One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer.

PURPOSE: We report the long-term results of a randomised trial comparing tamoxifen with tamoxifen plus cyclophosphamide, methotrexate and fluorouracil (CMF) in postmenopausal high-risk breast cancer patients. In addition, we analyse the prognostic and predictive value of centrally assessed subtypes. METHODS: Postmenopausal patients with breast cancer and positive nodes, deep invasion or size exceeding 5 cm were randomly assigned to 1 year of tamoxifen, or cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2 and fluorouracil 600 mg/m2 intravenously on day 1 every 4 weeks for nine cycles plus tamoxifen (CMFT). Tissue microarrays were constructed retrospectively and oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and proliferation-related Ki-67 antigen (Ki67) status were assessed. RESULTS: From October 1982 through March 1990 we randomised 1445 patients and 969 (67%) were eligible for the biomarker analysis. At 10-years 936 women had suffered a disease-free survival (DFS) event (tamoxifen, 495 events in 686 patients; CMFT, 441 events in 642 patients). The addition of CMF to tamoxifen significantly improved DFS (adjusted hazard ratio 0.82; 95% confidence interval (CI) 0.71-0.93; P = 0.003) but not overall survival (adjusted hazard ratio 0.95; 95% CI 0.85-1.08; P = 0.44). DFS was superior in Luminal A tumours (ER or PgR positive, HER2 negative and Ki67 ≤ 14%) when compared to Luminal B or non-luminal (ER and PgR negative) tumours. There was no statistical evidence of heterogeneity by subtype in the benefit from CMF (P(interaction) = 0.45). CONCLUSION: CMF added to 1 year of tamoxifen reduces the risk of a DFS event. The benefit from CMF was not significantly different in Luminal A and B subtypes.

Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer.

BACKGROUND: The Danish Breast Cancer Cooperative Group (DBCG) 77B trial examined the relative efficacy of levamisole, single-agent oral cyclophosphamide, and the classic combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) against no adjuvant systemic therapy in high-risk breast cancer patients. The authors report the results from that trial after a potential follow-up of 25 years. METHODS: Between 1977 and 1983, 1146 premenopausal patients who had tumors >5 cm or positive axillary lymph nodes were assigned randomly to 1 of 4 options: no systemic therapy, levamisole 5 mg weekly for 48 weeks (the levamisole arm), oral cyclophosphamide 130 mg/m(2) on Days 1 through 14 every 4 weeks for 12 cycles (the C arm), or oral cyclophosphamide 80 mg/m(2) on Days 1 through 14 plus methotrexate 30 mg/m(2) and fluorouracil 500 mg/m(2) intravenously on Days 1 and 8 every 4 weeks for 12 cycles (the CMF arm). RESULTS: The 10-year invasive disease-free survival (IDFS) rate was 38.6% in the control arm compared with 55.5% in the C arm, 48.8% in the CMF arm, and 35.2% in the levamisole arm. Compared with the control arm, the hazard ratio for an IDFS event was 0.62 in the C arm (P = .001) and 0.70 in the CMF arm (P = .01). The hazard ratio for death was 0.70 in both the C arm (P = .02) and the CMF arm (P = .02) at 10 years, and the overall survival (OS) benefit was maintained during 25 years of follow-up. No significant differences were observed in IDFS or OS between the C arm and the CMF arm or between the levamisole arm and the control arm. CONCLUSIONS: Compared with controls, both cyclophosphamide and CMF significantly improved disease-free survival and OS, and the benefits persisted for at least 25 years in premenopausal patients who had high-risk breast cancer.

HER2, TOP2A, and TIMP-1 and responsiveness to adjuvant anthracycline-containing chemotherapy in high-risk breast cancer patients.

