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Mr Giles Cunnick and Mr Nigel Sacks outline six of the most recent

medical and surgical advances

and look at what the future holds

1. Sentinel lymph node biopsy

This technique is likely to become more widely available over the next 18 months2. It has been developed as a minimally invasive method of assessing regional lymph node status in cancer patients. It was originally performed in patients with parotid carcinoma but is now predominantly carried out in patients with melanoma and, more recently, breast cancer.

The technique allows surgeons to determine whether the status of the axilla is positive or negative by removing only a small number of nodes with minimal morbidity.

This stages the disease so that appropriate adjuvant therapy may be planned to optimise chances of cure.

The sentinel nodes are the nodes through which malignant cells first spread before passing to the other lymph nodes in the lymphatic basin. Identification is performed by using a combination of a blue dye and radioisotope injection before surgery. If the sentinel nodes are negative, no further axillary surgery is required. Since the majority of patients with breast cancer do not have axillary metastasis at diagnosis, it means most can avoid the excess morbidity of an axillary node clearance (lymphoedema, shoulder stiffness, pain, armpit numbness, etc).

Furthermore, the majority of cases can be performed as a day case or single overnight stay. Results of a published randomised trial have confirmed the benefits of the technique1 and we have performed more than 500 cases at The Royal Marsden over the last six years. However, it is not yet widely available in the UK.

However, the results of the UK multicentre randomised trial (ALMANAC) have now been presented and so this is likely to change.

2. Aromatase inhibitors

In postmenopausal women the only source of oestrogen is the peripheral tissues (for example, muscle, adipose and breast tissue) where the aromatase enzyme converts steroid precursors into oestrogen.

Aromatase inhibitors block this conversion, drastically reducing circulating oestrogen levels available to stimulate oestrogen receptor (ER) positive breast cancer cells.

This mechanism of action differs from tamoxifen, which attaches to the ER and prevents the binding of oestrogen but does not affect circulating oestrogen levels.

There are three available aromatase inhibitors in the UK ­ anastrozole, letrozole and exemestane ­ which are all broadly similar in effect.

A large prospective randomised trial (ATAC) of more than 9,000 women with early breast cancer compared the outcome of either anastrozole, tamoxifen or both given as adjuvant therapy after surgery3.

After 68 months' follow-up, there were significant advantages for anastrozole alone over the other treatment arms in terms of disease-free survival (hazard ratio: 0.83) and the incidence of contralateral new primaries in the ER positive patients, although no overall survival advantage has yet been shown.

This drug also had significantly fewer side-effects than tamoxifen, such as endometrial cancer, vaginal bleeding, cerebrovascular events and venous thromboembolic events.

However, osteoporosis, fractures and musculoskeletal disorders were more common with anastrozole than with tamoxifen.

Two other recent trials have also shown benefit in changing adjuvant endocrine treatment after initial tamoxifen therapy4,5.

In the first, patients who had completed five years of tamoxifen and were randomised to receive subsequent letrozole were found to obtain significant benefit over placebo in terms of disease-free surviva · 4.

In the other trial, patients received two-three years of tamoxifen before being randomised to either continue tamoxifen for a total of five years or switch to exemestane5.

Results from this trial also showed significant benefit for the exemestane group in terms of disease-free survival.

Unfortunately, the aromatase inhibitors are not currently licensed for first-line adjuvant therapy but anastrozole may be used as a second-line agent after tamoxifen.

In addition, all three agents may be used as primary endocrine treatments for locally advanced tumours and metastatic breast cancer.

3. Changes in the NHS breast screening programme

From the beginning of 2005, the NHS breast screening programme was extended so that all women aged between 50 and 70 will now receive routine screening invitations every three years.

And since the end of 2003, all women now have two views of the breast taken at every screening round (craniocaudal and mediolateral) instead of just at the first screen. Research has shown this could increase cancer detection rates by up to 43 per cent.

These changes will result in the biggest expansion to the programme since it was launched.

4. Immediate breast reconstruction

Despite advances in early detection and screening, almost 50 per cent of women presenting with breast cancer require a mastectomy.

Immediate breast reconstruction at the time of mastectomy is now widely available in most specialist breast units. The cosmetic outcome can be excellent, especially when it is possible to spare the uninvolved skin of the breast (skin-sparing, or so-called scarless, mastectomy). This technique is oncologically safe, provided clear margins around the tumour are obtained. The latissimus dorsi muscle is harvested as a flap and used in combination with an implant to achieve better symmetry.

This operation can be performed by many breast surgeons although flaps using the skin and fat from the lower abdomen or buttock (DIEP TRAM or SGAP flaps) usually require a plastic surgeon and microsurgical free tissue transfer. A second smaller operation may sometimes be necessary to improve cosmetic outcome. Nipple reconstruction and areolar tattooing gives the reconstruction an even better appearance.

If it is known in advance that the patient is likely to require postoperative radiotherapy, it is usually desirable to perform the reconstruction as a delayed procedure, as radiotherapy often has a deleterious effect on the cosmetic outcome of immediate reconstruction.

5. Trastuzumab

Overexpression of the HER2/neu, or HER2, protein occurs in 20-25 per cent of breast cancers and is associated with aggressive, usually hormone-insensitive, disease and poor prognosis.

Trastuzumab is a humanised monoclonal antibody produced against the HER2 protein which has been licensed for use in women with metastatic HER2 positive breast

cancer.

