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1074 Background: In the Triple Negative Trial we observed no improved response rate (RR) to C over D in aTNBC [Tutt et al, Nat Med 2018], but we did in BRCA1/2 mutated (mut) patients (pts). We hypothesise tumors with other aberrant DNA damage response (DDR) characteristics having higher RR to DNA damage inducing C than D. Methods: We tested the predictive value of DDR process related gene expression signatures (PARPi7, chromosomal instability CIN70, TP53 & DDR Deficiency (DDRD)) on 192 treatment naïve primary tumours (PT) by total RNA-sequencing. Odds ratio (OR) for RR are reported. Paired PT & recurrent (REC) signature scores were compared. Results: Unexpectedly, high DDRD and PARPi7 were associated with higher RR to D than C ( p =0.01 & 0.06). No effect was observed for CIN70 or TP53 signature. To assess whether the unexpected results were due to biological changes 12 PT-REC pairs were available from pts who received chemotherapy (CT) between PT & REC. CIN70 increased from PT to REC, DDRD (non-significantly) & PARPi7 decreased. 4/5 TP53 wildtype classified PT samples classified as mut in REC. The BRCA1/2 & DDRD-treatment interactions only held in pts who received CT before trial entry (table). The PARPi7-treatment interaction only held in CT naïve pts. In CT naïve pts, high CIN70 tumors suggested higher C RR as hypothesized. Restricted to the 149 PAM50 basal-like pts, results were non-significant but similar trends seen. Conclusions: In this trial of aTNBC, DDRD high pts with prior CT had better RR to D than C. A possible explanation for this unexpected result is selective pressure of adjuvant DNA damaging CT and selection for relative taxane sensitivity in those who recur despite a high DDRD score. The hypothesised CIN70 treatment interaction was observed in CT naïve pts. Our results suggest care is required in application of signatures to initial diagnostic material when predicting response to DNA damaging agents at REC particularly in pts with prior CT. [Table: see text]

Background: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS. Methods: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0–1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing. Findings: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27–45). Median follow-up was 34·3 months (IQR 23·7–55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was −8·3% (IQR −26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase. Interpretation: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors. Funding: Cancer Research UK and AstraZeneca.

Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups - tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes - may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.

Background: Small-scale studies correlated the presence of thyroid autoimmunity with both improved or worsened breast cancer outcome. Objectives: We aimed to clarify this association in a large cohort using the phase III, randomized, controlled Taxotere as Adjuvant Chemotherapy Trial (TACT, CRUK01/001). Methods: TACT women >18 years old with node-positive or high-risk node-negative early breast cancer (pT1–3a, pN0–1, M0), with stored plasma (n = 1,974), taken 15.5 (median; IQR 7.0–24.0) months after breast surgery were studied. Patients had also received chemotherapy (100%), radiotherapy (1,745/1,974; 88.4%), hormonal therapy (1,378/ 1,974; 69.8%), or trastuzumab (48/1,974; 2.4%). History of thyroid diseases and/or related treatments was not available. The prognostic significance of autoantibodies to thyroid peroxidase (TPOAb; positive ≥6 kIU/L), free-thyroxine and thyrotropin (combined: euthyroid, hypothyroid, hyperthyroid) was evaluated for disease-free survival (DFS), overall-survival (OS), and time-to-recurrence (TTR), with Cox regression models in univariate and multivariable analyses. The extended median follow-up was 97.5 months. Results: No difference in DFS was found by TPOAb status (unadjusted hazard ratio [HR]: 0.97, 95%CI: 0.78–1.19; p = 0.75) and/or thyroid function (unadjusted HR [hypothyroid vs. euthyroid]: 1.15, 95% CI: 0.79–1.68; p = 0.46; unadjusted HR [hyperthyroid vs. euthyroid]: 1.14, 95% CI: 0.82–1.61; p = 0.44). Similar results were obtained for OS, TTR, multivariable analyses, when TPOAb titre by tertiles was considered, and in a subgroup of 123 patients with plasma collected before adjuvant treatments. Conclusions: No evidence for a prognostic role of TPOAb and/or thyroid function in moderate-to-high-risk early breast cancer was found in the largest and longest observational study to date.

Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non–breast cancer–related deaths now reported, breast cancer–free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with exemestane; the absolute difference (between exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, −0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, −0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

