Residual Cancer Burden (RCB) after neoadjuvant chemotherapy (NAC) has been validated to predict event-free survival (EFS) across breast cancer subtypes but its prognostic ability has not been specifically studied for invasive lobular carcinoma (ILC). We studied patient-level data (histologic subtype, RCB, and EFS) from a previously published pooled cohort from 12 institutions in the US and Europe. ILC was defined by local institutional protocols. Characteristics in pure ILC vs. non-ILC were compared using t-test or chi-squared test. Associations between continuous RCB index and EFS were assessed in both groups with mixed effect Cox models and multivariable analyses. Recursive partitioning was used in an exploratory model to stratify prognosis by individual clinicopathologic variables and the components of RCB. Of 5161 patients, the diagnosis was ILC in 216 (4.2%) and non-ILC in 4945. ILC cases were older, had lower grade, higher tumor (T) category, and more hormone receptor (HR) positive HER2 -negative subtype (73.6% vs 36.4%) (all p-values <0.05). Pathologic complete response (pCR/RCB 0) was achieved in 10.6% of ILCs and 33.4% of non-ILC (2.5% and 11.8% respectively among HR+HER2- cases, p<0.0005). Increased RCB index was significantly associated with worse EFS in both ILC and non-ILC (p<0.05) and remained prognostic when adjusted for age, grade, T category, baseline nodal status, and receptor subtype. While continuous RCB index had a linear relationship with probability of EFS event (log scale) in non-ILC, this relationship was non-linear in ILC cases; for ILC, prognosis was similar for RCB index ≤1.9, with increasing risk for RCB index >1.9. Recursive partitioning demonstrated residual tumor cellularity as most prognostic in ILC, followed by number of positive nodes and tumor dimensions. While pCR rate after NAC is low in ILC, RCB retains prognostic value, with residual cellularity providing the most information. RCB index values ≤1.9 had similar prognosis to pCR. These results underscore the utility of RCB for evaluating NAC response in those with ILC for clinical management and as an endpoint for clinical trials.

We planned an individual patient data (IPD) meta-analysis of non-inferiority (NI) RCTs to determine if a duration of less than the standard of 12 months (m) of adjuvant trastuzumab is non-inferior for treatment outcomes in HER-2 positive early breast cancer patients. A systematic review identified five NI RCTs, and trial groups agreed a meta-analysis collaboration. PERSEPHONE, PHARE and HORG compared 12m v 6m; SOLD and Short-HER compared 12m v 9weeks[w]. Primary outcome was invasive disease-free survival (IDFS). Secondary outcomes were distant relapse-free survival (DRFS); overall survival (OS) and breast cancer specific survival (BCSS). Analysis was intention-to-treat (ITT). Random effects modelling evaluated prognostic effects of patient and tumour characteristics, treatment and trial. Heterogeneity between studies was assessed using the Cochran's Q statistic. For the comparison of 12m v less (n≈11,500 pts), a 1-sided 2.5% significance was used. For the analyses of 12m v 6m (n≈8,000 pts) and 12m v 9w (n≈3,500 pts), 1-sided 5% significance was utilised. To date, IPD has been obtained from 4 trials and published data has been used from PHARE. For ITT analysis of the primary outcome of IDFS, non-inferiority limits for absolute 2% margins were calculated as 1.19 for all 5 trials, 1.20 for 3 trials comparing 12m v 6m and 1.25 for 2 trials comparing 12m v 9w. For 12m v less (all 5 trials combined), 5-year IDFS rates were 88.46% and 86.87% respectively. The adjusted HR for treatment was 1.14 (95% credibility interval (CI) 0.88-1.47), non-inferiority p=0.37. For 12m v 6m, 5-year IDFS rates were 89.26% and 88.56% respectively. The adjusted HR for treatment was 1.07 (90% CI 0.98-1.17), non-inferiority p=0.02. For 12m v 9w, 5-year IDFS rates were 91.40% and 89.22% respectively. The adjusted HR for treatment was 1.27 (90% CI 1.07-1.49), non-inferiority p=0.56. Cochran's Q is 5.5 for all 5 trials, 0.91 for the 3 trials comparing 12m v 6m and 1.1 for the 2 trials comparing 12m v 9w. Six months trastuzumab is non-inferior to 12months, although nine weeks is not.

