IMPORTANCE:Patients with breast cancer remain at risk of relapse after adjuvant therapy. Celecoxib has shown antitumor effects in preclinical models of human breast cancer, but clinical evidence is lacking. OBJECTIVE:To evaluate the role of celecoxib as an addition to conventional therapy for women with ERBB2 (formerly HER2)-negative primary breast cancer. DESIGN, SETTING, AND PARTICIPANTS:The Randomized European Celecoxib Trial (REACT) was a phase 3, randomized, double-blind study conducted in 160 centers across the UK and Germany testing 2 years of adjuvant celecoxib vs placebo among 2639 patients recruited between January 19, 2007, and November 1, 2012, with follow-up 10 years after treatment completion. Eligible patients had completely resected breast cancer with local and systemic therapy according to local practice. Patients with ERBB2-positive or node-negative and T1, grade 1 tumors were not eligible. Randomization was in a 2:1 ratio between celecoxib or placebo. Statistical analysis was performed from May 5, 2019, to March 5, 2020. INTERVENTIONS:Patients received celecoxib, 400 mg, or placebo once daily for 2 years. MAIN OUTCOMES AND MEASURES:The primary end point was disease-free survival (DFS), analyzed in the intention-to-treat population using Cox proportional hazards regression and log-rank analysis. Follow-up is complete. RESULTS:A total of 2639 patients (median age, 55.2 years [range, 26.8-86.0 years]) were recruited; 1763 received celecoxib, and 876 received placebo. Most patients' tumors (1930 [73%]) were estrogen receptor positive or progesterone receptor positive and ERBB2 negative. A total of 1265 patients (48%) had node-positive disease, and 1111 (42%) had grade 3 tumors. At a median follow-up of 74.3 months (interquartile range, 61.4-93.6 years), DFS events had been reported for 487 patients (19%): 18% for those who received celecoxib (n = 323; 5-year DFS rate = 84%) vs 19% for those who received placebo (n = 164; 5-year DFS rate = 83%); the unadjusted hazard ratio was 0.97 (95% CI, 0.80-1.17; log-rank P = .75). Rates of toxic effects were low across both treatment groups, with no evidence of a difference. CONCLUSIONS AND RELEVANCE:In this randomized clinical trial, patients showed no evidence of a DFS benefit for 2 years' treatment with celecoxib compared with placebo as adjuvant treatment of ERBB2-negative breast cancer. Longer-term treatment or use of a higher dose of celecoxib may lead to a DFS benefit, but further studies would be required to test this possibility. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02429427 and isrctn.org Identifier: ISRCTN48254013.

Background: The optimal sequence of adjuvant chemotherapy and radiotherapy for breast cancer is unknown. SECRAB assesses whether local control can be improved without increased toxicity. Methods: SECRAB was a prospective, open-label, multi-centre, phase III trial comparing synchronous to sequential chemo-radiotherapy, conducted in 48 UK centres. Patients with invasive, early stage breast cancer were eligible. Randomisation (performed using random permuted block assignment) was stratified by centre, axillary surgery, chemotherapy, and radiotherapy boost. Permitted chemotherapy regimens included CMF and anthracycline-CMF. Synchronous radiotherapy was administered between cycles two and three for CMF or five and six for anthracycline-CMF. Sequential radiotherapy was delivered on chemotherapy completion. Radiotherapy schedules included 40 Gy/15F over three weeks, and 50 Gy/25F over five weeks. The primary outcome was local recurrence at five and ten years, defined as time to local recurrence, and analysed by intention to treat. ClinicalTrials.gov NCT00003893. Findings: Between 02-July-1998 and 25-March-2004, 2297 patients were recruited (1150 synchronous and 1146 sequential). Baseline characteristics were balanced. With 10.2 years median follow-up, the ten-year local recurrence rates were 4.6% and 7.1% in the synchronous and sequential arms respectively (hazard ratio (HR) 0.62; 95% confidence interval (CI): 0.43-0.90; p = 0.012). In a planned sub-group analysis of anthracycline-CMF, the ten-year local recurrence rates difference were 3.5% versus 6.7% respectively (HR 0.48 95% CI: 0.26-0.88; p = 0.018). There was no significant difference in overall or disease-free survival. 24% of patients on the synchronous arm suffered moderate/severe acute skin reactions compared to 15% on the sequential arm (p < 0.0001). There were no significant differences in late adverse effects apart from telangiectasia (p = 0.03). Interpretation: Synchronous chemo-radiotherapy significantly improved local recurrence rates. This was delivered with an acceptable increase in acute toxicity. The greatest benefit of synchronous chemoradiation was in patients treated with anthracycline-CMF. (C) 2019 The Authors. Published by Elsevier B.V.

