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Background:TLE3, a nuclear transcriptional repressor downstream of WNT signalling pathways, has been hypothesised as predictive of benefit from adjuvant taxane.Methods:MA.21 tissue microarrays were constructed from 1097 out of 2104 (52%) patients. TLE3 staining by immunohistochemistry used validated methodology. Continuous TLE3+ (percentage of cells staining positive) was assessed with both visual and automated scoring. The primary objective was to test the predictive effect of TLE3 on relapse-free survival using the MA.21 EC/T and CEF arms and the previously defined cut-point of 30% of cells staining positive in ⩾1 core/tumour.Results:MA.21 patients had 83.2% TLE3 positive (TLE3+) tumours by visual score and 80.6% TLE3+ by automated image analysis while the previously observed rate of TLE3+ cases was 58.6%. TLE3 expression was significantly associated with ER expression (91.2% of ER-positive tumours were TLE3+; P<0.0001). At median 8-year follow-up, there was no evidence of a predictive effect of TLE3 expression with respect to taxane benefit using the established 30% or exploratory quartile cut-points.Conclusions:Proportionately more MA.21 patient tumours than expected were TLE3+. The pre-specified TLE3+ cut-point of 30% was not predictive of taxane benefit. TLE3 expression does not represent a viable biomarker for taxane benefit in breast cancer. [ABSTRACT FROM AUTHOR]

Background: In 2000, cyclophosphamide(C), epirubicin(E) and fluorouracil (F) (CEF) and doxorubicin (A) and C followed by paclitaxel (T) (AC/T) given every three weeks were commonly used regimens in Canada and the USA to treat women with node positive or high risk node negative operable breast cancer. In a previous trial in women with locally advanced breast cancer, 3 months of dose-dense EC was equivalent to six months of CEF. We hypothesized that the addition of 3 months of a taxane following dose-dense EC would be superior to CEF alone or AC/T. In a randomized trial in women with early breast cancer we compared CEF, dose dense EC/T and AC/T. An interim analysis (JCO, 2010) conducted when 50% of the events for the relapse-free-survival (RFS) analysis were observed, demonstrated that AC/T administered every 3 weeks was significantly inferior to CEF or EC/T. The results of the final RFS including CEF versus EC/T will be presented. Methods: Women, 60 years or younger, with operable axillary node positive or high risk node negative breast cancer were randomized to adjuvant CEF, EC/T or AC/T. CEF was given for 6 cycles and consisted of: C 75 mg/m2 orally on Days 1-14, and E 60 mg/m2 and F 500 mg/m2, IV on Days 1 and 8. CEF patients received concurrent antibiotic prophylaxis. EC/T consisted of 6 cycles of EC every 14 days; E 120 mg/m2 and C 830 mg/m2, both IV on Day 1 with filgrastim 5 [ug]/kg/day subcutaneous from Days 2-13 and epoetin alpha 40,000 units subcutaneous once weekly. After completion of EC, 4 cycles of T 175 mg/m2 every 21 days with filgrastim and epoetin alpha were given. The AC/T regimen consisted of A 60 mg/m2 and C 600 mg/m2 IV every 21 days for 4 cycles. This was followed by T 175 mg/m2 every 21 days for 4 cycles. The final analysis for RFS was planned when 453 events were observed permitting the detection of a hazard ratio (HR) of 1.43 between CEF and AC/T and a HR of 1.43 between EC/T and the best of the other two arms. Quality of Life data using the EORTC C-30 and the Breast Cancer Chemotherapy questionnaires were collected throughout the study. The results will be available at the time of the presentation. Results: A total of 2104 women were enrolled between December 2000 and April 2005. The required 453 events for the RFS analysis were observed by the clinical cut-off date of March 30, 2012. At this point 369 deaths had been observed. The median follow-up is 87.5 months. Outstanding data and queries are currently being collected and reviewed with an expected database lock and final analysis mid August, 2012. Febrile neutropenia remains higher on the CEF and EC/T arms while more neuropathy was seen in the taxane containing regimens. Conclusions: Although the two regimens considered a standard of care at the time the study was initiated are no longer widely used, the trial results will enhance our understanding of the magnitude of benefit of taxane following an anthracycline, the significance of cumulative anthracycline dose, and the role of dose density/ intensity as backbone of conventional chemo regimens. [ABSTRACT FROM AUTHOR]