Background: No specific targeted therapies are available for Triple Negative Breast Cancers (TNBC), an aggressive and diverse subgroup. The basal TNBC subgroup show some phenotypic and molecular similarities with germline BRCA (gBRCA). In gBRCA patients, and potentially other homologous recombination deficiencies, these already compromised pathways may allow drugs called PARP inhibitors (olaparib) to work more effectively.Aims: To establish if the addition of olaparib to neoadjuvant platinum based chemotherapy for basal TNBC and/or gBRCA breast cancer is safe and improves efficacy (pathological complete response (pCR)).Trial design: 3 stage open label randomised phase II/III trial of neoadjuvant paclitaxel and carboplatin +/olaparib, followed by clinicians9 choice of anthracycline regimen.Stage 1 and 2: Patients are randomised (1:1:1) to either control (3 weekly carboplatin AUC5/weekly …

Background: We have previously shown lymphocyte density, measured using computational pathology, is associated with pathological complete response (pCR) in breast cancer. The clinical validity of this finding in independent studies, among patients receiving different chemotherapy, is unknown.Patients and methods: The ARTemis trial randomly assigned 800 women with early stage breast cancer between May 2009 and January 2013 to three cycles of docetaxel, followed by three cycles of fluorouracil, epirubicin and cyclophosphamide once every 21 days with or without four cycles of bevacizumab. The primary endpoint was pCR (absence of invasive cancer in the breast and lymph nodes). We quantified lymphocyte density within haematoxylin and eosin (H&E) whole slide images using our previously described computational pathology approach: for every detected lymphocyte the average distance to the nearest 50 lymphocytes was calculated and the density derived from this statistic. We analyzed both pre-treatment biopsies and post-treatment surgical samples of the tumour bed.Results: Of the 781 patients originally included in the primary endpoint analysis of the trial, 609 (78%) were included for baseline lymphocyte density analyses and a subset of 383 (49% of 781) for analyses of change in lymphocyte density. The main reason for loss of patients was the availability of digitized whole slide images. Pre-treatment lymphocyte density modelled as a continuous variable was associated with pCR on univariate analysis (odds ratio [OR], 2.92; 95% CI, 1.78-4.85; P<0.001) and after adjustment for clinical covariates (OR, 2.13; 95% CI, 1.24-3.67; P = 0.006). Increased pre- to post-treatment lymphocyte density showed an independent inverse association with pCR (adjusted OR, 0.1; 95% CI, 0.033-0.31; P<0.001).Conclusions: Lymphocyte density in pre-treatment biopsies was validated as an independent predictor of pCR in breast cancer. Computational pathology is emerging as a viable and objective means of identifying predictive biomarkers for cancer patients.

Abstract Background TNT previously reported that patients(pts) with advanced triple negative breast cancer(TNBC) and germline BRCA1/2(gBRCA+) mutations are more likely to respond to carboplatin(C) than to docetaxel(D), and have longer progression-free survival with C. Here, we report results from a pre-planned biological analysis to test whether BRCA silencing or methylation status confer sensitivity to platinum. Methods Pts eligible for TNT had ER-, PgR-, HER2- BC or were known gBRCA+(any ER/PgR/HER2). Pts were randomized to C(AUC 6 q3wk) or D(100mg/m2 q3wk) for 6-8 cycles or until disease progression if sooner, with crossover possible on progression. Blood and archival tissue samples were requested for BRCA1/2 genotyping, central analysis of TN and DNA repair deficiency biomarkers. Primary endpoint was intention-to-treat objective response rate(ORR) up to cycle 6. BRCA1 mRNA level was estimated from whole-genome total RNA sequencing(RNA-Seq). BRCA1 methylation analysis was quantified by bisulfite sequencing. A methylation score for the sample was computed as percentage of methylated reads relative to total number of reads that were either methylated or not methylated for CpG sites. A sample with a score >10% was considered methylated(BRCA1meth)? a BRCA1 mRNA level "silenced" subgroup(BRCA1 silencing) was defined as value of log2(mRNA)<8.4, based on bimodal distribution. Results 212 and 191 pts' samples were assessed for BRCA1 methylation and mRNA levels. 