Abstract Background Inhibition of COX-2 has been shown to attenuate the metastatic process in pre-clinical models of human breast cancer (BC). The primary aim of this study was to assess the effect of 2 years adjuvant therapy with the COX-2 inhibitor celecoxib compared with placebo in HER2-ve primary BC patients. Patients & Methods Patients were randomised in a 2:1 ratio to receive celecoxib 400mg once daily or placebo for 2 years. Patients had to have completely resected BC with prior local and systemic adjuvant treatment according to local practice. Concurrent radiotherapy was permitted and hormone receptor +ve patients received endocrine therapy according to local practice. Patients with HER2+ or node negative, T1 and grade 1 disease were excluded. Median age of patients was 55 years (IQR: 49-63). 50% of patients had tumours >2cm; 42% were grade 3; 48% had node +ve disease. According to local assessment 73% were ER/PgR +ve. Primary endpoint was Disease Free Survival (DFS); defined as time from randomisation to date of first event, with events contributing to analysis defined as recurrence (distant/local), new primary BC (ipsilateral/contralateral) and death. Secondary endpoints included Overall Survival (OS), toxicity, cardiovascular mortality and incidence of second primaries. Subgroup analysis by hormone receptor status was pre-planned. Survival endpoints are analysed using Cox-proportional hazards and log-rank tests; restricted mean survival is used where proportional hazards do not hold. Results Between January 2007 and November 2012, 2639 patients were randomised (1763 celecoxib; 876 placebo) from 181 centres across the UK and Germany. At 13th April 2017, median follow up was 60 months (IQR: 48-72) with 428 DFS events reported. Unadjusted survival analysis results are presented below, with hazard ratio<1 favouring celecoxib: 5 year survival estimate (95% CI)Hazard ratio (95% CI)p-valueDFS (all patients) Celecoxib83% (81, 85)1.02 (0.83 – 1.24)0.88Placebo83% (80, 86)1- DFS within ER+ Celecoxib87% (85, 89)0.89 (0.69 – 1.16)0.40Placebo86% (83, 89)1- DFS within ER- Celecoxib72% (68, 76)1.17 (0.85 – 1.61)0.33Placebo75% (69, 80)1- OS (all patients) Celecoxib90% (88, 91)0.97 (0.75 – 1.25)0.81Placebo90% (88, 92)1- The interaction between ER status and treatment was not significant; p=0.36. In the celecoxib and placebo groups there were 17 and 8 deaths respectively in patients who had not relapsed. These were due to cardiac (n=3; 2) and other (n=14; 6) in the celecoxib and placebo groups respectively; none were GI related. In total 304 serious adverse events were observed in 265 patients (186/1763 celecoxib; 79/876 placebo). In the celecoxib and placebo groups respectively these were related to cardiac (n=12; 7), GI (n=9; 2) and other (n=193; 81). Work is ongoing to determine whether a subset of ER+ patients whose primary tumours show the characteristics of a COX-2 signature receive greater benefit from celecoxib. Conclusions There is no benefit of celecoxib in the ITT population. Further exploratory studies focussing on the ER+ subpopulation are ongoing. Celecoxib treatment is not associated with significant toxicity when compared to placebo in this population of BC patients. Citation Format: Coombes RC, Tovey H, Kilburn L, Mansi J, Palmieri C, Bartlett J, Hicks J, Makris A, Evans A, Loibl S, Denkert C, Murray E, Grieve R, Coleman R, Schmidt M, Klare P, Rezai M, Rautenberg B, Klutinus N, Rhein U, Mousa K, Ricardo-Vitorino S, von Minckwitz G, Bliss J. A phase III multicentre double blind randomised trial of celecoxib versus placebo in primary breast cancer patients (REACT – Randomised EuropeAn celecoxib trial) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr GS3-03.

