An update on breast cancer treatment

The NICE guidance on aromatase inhibitors will benefit women, but may challenge GPs. By Mr Robert Carpenter

ABSTRACT

NICE recommends the treatment of early breast cancer with the aromatase inhibitors anastrozole, exemestane and letrozole as adjuvant therapy after surgery in postmenopausal women.This applies to the 80 per cent of women aged >50 years with early breast cancer, who have oestrogen-receptor (ER)-positive disease; that is, where growth of the tumour depends on the presence of oestrogen. Adjuvant hormone therapy is designed to prevent recurrence by depriving the tumour of oestrogen. Until now, five years of treatment with the anti-oestrogen drug tamoxifen has been the gold standard adjuvant therapy for postmenopausal women with ER-positive tumours.

Key words
Breast cancer, aromatase inhibitors, oestrogen receptor

In its guidance (see boxes 1 and 2), NICE has recognised not only the clinical effectiveness of aromatase inhibitors, 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 aromatase inhibitor are cost-effective when compared to tamoxifen, while extended adjuvant treatment with letrozole is also cost-effective when compared to 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.

BOX 1: 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.

Hormone manipulation with tamoxifen has been a major contributor to the reduction in deaths from breast cancer in the UK and other developed countries 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

Aromatase inhibitors were developed as a more effective approach to the adjuvant treatment of oestrogen-receptor (ER)-positive tumours. Tamoxifen blocks activation of the ER in the nucleus of responsive cells; aromatase inhibitors reduce circulating oestrogen by blocking the enzyme aromatase, which converts androgens to oestrogens 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 aromatase inhibitor.

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 with an aromatase inhibitor. 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 aromatase inhibitor.

Choosing an aromatase inhibitor
NICE based its guidance on the overwhelming evidence that aromatase inhibitors improve clinical outcomes, compared with tamoxifen in primary adjuvant treatment, unplanned switching or as extended adjuvant treatment. However, it is inappropriate to regard the aromatase inhibitors 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 currently 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 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 both the BIG 1-98 (letrozole) and ATAC (anastrozole) studies have demonstrated disease-free survival benefits over tamoxifen.7,8 For patients starting tamoxifen who are intolerant, I would recommend anastrozole, which is within its licensed indications. Patients who have completed two years of tamoxifen are advised to commence either anastrozole, based on the ABCSG-ARNO study,9 or exemestane, based on the IES study.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

BOX 2: DOSAGE, INDICATIONS, CONTRAINDICATIONS

ANASTROZOLE
Dosage 1mg a day

Indications Adjunct therapy in the treatment of early ER-positive breast cancer in postmenopausal women as monotherapy or after two to three years of tamoxifen treatment

Contraindications
Pregnancy
Breastfeeding
Moderate to severe hepatic impairment
Moderate to severe renal impairment
Premenopausal women

EXEMESTANE
Dosage 25mg a day

Indications Adjunct therapy in the treatment of early ER-positive breast cancer in postmenopausal women after two to three years of tamoxifen treatment

Contraindications
Pregnancy
Breastfeeding
Premenopausal wome

LETROZOLE
Dosage 2.5mg a day

Indications Adjunct therapy in the treatment of early ER-positive breast cancer in postmenopausal women

Contraindications
Pregnancy
Breastfeeding
Moderate to severe hepatic impairment
Premenopausal women.

The aim of aromatase inhibition is to reduce oestrogen synthesis after the menopause, so oestrogen-containing therapies should be withdrawn before initiating treatment with an aromatase inhibitor. In practice, there are very few patients in whom aromatase inhibitors 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 aromatase inhibitors 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 oestrogen levels, aromatase inhibitors decrease bone mineral density (BMD) and as a result, increase the risk of osteoporosis and fracture. Recent management guidelines on bone health have been devised, which include women on aromatase inhibitors. Interventional strategies are advised for those few women with deteriorating osteoporosis and fracture risk while on therapy.12

In the past, the GP's involvement in breast cancer care often ended after referral. However, GPs are playing an increasingly important part in following up and 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 aromatase inhibitor.

- Mr Robert Carpenter is consultant breast surgeon at Barts and The London NHS Trust.

Competing interests: Mr Carpenter sits on advisory boards and holds research grants from Pfizer, Astra Zeneca, Novartis and Roche

References
1. NICE. Hormonal therapies for the adjuvant treatment of early oestrogen-receptor positive breast cancer. Technology Appraisal 112. NICE, London, November 2006.
2. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer. Lancet 1998; 351: 1451-67.
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. NICE, 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: 2747-57.
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 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: 1081-92.
11. Goss PE, Ingle JN, 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: 1793-802.
12. Reid DM, 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(1): S3-S18.

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