33 pts (15.6%) were found to be BRCA1meth. Pts with BRCA1meth had a better response to D (42%, 95%CI: 20, 64) than C (21%, 95%CI: -0.1, 43)? absolute difference (C-D) -21% (95%CI: -52, 10)? p=0.28), but not statistically significant. There was no evidence of a difference when gBRCA+ tumours were excluded. 31 pts (16%) had BRCA1 silencing. Concordant with BRCA1meth, pts with BRCA1 silencing had a better response to D (65%, 95%CI: 42, 87) than C (29%, 95%CI: 4.9, 52)? absolute difference (C-D) -36% (95%CI: -69, -3.3)? p=0.07), with an odds ratio 0.22 (95%CI: 0.035, 1.2) in favor of D, interaction with treatment not significant (p=0.066). 19 pts with BRCA1meth and BRCA1 silencing had a better response to D (60%, 95%CI: 30, 90) than C (22%, 95%CI: -5.0, 49)? absolute difference (C-D) -38% (95%CI: -79, 2.9) in favor of D (p=0.17), and the interaction was not significant (p=0.15). Further exploratory analyses examining any relationship between a response to C and new cutpoints for BRCA1meth or BRCA1 mRNA level did not suggest any evidence of a signal. Conclusion Our data did not support a priori hypotheses that BRCA1 methylation or silencing would be associated with a greater response to C than D, which is consistent with other reports in ovarian cancer. As BRCA1 methylation will not always lead to significant silencing or be the only cause of low BRCA1 gene expression, exploratory analysis is investigating the interaction of BRCA silenced group with D sensitivity. RNA-seq is ongoing and results from the final database will be presented. Citation Format: Tutt A, Cheang MCU, Kilburn L, Tovey H, Gillett C, Pinder S, Lanchbury J, Abraham J, Barrett S, Barrett-Lee P, Chan S, Gazinska P, Grigoriadis A, Kernaghan S, Hoadley K, Gutin A, Harper-Wynne C, Hatton M, Owen J, Parker P, Roylance R, Shaw A, Smith I, Thompson R, Timms K, Wardley A, Wilson G, Harries M, Ellis P, Ashworth A, Perou C, Bliss J, Rahman N, Brown R, On Behalf of the TNT Trial Management Group and Investigators. BRCA1 methylation status, silencing and treatment effect in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [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 S6-01.

Abstract Management of metastatic TNBC remains a challenge. Chemotherapy is the mainstay of treatment but benefits are frequently short-lived with rapid development of resistance. The PI3K/AKT/mTOR pathway has been implicated in many ways in TNBC, making inhibition of AKT an attractive therapeutic target. Based on downstream pathway activation signatures, PI3K pathway activation appears higher in TNBC compared to other molecular subtypes, despite a relatively low percentage of activating PI3K mutations. Alternative means of activating the PI3K pathway have been identified in TNBC, including loss or mutation of PTEN (up to 35%) and INPP4B (up to 30%) and/or amplification of PIK3CA, AKT2 or AKT3, resulting in increased activation of AKT. Induction of AKT by chemotherapy can be an early compensatory mechanism that can be exploited therapeutically to increase the efficacy of chemotherapy. Preclinical TNBC models with activated AKT signalling have been shown to be highly sensitive to AKT inhibitors. AZD5363 is a potent pan-AKT inhibitor with good oral bioavailability. Multiple lines of investigation have demonstrated strong synergistic effects between AKT inhibition and taxane chemotherapy in models of TNBC both in vitro and in vivo, providing rationale for the combination of AZD5363 and paclitaxel in TNBC. PAKT is designed to test the hypothesis that inhibition of AKT will increase the anti-tumour activity of paclitaxel chemotherapy in TNBC. The study will try to characterize those patients who may benefit from this treatment to identify potential predictors of sensitivity. PAKT is an international investigator led and sponsored, double-blind, placebo controlled, randomised phase II trial. Patients are randomised 1:1 to receive paclitaxel weekly (90mg/m2) on days 1,8, and 15 plus AZD5363 (400mgBD) or placebo (400mgBD) on days 2-5, 9-12, 15-19 (28 day treatment cycles). Patients are stratified by the number of metastatic sites and the interval from the end of adjuvant chemotherapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Tumour assessments are carried out every 8 weeks. PAKT enrols patients with histologically documented locally advanced/metastatic TNBC (ER≤Allred2, PR≤Allred2, HER2=0,1+or2+), no prior systemic therapy for advanced TNBC, ECOG PS 0-2 and measurable disease per RECIST v1.1. Patients with brain metastases, significant cardiovascular disease, motor polyneuropathy are excluded. The primary endpoint is progression-free survival. Secondary endpoints are objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, and patient reported outcomes. Archival tumour tissue must be available to evaluate potential biomarkers associated with therapeutic response and resistance. PFS will be compared between treatment arms by the stratified log-rank test. HR for disease progression/death will be estimated using a stratified Cox proportional hazards model. Kaplan-Meier methodology will be used to estimate the median PFS for each arm. Approximately 140 patients will be enrolled at ≈65 sites in the UK, France, Hungary, Romania, Georgia & South Korea. Citation Format: Schmid P, Wheatley D, Baird R, Chan S, Abraham J, Tutt A, Kristeleit H, Patel G, Bathakur U, Bishop J, Harper-Wynne C, Sims E, Copson E, Perren T, Stein R, Poole C, Cartwright H, Sarker S-J, Mousa K, Turner N. A phase II, double blind, randomised, placebo-controlled study of the AKT Inhibitor AZD5363 in combination with paclitaxel in triple-negative advanced or metastatic breast cancer (TNBC)(NCT02423603). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-13.

Background: Patients with high risk early breast cancer undergoing chemotherapy are frequently treated with both anthracycline and taxane-based chemotherapy exposing patients to multiple toxicities. Molecular predictors of response to specific chemotherapy agents are emerging. Abnormal duplication of the centromeric region of chromosome 17 (CEP17) and either Topoisomerase 2A (TOP2A) gene amplification or deletion, have been identified in a recent meta-analysis as potent markers of anthracycline sensitivity (Bartlett et al JCO 2015). The ROSCO study has been designed to prospectively test the utility of these markers to select anthracycline or taxane based chemotherapy in the neoadjuvant setting. Key entry criteria: Confirmed invasive breast cancer; centrally confirmed CEP17 duplication and TOP2A status; primary tumour>2cms or documented axillary node metastasis Exclusion criteria include breast cancer with good risk features i.e. Grade 1/2 ER PR rich (Q score 7/8), HER2 negative tumours. Study treatment: Patients will undergo central testing for CEP-17 and TOP2A and be randomised to 4 cycles of FEC100 (5-Flourouracil 500mg/m2 Epirubicin 100mg/m2 cyclophosphamide 600mg/m2) or 4 cycles of TC (Docetaxel 75mg/m2 Cyclophosphamide 600 mg/m2). Following chemotherapy patients will undergo surgical resection, (Institutional standard). Patients with residual invasive cancer will receive 4 cycles of the alternative chemotherapy to that received in the neoadjuvant setting. HER2 positive patients will receive concurrent trastuzumab and continue standard adjuvant trastuzumab. . Patients with biopsy proven axillary node metastases will undergo combined blue dye and radioisotope tracer guided sentinel lymph node biopsy (SLNB) and axillary lymph node clearance as a single procedure during breast surgery. Adjuvant endocrine and radiation therapy will be Institutional standard Endpoints: The primary endpoint is pathological complete response (no invasive disease in breast or axilla (pCR)). Secondary endpoints include: clinical and radiological response; rate of breast conservation; patient reported outcomes; safety, tolerability and long term outcomes. In patients with proven nodal involvement the false negative rate of a negative post treatment SLNB compared to axillary node clearance will be reported. Sample size and stratification: 1050 patients will be randomised in a 1:1 ratio stratified by nodal status, ER, HER2, and biomarker status (CEP-17 amplified or TOP2A amplified/deleted) vs normal (CEP-17 normal TOP2A normal). Analysis: The primary analysis will assess the interaction between the treatment effect and CEP17/TOP2A status to determine if a differential treatment effect exists between CEP17/TOP2A Normal and CEP17/TOP2A Abnormal patients. pCR will be analysed using a logistic regression model including co-variates for treatment, CEP17/TOP2A status and an interaction term of the two effects Sample size is based on the ability to detect an absolute improvement in pCR in the biomarker abnormal group from 21% in the TC treated group to 30% in the FEC treated group. With 90% power at 10% significance level. Contact Information: the ROSCO Trial Office ROSCO@trials.bham.ac.uk. Citation Format: Rea DW, Haywood L, Francis AM, Bowden SJ, Brookes CM, MacKenzie M, Cameron D, Stein R, Earl HM, Thomas J, Abraham J, Stanley A, Starczinski J, McGoldrick T, Treharne-Jones P, Billingham L, Bartlett JM. ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-02.