Purpose: Total skin electron beam radiation therapy (TSEB) is a very effective treatment of mycosis fungoides. Following reports of similar durations of response to lower doses of TSEB, a low-dose schedule of TSEB was introduced in the United Kingdom. Methods and Materials: A protocol of 12 Gy in 8 fractions over a period of 2 weeks was agreed on by use of the Stanford University technique. Data were collected prospectively, and the results were analyzed according to the European Organisation for Research and Treatment of CancereInternational Society for Cutaneous Lymphomas endpoints (EORTC-ISCL). Toxicity was scored according to CTCAE v4.0 (Common Terminology Criteria for Adverse Events version 4.0). Results: One hundred three patients received treatment, with a median follow-up period of 20.6 months (range, 3.3-53 months). Of these patients, 54 had stage IB disease, 33 had stage IIB, 12 had stage III, and 4 had stage IV. The median age was 68 years (range, 26-91 years). The complete response rate was 18%, the partial response rate was 69%, stable disease was present in 8%, and progression on treatment was found in 5%. In the patients who had a complete response, the median time to relapse was 7.3 months. The median response duration was 11.8 months. Median progression-free survival for all patients was 13.2 months. It was significantly longer, at 26.5 months, in patients with stage IB disease compared with 11.3 months in patients with stage IIB (P = .003; hazard ratio, 2.66) and 10.2 months in patients with stage III (P = .002; hazard ratio, 4.62). The treatment was well tolerated with lower toxicity than higher-dose schedules. Conclusions: The low-dose TSEB schedule of 12 Gy in 8 fractions over a period of 2 weeks is well tolerated and is an effective option for patients with mycosis fungoides. (C) 2017 Elsevier Inc. All rights reserved.

3609 Background: Feasibility was assessed of giving NAC prior to SCPRT then immediate surgery in ORC at high risk of metastatic relapse. Methods: Patients (pts) had non-metastatic rectal adenocarcinoma. Pre-treatment pelvic MRI showed resection margin was not at risk (disease > 1mm from mesorectal fascia) but adverse risk factors were present (disease > T3b or node positive or extramural vascular invasion). Pts received 4x2-weekly cycles of oxaliplatin 85mg/m² + levofolinic acid 175 mg, fluorouracil (FU) 400 mg/m² (bolus), then FU 2400 mg/m² (continuous IV in 46 hr). Within 14 days pts had pelvic SCPRT to 25 Gy in 5 daily fractions. Definitive surgery then occurred within a week. Post surgery pts received 16 weeks of OxMdG or oxaliplatin/capecitabine. The primary endpoint was the proportion of pts completing protocol treatment including surgery. Results: 60 UK pts were recruited May 2012-June 2014. At baseline: male 44 (73%), median age 63 (IQR: 56.5-70), WHO PS 0/1 55/5. On pre-treatment MRI tumour was T2/3x/3a/3b/3c/3d/4 in 2/2/16/24/12/1/3 and N0/1/2 in 7/40/13 pts. All pts commenced OxMdG with 57(95%) receiving all 4 cycles. 20 pts (33%) needed a dose reduction and 22 (37%) a dose delay. 58 pts commenced SCPRT (all received full dose) and 57 underwent surgery: anterior resection in 43 (75%), abdominoperineal resection in 11 (19%), Hartmanns in 3 (5%). Three pts withdrew prior to surgery: one lost to follow up after SCPRT, one pt choice and one due to cardiospasm during NAC. Median gap between OxMdG and starting SCPRT was 10 days (IQR: 5-15) and between completing SCPRT and surgery 10 days (IQR: 5-13). Postoperative histology was T0/1/2/3a/3b/3c/4a in 7/3/19/8/9/10/1 pts, N0/1/2 in 39/13/5 pts and ypT0ypN0 in 7/57 pts (12%). All 57 resected pts had a clear (R0) resection margin with no 30 day postoperative mortality. Conclusions: This is the first trial to report on giving NAC prior to SCPRT then surgery within a short time interval in ORC, which proved feasible with good compliance and promising efficacy. The UK NCRI intend to include a similar regimen in a future phase III trial. Clinical trial information: NCT01263171.