PURPOSE To evaluate whether the combination of HER2 with TIMP-1 (HT) or TOP2A with TIMP-1 (2T) more accurately identifies patients who benefit from cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) than these markers do when analyzed individually. PATIENTS AND METHODS The Danish Breast Cancer Cooperative Group (DBCG) 89D trial randomly assigned 980 high-risk Danish breast cancer patients to CMF or CEF. Archival tumor tissue was analyzed TIMP-1, and HER2-negative and TIMP-1 immunoreactive tumors were classified as HT nonresponsive and otherwise HT responsive. Similarly, the 2T panel was constructed by combining TOP2A and TIMP-1; tumors with normal TOP2A status and TIMP-1 immunoreactivity were classified as 2T-nonresponsive and otherwise 2T-responsive. Results In total, 623 tumors were available for analysis, of which 154 lacked TIMP-1 immunoreactivity, 188 were HER2 positive, and 139 had a TOP2A aberration. HT status was a statistically significant predictor of benefit from CEF compared with CMF (P(interaction) = .036 for invasive disease-free survival [IDFS] and .047 for overall survival [OS]). The 269 (43%) patients with a 2T-responsive profile had a significant reduction in IDFS events (adjusted hazard ratio, 0.48; 95% CI, 0.34 to 0.69; P < .001) and OS events (adjusted hazard ratio, 0.54; 95% CI, 0.38 to 0.77; P < .001). 2T status was a highly significant predictor of benefit from CEF compared with CMF (P(interaction) < .0001 for IDFS and .004 for OS). CONCLUSION The 2T profile is a more accurate predictor of incremental benefit from anthracycline-containing chemotherapy than HER2, TIMP-1, or TOP2A individually, and compared with these, 2T classifies a larger proportion of patients as sensitive to anthracyclines.

Oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy in breast cancer patients.

OBJECTIVE: The aim of the study was to examine oral mucosal lesions, microbial changes, and taste disturbances induced by adjuvant chemotherapy (CT) in breast cancer patients during and 1 year after treatment. STUDY DESIGN: Forty-five consecutive breast cancer patients, eligible for adjuvant CT with cyclophosphamide, epirubicin or methotrexate, and 5-fluorouracil were followed before, during, 6 months and 1 year after CT and were compared to a control group of 31 breast cancer patients not receiving adjuvant CT. RESULTS: During CT, oral mucosal lesions developed including erythema (n = 10, 22%) and ulceration (n = 7, 16%). Five patients (11%) were diagnosed with oral candidosis. Scores of dental bacterial plaque and gingival inflammation increased during CT and the oral microbial composition changed towards a more acidophilic flora. Taste disturbances were experienced by 84% (n = 38) of the patients in the CT group. CONCLUSION: In breast cancer patients, moderate-intensive adjuvant CT caused oral mucosal lesions, oral candidosis, taste disturbances and a more acidophilic oral microflora. These adverse effects were temporary and the majority of the patients were mildly affected.

Adjuvant cyclophosphamide, methotrexate, and fluorouracil in premonopausal patients with node-positive breast cancer: indirect comparison of dose and schedule in DBCG trials 77, 82, and 89.

UNLABELLED: A significant reduction in the risk of recurrence and death was achieved three decades ago with adjuvant chemotherapy in patients with operable breast. The major pivotal trials used oral cyclophosphamide (C) days 1-14 with intravenous methotrexate (M) and fluorouracil (F) on days 1 and 8, repeated every 28 days. The classical CMF has later been modified as concerns dose and schedule, without formal comparisons in randomised trials between the classical CMF and the modifications. MATERIAL AND METHODS: Classical CMF was used in the first adjuvant chemotherapy trial performed by the Danish Breast Cancer Cooperative Group (DBCG), and two succeeding randomised trials in premenopausal patients with node positive breast cancer used three-weekly or four-weekly intravenous CMF in one of the treatment arms. RESULTS: Between November 1977 and January 2001 these trials included 2 213 patients who in addition to surgery and radiotherapy received CMF. Ten-year disease-free survival (DFS) rates were 48% following classical CMF, 45% following four-weekly and 47% following three-weekly CMF. Major differences in patient characteristics were observed across these three cohorts, and a multivariate analysis was performed adjusting for the known prognostic factors. In the adjusted analysis a 30% increase in the risk of recurrence was observed for two the intravenous regimens as compared to classical CMF. As concerns survival a significant 40% increase in the risk of death was observed with the four-weekly regimen, while a similar risk of death was observed with the three-weekly intravenous. Classical CMF was associated with a higher risk of amenorrhoea, and this may at least in part explain an observed interaction between age and efficacy. DISCUSSION: This cross trial comparison suggests a detrimental effect in premenopausal patients with node positive breast cancer when shifting from classical CMF to intravenous regimens with lower dose-intensity. Caution is required in the interpretation of these results due to the non-experimental study design.

DBCG trial 89B comparing adjuvant CMF and ovarian ablation: similar outcome for eligible but non-enrolled and randomized breast cancer patients.

