Abstract Background: The optimal sequence of CT and RT for women with EBC has yet to be defined. SECRAB aimed to determine i) if synchronous (Syn) CT-RT improves loco-regional relapse rates (LRR) and ii) whether the treatments could be given together without increased toxicity or compromising the dose intensity of either CT or RT. The first endpoint of this study is presented in this abstract. Methods: SECRAB was a prospective, randomised trial comparing sequential (Seq) to Syn CT-RT. Permitted RT schedules included 40Gy/15F over 3 weeks, 45Gy/20F over 4 weeks and 50Gy/25F over 5 weeks. Syn RT was administered between cycles 2 and 3 for CMF or 5 and 6 for anthracycline-CMF. Syn patients treated using 15F were treated predominantly using a sandwich schedule while those receiving >15F were treated concurrently with CT. Seq RT was delivered on CT completion. Key eligibility criteria were completely excised EBC, fit for and requiring adjuvant CT and RT. The trial was powered to produce a definitive event driven analysis: 150 loco-regional relapses having 85% power to detect 4% 2-sided differences in the primary endpoint of overall LRR. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Baseline characteristics were well balanced. 63% of patients were node positive indicating a high risk population. 2 patients did not receive CT and 23 did not receive RT. 5 patients in the latter group had a loco-regional relapse prior to planned RT (Seq n=3). With a median follow-up of 8.8 years there were 93 and 76 loco-regional relapses in the Seq and Syn arms and 5-year LRR were 7.4% (95% CI 5.9-9.1) and 5.4% (95% CI 4.2-7.0) respectively. There was no significant difference in overall LRR (HRSyn 0.82; 95% CI 0.6-1.1; p=0.19). There was a trend for benefit for Syn treatment which was consistent across different subgroups (grade, lymph node status, tumour size, vascular invasion and excision margin). In an unplanned subgroup analysis, a trend for benefit for Syn treatment was seen predominantly in patients with the presence of lymphovascular invasion (LRR 11.9% Seq vs 8.2% Syn) and also in patients with 0 and 1-3 positive nodes (LRR 7.8% Seq vs 5.2% Syn) but not in those with 4 or more positive nodes. Similar rates were observed for distant recurrences (22.2% vs 22.2%), contralateral recurrences (2.9% vs 2.7%), and new primary cancers (2.9% vs 2.6%) in the Seq and Syn arms respectively. There was also no significant difference in overall survival which was 83% and 82% in the Syn and Seq arms respectively at 5-years (HRSyn 0.99; 95% CI 0.8-1.2; p=0.87). Modest differences in acute skin toxicity and telangiectasia were observed between the two study arms. There was no difference in other late toxicities. The second primary endpoint of safety, toxicity and dose intensity is described in detail elsewhere (abstract no 850168). Conclusions: SECRAB is the largest sequencing trial in EBC to date. Delivering Syn CT-RT using CMF or anthracycline-CMF and a 3 weekly RT fractionation shortens the overall treatment time. Although not statistically significant there was a trend to improved locoregional control with Syn treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-4.

Background: The optimal sequence of CT and RT for women with EBC has yet to be defined. SECRAB aimed to determine i) if synchronous (Syn) CT-RT improves loco-regional relapse rates (LRR) and ii) whether the treatments could be given together without increased toxicity or compromising the dose intensity of either CT or RT. The first endpoint of this study is presented in this abstract. Methods: SECRAB was a prospective, randomised trial comparing sequential (Seq) to Syn CT-RT. Permitted RT schedules included 40Gy/15F over 3 weeks, 45Gy/20F over 4 weeks and 50Gy/25F over 5 weeks. Syn RT was administered between cycles 2 and 3 for CMF or 5 and 6 for anthracycline-CMF. Syn patients treated using 15F were treated predominantly using a sandwich schedule while those receiving >15F were treated concurrently with CT. Seq RT was delivered on CT completion. Key eligibility criteria were completely excised EBC, fit for and requiring adjuvant CT and RT. The trial was powered to produce a definitive event driven analysis: 150 loco-regional relapses having 85% power to detect 4% 2-sided differences in the primary endpoint of overall LRR. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Baseline characteristics were well balanced. 63% of patients were node positive indicating a high risk population. 2 patients did not receive CT and 23 did not receive RT. 5 patients in the latter group had a loco-regional relapse prior to planned RT (Seq n=3). With a median follow-up of 8.8 years there were 93 and 76 loco-regional relapses in the Seq and Syn arms and 5-year LRR were 7.4% (95% CI 5.9-9.1) and 5.4% (95% CI 4.2-7.0) respectively. There was no significant difference in overall LRR (HR Syn 0.82; 95% CI 0.6-1.1; p=0.19). There was a trend for benefit for Syn treatment which was consistent across different subgroups (grade, lymph node status, tumour size, vascular invasion and excision margin). In an unplanned subgroup analysis, a trend for benefit for Syn treatment was seen predominantly in patients with the presence of lymphovascular invasion (LRR 11.9% Seq vs 8.2% Syn) and also in patients with 0 and 1-3 positive nodes (LRR 7.8% Seq vs 5.2% Syn) but not in those with 4 or more positive nodes. Similar rates were observed for distant recurrences (22.2% vs 22.2%), contralateral recurrences (2.9% vs 2.7%), and new primary cancers (2.9% vs 2.6%) in the Seq and Syn arms respectively. There was also no significant difference in overall survival which was 83% and 82% in the Syn and Seq arms respectively at 5-years (HR Syn 0.99; 95% CI 0.8-1.2; p=0.87). Modest differences in acute skin toxicity and telangiectasia were observed between the two study arms. There was no difference in other late toxicities. The second primary endpoint of safety, toxicity and dose intensity is described in detail elsewhere (abstract no 850168). Conclusions: SECRAB is the largest sequencing trial in EBC to date. Delivering Syn CT-RT using CMF or anthracycline-CMF and a 3 weekly RT fractionation shortens the overall treatment time. Although not statistically significant there was a trend to improved locoregional control with Syn treatment. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr S4-4.

Tumour hypoxia is a microenvironmental factor related to poor response to radiation, chemotherapy, genetic instability, selection for resistance to apoptosis, and increased risk of invasion and metastasis. Hypoxia-regulated carbonic anhydrase IX (CA IX) has been studied in various tumour sites and its expression has been correlated with the clinical outcome. The purpose of this study was to investigate the correlation of CA IX expression with outcome in patients with invasive breast cancer. We conducted a retrospective study examining the effects of carbonic anhydrase IX (CA IX) on survival in patients with breast cancer. To facilitate the screening of multiple tissue blocks from each patient, tissue microarrays were prepared containing between two and five representative samples of tumour per patient. Immunohistochemistry was used to examine expression of CA IX in patients with breast cancer. The study includes a cohort of 144 unselected patients with early invasive breast cancer who underwent surgery, and had CA IX expression and follow-up data available for analysis. At the time of analysis, there were 28 deaths and median follow-up of 48 months with 96% of patients having at least 2 years of follow-up. CA IX was negative for 107 patients (17 deaths) and positive for 37 patients (11 deaths). Kaplan–Meier survival curves show that survival was superior in the CA IX-negative group with a 2-year survival of 97% for negatives and 83% for positives (log-rank test P =0.01). Allowing for potential prognostic variables in a Cox regression analysis, CA IX remained a significant independent predictor of survival ( P =0.035). This study showed in both univariate and multivariate analysis that survival is significantly inferior in patients with tumour expressing CA IX. Prospective studies are underway to investigate this correlation in clinical trial setting.