Abstract Introduction: TACT2 (CRUK/05/019), a multicentre randomized phase III trial in patients with node +ve or high risk node -ve invasive EBC with E-CMF as control tested two hypotheses in a 2x2 factorial design, with previously presented results showing: i) no evidence of a benefit from accelerated 2-weekly epirubicin (aE) compared to standard 3-weekly epirubicin (E) (Cameron 2012); and ii) capecitabine (X) gives equivalent efficacy but preferential side-effect profile to CMF (Canney 2014). Studies suggest that Androgen receptor (AR) expression may be associated with improved outcome in early breast cancer. We performed an analysis of AR expression in TACT2 patients to test the hypothesis that AR would represent an independent predictor of residual risk following adjuvant therapy. Methods: Tumour samples were collected prospectively from 3803/4391 TACT2 patients, Tissue micro-arrays were constructed as per published guidelines and central AR, ER, PgR, HER2, Ki67, CK5/6, EGFr and BCL2 staining performed and quantified by imaged analysis for ER, PgR, HER2, Ki67 and BCL2. EGFr and CK5/6 were dichotomised by light microscopy evaluation of cores. After planned biomarker analyses had been performed, a subset of TACT2 cases for whom remaining tissue was available were analysed for AR expression. Data for 1878 cases was available for this analysis (49% of those consenting to tissue collection). AR expression was dichotomised as AR-ve (<10%) vs AR+ve (>10%). Log-rank tests were used to explore the prognostic value of AR on time to recurrence (TTR). Cox-regression models were used to test the independent prognostic value of AR in the presence of tumour size, grade, nodal status, and biological subtypes. Marker by treatment interaction terms were included in models to test the predictive value of AR for both randomised treatment comparisons. Results: 1398/1878 (74%) patients were classed as AR+ve and 480/1878 (26%) as AR-ve. The proportion of AR+ve patients differed significantly between biological subtypes (Luminal A 269/293 (92%); Luminal B 784/928 (84%); HER+ve 86/111 (77%); Basal-like 37/216 (17%); 5-marker-ve 37/93 (40%); χ2 p<0.001) 117/480 (24%) AR-ve patients had a TTR event compared with 183/1398 (13%) AR+ve patients (HR for AR-ve compared to AR+ve =2.05 95%CI 1.63-2.59; p<0.001). AR expression remained independently prognostic following adjustment for nodal status, grade, tumour size and biological subtype (HR1.68, 95%CI 1.26-2.25; p<0.001). Exploratory analysis suggested the prognostic impact of AR might be predominantly in luminal B and 5-marker-ve breast cancers; however the interaction between subtype and AR was not statistically significant. No differential treatment effect between AR subtypes was observed for either randomised treatment comparison (E/aE or CMF/X). Conclusion: AR is an independent prognostic marker for residual risk following chemotherapy in this large study which included patients with both luminal and non-luminal cancers. AR expression patterns differ between molecular subtypes of early breast cancer, with evidence suggesting the impact of AR on residual risk may also differ between subtypes. AR is currently being explored as another potential target for therapy so these data could have future clinical relevance. Citation Format: Jane Bayani, James Morden, Sunil Skaria, Peter Bliss, Robert Grieve, Adrian Harnett, Chris Bradley, Diana Ritchie, Peter Barrett-Lee, Peter Canney, David Cameron, Judith Bliss, John Bartlett. Androgen receptor expression is an independent marker of lower residual risk in the TACT2 trial (CRUK/05/019) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-03.

BACKGROUNDGuidelines on the use of haematopoietic colony-stimulating factors for patients having adjuvant chemotherapy for breast cancer are designed to minimise the risk of neutropaenic infection (Smith TJ, Khatcheressian J, Lyman GH et al. Update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 2006; 3: 187-205; Aapro MS, Bohlius J, Cameron DA et al. Effect of primary prophylactic G-CSF use on systemic therapy administration for elderly breast cancer patients. Breast Cancer Res Treat 2011; 47: 8-32; Carlson RW, Allred DC, Anderson BO et al. Breast cancer. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2009; 7: 122-192). Non-randomised data suggest that the achievement of planned dose intensity (DI) may have an important effect on survival. This trial compared the effects of granulocyte colony-stimulating factor, GCSF, against standard management following a first neutropaenic event (NE) in achieving planned DI.PATIENTS AND METHODSAdult patients receiving adjuvant or neoadjuvant chemotherapy were randomised following a first NE, defined as hospitalisation due to neutropaenic fever, an absolute neutrophil count (ANC) ≤1.5 × 10(9)/l requiring treatment delay or dose reduction of 15% or more of planned dose. The study was initially planned to enrol 816 patients to detect a difference of 10%. This was difficult to achieve in the timeframe and the trial size was amended. Thus, 407 patients were randomly assigned to filgrastim for 7 days or pegfilgrastim versus standard care. The amended study was designed to have 80% power to detect an absolute difference of 14% of planned DI between the two groups.RESULTSMost regimens were anthracycline-based many of which included a sequential taxane and/or were in clinical trials. Around 82.7% had an NE in the first three cycles. A total of 401 had calculable relative dose intensity (RDI) data. A target of 85% planned RDI was achieved in only 50% of patients in the control arm compared with 75% in the GCSF arm (P < 0.0001). A secondary end point revealed a reduction in post-randomisation NEs, 65.7% controls versus 18.2% with GCSF.CONCLUSIONSSecondary intervention with GCSF showed a statistically significant improvement in the achievement of adequate RDI in non-intensive regimens. This may have important clinical implications for outcome.