Its benefits have been confirmed in two seminal clinical trials9,10. One study showed benefit for women with HER2 positive metastatic cancer who had relapsed after chemotherapy9 and the other compared chemotherapy with chemotherapy plus trastuzumab in women previously untreated for metastatic disease10.

Both trials showed a small but significant benefit in terms of overall survival. Although well-tolerated, trastuzumab may cause cardiotoxicity, particularly in patients previously exposed to anthracyclines.

The drug has now been approved by NICE for the following women with HER2 overexpressed metastatic cancer:

·in combination with paclitaxel for women who have not previously had chemotherapy and for whom anthracycline treatment is not appropriate.

·on its own for relapses in women who have had at least two previous chemotherapy treatment courses.

Finally, trastuzumab has now been studied in the adjuvant setting in the HERA trial.

Women with HER2 positive cancers who received chemotherapy were randomised to receive either no further treatment or trastuzumab for one or two years. Recruitment has closed and results are not expected for two years.

6. HRT and breast cancer

Many patients experience menopausal symptoms either as a result of adjuvant therapy (tamoxifen, aromatase inhibitors or chemotherapy) or following a natural menopause.

Clinicians are frequently asked about the safety of using hormone replacement therapy after previous breast cancer, and until recently there has been very little published evidence.

Last year, the results of the HABITS trial (hormonal replacement therapy after breast cancer ­ is it safe?) were published. This randomised prospective trial compared the effects of HRT versus best non-hormonal treatment in women who had previously had breast cancer. The trial was stopped early after two years of follow-up of 345 women because of an excess of new breast cancer events in the HRT arm. Although criticisms of this study have been made, breast cancer patients are now generally advised to avoid HRT and try other treatments, such as a progestogen, venlafaxine, complementary therapy and topical oestrogen preparations.

In the meantime, a trial of a synthetic steroid, tibolone, a drug with progestogenic and some androgenic properties as well as oestrogenic effects, is under way.

There is now evidence from the Women's Health Initiative (WHI) study (16,608 patients) and the Million Women (MW) study that the use of oestrogen/progestin combined HRT in previously healthy women leads to a significantly increased risk of developing breast cancer6,7.

The WHI study found a significant excess of breast cancers in a treatment group compared with placebo (hazard ratio:1.26) after five years.

The MW study7, a seriously flawed and much criticised study, found that current users of HRT had twice the risk of developing breast cancer as that of non-users after 2.6 years' follow-up.

Furthermore, overall health risks exceeded benefits from the use of HRT in the WHI study.

In contrast, however, the oestrogen-only component of the WHI (10,739 hysterectomised women) recently reported that there was no increased risk with oestrogen alone in the form of Premarin and even a possible reduction in the incidence of breast cancer in women taking this preparation when compared with placebo (HR: 0.77), although the difference was not quite statistically significant8.

And on its way....

five things that the future holds

1Intra-operative radiotherapy

Current trials are comparing standard external beam radiotherapy with the temporary insertion of a radiotherapy source into the breast wound after surgery. The technique is as yet unproven.

2Shorter chemotherapy

Trials are showing possible benefit for shorter course chemotherapy with growth factor support (for example FEC every two weeks) with no increase in bone marrow toxicity.

3More use of adjuvant aromatase inhibitors Adjuvant aromatose inhibitors are likely to be increasingly used, possibly with bisphosphonates for bone protection in selected patients, for example those with low baseline bone density.

4More use of third-generation selective oestrogen receptor modulators Raloxifene and other third-generation selective oestrogen receptor modulators show potential for breast cancer prevention and bone protection against osteoporosis, although these are not yet routinely used for these purposes.

5Bisphosphonates in early breast cancer Recent evidence is suggesting that survival may be prolonged by administering long-acting bisphosphonates as adjuvant therapy for earlier stage breast cancer.

Useful websites

www.breastcancer.org

www.breastcancercare.org.uk

www.bco.org

References

01 Veronesi U et al. A randomised comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med 2003; 349:546-53

02 Mansel RE et al, on behalf of ALMANAC Trialists Group. Sentinel node biopsy in breast cancer: The first results of the randomised multicenter ALMANAC Trial. ASCO proceedings: June 2004: A506

03 ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial after five years' adjuvant treatement for breast cancer. Lancet 2005; 365:60-2

04 Goss PE et al. A randomised 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

05 Coombes RC et al; Intergroup Exemestane Study. A randomised 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

06 Rossouw JE et al; Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomised controlled trial. JAMA 2002;288:321-33

07 Beral V; Million Women Study Collaborators. Breast cancer and

hormone replacement therapy in the Million Women Study.

Lancet 2003;362(9382):419-27

08 The Women's Health Initiative Steering Committee. Effects of

conjugated equine estrogen in postmenopausal women with hysterectomy.

The Women's Health Initiative Randomised Controlled Trial.

JAMA 2004;291: 1701-12

09 Cobleigh MA et al. Multinational study of the efficacy and safety of humanised anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639-48

10 Slamon DJ et al. Use of chemotherapy plus a monoclonal antibody

against HER2 for metastatic breast cancer that Overexpresses HER2.

N Engl J Med 2001;344:783-92

Giles Cunnick consultant breast surgeon,

Wycombe General Hospital, Buckinghamshire

Nigel Sacks senior consultant breast surgeon, department of academic surgery, The Royal

Marsden Hospital, London

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