In its recent guidance (see box), NICE has recognised not only the clinical effectiveness of aromatase inhibitors (AIs), but also their cost-effectiveness at an incremental cost of less than £20,000 per quality adjusted life year.1
The licensed indications for each AI are cost-effective when compared with tamoxifen, while extended adjuvant treatment with letrozole is also cost-effective when compared with placebo.
Tamoxifen became the standard of care based on its proven efficacy in reducing risk of recurrence by 47 per cent and risk of death by 26 per cent over 10 years.2
Aromatase inhibitors have been found to be cost-effective in estrogen-receptor positive breast cancer
Hormone manipulation with tamoxifen has been a major contributor to the reduction in deaths from breast cancer in the UK since the late 1980s,3 which has occurred despite increasing incidence of the disease.4
However, adjuvant treatment with tamoxifen has its limitations. Treatment beyond the recommended five years does not further improve survival5 and breast cancer recurs in a substantial proportion of patients who undergo five years of tamoxifen therapy.2
AIs were developed as a more effective approach to the adjuvant treatment of estrogen-receptor (ER)-positive tumours. Tamoxifen blocks activation of the ER in the nucleus of responsive cells; AIs reduce circulating estrogen by blocking the enzyme aromatase, which converts androgens to estrogens in the peripheral tissues of postmenopausal women.
The NICE guidance is good news for postmenopausal women with ER-positive breast cancer, but it is likely to present some challenges for GPs and local cancer networks.
In 2002, NICE recommended against routine long-term specialist follow up after treatment of early breast cancer.6 Instead, GPs were given the responsibility not only for routine follow up, but also for withdrawing tamoxifen after five years.6
NICE is not scheduled to issue clinical guidelines on early breast cancer until February 2009 so, for now, GPs need to liaise with local breast cancer units to ensure that all suitable women are offered treatment with an AI.
This choice of treatment is not straightforward and doctors need to be able to advise each woman about her personal risks and benefits of treatment. This discussion should take into account each woman's previous tamoxifen use and risk of recurrence, as well as the efficacy and tolerability of each AI.
Choice of AI
NICE based its guidance on the overwhelming evidence that AIs improve clinical outcomes, compared with tamoxifen in primary adjuvant treatment, unplanned switching or as extended adjuvant treatment. However, it is inappropriate to regard the AIs as interchangeable, because the clinical trials have recruited distinct populations of women, used different treatment protocols and adopted varying primary endpoints.
In the absence of results from head-to-head studies that are under way, doctors and postmenopausal women with early ER-positive invasive breast cancer should be able to choose any of the three drugs, but within their licensed indications.
These indications may change as the evidence evolves, but, at present, anastrozole and letrozole are licensed in the UK for initial adjuvant treatment and following two to three years (anastrozole) or five years (letrozole) of initial adjuvant tamoxifen. The licence for exemestane is currently limited to adjuvant treatment following two to three years of initial adjuvant tamoxifen.
My practice is to advise letrozole or anastrozole as initial adjuvant therapy for patients at medium to high risk of breast cancer recurrence, as studies have demonstrated disease-free survival benefits over tamoxifen.7,8
For patients starting tamoxifen who are intolerant, I recommend anastrozole, which is within its licensed indications. Patients who have completed two years of tamoxifen are advised to commence either anastrozole9 or exemestane.10 Patients who have completed five years of tamoxifen and who are at medium to high risk of recurrence are advised to commence letrozole, based on the results of the MA-17 study.11
The aim of aromatase inhibition is to reduce estrogen synthesis after the menopause, so estrogen-containing therapies should be withdrawn before initiating treatment with an AI. In practice, there are very few patients in whom AIs are absolutely contraindicated, although the drugs should be used with caution in patients with severe hepatic or renal impairment.
Monitoring and follow-up
Following initiation of treatment, all patients require regular monitoring and follow-up. Although AIs are not associated with the progressively increased risk of endometrial cancer and thromboembolic events seen with long-term tamoxifen treatment,5 they do have side-effects.
In particular, by reducing circulating estrogen levels, AIs decrease bone mineral density and, as a result, increase the risk of osteoporosis and fracture.
Recent management guidelines on bone health have been devised, which include women on AIs. Interventional strategies are advised for those women with deteriorating osteoporosis and fracture risk while on therapy.12
GPs are playing an increasingly important role in supporting postmenopausal women with early breast cancer. By working with their local breast cancer unit to implement the NICE guidance, GPs can help to ensure that as many suitable patients as possible can consider adjuvant treatment with an AI.
- Mr Carpenter is consultant breast surgeon at Barts and The London NHS Trust. He sits on advisory boards and holds research grants from Pfizer, Astra Zeneca, Novartis and Roche
- This article was orginally published in MIMS Women's Health. To subscribe go to www.hayreg.co.uk/specials
- October is Breast Cancer Awareness month. For more information go to www.breastcancercare.org.uk
NICE guidance on AROMATASE INHIBITORS
- The aromatase inhibitors anastrozole, exemestane and letrozole, within their licensed indications, are recommended as options for the adjuvant treatment of early ER-positive invasive breast cancer in postmenopausal women.
- This means:
- anastrozole for primary adjuvant therapy.
- exemestane for adjuvant therapy following two to three years of adjuvant tamoxifen therapy.
- letrozole for primary adjuvant therapy and extended adjuvant therapy following standard tamoxifen therapy.
- The choice of treatment should be made after the clinician and the patient have discussed the risks and benefits.
- Factors to consider when making the choice include whether the woman has received tamoxifen before, the licensed indications and side-effect profiles of the individual drugs and, in particular, the assessed risk of recurrence.
Source: Hormonal therapies for the adjuvant treatment of early oestrogen-receptor positive breast cancer. Technology Appraisal 112. NICE, London, 2006.
1. NICE. Hormonal therapies for the adjuvant treatment of early oestrogen-receptor positive breast cancer. Technology Appraisal 112. London, November 2006.
2. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer. Lancet 1998; 351: 1,451-67.
3. Cancer Research UK. UK breast cancer mortality statistics. (accessed June 2008).
4. Cancer Research UK. UK breast cancer incidence statistics. (accessed June 2008).
5. Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer. J Natl Cancer Inst 2001; 93: 684-90.
6. NICE. Guidance on cancer services: improving outcomes in breast cancer. Manual update. London, 2002.
7. Breast Cancer International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 2005; 353: 2,747-57.
8. 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: 60-2.
9. Jakesz R, Jonat W, Gnant M et al. Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen. Lancet 2005; 366: 455-62.
10. Coombes R C, Hall E, Gibson L J 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: 1,081-92.
11. Goss P E, Ingle J N, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med 2003; 349: 1,793-802.
12. Reid D M, Doughty J, Eastell R 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: S3-S18.