Neoadjuvant endocrine therapy is an alternative to chemotherapy for women with oestrogen receptor (ER)-positive early breast cancer (BC). We aimed to assess feasibility of recruiting patients to a study comparing chemotherapy versus endocrine therapy in postmenopausal women with ER-rich primary BC, and response as well as translational endpoints were assessed. Patients requiring neoadjuvant therapy were randomised to chemotherapy: 6 x 3-weekly cycles FE100C or endocrine therapy: letrozole 2.5 mg, daily for 18-23 weeks. Primary endpoints were recruitment feasibility and tissue collection. Secondary endpoints included clinical, radiological and pathological response rates, quality of life and translational endpoints. 63/80 patients approached were eligible, of those 44 (70, 95 % CI 57-81) were randomised. 12 (54.5, 95 % CI 32.2-75.6) chemotherapy patients showed radiological objective response compared with 13 (59.1, 95 % CI 36.4-79.3) letrozole patients. Compared with baseline, mean Ki-67 levels fell in both groups at days 2-4 and at surgery [fold change: 0.24 (95 % CI 0.12-0.51) and 0.24; (95 % CI 0.15-0.37), respectively]. Plasma total cfDNA levels rose from baseline to week 8 [fold change: chemotherapy 2.10 (95 % CI 1.47-3.00), letrozole 1.47(95 % CI 0.98-2.20)], and were maintained at surgery in the chemotherapy group [chemotherapy 2.63; 95 % CI 1.56-4.41), letrozole 0.95 (95 % CI 0.71-1.26)]. An increase in plasma let-7a miRNA was seen at surgery for patients with objective radiological response to chemotherapy. Recruitment and tissue collection endpoints were met; however, a larger trial was deemed unfeasible due to slow accrual. Both regimens were equally efficacious. Dynamic changes were seen in Ki-67 and circulating biomarkers in both groups with increases in cfDNA and let-7a miRNA persisting until surgery for chemotherapy patients.

Background: Optimal endocrine treatment (trt) for post-menopausal women with ER+ advanced breast cancer (ABC) progressing on or following a non-steroidal (NS) aromatase inhibitor (AI) is unclear. The EFECT study showed no difference in efficacy between the steroidal antiestrogen fulvestrant (F) & steroidal AI exemestane (E) in this setting (HR = 0.96, 95%CI: 0.82, 1.13; p = 0.65). Pre-clinical data suggest F may be more effective in a low estrogen environment. SoFEA investigated F combined with anastrozole (F+A) in patients (pts) with acquired resistance to previous AI compared with F alone & F alone vs. E. The combination of F+A was no better than F (HR = 1.00, 95%CI: 0.83, 1.21; p = 0.98) nor F alone better than E (HR = 0.95, 95%CI: 0.79, 1.14; p = 0.56); the lack of added benefit for F+A is consistent with previous 1st-line studies that have assessed this combination versus A alone (FACT & SWOG-S0226). Methods: SoFEA is a multi-center partially blinded randomized phase III study postmenopausal women were allocated to F plus A (F+A n=243), F plus placebo (n = 231) or E (n = 249). Similarly, EFECT is a randomized, double-blind, placebo controlled, multi-center phase III trial of F (n = 351) versus E (n = 342) in postmenopausal women (see table). However, given the differences in prior endocrine therapy/responsiveness within SoFEA & EFECT populations, an individual pt meta-analysis combining data from SoFEA & EFECT will be conducted enabling exploration of putative effects within specific pt subgroups to establish evidence in support, or not, of a pt subgroup sensitive to F at the dose used in these trials. Subgroups to be analysed include receptor status, visceral involvement, AI sensitivity, age, NSAI setting & time on NSAI. Results: 723 pts (480 in F & E) were enrolled from 82 UK & 4 South Korean centers (03/2004-04/2010) in SoFEA. 693 pts were enrolled from 138 centers worldwide (08/2003-11/2005) in EFECT. Trt was well tolerated in both trials; serious adverse events were rare. The meta-analysis will be conducted in July 2012 & results presented. Conclusion: Combining individual pt data from SoFEA & EFECT via meta-analysis will provide definitive clinical information on pt's response to F at the dose used in these studies, in particular whether certain pts with acquired resistance to NSAI do experience benefit of use of this antiestrogen as opposed to E. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-01.

Introduction: TACT, an investigator-led study in 4162 women with node positive (N+ve) or high risk node negative (N-ve) early breast cancer (EBC), is the largest taxane trial unconfounded by treatment (trt) duration. At principal analysis, with 5 years follow-up (fup), no evidence of improved disease-free survival (DFS) was observed by switching to 4 cycles of docetaxel (D) after 4 cycles of FEC (Ellis, Lancet 2009). Results were provocative in suggesting differential effects according to ER & HER2 status. Longer fup provides opportunity to detect emergence of late trt effects overall & within phenotypic subgroups & explore patterns of recurrence, by tumor characteristics. Patients & methods: TACT recruited women with histologically confirmed completely resected invasive EBC from 104 centers (UK (103), Belgium (1)) between 02/2001 & 07/2003. Centers chose FEC (600/60/600 mg/m2 q3wk × 8) or E-CMF (E 100mg/m2 q3wk × 4 → CMF 100mg/m2 PO d1-14 or 600mg/m2 IV d1&8/40/600 mg/m2 q4wk × 4) as their control, reflecting standard UK practice. Patients (pts) were randomized to FEC-D (FEC q3wk × 4 → D 100 mg/m2 q3wk × 4) or control. 2523 pts were from FEC centers (FEC = 1265: FEC-D = 1258) & 1639 from E-CMF centers (E-CMF = 824; FEC-D = 815). Endocrine therapy was given for 5 years. Few pts received HER2 directed therapy; 589 pts had unknown HER2 status. Median fup is now 97.5 months; this analysis updates DFS & overall survival in the ITT population. It also explores patterns of relapse by phenotypic & clinical characteristics. Analyses of trt effect are stratified by ER status due to issues of non-proportionality of hazard associated with length of fup. Results: DFS events have been reported for 1329 pts (FEC-D=640, Control=689) giving an unadjusted hazard ratio (HR) & 95%CI (stratified by control regimen & ER status) of 0.93 (0.83, 1.03) overall; p = 0.16 in favor of FEC-D & for ER+ve/HER2-ve of 0.99 (0.84, 1.17), for ER+ve/HER2+ve) 0.97 (0.73, 1.30), for ER-ve/HER2+ve 0.74 (0.53, 1.03), & ER-ve/HER2-ve 0.93 (0.73, 1.17). 1017 patients have died (FEC-D=500, Control=517); unadjusted HR=0.98 (95%CI: 0.86, 1.10); p = 0.69 with intercurrent deaths (prior to distant relapse) reported for 80 pts (FEC-D=40, Control=40). Annual event rates show different pattern of disease relapse by phenotypic subgroup Graphical representation will further explore these patterns & associated sites of relapse. Discussion: With a median fup of >8 years no clear benefit has emerged for D over standard anthracyclines within the TACT pt group. Differential effects associated with different patterns of relapse remain of interest. TACT precedes use of antiHER2 therapy which is known to have impacted on early relapse risk in HER2+ve pts. The high relapse risk observed for pts with ER-ve/HER2-ve disease remains a current clinical challenge. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-03.