Background Bisphosphonates are routinely used in the treatment of metastatic bone disease from breast cancer to reduce pain and bone destruction. Zoledronic acid given by intravenous infusion has been widely used, but places a substantial logistical burden on both patient and hospital. As a result, the use of oral ibandronic acid has increased, despite the absence of comparative data. In the ZICE trial, we compared oral ibandronic acid with intravenous zoledronic acid for the treatment of metastatic breast cancer to bone.Methods This phase 3, open-label, parallel group active-controlled, multicentre, randomised, non-inferiority phase 3 study was done in 99 UK hospitals. Eligibility criteria included at least one radiologically confirmed bone metastasis from a histologically confirmed breast cancer. Patients with ECOG performance status 0 to 2 and clinical decision to treat with bisphosphonates within 3 months of randomisation were randomly assigned to receive 96 weeks of treatment with either intravenous zoledronic acid at 4 mg every 3-4 weeks or oral ibandronic acid 50 mg daily. Randomisation (1:1) was done via a central computerised system within stratified block sizes of four. Randomisation was stratified on whether patients had current or planned treatment with chemotherapy; current or planned treatment with hormone therapy; and whether they had a previous skeletal-related event within the last 3 months or had planned radiotherapy treatment to the bone or planned orthopaedic surgery due to bone metastases. The primary non-inferiority endpoint was the frequency and timing of skeletal-related events over 96 weeks, analysed using a per-protocol analysis. All active (non-withdrawn) patients have now reached the 96-week timepoint and the trial is now in long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT00326820.Findings Between Jan 13, 2006, and Oct 4, 2010, 705 patients were randomly assigned to receive ibandronic acid and 699 to receive zoledronic acid; three patients withdrew immediately after randomisation. The per-protocol analysis included 654 patients in the ibandronic acid group and 672 in the zoledronic acid group. Annual rates of skeletal-related events were 0.499 (95% CI 0.454-0.549) with ibandronic acid and 0.435 (0.393-0.480) with zoledronic acid; the rate ratio for skeletal-related events was 1.148 (95% CI 0.967-1.362). The upper CI was greater than the margin of non-inferiority of 1.08; therefore, we could not reject the null hypothesis that ibandronic acid was inferior to zoledronic acid. More patients in the zoledronic acid group had renal toxic effects than in the ibandronic acid group (226 [32%] of 697 vs 172 [24%] of 704) but rates of osteonecrosis of the jaw were low in both groups (nine [1%] of 697 vs five [<1%] of 704). The most common grade 3 or 4 adverse events were fatigue (97 [14%] of 697 patients allocated zoledronic acid vs 98 [14%] of 704 allocated ibandronic acid), increased bone pain (92 [13%] vs 86 [12%]), joint pain (42 [6%] vs 38 [5%]), infection (33 [5%] vs 24 [3%]), and nausea or vomiting (38 [5%] vs 41 [6%]).Interpretation Our results suggest that zoledronic acid is preferable to ibandronic acid in preventing skeletal-related events caused by bone metastases. However, both drugs have acceptable side-effect profiles and the oral formulation is more convenient, and could still be considered if the patient has a strong preference or if difficulties occur with intravenous infusions.

BACKGROUND:The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. METHODS:In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020. FINDINGS:3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4). INTERPRETATION:These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. FUNDING:Novartis Global and NIHR Cancer Research Network.

