Editorials

Treating young patients with breast cancer

The evidence suggests that all should be treated with adjuvant therapy

Papers p   474

Breast cancer is uncommon in young women, but when it strikes it has a devastating effect on patients and their families. Several studies have shown that women who develop breast cancer in their 20s and 30s have worse survival and more biologically aggressive cancers with higher rates of proliferation and lymphovascular invasion and lower levels of oestrogen receptors than older patients with cancers of the same stage.¹ Yet despite their apparently worse survival, younger women get more benefit from chemotherapy than older women. An overview of randomised trials showed that patients with operable breast cancer aged under 40 have a 37% (SD 7) proportional reduction in the odds of recurrence and a 27% (SD 8) reduced risk of death with adjuvant chemotherapy compared with reductions of 20.3% (SD 2.6) and 11.3% (SD 2.9) respectively for women aged 50-69.² These proportionally greater benefits from adjuvant chemotherapy seem to be independent of node status.

There has been an increasing trend to give chemotherapy to almost all young patients with operable breast cancer regardless of lymph node status.³ This change in practice is supported by data from a study in Denmark by Kroman et al in this week's BMJ (p 474).⁴ Among 867 patients aged under 35 they identified 315 who were considered low risk (based on tumour size <5 cm, no skin invasion, clear margins of excision, and negative lymph nodes) and who did not receive chemotherapy. These younger women had a significantly increased risk of dying of breast cancer than older women with similar stage cancers. Yet an increased risk of death with decreasing age was not seen in women considered high risk who received adjuvant chemotherapy. These findings are consistent with the St Gallen consensus guidelines, which state that no patient aged under 35 should be truly considered low risk.⁴

Adjuvant chemotherapy in younger women with breast cancer is cost effective in terms of cost per quality adjusted life year gained in patients with both node negative and node positive disease.⁵ Randomised trials have not so far identified a subgroup of younger women who do not derive some benefit from adjuvant chemotherapy, although the size of this benefit varies considerably and is directly related to the risk of recurrence and mortality. Whether an individual patient chooses to receive adjuvant chemotherapy depends on the ratio of benefits to risks of treatmentwhich for some cancers is very small.

What adjuvant chemotherapy regimen should these young women with breast cancer receive? Most patients in the Danish study were treated with cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy, the dose and schedule of which have been criticised.⁶ The overview showed that, compared with this regimen, anthracycline based chemotherapy regimens yielded significantly lower rates of recurrence and marginally but significantly improved rates of survival.² For this reason anthracycline based adjuvant regimens are currently the most widely used in younger women. Studies in women with high risk breast cancer have shown that four cycles of adriamycin followed by eight of cyclophosphamide, methotrexate, and fluorouracil produce greater benefits than alternating these agents.⁷ More recently sequencing four cycles of adriamycin plus cyclophosphamide and four cycles of paclitaxel has shown improved survival compared with adriamycin plus cyclophosphamide alone.⁸ This sequence of anthracyclines and taxanes may become the adjuvant therapy of choice, at least in high risk younger women if subsequent randomised trials confirm its benefit over other regimens. High dose adjuvant chemotherapy and autologous stem cell rescue provides little or no added benefit over standard adjuvant regimens, even for younger women with high risk disease, and should not be used outside trials.

Although a greater proportion of breast cancers in young women are oestrogen receptor negative, more than half express some level of oestrogen receptor. Tamoxifen given for five years produces similar benefits in both premenopausal and postmenopausal women.⁹ Side effects are commoner in young women, but the increase in the incidence of thromboembolism and endometrial cancer occurs predominantly in postmenopausal women.¹⁰ In premenopausal women with oestrogen receptor positive breast cancers a combination of gonadotrophin releasing hormone analogues and tamoxifen seems to be better tolerated and has been reported to significantly reduce recurrence compared with cyclophosphamide, methotrexate, and fluorouracil.¹¹ The combination of gonadotrophin releasing hormone analogues and tamoxifen also produces more benefit than tamoxifen alone in patients with oestrogen receptor positive breast cancers after anthracycline based chemotherapy.¹² These data suggest that adjuvant hormonal therapy should be considered in all young women whose tumours express any level of oestrogen receptors.

Young women are at increased risk of local recurrence, contralateral disease, and systemic recurrence, so any systemic therapy needs to be combined with optimal local treatments.¹² In some young women with a strong family history of bilateral disease bilateral mastectomy for a small localised breast cancer should be considered and discussed with the patient. Younger women with breast cancer suffer much greater disruption to their lives than older women and have a higher incidence of depression and disease specific intrusive thoughts.

Current evidence suggests that survival of women with breast cancer is improved if they are treated in major centres by multidisciplinary teams. These centres provide the ideal environment for providing support for patients and their families and exploring through clinical trials the most effective adjuvant therapy for individual patients and their cancer.

J M Dixon, consultant surgeon and senior lecturer. 

Edinburgh Breast Unit, Western General Hospital, Edinburgh EH4 2XU (jmd{at}wght.demon.co.uk)

G Hortobagyi, professor of medicine. 

Department of Breast Medical Oncology, Texas Medical Center, Houston, Texas 77030, USA