cancer (ABC) Disease Awareness Initiative. Risk of recurrence in early breast cancer. Accessed June 2006. Available at: http://www.lifeabc.org/risk_recurrence_more.html

8.      Breakthrough Breast Cancer. Anti-oestrogens. Accessed June 2006. Available at: http://www.breakthrough.org.uk/about_breast_cancer/treatment/drug_therapy/hormone_treatment/antioestrogens.html

9.      Breakthrough Breast Cancer. Aromatase inhibitors. Accessed June 2006. Available at:  http://www.breakthrough.org.uk/about_breast_cancer/treatment/drug_therapy/hormone_treatment/aromatase.html

10.   The Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. NEJM. 2005; 353: 2747-2757

11.   ATAC TrialistsÕ Group Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 yearsÕ adjuvant treatment for breast cancer. www.thelancet.com Published online December 8, 2004 http://image.thelancet.com/extras/04let11120webappendix.pdf

12.   R. C. Coombes, R. Paridaens, J. Jassem, C. J. Van de Velde, T. Delozier, S. E. Jones, E. Hall, L. S. Kilburn, C. F. Snowdon, J. M. Bliss, for the Intergroup Exemestane Study (IES)

First mature survival analysis of the Intergroup Exemestane Study: a randomised trial in disease-free, postmenopausal patients with early breast cancer randomized to continue tamoxifen or switch to exemestane following an initial 2-3 years of adjuvant tamoxifen.

Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: LBA527

13.   Jonat W et al. Switching from adjuvant tamoxifen to anastrozole in
postmenopausal women with hormone-responsive early breast cancer: a
meta-analysis of the ARNO 95 trial, ABCSG Trial 8, and the ITA trial. Abstract
No. 18. San Antonio Breast Cancer Symposium 2005.

14.   Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomized trials. Lancet. 1998;351:1451-1466.

15.   Fisher B, Dignam J, Bryant J, DeCillis A et al. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Can Inst. 1996; 88: 1529-1542.

16.   Wardley AM.   Emerging data on optimal adjuvant endocrine therapy: Breast International Group trial 1-98/MA.17. Clin Breast Cancer. 2006 Feb;6 Suppl 2:S45-50. Review.  

17.   Goldhirsch A, Glick JH, Gelber RD et al. Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005. Ann Oncol 2005; 16: 1569–1583

18.   NICE Appraisal Committee's Preliminary Recommendations Improving Outcomes in Breast Cancer – Manual Update. Updated 28.08.06.  Available at: http://www.nice.org.uk/page.aspx?o=csgbcguidance

19.   Robert N, Goss PE, Ingle JN, Tu D, Shepherd L, Palmer M, Pater J.  Updated analysis of NCIC CTG MA.17 (letrozole vs. placebo to letrozole vs placebo) post unblinding.  Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement), 2006: 550