5 Background: In estrogen-receptor-positive (ER+) early breast cancer, 5 years of tamoxifen reduces breast cancer death rates by about a third throughout years 0-14. It has been uncertain how 10 years of tamoxifen compares with this. Methods: During 1991-2005, 6,953 women with ER+ (n=2755), or ER untested (4198, estimated 80% ER+ if status known) invasive breast cancer from 176 UK centres were, after 5 years of tamoxifen, randomized to stop tamoxifen or continue to year 10. Annual follow-up recorded compliance, recurrence, mortality, and hospital admissions. Results: Allocation to continue tamoxifen reduced breast cancer recurrence (580/3468 vs 672/3485, p=0.003). This reduction was time dependent: rate ratio 0.99 during years 5-6 [95%CI 0.86-1.15], 0.84 [0.73-0.95] during years 7-9, and 0.75 [0.66-0.86] later. Longer treatment also reduced breast cancer mortality (392 vs 443 deaths after recurrence, p=0.05), rate ratio 1.03 [0.84-1.27] during years 5-9 and 0.77 [0.64-0.92] later; and overall mortality (849 vs 910 deaths, p=0.1), rate ratio 1.05 [0.90-1.22] during years 5-9 and 0.86 [0.75-0.97] later. Non-breast-cancer mortality was little affected (457 vs 467 deaths, rate ratio 0.94 [0.82-1.07]). There were 102 vs 45 endometrial cancers RR=2.20 (1.31-2.34, p<0.0001) with 37 (1.1%) vs 20 (0.6%) deaths (absolute hazard 0.5%, p=0.02). Combining the similar results of aTTom and its international counterpart ATLAS (Lancet 2013) enhances statistical significance of recurrence (p<0.0001), breast cancer mortality (p=0.002) and overall survival (p=0.005) benefits. Conclusions: aTTom confirms that, in ER+ disease, continuing tamoxifen to year 10 rather than just to year 5 produces further reductions in recurrence, from year 7 onward, and breast cancer mortality after year 10. Taken together with the reduction in breast cancer deaths seen in trials of 5 years of tamoxifen vs none, these results indicate that 10 years of adjuvant tamoxifen, compared to no tamoxifen, reduces breast cancer mortality by about one third in the first 10 years following diagnosis and by a half subsequently. Clinical trial information: ISRCTN17222211.

Background: The National Epirubicin Adjuvant Trial (NEAT) and BR9601 trials tested the benefit of epirubicin when added to cyclophosphamide, methotrexate and 5-fluorouracil (E-CMF) compared with standard CMF in adjuvant chemotherapy for women with early breast cancer. This report details longer follow-up with interesting additional time-dependent analyses. Methods: National Epirubicin Adjuvant Trial used epirubicin (E) 3-weekly for four cycles followed by classical (c) CMF for four cycles (E-CMF) compared with cCMF for six cycles. BR9601 used E 3-weekly for four cycles followed by CMF 3-weekly for four cycles, compared with CMF 3-weekly for eight cycles. Results: In all, 2391 eligible patients were randomised and with a median 7.4-year follow-up, E-CMF confirmed a significant benefit over CMF in both relapse-free survival (RFS) (78% vs 71% 5 years RFS, respectively, hazard ratio (HR)=0.75 (95% CI: 0.65–0.86), P <0.0001) and overall survival (OS) (84% vs 78% 5 years OS, respectively, HR=0.76 (95% CI: 0.65–0.89), P =0.0007). Interaction of treatment effect and prognostic factors was demonstrated for duplication of chromosome 17 centromeric enumeration (Ch17CEP) as previously reported. Poor prognostic factors at diagnosis (ER and PR negative and HER2 positive) showed time-dependent annual hazard rates for RFS and OS. In univariate analysis, these factors demonstrated more favourable HRs for RFS after 5 years. Treatment effects also suggested a differential benefit for E-CMF within the first 5 years for poor prognosis tumours. Conclusion: Longer follow-up has confirmed E-CMF as significantly superior to CMF for all patients. Ch17CEP duplication was the only biomarker that demonstrated significant treatment interaction. Standard poor prognostic factors at diagnosis were time-dependent, and after 5 years disease-free, poor prognosis patients demonstrated favourable HRs for survival.