Background: The hormonal manipulation 5-Fluoro-uracil Epirubicin Cyclophosphamide (HMFEC) trial was developed at a time of uncertainty around the dose intensity of chemotherapy given to premenopausal patients with node positive breast cancer and to the benefits of tailored endocrine therapy in such patients. Patients and methods: HMFEC was a multi-centre, phase III, open label, randomised controlled trial with a 2 x 2 factorial design. Eligible patients were premenopausal with node positive early breast cancer; significant cardiac disease or uncontrolled hypertension was exclusion criterion. Patients were allocated to receive either eight cycles of FE50C or FE75C (given 3 weekly) with or without hormone manipulation (HM; tamoxifen or luteinising hormone releasing hormone (LHRH) agonists according to residual hormone levels at the end of chemotherapy) irrespective of ER status. The primary end-point was disease free survival (DFS). Principal analyses were by intention to treat (ITT); however, to reflect contemporary practice, subgroup analyses according to ER status were also conducted. The mature follow-up now available from this modest sized trial enables presentation of definitive results. Results: Between 1992 and 2000 a total of 785 patients were randomised into the HMFEC trial (203 FE50C-HM, 191 FE50C+HM, 198 FE75C-HM, 193 FE75C+HM). At a median follow-up of 7.4 years, 245 DFS events have been reported (92 ER-, 153 ER+/unknown). The effects on DFS were not statistically significantly different according to epirubicin dose (hazard ratio [HR] = 0.82, 95% confidence interval [CI] 0.63-1.06; p = 0.13 FE75C versus FE50C); however, FE75C appeared to induce more alopecia and neutropenia. No statistically significant evidence was observed to support an improvement in DFS in patients allocated HM either overall (HR = 0.88, 95% CI 0.68-1.13; p = 0.32) or in patients with ER+/unknown disease (HR = 0.85, 95% CI 0.62-1.17; p = 0.32) although effect sizes are consistent with worthwhile clinical effects. Overall, there was no evidence of a difference in survival between any of the four treatment groups of the trial. Conclusion: Higher doses of epirubicin cause more adverse events in the absence of clear improvement in overall survival. Endocrine therapy with either tamoxifen or goserelin provided no significant added benefit to cytotoxic chemotherapy in this group of patients. Trial Registration Number: ISRCTN98335268 (C) 2016 Elsevier Ltd. All rights reserved.

Background In a previous proof-of-principle study we demonstrated that detection of circulating tumour DNA (ctDNA) in the adjuvant setting, after completion of surgery and chemotherapy for early stage breast cancer, was associated with a high risk of early relapse. Here we present longer follow-up of the same series, to define the predictive power of ctDNA analysis for disease free survival, and assess the potential to predict overall survival. Methods We recruited a cohort of 55 women presenting with early stage, primary breast cancer, who were all scheduled to receive neo-adjuvant chemotherapy. The primary tumour was sequenced to identify somatic mutations, identifying at least one mutation in 43 patients. Mutations were tracked with digital PCR to identify ctDNA, in plasma samples taken either at a single post-surgical time point (2-6 weeks post-surgery) or with serial plasma samples taken every 6 months in the adjuvant setting. Results At a median 31.7 months follow-up, 42% (18/43) patients had relapsed. Detection of ctDNA at the single post-surgical time point was associated with poor disease free survival, HR=13.6 95%CI (4.5, 41.2) p Conclusion Detection of ctDNA in the adjuvant setting has a high predictive power for future relapse and death from breast cancer. Therapeutic trials are required to determine whether mutation tracking identifies relapse sufficiently early to allow for further adjuvant therapy. Citation Format: Turner NC, Garcia-Murillas I, Chopra N, Beaney M, Kilburn L, Cutts R, Osin P, Nerurkar A, Schiavon G, Hrebien S, Bliss J, Dowsett M, Smith I. Circulating tumor DNA analysis to predict relapse and overall survival in early breast cancer – Longer follow-up of a proof-of-principle study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-02-01.