INTRODUCTION: A cohort of premenopausal patients with primary hormone receptor positive breast cancer was prospectively identified to be eligible for the DBCG 89B trial. We perform a long-term follow-up and evaluate the external validity of the trial. MATERIAL AND METHODS: Following registration in a population-based registry, patients were invited to be randomized to ovarian ablation (OA) versus nine courses of three-weekly cyclophosphamide, methotrexate and 5-fluorouracil (CMF). The same procedures were used in all patients, including report forms, central review, querying, and analysis of data. Multivariate analysis was used to adjust for differences in base-line characteristics. RESULTS: Participation in the randomization varied according to center and time period. One thousand six hundred and twenty eight eligible patients were registered and 525 randomized in the DBCG 89B trial. Median estimated follow-up was 9.5 years for disease-free survival and 12.1 years for overall survival. Non-enrolled patients had a disease-free and overall survival similar to randomized patients. Within 5 years of surgery, results were similar following OA and CMF, but disease-free survival was significant inferior with OA more than five years after surgery, adjusted hazard ratio 1.38 (95% CI 1.03 to 1.85; p=0.03). This convened ten years after surgery to an inferior survival with OA, and the adjusted hazard ratio was 2.37 (95% CI 1.43 to 3.91; p<0.01). DISCUSSION: This prospective cohort study indicates that eligible patients not participating in the DBCG 89B trial had a similar disease-free and overall survival as participants. Survival was similar after OA and CMF in the first ten years, but became inferior in the OA group 10 or more years after surgery.

The value of TOP2A gene copy number variation as a biomarker in breast cancer: Update of DBCG trial 89D.

BACKGROUND: Previous analyses of TOP2A and HER2 in the Danish Breast Cancer Coopererative Group (DBCG) trial 89D suggested that TOP2A amplifications and possible also deletions are predictive markers for the effect of adjuvant epirubicin in patients with primary breast cancer. We present an updated and extended statistical analysis, requested for IVD-labeling of TOP2A testing. MATERIAL AND METHODS: In the DBCG trial 89D 980 Danish patients were randomly assigned to nine cycles of intravenous CMF (cyclophosphamide, methotrexate, and fluorouracil) or CEF (cyclophosphamide, epirubicin, and fluorouracil). Archival tumor tissue was collected retrospectively from 806 of these patients in a prospectively designed, biological sub-study, and was successfully analyzed for TOP2A aberrations and HER2 status in 773 samples (96%). Recurrence-free survival (RFS) was the primary endpoint. RESULTS: TOP2A aberrations (amplifications and deletions) were significantly associated with shorter RFS (p<0.0001) and overall survival (OS) (p<0.0001). Deleted cases had worse prognosis than amplified cases. In a Cox proportional hazard model TOP2A was an independent prognostic marker for RFS and OS. Patients with amplifications had a 61% reduction in the risk of an event (p=0.002) and a 51% reduction in the risk of death (p=0.01) if allocated to CEF compared to 6% and 10% in TOP2A normal patients. A similar but non-significant trend (p=0.08) was shown in patients with TOP2A deletions. Clear statistical evidence of a differential benefit, favoring CEF among patients with TOP2A aberrations was found for RFS (p=0.02 for interaction) but not for OS (p=0.14 for interaction). CONCLUSION: In conclusion, this updated analysis of TOP2A aberrations in DBCG trial 89D suggests a differential benefit of adjuvant chemotherapy in patients with primary breast cancer, favoring treatment with epirubicin in patients with TOP2A amplifications, and perhaps deletions. Additional studies are needed to clarify the exact importance of TOP2A deletions on outcome, but deletions have proven to be associated with a very poor prognosis.

Bisphosphonate treatment in primary breast cancer: results from a randomised comparison of oral pamidronate versus no pamidronate in patients with primary breast cancer.

PURPOSE AND PATIENTS: During the period from January 1990 to January 1996 a total of 953 patients with lymph node negative primary breast cancer were randomised to oral pamidronate (n=460) 150 mg twice daily for 4 years or no adjuvant pamidronate (n=493) in order to investigate whether oral pamidronate can prevent the occurrence of bone metastases and fractures. The patients received adjuvant chemotherapy, loco-regional radiation therapy, but no endocrine treatment. RESULTS: During the follow-up period the number of patients with pure bone metastases was 35 in the control group and 31 in the pamidronate group. The number of patients with a combination of bone and other distant metastases were 22 in the control group and 20 in the pamidronate group. The hazard rate ratio for recurrence in bone in the pamidronate group compared to the control group was 1.03 (95% confidence interval 0.75-1.40) and p=0.86. No effect was observed on overall survival. In a small subgroup of 27 patients from the study, 12 of whom were treated with pamidronate a significant bone preserving effect was observed on bone mineral density in the lumbar spine, but not in the proximal femur. CONCLUSION: The results from the trial do not support a beneficial effect of oral pamidronate on the occurrence of bone metastases or fractures in patients with primary breast cancer receiving adjuvant chemotherapy.

