The role of adjuvant systemic therapy in node-negative breast cancer

Question: What is the role of systemic adjuvant therapy for women with node-negative breast cancer?. Perspective: Evidence was selected and reviewed by two members of the Cancer Care Ontario Practice Guidelines Initiative Breast Cancer Disease Site Group (DSG). This practice guideline report has been reviewed and approved by the Breast Cancer DSG, which comprises surgeons, medical oncologists, radiation oncologists, epidemiologists, a pathologist, a medical sociologist, and a community representative. Outcomes: Disease-free survival and overall survival were the primary outcomes of interest. Toxicity was also considered. Results: Quality of Evidence: Two individual patient data meta-analyses were available for review. One analyzed data from 2710 patients with node-negative breast cancer enrolled in trials of long-term polychemotherapy versus no chemotherapy. The other compared tamoxifen with control in 12 910 women with node-negative breast cancer. Benefits: Adjuvant systemic therapy reduces recurrence of disease (26% relative reduction in the annual odds of recurrence for both chemotherapy and tamoxifen compared with control) and improves survival (18% relative reduction in the annual odds of death compared with control for chemotherapy and 17% for tamoxifen) in patients with node-negative breast cancer. The choice of therapy (chemotherapy or tamoxifen) should be based on the patient's risk of recurrence and on factors that predict responsiveness to therapy (age and receptor status). Harms: Chemotherapy can be associated with a variety of side effects such as hair loss, nausea and vomiting, and infection. Relatively few side effects are associated with tamoxifen; very rarely tamoxifen can cause venous thromboembolism or endometrial cancer. Practice Guideline: Choice of Therapy: Pre- and post-menopausal women at minimal or low risk of recurrence (< 2 cm, well differentiated, and all other factors favorable; or <1 cm, intermediate grade, and all other factors favorable) should receive no adjuvant systemic treatment. They should, however, be made aware that systemic therapy is offered to women at higher risk of recurrence. Pre-menopausal women (age < 50 years) at moderate risk of recurrence (1-3 cm and intermediate grade; or 2-3 cm and well differentiated) and with oestrogen-receptor-positive tumours should be offered tamoxifen. Chemotherapy added to tamoxifen may provide a modest incremental benefit over tamoxifen alone. This is an ideal situation for a decision aid. Pre- menopausal women (age < 50 years) at high risk of recurrence (> 3 cm, irrespective of any other factors; or > 1 cm with either oestrogen-receptor negative, high grade, or lymphatic and vascular invasion) should be offered chemotherapy. Insufficient data currently exist to recommend the addition of tamoxifen to chemotherapy in this subgroup. If the patient refuses chemotherapy and the tumour is oestrogen-receptor-positive, tamoxifen may be considered. Insufficient data exist to determine the risk category of a tumour less than 1 cm in diameter associated with a poor prognostic factor (e.g., grade III, oestrogen-receptor-negative, lymphatic and vascular invasion). Post-menopausal women (age > 50 years) at moderate risk of recurrence (1-3 cm and intermediate grade; or 2-3 cm and well differentiated) and with oestrogen-receptor-positive tumours should be offered tamoxifen. Chemotherapy added to tamoxifen may provide a modest incremental benefit over tamoxifen alone. This is an ideal situation for the use of a decision aid. Post-menopausal women (age > 50 years) at high risk of recurrence (> 3 cm; or > 1 cm with high grade, or lymphatic and vascular invasion) and with oestrogen receptor-positive tumours should be offered tamoxifen plus chemotherapy. The benefits and risks of additional chemotherapy should be discussed with the patient. If the patient refuses chemotherapy, then tamoxifen alone should be considered. Post menopausal women at high risk of recurrence and with oestrogen-receptor-negative tumours should be offered chemotherapy. Duration of Tamoxifen: Hormonal therapy should consist of oral tamoxifen 20 mg daily for 5 years. Chemotherapy Regimen: Polychemotherapy should reasonably comprise 6 cycles of cyclophosphamide (oral), methotrexate, and fluorouracil (CMF); or 4 cycles of doxorubicin and cyclophosphamide (AC). Process of Decision-making: A patient with node-negative breast cancer should be informed of the availability of adjuvant systemic therapy and should be offered the opportunity of discussing such therapy with an expert clinician. She should be provided with detailed information concerning her risk of recurrence if untreated, the potential efficacy of adjuvant therapy in terms of recurrence and mortality, and the potential side effects of therapy.