Stereotactic body radiotherapy (SBRT) is increasingly becoming a key treatment option for patients with oligometastatic disease. However, a lack of randomised data limits interpretation of results from retrospective and prospective cohort studies. Whilst these studies indicate higher rates of local control with acceptable toxicity the true benefit of adding SBRT to standard therapy remains unclear. Potential therapeutic benefit may also vary between tumour sites (underlying tumour biology, natural disease course). CORE investigates whether the addition of SBRT to standard therapy improves patient outcomes in common primary tumour sites where oligometastatic disease is encountered (prostate, breast, NSCLC).

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 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.

Background Improved survival rates in early breast cancer and the chronic nature of disease relapse result in a large cohort of patients being available for long-term follow-up (LTFUP) in randomised controlled trials. Whilst of recognised scientific value to assess long-term treatment-related sequelae, the volume of this activity can be challenging for trialists and participating sites, and comes at a considerable cost to research funders and the National Health Service (NHS). A National Cancer Research Institute Breast Clinical Studies Group supported project aimed to characterise UK LTFUP data collection procedures in order to propose improvements. Methods Protocols and case report forms for UK non-commercial National Institute for Health Research portfolio early breast cancer randomised controlled trials were reviewed and a questionnaire sent to associated participating NHS sites. Responders were asked to give opinions on issues with follow-up and LTFUP data collection procedures and to suggest potential improvements to practice. Results were used to inform design of a proposed standard LTFUP case report form. Results Thirty-four trials, involving eight Clinical Trials Units were eligible for inclusion in the review. All trials requested follow-up at least annually up to 5 years, with two-thirds requesting LTFUP after that time point. Information relating to efficacy endpoints was captured for all trials via case report forms; however, precise detail on recording of recurrence, second malignancies and death varied. Separately, questionnaires were returned from 66 NHS sites. Main concerns identified included difficulties in identifying all adverse events from hospital notes, volume of work, bureaucratic data management practices in Clinical Trials Units and perceptions of prioritisation of recruitment over follow-up. Conclusion Variation has existed with respect to detail of LTFUP information requested for UK trials. Improved communication, simplification and standardisation of data and associated collection methods are possible without compromising data requirements for efficient and effective trial reporting. Future use of routinely collected data, captured via electronic means, could transform practices and alleviate resource usage. Electronic supplementary material The online version of this article (doi:10.1186/1745-6215-15-379) contains supplementary material, which is available to authorized users.

Summary Background The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen fulvestrant in combination with continued oestrogen deprivation. Methods In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea, postmenopausal women with hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone receptor [PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months). Additionally, patients had to have adequate organ function and a WHO performance status of 0–2. Participants were randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched placebo; or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and stratification was by centre and previous use of an NSAI as adjuvant treatment or for locally advanced or metastatic disease. Participants and investigators were aware of assignment to fulvestrant or exemestane, but not of assignment to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea). Findings Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was 4·4 months (95% CI 3·4–5·4) in patients assigned to fulvestrant plus anastrozole, 4·8 months (3·6–5·5) in those assigned to fulvestrant plus placebo, and 3·4 months (3·0–4·6) in those assigned to exemestane. No difference was recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio 1·00, 95% CI 0·83–1·21; log-rank p=0·98), or between those assigned to fulvestrant plus placebo and exemestane (0·95, 0·79–1·14; log-rank p=0·56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant plus anastrozole, 22 in those assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3–4 adverse events were rare; the most frequent were arthralgia (three in the group assigned to fulvestrant plus anastrozole; seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and nausea or vomiting (five; two; eight). Interpretation After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation is no better than either fulvestrant alone or exemestane. Funding Cancer Research UK and AstraZeneca.