Purpose: Phase III trials in the 1990s for squamous cell carcinoma of the anus (SCCA) demonstrated 5-fluorouracil (5FU) and mitomycinC (MMC) chemoradiation (CRT) improved outcome compared to radiation (RT) alone, but local recurrence remained significant. This prospective pilot study intensified treatment by integrating 3 cytotoxic drugs into CRT and maintenance chemotherapy.Methods: CRT comprised 5-FU 1000 mg/m(2) days1-4,29-32, MMC 10 mg/m(2) day1 and Cisplatin (CDDP) 60 mg/m(2) days1 and 29, with 45 Gy in 25 daily fractions, followed by a 15 Gy boost. Maintenance chemotherapy started 4-8 weeks later, three courses repeated every 21 days, using 5-FU/CDDP doses above, with MMC reduced to 7 mg/m2 and administered with the first and third cycles.Results: In CRT only 14/19(74%) patients received protocol-defined chemotherapy doses in week 5. Compliance to maintenance chemotherapy was poor. 15/19 started cycle 1, 13 started cycle 2 and 11 cycle 3. 17/19 experienced G3-G5 toxicity (16 Grade 3/4 and one Grade 5). 16/19 patients (84%) remain alive and disease-free - median follow-up 79 months (34-115).Conclusions: Despite favourable results, the significant toxicity and low compliance of the three-drug CRT regimen used, deemed it unsuitable for testing in a phase III trial. A two-drug maintenance regimen was explored in the ACT II trial. (c) 2012 Elsevier Ireland Ltd. All rights reserved. Radiotherapy and Oncology 104 (2012) 155-160

Purpose The Medical Research Council CR07/National Cancer Institute of Canada Clinical Trials Group C016 (MRC CR07/NCIC CTG C016) trial showed that, in patients with operable rectal cancer, short-course preoperative radiotherapy (PRE) reduced the rate of local recurrence compared with surgery followed by selective postoperative chemoradiotherapy for patients with a positive circumferential resection margin. However, the advantages of giving PRE to all patients needs to be balanced against any negative impact on patients' quality of life. Patients and Methods All 1,350 patients were asked to complete the Medical Outcomes Study Short-Form 36-item (MOS SF-36) and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Colorectal 38-item (EORTC QLQ-CR38) questionnaires. A priori hypotheses related to the impact of treatment on sexual, bowel, and physical function and general health. Results Male sexual dysfunction was significantly increased following surgery (P < .001), although there was no difference between treatment arms. However, a treatment difference had emerged at 6 months (PRE patients reporting significantly greater dysfunction; P = .004), which persisted out to at least 2 years (an insufficient number of female patients completed the sexual dysfunction questions to draw firm conclusions). Both treatment groups reported similar levels of decreased physical function at 3 months, but thereafter it returned to baseline levels. There was no evidence of any major changes between treatments or time points in terms of general health or bowel function, but exploratory analysis indicated a significant (P = .006 at 2 years) increase in the level of fecal incontinence with PRE. Conclusion These results from a large randomized trial using validated patient-completed questionnaires show that, for males, the main adverse effect was sexual dysfunction, and the main cause of this was surgery, but that PRE also affected sexual and some aspects of bowel functioning.

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 &gt;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.