Background: We hypothesized that increased baseline BMI and BMI change would negatively impact clinical outcomes with adjuvant breast cancer systemic therapy. Methods: Data from chemotherapy trials MA.5 and MA.21; endocrine therapy MA.12, MA.14 and MA.27; and trastuzumab HERA/ MA.24 were analyzed. The primary objective was to examine the effect of BMI change on breast cancer-free interval (BCFI) landmarked at 5 years; secondary objectives included BMI changes at 1 and 3 years; BMI changes on disease-specific survival (DSS) and overall survival (OS); and effects of baseline BMI. Stratified analyses included trial therapy and composite trial stratification factors. Results: In pre-/peri-/early post-menopausal chemotherapy trials (N=2793), baseline BMI did not impact any endpoint and increased BMI from baseline did not significantly affect BCFI (P=0.85) after 5 years although it was associated with worse BCFI (P=0.03) and DSS (P=0.07) after 1 year. BMI increase by 3 and 5 years was associated with better DSS (P=0.01; 0.01) and OS (P=0.003; 0.05). In pre-menopausal endocrine therapy trial MA.12 (N=672), patients with higher baseline BMI had worse BCFI (P=0.02) after 1 year, worse DSS (P=0.05; 0.004) after 1 and 5 years and worse OS (P=0.01) after 5 years. Increased BMI did not impact BCFI (P=0.90) after 5 years, although it was associated with worse BCFI (P=0.01) after 1 year. In post-menopausal endocrine therapy trials MA.14 and MA.27 (N=8236), baseline BMI did not significantly impact outcome for any endpoint. BMI change did not impact BCFI or DSS after 1 or 3 years, although a mean increased BMI of 0.3 was associated with better OS (P=0.02) after 1 year. With the administration of trastuzumab (N=1395) baseline BMI and BMI change did not significantly impact outcomes. Conclusions: Higher baseline BMI and BMI increases negatively affected outcomes only in pre-/peri-/early post-menopausal trial patients. Otherwise, BMI increases similar to those expected in healthy women either did not impact outcome or were associated with better outcomes. Clinical Trials numbers: CAN-NCIC-MA5; National Cancer Institute (NCI)-V90-0027; MA.12-NCT00002542; MA.14-NCT00002864; MA.21-NCT00014222; HERA, NCT00045032;CAN-NCIC-MA24; MA-27-NCT00066573. [ABSTRACT FROM AUTHOR]

Autologous bone marrow transplantation (ABMT) is becoming increasingly prevalent for treatment of advanced malignant disease. In order to increase the availability and utility of this therapy, we assessed the feasibility of transferring patients to their regional referral centers on the day after marrow infusion (day 1), for management post-transplant. This prospective study compares the outcome of 77 patients either transferred the day after marrow transplant for subsequent management at one of six selected Canadian regional centers closest to their domicile, or treated entirely at The Toronto Hospital, according to a common protocol. Study end-points included frequency of complications during transfer, transplant-related morbidity and mortality and hematopoietic recovery. Assessment of eligibility for transplant, bone marrow harvesting, autograft cryopreservation, administration of intensive therapy and marrow infusion were conducted in all cases at The Toronto Hospital. Thirty patients received marrow transplants and were transferred on day 1. There were no complications during transfer. Compared with 47 consecutive patients treated entirely at The Toronto Hospital, there were no differences in treatment-related morbidity or mortality, use of intravenous antifungal therapy or total days of hospitalization. We conclude that day 1 transfer of patients after ABMT to designated centers is feasible and safe. The operation of a regional ABMT network appears to benefit patients, relatives, referring physicians, the transplant center and may also improve health care delivery.