Background. ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy for advanced breast cancer. We addressed the impact of ESR1 mutations on sensitivity to standard therapies in SoFEA and PALOMA3, two phase III randomised trials that represent the trends in the current therapy for estrogen receptor positive advanced breast cancer. Methods. We assessed plasma DNA ESR1 mutations in the SoFEA trial that compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to non-steroidal AI, and in the PALOMA3 trial that compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression on prior endocrine therapy. We developed and validated multiplex digital droplet PCR assays to detect ESR1 mutations in circulating free DNA. Plasma had been immediately processed in PALOMA3 but there was a delay of up to 9 days before processing of EDTA samples in the SoFEA trial. Results. In SoFEA we demonstrated that delayed processing of plasma samples had no effect on detection rate of ESR1 mutations (p = 0.71), which were found in 39.1%(63/161) patients. Patients with ESR1 mutations had improved progression free survival (PFS) on fulvestrant compared to exemestane (HR = 0.52, 95%CI 0.30 to 0.92, p = 0.02), while patients with wild type ESR1 had similar PFS on either treatment (HR = 1.07, 95%CI 0.68 to 1.67, p = 0.77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3%(91/360) patients. ESR1 mutations were almost exclusively found in patients with prior AI exposure with or without tamoxifen, and were very rare with prior tamoxifen exposure only (28.9% (90/311) versus 2.0% (1/49) respectively, p endocrine therapy (sensitive to prior endocrine therapy, 29.8% (85/285) versus resistant 8.0% (6/75), p Conclusions. ESR1 mutation analysis in plasma after progression on prior AI therapy has clinical utility in directing choice of further endocrine therapy. Citation Format: Ben O’Leary, Charlotte Fribbens, Lucy Kilburn, Sarah Hrebein, Isaac Garcia-Murillas, Matthew Beaney, Massimo Cristofanilli, Fabrice Andre, Sherene Loi, Sibylle Loibl, John Jiang, Cynthia Huang Bartlett, Maria Koehler, Mitch Dowsett, Judith Bliss, Stephen Johnston, Nicholas Turner. ESR1 mutations in circulating tumour DNA predict outcome to endocrine treatment in patients with estrogen receptor positive advanced breast cancer; analysis of 521 patients in the SoFEA and PALOMA3 trials. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-069.

Purpose Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to exemestane. Now, with longer follow-up, a large number of non–breast cancer–related events have been reported. Exploratory analyses describe breast cancer–free survival (BCFS) and explore incidence and patterns of the different competing events. Patients and Methods Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) –positive and 547 with ER-unknown tumors. Results In all, 930 BCFS events have been reported (exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of 0.81 (95% CI, 0.71 to 0.92; P = .001) in favor of exemestane in the ER-positive/ER unknown group. Analysis partitioned at 2.5 years after random assignment showed that the on-treatment benefit of switching to exemestane (HR, 0.60; 95% CI, 0.48 to 0.75; P < .001) was not lost post-treatment, but that there was no additional gain once treatment had ceased (HR, 0.94; 95% CI, 0.80 to 1.10; P = .60). Improvement in overall survival was demonstrated, with 352 deaths in the exemestane group versus 405 deaths in the tamoxifen group (HR, 0.86; 95% CI, 0.75 to 0.99; P = .04). Of these, 222 were reported as intercurrent deaths (exemestane, 107; tamoxifen, 115). Conclusion The protective effect of switching to exemestane compared with continuing on tamoxifen on risk of relapse or death was maintained for at least 5 years post-treatment and was associated with a continuing beneficial impact on overall survival.

Background: The ACTION trial was initiated to provide evidence from a randomised trial on the effects of chemotherapy in women aged over 70 years where evidence for risk and benefit are lacking. Methods: This was a randomised, phase III clinical trial for high risk, oestrogen receptor (ER) negative/ER weakly positive early breast cancer. The trial planned to recruit 1000 women aged 70 years and older, randomised to receive 4 cycles of anthracycline chemotherapy or observation. The primary endpoint was relapse-free interval. The trial included a pilot phase to assess the acceptability and feasibility of recruitment. Results: The trial opened at 43 UK centres. Information on number of patients approached was available from 38 centres. Of the 43 eligible patients that were approached, 39 were not randomised due to patients declining entry. After 10 months only 4 patients had been randomised and after discussion with the research funder, the trial was closed and funding terminated. Conclusion: Despite widespread support at several public meetings, input from patient groups including representation on the Trial Management Group, the trial failed to recruit due to the inability to convince patients to accept randomisation. It would therefore seem that randomising the patients to receive chemotherapy vs observation is not a viable design in the current era for this patient population.

Purpose The Docetaxel Epirubicin Adjuvant (DEVA) trial evaluated the efficacy and toxicity of incorporating docetaxel after epirubicin to create a sequential anthracycline-taxane regimen in early breast cancer. Patients and Methods After complete tumor excision, postmenopausal women with node-positive early breast cancer were randomly assigned to either epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks for six cycles (EPI × 6) or three cycles of epirubicin 50 mg/m2 on days 1 and 8 every 4 weeks followed by three cycles of docetaxel 100 mg/m2 on day 1 every 3 weeks (EPI-DOC). A subset of patients also participated in a quality of life (QOL) study. The primary end point was disease-free survival (DFS). Results From 1997 to 2005, 803 patients entered DEVA (EPI × 6, n = 397; EPI-DOC, n = 406). At a median follow-up of 64.7 months (interquartile range, 45.2 to 84.4 months), 198 DFS events had been reported (EPI × 6, n = 114; EPI-DOC, n = 84). The 5-year DFS rates were 72.7% (95% CI, 68.0% to 77.3%) for epirubicin alone and 79.5% (95% CI, 75.2% to 83.8%) for epirubicin followed by docetaxel; evidence of improvement in DFS was observed with EPI-DOC (hazard ratio [HR], 0.68; 95% CI, 0.52 to 0.91; P = .008). One hundred twenty-seven patients have died (EPI × 6, n = 75; EPI-DOC, n = 52); a reduction in deaths was observed with EPI-DOC (HR, 0.66; 95% CI, 0.46 to 0.94; P = .02). The 5-year overall survival rates were 81.8% (95% CI, 77.7% to 85.9%) for epirubicin and 88.9% (95% CI, 85.5% to 92.2%) for epirubicin followed by docetaxel. Assessment of toxicity and QOL showed that EPI-DOC was associated with greater toxicity but with no difference in QOL between arms during follow-up. Conclusion These results suggest, within a relatively small trial, that substitution of docetaxel for epirubicin for the last three cycles of chemotherapy results in improved outcome in postmenopausal women with node-positive, early breast cancer compared with six cycles of epirubicin monotherapy.

