Breast cancer molecular subclassification and estrogen receptor expression to predict efficacy of adjuvant anthracyclines-based chemotherapy: a biomarker study from two randomized trials.

BACKGROUND: The purpose of this study was to determine the predictive value of breast cancer molecular subclassification regarding the benefit of adjuvant anthracycline-based chemotherapy. PATIENTS AND METHODS: Tumor samples from 823 patients included in two randomized trials that compared an anthracycline-based chemotherapy with no treatment were used to construct a tissue array. Estrogen receptor (ER), Her2, epidermal growth factor receptor, cytokeratine 5/6 expressions were determined by immunohistochemistry (IHC). The potential predictive factors of treatment effect on disease-free survival (DFS) were assessed by interaction tests and multivariate analysis. RESULTS: Sixty-four (8%), 98 (12%), 109 (14%) and 527 (66%) patients presented a Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like breast cancer. ER expression, when assessed by IHC, was an independent predictive factor for the benefit of chemotherapy on DFS (test for interaction, P = 0.0015). The molecular subclassification significantly predicted the efficacy of chemotherapy (test for interaction, P = 0.01), but had no significant added value (P = 0.32) as compared to the ER by treatment interaction. Adjuvant chemotherapy was associated with an adjusted hazard ratio for relapse or death of 0.42 [95% confidence interval (CI): 0.17-1.05], 0.54 (95% CI: 0.27-1.08), 0.35 (95% CI: 0.18-0.68), 1.07 (95% CI: 0.81-1.41) for patients with Her2+/ER-, basal-like, Her2-/ER-/nonbasal and luminal-like tumors, respectively. CONCLUSION: The breast cancer molecular subclassification was predictive for chemotherapy efficacy in adjuvant setting, but did not provide significant additional information to ER.

Patterns of failure in a randomized trial of adjuvant chemotherapy in postmenopausal patients with early breast cancer treated with tamoxifen.

BACKGROUND: We studied the effect of adjuvant anthracycline-based chemotherapy in postmenopausal patients with resected early breast cancer treated with adjuvant tamoxifen. PATIENTS AND METHODS: The trial included 835 patients with either axillary lymph node involvement, or tumors with histological grade II or III. They were randomized after local surgery to receive either tamoxifen (TAM group) or tamoxifen plus chemotherapy (TAM-CT group) consisting of six courses of 5-fluorouracil, doxorubicin and cyclophosphamide (FAC), or 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC). Radiotherapy was given after completion of adjuvant chemotherapy in the TAM-CT group and after surgery in the TAM group. RESULTS: The 5-year disease-free survival (DFS) rates were 73% in the TAM group and 79% in the TAM-CT group (log-rank test, P = 0.06). The 5-year overall survival rates were 82% and 87%, respectively (P = 0.06). The 5-year distant metastasis rates were 22% and 16% (P = 0.02), and the 5-year local recurrence rates were 6% and 4%, respectively (P = 0.23). There were no significant differences for contralateral breast cancer or other new primary malignancies. Chemotherapy tended to be more effective for patients who had tumors without estrogen receptors (trend test, P = 0.05). CONCLUSIONS: Anthracycline-based chemotherapy administered to postmenopausal patients receiving adjuvant tamoxifen gave a borderline significant benefit on overall and DFS, mainly by a reduction in distant metastases. Delaying radiotherapy after six courses of chemotherapy did not affect local control after up to 10 years of follow-up.

Primary nephrectomy for emergency: a rare event in the International Society of Paediatric Oncology Nephroblastoma Trial and Study no. 9.

Experience of the International Society of Paediatric Oncology (SIOP) Trials and Studies indicates that the preoperative chemotherapy in Wilms' tumour improves stage distribution, decreases complication rate and reduces postoperative treatment. However, some situations may lead to prompt primary surgery. The aim of the study is to assess reasons leading to primary emergency nephrectomy. Records of 720 patients with non-metastatic unilateral nephroblastoma who were registered in the SIOP Trial and Study 9 were reviewed. Twenty-four (3%) cases of primary emergency nephrectomy were identified. Reasons leading to emergency nephrectomy were massive bleedings from ruptured tumours in 13 patients, suspicion of an "acute abdomen" in 7, bowel occlusion in 2 and other in 2. Postoperative treatment included radiotherapy in 71% of cases and anthracyclines in 92%. Complications were frequent and happened in 25% of patients, the outcome however, was favourable and 22 of 24 patients are alive (from 9 to 79 months). The 7 patients with a suspicion of an "acute abdomen" probably constitute the group which could have been markedly reduced if adequately diagnosed and observed prior to surgery.

The role of preoperative chemotherapy in the treatment of nephroblastoma: the SIOP experience. Societe Internationale d'Oncologie Pediatrique.

Treatment of Wilms' tumor is an example of success of modern oncology. A combination of surgery, radiotherapy, and chemotherapy is widely accepted as the efficacious treatment of nephroblastoma. However, timing of each part of the treatment differs, in various protocols: the Societe Internationale d'Oncologie Pediatrique (SIOP) recommends the diagnosis based on imaging and metabolic exclusion of neuroblastoma to reduce the biopsy-related risk of spillage. In patients more than 6 months old, the treatment starts with the preoperative chemotherapy to improve the stage distribution at surgery and decrease the complications rate. Patients with advanced nephroblastoma, as those with vena cava thrombus and lung metastases, can benefit the most from the pretreatment. Results from the SIOP studies 6 and 9 confirm these statements: the stage distribution after the pretreatment reveals more than 50% of cases staged I, the 4-year disease-free survival in pulmonary stages IV was 83%, and of 42 patients with vena cava thrombus still present at surgery, 38 are alive from 27 to 109 months.

[Problems which arise when testing the equivalence of 2 survival distributions]. / Problèmes posés par la recherche de l'équivalence de deux distributions de survie.

Clinicians' interest in equivalence trials has been increasing for many years. In cancer research we are more often concerned with survival or event free survival (EFS). The usual logrank test has to be modified to test whether the true value r of the relative risk is at least equal to a limit value rL. An equivalence trial of post-operative therapy was carried out in children with stage II nephroblastomas without lymph node involvement, and serves as an illustration of some problems, discussed here, which arise in such design: ethical questions when defining the equivalence region, the choice of a one sided or a two sided formulation, the required number of patients or the power of the comparison. A formula is given in order to allow calculation for the required number of patients to ensure a given power when the treatment effects are the same. Other problems are also encountered when analyzing the observed results as the number of events which is evidently low in a de-escalation trial, may be reduced due to a stopping rule. We also discuss about the possibility to use event free survival as a surrogate of overall survival, and about the difficulties encountered when interpreting the results in terms of significance level.