Letrozole in advanced breast cancer: the PO25 trial.

Tamoxifen has been a standard first-line endocrine therapy for post-menopausal women with hormone-responsive advanced breast cancer, but more than half of patients fail to respond and time to progression is less than 12 months in responders. The third-generation aromatase inhibitors were developed to provide more effective alternatives to tamoxifen. In the Femara Study PO25, post-menopausal women with advanced breast cancer were randomized to receive letrozole 2.5 mg (n=453) or tamoxifen 20 mg (n=454) given orally daily until progressive disease occurred. Patients were permitted to cross over to the other treatment at progression. In the primary efficacy analysis, median time to progression (TTP) was significantly longer with letrozole than with tamoxifen (9.4 months vs. 6.0 months, respectively; P<0.0001). The objective response rate (ORR) was significantly higher for letrozole than for tamoxifen (32% vs. 21%; P=0.0002). Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival (OS) compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. Letrozole is the only third-generation aromatase inhibitor that has demonstrated significant improvements in ORR, TTP, and early OS.

Similar efficacy for ovarian ablation compared with cyclophosphamide, methotrexate, and fluorouracil: from a randomized comparison of premenopausal patients with node-positive, hormone receptor-positive breast cancer.

PURPOSE: To compare the efficacy of ovarian ablation versus chemotherapy in early breast cancer patients with hormone receptor-positive disease. PATIENTS AND METHODS: We conducted an open, randomized, multicenter trial including premenopausal breast cancer patients with hormone receptor-positive tumors and either axillary lymph node metastases or tumors with a size of 5 cm or more. Patients were randomly assigned to ovarian ablation by irradiation or to nine courses of chemotherapy with intravenous cyclophosphamide, methotrexate, and fluorouracil (CMF) administered every 3 weeks. RESULTS: Between 1990 and May 1998, 762 patients were randomly assigned, and the present analysis is based on 358 first events. After a median follow-up time of 8.5 years, the unadjusted hazard ratio for disease-free survival in the ovarian ablation group compared with the CMF group was 0.99 (95% CI, 0.81 to 1.22). After a median follow-up time of 10.5 years, overall survival (OS) was similar in the two groups, with a hazard ratio of 1.11 (95% CI, 0.88 to 1.42) for the ovarian ablation group compared with the CMF group. CONCLUSION: In this study, ablation of ovarian function in premenopausal women with hormone receptor-positive breast cancer had a similar effect to CMF on disease-free and OS. No significant interactions were demonstrated between treatment modality and hormone receptor content, age, or any of the well-known prognostic factors.

Chemotherapy versus ovarian ablation as adjuvant therapy for breast cancer: impact on health-related quality of life in a randomized trial.

BACKGROUND: Ovarian ablation is an effective adjuvant therapy for primary breast cancer but little is known about its quality of life impact relative to the more widely used adjuvant chemotherapy. This randomized study compared quality of life outcomes of adjuvant ovarian ablation versus cyclophosphamide, methotrexate, fluoracil (CMF) chemotherapy. METHODS: The Danish Breast Cancer Cooperative Group (DBCG) trial 89-b randomized premenopausal patients with receptor-positive, primary breast cancer between nine cycles of CMF chemotherapy given every 3 weeks and ovarian ablation by oophorectomy. In total, 317 randomized patients were invited to take part in a longitudinal quality of life study with assessments at 1, 3, 5, 9, 15, and 24 months after randomization. The questionnaire included the EORTC QLQ-C30, the Hospital Anxiety and Depression Scale, and additional items assessing potential symptoms not included in the standard instruments. RESULTS: After 2 years, 260 women were alive and recurrence-free, and 196 of these (75%) had completed all six questionnaires. Overall, patients in the chemotherapy group had more symptomatology at the first three assessments (i.e., during the 6 months treatment period), except for hot flushes/sweats. There were few differences between groups at later assessments. In chemotherapy patients, the likelihood of preserving ovarian function decreased steeply with increasing age. CMF chemotherapy and ovarian ablation have similar impact on recurrence and survival. CONCLUSION: Chemotherapy had more negative impact on health-related quality of life but preserved ovarian function in some younger patients.