The adjuvant use of aromatase inhibitors in breast cancer is associated with adverse effects on bone health. We previously reported a decline in bone mineral density (BMD) following the switch from tamoxifen to exemestane in the Intergroup Exemestane Study (IES). Here we report effects of endocrine treatment withdrawal on BMD, bone turnover markers (BTM) and fracture rates. 4, 724 patients took part in IES, and 206 patients were included in a bone sub-study. BMD and BTM were assessed pre-randomization, during and after the end of treatment (EOT). To evaluate treatment withdrawal effects, 12- and 24-month post EOT BMD results are available for 122 and 126 patients, respectively. Similar patient numbers had BTM measured post EOT. Following treatment withdrawal, the differences in BMD observed between the two endocrine strategies were partially reversed. At 24 months from EOT, spine BMD increased by 1.53% (95%CI 0.63-2.43 ; p = 0.001) after stopping exemestane and fell by 1.93% (95%CI -2.91 to 0.95 ; p = 0.0002) following tamoxifen withdrawal. A similar pattern of changes was observed at the hip. At 2 years post EOT, BMD changes from baseline were similar with both treatment strategies. Corresponding inverse changes in BTM were seen, with an increase following tamoxifen withdrawal and a reduction after exemestane. A higher number of fractures occurred during exemestane treatment, but fracture rates were similar after treatment withdrawal. With the switch strategy used in IES, the on treatment adverse bone effects of exemestane are reversed. Ongoing monitoring of BMD is therefore not routinely required

Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer.Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2-3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website .Within 6 months of switching to exemestane, BMD was lowered by 0.051 g/cm(3) (2.7%; 95% CI 2.0-3.4; p0.0001) at the lumbar spine and 0.025 g/cm(3) (1.4%; 0.8-1.9; p0.0001) at the hip compared with baseline. BMD decreases were only 1.0% (0.4-1.7; p=0.002) and 0.8% (0.3-1.4; p=0.003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p0.001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1.45 [1.13-1.87]; p=0.003).These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed.

BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS: 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS: After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS: Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival. Udgivelsesdato: 2007-Feb-17

Hormone sensitive breast cancer (BC) is a common disease in postmenopausal women. Generally seen as less aggressive than other BC subtypes patients have a continued risk of relapse for 15+ years (EBCTCG, 2011) thus the cumulative risk is not insubstantial. Efforts continue to identify patients who are at continued residual risk of relapse in order to develop new treatment strategies. Previous trials (IMPACT, 2007) suggested that aromatase inhibitor (AI) treatment for 2 weeks in the peri-surgical window-of-opportunity results in detectable biomarker changes (Ki67) and predicts long term outcome. Gene expression profiling offers opportunities to identify patients demonstrating early resistance to endocrine therapy. POETIC was a UK-wide RCT devised to provide definitive results on the role of perioperative (AI) treatment. Biopsies were taken at diagnosis and 2 weeks later at surgery thus allowing an in vivo assessment of AI sensitivity. To succeed, POETIC needed to overcome substantial barriers in relation to compliance with cancer wait times, recruitment of women at diagnosis, varied clinical practice and to ensure receipt of sufficient quality tissue samples for analysis of biomarker endpoints. Patient advocates were involved from inception. POETIC succeeded in recruiting 4486 women from 130 UK centres. Paired tissue samples were received for 96% patients. Lessons learnt in rolling out the world's largest window-of-opportunity BC trial illustrate the viability and potential of this experimental model as a vehicle for testing early biological effects of novel agents and to identify women most likely to be at long term residual risk of relapse.

TNT is a trial comparing carboplatin with docetaxel for advanced TN or BRCA1/2 BC patients. TNBC is heterogeneous; median progression-free survival (PFS) is short but some patients have prolonged PFS following treatment. BRCA1/2 patients were hypothesised to respond better to carboplatin. This interaction, with the heterogeneous population, was expected to cause a failure of PH assumptions required for Cox-PH analysis. Therefore, TNT required alternative analysis methods.

1019 Background: The majority of triple negative breast cancers are of basal-like subtype (BLBC). There is uncertainty about concordance of intrinsic subtypes and ROR scores by PAM50 between matche...

