p53 immunohistochemical staining and survival after adjuvant chemotherapy for breast cancer.

We have investigated the relationship between immunohistochemically determined p53 status and outcome in 277 women with node-positive primary breast cancer who, following tumour excision and axillary clearance, were randomised to receive either 6 cycles of cyclophosphamide/methotrexate/S-fluorouracil (CMF) (n = 130) or no such post-operative treatment (n = 147). Follow-up data (median = 9 years) were available on all patients. A significant association was found between p53 status and survival. Patients with p53-positive tumours had a less favourable outcome than those with p53-negative disease. Women receiving adjuvant CMF chemotherapy had a significantly more favourable outcome compared to those who did not. The effect was seen both in women with p53-positive and p53-negative tumours; multivariate analysis showed relative risks for overall survival attributable to chemotherapy of 2.3 (95% CI 1.2-4.3) for women with p53-positive tumours and of 2.1 (95% CI 1.4-3.0) for those with p53-negative tumours. Thus, adjuvant chemotherapy with CMF is associated with a survival benefit in women with node-positive breast cancer irrespective of immunohistochemically determined p53 status.

Adjuvant chemotherapy for premenopausal breast cancer: a meta-analysis using quality-adjusted survival.

PURPOSE: Adjuvant chemotherapy for early breast cancer has been shown to offer an improvement in recurrence-free and overall survival, especially for younger women, but the acute toxic effects of this treatment discourage some physicians from prescribing it. The purpose of this analysis was to determine whether the benefit of 6 months of adjuvant CMF (cyclophosphamide, methotrexate, fluorouracil) treatment outweighs its costs in terms of toxic effects. METHODS: A meta-analysis of quality-adjusted survival was performed based on data from 1229 patients, aged 49 years or younger, randomized in eight trials comparing CMF versus no adjuvant systemic therapy. The eight trials were included in the worldwide overview conducted by the Early Breast Cancer Trialists' Collaborative Group. The Q-TWiST method was used in a meta-analysis that provided treatment comparisons incorporating differences in quality of life associated with the amount of time patients spend with subjective toxic effects, after relapse, and without symptoms of relapse. RESULTS: Within 6 years of follow-up evaluation for patients with node-positive disease, the benefit in terms of increased relapse-free and overall survival balanced the costs in terms of acute toxic side effects. This was true even for the extreme case in which a zero value was assigned to all 6 months during which patients might receive adjuvant CMF chemotherapy. Within 10 years of follow-up evaluation, treated patients gained an average of 1.5 years of relapse-free survival time, almost 1 year of overall survival time, and 1 year of time without symptoms and toxicity. CONCLUSIONS: Adjuvant chemotherapy for younger women with node-positive breast cancer provided substantial amounts of quality-adjusted survival time, even after accounting for costs associated with toxic effects of the treatment. The Q-TWiST method represents a valuable tool for comparing treatments because it incorporates patients' perceptions of their quality of life for therapeutic decision-making.

Phosphorus-31 metabolism of post-menopausal breast cancer studied in vivo by magnetic resonance spectroscopy.

We have studied the metabolism of 31P-containing metabolites of post-menopausal breast cancers in vivo using magnetic resonance spectroscopy (MRS) and a 5.5 cm surface coil. Spectra were acquired from 23 diameter. The spectra of the 19 previously untreated tumours had significantly higher phosphomonoester (PME) 31P relative peak areas than the normal breasts of eight post-menopausal women (11.7% and 7.7% respectively, P = 0.002). Although an increased PME relative peak area was characteristic of malignancy, PME relative peak area is similarly raised in lactating breast and, therefore, not a specific feature of cancer. An apparently lower nucleotide triphosphate (NTP) relative peak area in tumours than healthy postmenopausal breast was secondary to the differences in PME relative peak area; contamination by signal from chest wall muscle probably accounts for the ostensibly higher phosphocreatine (PCr) relative peak area of the tumours. Spectroscopy was repeated following chemotherapy in six women. An increase in PCr relative peak area was seen in all five patients who responded, but again this may represent increased contamination secondary to changes in tumour size. A fall in PME relative peak area was noted in four responders, but also one non-responder, so this finding may not be sufficiently specific to be of use clinically. Further studies are need to elucidate fully the role of MRS in breast cancer.

The influence of adjuvant chemotherapy on outcome after relapse for patients with breast cancer.

This study examines the outcome following relapse for 176 patients who had been entered into a randomised trial comparing adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) with no adjuvant therapy (controls). Relapse has occurred in 65/144 (45%) of the CMF group and 111/158 (70%) of controls (P < 0.0001). 123/176 patients received endocrine treatment after relapse with higher response rates (38 vs. 18%, P < 0.05) and longer time to progression (23 vs. 19 weeks, P = 0.03) for controls. 94/176 received chemotherapy after relapse again with higher response rates (47 vs. 23%, P = 0.05) and longer time to progression (17 vs. 9 weeks, P = 0.03) for controls. Despite this, survival after relapse was the same for the two groups (median 16 months). However, on subgroup analysis, postmenopausal patients who had received adjuvant CMF had shorter survival (P = 0.03). These results suggest that prior adjuvant therapy should be a stratification factor in clinical trials in advanced disease.

Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial.

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.

Proliferative activity, histological grade and benefit from adjuvant chemotherapy in node positive breast cancer.

The influence of S-phase fraction (SPF), measured by DNA flow cytometry, and histological grade on outcome following adjuvant chemotherapy was analysed for 214 patients with node positive breast cancer treated at Guy's Hospital who were entered into the Guy's/Manchester trial of combination chemotherapy with cyclophosphamide/methotrexate/5-fluorouracil (CMF) vs. no adjuvant treatment. Adjuvant CMF significantly improved relapse-free survival (RFS) for premenopausal patients whose tumours had an SPF of 10% or less (control vs. CMF, P = 0.05) and premenopausal patients whose tumours had an SPF over 10% (control vs. CMF, P = 0.003). No significant improvement in RFS attributable to CMF was seen for either subgroup of postmenopausal patients. When patients were divided into subgroups based on histological grade of tumour, an improvement in RFS attributable to CMF was seen for premenopausal patients with well differentiated (grade 1 or 2) tumours (control vs. CMF, P = 0.03) and premenopausal patients with poorly differentiated (grade 3) tumours (control vs. CMF, P = 0.006). Again, no improvement in RFS was noted for any subgroup of postmenopausal patients defined by tumour grade.

Influence of radiotherapy on the dose of adjuvant chemotherapy in early breast cancer.

399 patients with early breast cancer were randomly allocated to treatment by either modified radical mastectomy or lumpectomy and radiotherapy. 169 had histologically involved axillary nodes and were randomised to receive either adjuvant cytotoxic chemotherapy (76 patients) or no systemic adjuvant treatment (93 patients). Chemotherapy comprised a combination of oral cyclophosphamide and intravenous methotrexate and 5-fluorouracil (CMF) for 12 cycles over one year. Patients in the mastectomy group received a significantly higher percentage of the planned chemotherapy dose compared with those in the radiotherapy group (median 85% v. 71% p less than 0.05). Patients treated with radiotherapy were more frequently nauseated and developed more severe alopecia, but these differences were not statistically significant. At median follow-up of 37 months the relapse-rate and pattern of relapse were similar in both groups of patients receiving CMF.

Ovarian function and adjuvant chemotherapy for early breast cancer.

The effect of cyclophosphamide, methotrexate and fluorouracil (CMF) on ovarian function has been studied in 74 pre-menopausal patients with operable breast cancer. After median follow-up of 47 months, 50, 70 and 80% of 35 patients receiving CMF became permanently amenorrhoeic within 3, 6 and 12 months respectively; in contrast, only 5 in the no treatment (control) group of 39 patients became permanently amenorrhoeic within 12 months. Younger patients (less than 35 years) were more likely to retain or regain menstrual function while on or after CMF treatment. Estimation of ovarian and pituitary hormones in a subset of these women showed that CMF treatment was associated with a decrease in serum oestradiol and progesterone and an increase in serum follicle stimulating hormone and luteinizing hormone to post-menopausal levels. These hormonal changes are consistent with the induction of amenorrhoea during CMF treatment and the absence of resumption of menstrual function after completion of treatment suggests that CMF causes permanent ovarian ablation in a majority of these patients.

Mechanism of action of adjuvant chemotherapy in early breast cancer.

The relation between tumour oestrogen and progesterone receptor status, menstrual status, relapse-free survival, and overall survival was analysed in 411 patients with early breast cancer randomised to receive either postoperative adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF) or no additional treatment (control). Prolongation of time to recurrence and survival was seen predominantly in premenopausal patients; these effects were seen only with tumours positive for steroid receptors, particularly progesterone. Chemotherapy led to permanent amenorrhoea in 61% of premenopausal patients. The therapeutic effects of chemotherapy were seen only when CMF induced permanent amenorrhoea in premenopausal patients. These findings support the hypothesis that the effect of adjuvant chemotherapy in early breast cancer may be mediated by ovarian suppression.

Controlled trial of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for breast cancer.

327 patients with cancer of the breast and involvement of axillary lymph nodes were randomised, after total mastectomy and axillary clearance, to receive either no additional treatment or oral cyclophosphamide 80 mg/m2 on days 1-14, intravenous methotrexate 32 mg/m2 on days 1 and 8, and intravenous fluorouracil 480 mg/m2 on days 1 and 8 (CMF), which was repeated every 28 days for twelve cycles. There was a significantly longer relapse-free survival (RFS) in patients treated with CMF. A prolonged RFS was seen in premenopausal patients, those with 1-3 nodes involved, and those with 4 or more nodes involved, but a similar trend in postmenopausal patients failed to reach statistical significance. RFS was greater in patients with CMF-induced amenorrhoea than in controls and in treated patients whose primary tumour contained progesterone receptors. Dose of chemotherapy did not have a significant effect on RFS. Survival was not influenced by treatment.