Abstract Background: SECRAB is a large multicentre randomised controlled trial designed to determine the optimal sequence of CT and RT for women with EBC. The second objective of this trial was to determine if CT and RT treatment modalities could be given together without increased toxicity or compromising either modality. See abstract no 851519 for details of CT and RT scheduling. Methods: Data on acute skin reaction was collected on completion of RT and graded as mild, moderate or severe. Late toxicity data was collected annually and included lymphoedema, telangiectasia, severe subcutaneous fibrosis, brachial plexopathy, rib fracture, ischaemic heart disease, symptomatic lung fibrosis, and clinical radiation pneumonitis. Results: Between Jul 98 and Mar 04, 2296 women were randomised. Acute toxicity data was collected on 2267 patients who received RT. The distribution of RT schedules was balanced across treatment arms, with the majority of patients (67%) receiving 40Gy/15F (15F). Significantly more patients in the Syn arm experienced a delay of >10 days in CT delivery (11% vs 5%, p < 0.0001). Very few patients experienced a >7 days delay in RT in either arm (Syn n=12 vs Seq n=3). In a sub-set of 880 patients dose intensity of CT was not significantly different between the two arms. Percentage skin toxicities for the Syn and Seq arms respectively were: None 22.9 vs 36.3; Mild 52.4 vs 48.1; Moderate 20.2 vs 13.6; Severe 3.8 vs 1.1. A significantly (p < 0.001) higher proportion of patients on the Syn arm suffered a moderate or severe skin reaction compared to those on the Seq arm. An unplanned exploratory analysis by duration of RT showed that patients receiving >15F (45Gy/20F or 50Gy/25F) had a significantly worse acute skin reaction than those receiving 15F (25% vs 16%, p=<0.001). 5 patients on the Syn arm were admitted to hospital as a result of a severe RT reaction, 3 received >15F. Acute radiation pneumonitis was 0.3% in both arms (n=5 in total). Percentage late toxicities for the Syn and Seq arms respectively were not significantly different for: moderate/severe lymphoedema 6.1 (n=70) vs 5.5 (n=64); severe subcutaneous fibrosis 1.3 (n= 15) vs 0.6 (n=7); brachial plexopathy 0.2 (n=2) vs 0.1 (n=1); rib fracture 0.6 (n=7) vs 0.4 (n=5); ischaemic heart disease 0.4 (n=5) vs 0.4 (n=2); symptomatic lung fibrosis 0.3 (n=15) vs 0.3 (n=7); and late clinical radiation pneumonitis 0.1 (n=1) vs 0.1 (n=1). Howevermoderate/severe telangiectasia was 2.5% vs 1.3% in the Syn and Seq arms respectively (p =0.05). This difference was not seen in patients receiving 15F. Conclusions: The delivery of Syn CT-RT in the adjuvant treatment of EBC is associated with an increase in acute skin toxicity however the percentage of severe reactions is less than 5%. These skin reactions were seen predominantly in patients treated with concurrent RT (>15F). An increase in late skin telangiectasia was also seen in patients receiving >15F. There was no difference in other late toxicities recorded. Syn CT-RT is feasible in the adjuvant treatment of EBC and does not result in a reduction in dose intensity of delivered CT. The optimal schedule is 40Gy/15F which is now the standard regime used in the UK. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-11-05.

Background Preoperative or postoperative radiotherapy reduces the risk of local recurrence in patients with operable rectal cancer. However, improvements in surgery and histopathological assessment mean that the role of radiotherapy needs to be reassessed. We compared short-course preoperative radiotherapy versus initial surgery with selective postoperative chemoradiotherapy.Methods We undertook a randomised trial in 80 centres in four countries. 1350 patients with operable adenocarcinoma of the rectum were randomly assigned, by a minimisation procedure, to short-course preoperative radiotherapy (25 Gy in five fractions; n=674) or to initial surgery with selective postoperative chemoradiotherapy (45 Gy in 25 fractions with concurrent 5-fluorouracil) restricted to patients with involvement of the circumferential resection margin (n=676). The primary outcome measure was local recurrence. Analysis was by intention to treat. This study is registered, number ISRCTN 28785842.Findings At the time of analysis, which included all participants, 330 patients had died (157 preoperative radiotherapy group vs 173 selective postoperative chemoradiotherapy), and median follow-up of surviving patients was 4 years. 99 patients had developed local recurrence (27 preoperative radiotherapy vs 72 selective postoperative chemoradiotherapy). We noted a reduction of 61% in the relative risk of local recurrence for patients receiving preoperative radiotherapy (hazard ratio [HR] 0.39, 95% CI 0.27-0.58,p<0.0001), and an absolute difference at 3 years of 6.2% (95% CI 5.3-7.1) (4.4% preoperative radiotherapy vs 10.6% selective postoperative chemoradiotherapy). We recorded a relative improvement in disease-free survival of 24% for patients receiving preoperative radiotherapy (HR 0.76, 95% CI 0.62-0.94, p=0.013), and an absolute difference at 3 years of 6.0% (95% CI 5.3-6.8) (77.5% vs 71.5%). Overall survival did not differ between the groups (HR 0.91, 95% CI 0.73-1.13, p=0.40).Interpretation Taken with results from other randomised trials, our findings provide convincing and consistent evidence that short-course preoperative radiotherapy is an effective treatment for patients with operable rectal cancer.Funding Medical Research Council (UK) and the National Cancer Institute of Canada.