Introduction: Subgroups within sporadic triple negative breast cancers (TNBCs) appear to share impaired DNA damage response mechanisms with BRCA1/2 mutation-associated breast cancers. This has been hypothesised to confer particular sensitivity to DNA-damaging platinum chemotherapy. The TNT trial, a randomized phase III trial in women with metastatic or recurrent locally advanced TNBC or BRCA1/2 mutation-associated breast cancer, aimed to test this hypothesis and examine treatment effect in biological subgroups. Patients & Methods: Eligible patients had either ER-, PR-, HER2- breast cancer or were known BRCA1/2 carriers (any ER/PR/HER2). Patients were randomized (1:1) to receive either C (AUC 6 q3wk) or D (100mg/m2 q3wk) for 6-8 cycles or until disease progression if sooner and could cross over to the alternative treatment on confirmed progression. Ineligible patients included those who had ECOG performance status >2, received adjuvant taxane therapy in the last 12 mths, any previous treatment with a platinum chemotherapy, or previous non-anthracycline chemotherapy for metastatic disease. For consenting patients a blood sample and archived tissue samples were obtained for BRCA1/2 genotyping and central biomarker analysis (primary tumour, lymph nodes and recurrent tumour biopsy if available) of subtypes within TNBC and biomarkers of DNA repair deficiency. The primary endpoint was RECIST objective tumour response up to cycle 6 of randomised treatment. Secondary endpoints included toxicity, progression free survival (PFS), time to progression and overall survival. TNT aimed to detect a 15% improvement in ORR with C compared to D, with planned target sample size range of 370-450 depending on assumed ORR in D patients (2-sided α=0.05, power=90%). 376 (188 C, 188 D) were recruited from 74 UK centres between Apr 08 and Mar 14. Results: A snapshot of the data was taken on 30/5/14 at which point 336 (89.4%) patients had experienced a PFS event, with overall median PFS time of 4.4 mths. Median age of patients was 55 yrs (IQR 48-63). 366/376 (97%) patients had TNBC of whom 18 were also known BRCA1/2 mutation carriers, with the remaining 10 patients receptor +ve and BRCA1/2 carriers. 338/376 (90%) had metastatic and 38/376 (10%) recurrent locally advanced disease. 53% had liver or lung metastases affecting the parenchyma and 34% had received previous adjuvant taxane therapy. Median time from initial diagnosis to entering TNT was 2.2 yrs (IQR 1.5-3.5). Primary tumour tissue has currently been received for 277 patients, blood from 286 patients and recurrent tumour tissue from 85 patients. Discussion: TNT will report evidence on the activity of single agent platinum chemotherapy compared with single agent taxane in patients with TNBC and BRCA1/2 associated breast cancer. Correlative analyses of BRCA1/2 mutation status, subtypes and DNA repair biomarkers will also be reported. TNT will be the first randomised trial to report the activity of platinum compared with standard chemotherapy within TNBC subtypes and in relation to BRCA1/2 mutation status and DNA repair biomarkers. Safety, tolerability and response to crossover treatment will also be presented. Citation Format: Andrew Tutt, Paul Ellis, Lucy Kilburn, Cheryl Gilett, Sarah Pinder, Jacinta Abraham, Sophie Barrett, Peter Barrett-Lee, Stephen Chan, Maggie Cheang, Mitch Dowsett, Lisa Fox, Patrycja Gazinska, Anita Grigoriadis, Alexander Gutin, Catherine Harper-Wynne, Matthew Hatton, Sarah Kernaghan, Jerry Lanchbury, James Morden, Julie Owen, Jyoti Parikh, Peter Parker, Nazneen Rahman, Rebecca Roylance, Adam Shaw, Ian Smith, Rose Thompson, Kirsten Timms, Holly Tovey, Andrew Wardley, Gregory Wilson, Mark Harries, Judith Bliss. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [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 S3-01.

Background Perioperative therapy offers the opportunity to measure biological response to treatment in the primary tumor in early breast cancer (EBC), enhancing prospects for personalised medicine. Perioperative trials form an expanding component of the UK national breast cancer trials portfolio. Unlike traditional neoadjuvant studies, activity dovetails around timelines for standard treatment with no planned delay to primary surgery. Tissue samples collected prior to randomisation (baseline) & again at surgery address key biological endpoints & are essential for perioperative studies. Methods: As the UK's largest perioperative trial, POETIC (ER+ve postmenopausal EBC, +/− aromatase inhibitor therapy, biomarker & disease outcome) aims to recruit 4000 patients from 100+ centres. EPHOS-B (HER2+ve EBC, +/− lapatinib or trastuzumab) focuses on biomarker endpoints & aims to recruit 250 patients. Barriers to recruitment included 1) integration of research protocols into busy breast surgical clinics, extending a clinical trials culture across a multidisciplinary breast diagnostic team, & ensuring appropriate GCP training, 2) satisfying requirements for storing research tissue, 3) complying with government cancer wait times, 4) obtaining biomarker results within required timelines 5) ensuring completeness & quality of tissue samples. Additional challenges for EPHOS-B include managing requirements for scheduling of oncological therapy (e.g. trastuzumab) in pre-operative setting, delivery of such therapy outside the randomising hospital & rapid access to cardiac screening before randomisation. Results: The following strategies were developed to overcome barriers 1) increasing collaborative working at sites & adopting a pragmatic approach to type of tissue required. Centres choose to provide both FFPE tissue & tissue in RNA-later, or FFPE tissue only; 2) working with national regulators to agree interpretation of current legislation in designation of when tissue is “in transit” (enabling it to reside outside a tissue bank) & “research” tissue (where transfer to a tissue bank is required); 3) agreement with government that procedures integral to perioperative trials comply with cancer wait times; 4) promoting reorganisation of site processes for obtaining essential biomarker results; 5) pilot lab work to inform site guidance on tissue collection procedures to ensure quality of samples received. A tracking database allows completeness of tissue samples to be monitored. Work to improve timelines for HER2 testing in EPHOS-B is ongoing, & challenges of delivering anti-HER2 therapy in this setting have been addressed. Conclusions: Assessment of biological response to therapy in the primary tumor in EBC within national trials is feasible. Many barriers faced by POETIC have been overcome, & with recruitment now 100+ patients per month, newer centres benefit from earlier experience. Lessons learnt in POETIC apply to EPHOS-B, allowing investigators to focus on resolving more challenging issues specific to that trial. In many centres both trials have been important drivers in improving timeliness of molecular testing & therefore benefited the patient pathway in general as well as securing high quality trial data. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-03-04.

Background: IES is an investigator-led study in 4724 postmenopausal patients with early breast cancer (sponsored by Pfizer Ltd; ISRCTN11883920) that has already demonstrated significant, clinically important benefits from switching adjuvant endocrine therapy after 2-3 years tamoxifen (T) to exemestane (E) (NEJM 2004, Lancet 2007). With longer follow-up the sensitivity of a disease free survival analysis may be reduced by the increasing number of non breast cancer-related deaths. Analysis of breast cancer free survival (BCFS), censoring intercurrent deaths, provides a sensitive estimate of the true impact of an adjuvant intervention on breast cancer outcome.Materials and methods: Patients who were disease-free after 2-3 years of adjuvant T, were randomized to continue T or switch to E to complete a total of 5 years of adjuvant endocrine therapy. At the time of this planned analysis in June 2009, the median follow-up was 91 months, and 91% of surviving patients had ≥6 years followup. The analysis focuses on 4052 pts known to be ER positive (+) and 547 with ER unknown (unk) tumors. The remaining 125 patients now known to be ER negative are excluded from this analysis.Results: 933 BCFS events have been reported (E=425 T=508) giving an unadjusted hazard ratio (HR) of 0.81 (95%CI: 0.71, 0.92); p=0.001 in favor of E in the ER+ and ER unk groups. With mature follow-up, the benefits of E appear similar in the ER unk and ER+ sub-groups (HR=0.85 95%CI (0.60, 1.20); p=0.36 and HR=0.80 95%CI (0.70, 0.92); p=0.002 respectively). Similarly, all other prognostic subgroups show consistency with the overall BCFS effect. An analysis partitioned at 2.5 years post randomization showed the on-treatment BCFS benefit of switching to E (HR=0.60 95%CI (0.48, 0.75); p Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 12.

LBA527 Background: We have previously shown that switching to exemestane (E) after 2–3 years tamoxifen (T) improves disease free survival (DFS) in postmenopausal (PM) women with early breast cancer (BC). We report results with 95% of patients (pts) having ≥3 years follow-up. Methods: 4724 PM pts (2352 E vs 2372 T) with ER +ve/unknown unilateral BC, disease-free after 2–3 years T, were randomized to continue T or switch to E to complete a total of 5 years adjuvant endocrine therapy. 122 pts (56 E vs 66 T) originally reported as ER unknown were later found to be ER −ve. In addition to intention to treat (ITT), we repeated analyses excluding ER −ve pts. Adverse events (pre relapse) by treatment received were analysed on treatment (TRT) and also including follow-up (TRTFU). In safety analyses P < 0.01 was taken as significant due to multiple testing. Results: With median follow up of 58 months there were 808 first events (disease relapse, contralateral breast cancer (CLBC), intercurrent death) and 483 deaths. See table for unadjusted hazard ratios (HR). In ER +ve/unknown pts, adjusting for pre-specified prognostic factors of nodal status, chemo use, HRT use, gave HR for DFS of 0.74 (0.64, 0.85); p < 0.0001 and for overall survival (OS) of 0.83 (0.69, 0.99); P = 0.04. There were 145 intercurrent deaths (65 E vs 80 T), including deaths from cardiac (14 E vs 13 T), vascular (17 E vs 11 T) and other cancers (20 E vs 35 T). No statistically significant differences in myocardial infarctions, angina, or cerebrovascular accidents were observed. In T pts there were more thromboembolic (TRT p = 0.006, TRTFU p = NS) and serious gynaecologic events (TRT p < 0.001, TRTFU p < 0.001) and less fractures (TRT p = NS, TRTFU p = 0.003). Conclusions: Switching to E following 2–3 years of T significantly improves DFS, reducing chance of first event, CLBC and distant recurrence. In ER +ve/unknown pts, the switching strategy with E significantly reduces the risk of dying. [Table: see text] [Table: see text]