Management of metastatic TNBC remains a challenge. Chemotherapy is the mainstay of treatment but benefits are frequently short-lived with rapid development of resistance. The PI3K/AKT/mTOR pathway has been implicated in many ways in TNBC, making inhibition of AKT an attractive therapeutic target. Based on downstream pathway activation signatures, PI3K pathway activation appears higher in TNBC compared to other molecular subtypes, despite a relatively low percentage of activating PI3K mutations. Alternative means of activating the PI3K pathway have been identified in TNBC, including loss or mutation of PTEN (up to 35%) and INPP4B (up to 30%) and/or amplification of PIK3CA, AKT2 or AKT3, resulting in increased activation of AKT. Induction of AKT by chemotherapy can be an early compensatory mechanism that can be exploited therapeutically to increase the efficacy of chemotherapy. Preclinical TNBC models with activated AKT signalling have been shown to be highly sensitive to AKT inhibitors. AZD5363 is a potent pan-AKT inhibitor with good oral bioavailability. Multiple lines of investigation have demonstrated strong synergistic effects between AKT inhibition and taxane chemotherapy in models of TNBC both in vitro and in vivo, providing rationale for the combination of AZD5363 and paclitaxel in TNBC. PAKT is designed to test the hypothesis that inhibition of AKT will increase the anti-tumour activity of paclitaxel chemotherapy in TNBC. The study will try to characterize those patients who may benefit from this treatment to identify potential predictors of sensitivity. PAKT is an international investigator led and sponsored, double-blind, placebo controlled, randomised phase II trial. Patients are randomised 1:1 to receive paclitaxel weekly (90mg/m 2 ) on days 1,8, and 15 plus AZD5363 (400mgBD) or placebo (400mgBD) on days 2-5, 9-12, 15-19 (28 day treatment cycles). Patients are stratified by the number of metastatic sites and the interval from the end of adjuvant chemotherapy. Treatment is given until disease progression (RECIST 1.1), intolerable toxicity or elective withdrawal. Tumour assessments are carried out every 8 weeks. PAKT enrols patients with histologically documented locally advanced/metastatic TNBC (ER≤Allred2, PR≤Allred2, HER2=0,1+or2+), no prior systemic therapy for advanced TNBC, ECOG PS 0-2 and measurable disease per RECIST v1.1. Patients with brain metastases, significant cardiovascular disease, motor polyneuropathy are excluded. The primary endpoint is progression-free survival. Secondary endpoints are objective response rate, change in tumour size, clinical benefit rate, overall survival, duration of response, and patient reported outcomes. Archival tumour tissue must be available to evaluate potential biomarkers associated with therapeutic response and resistance. PFS will be compared between treatment arms by the stratified log-rank test. HR for disease progression/death will be estimated using a stratified Cox proportional hazards model. Kaplan-Meier methodology will be used to estimate the median PFS for each arm. Approximately 140 patients will be enrolled at ≈65 sites in the UK, France, Hungary, Romania, Georgia u0026 South Korea. Citation Format: Schmid P, Wheatley D, Baird R, Chan S, Abraham J, Tutt A, Kristeleit H, Patel G, Bathakur U, Bishop J, Harper-Wynne C, Sims E, Copson E, Perren T, Stein R, Poole C, Cartwright H, Sarker S-J, Mousa K, Turner N. A phase II, double blind, randomised, placebo-controlled study of the AKT Inhibitor AZD5363 in combination with paclitaxel in triple-negative advanced or metastatic breast cancer (TNBC)(NCT02423603). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-03-13.

Background: Patients with high risk early breast cancer undergoing chemotherapy are frequently treated with both anthracycline and taxane-based chemotherapy exposing patients to multiple toxicities. Molecular predictors of response to specific chemotherapy agents are emerging. Abnormal duplication of the centromeric region of chromosome 17 (CEP17) and either Topoisomerase 2A (TOP2A) gene amplification or deletion, have been identified in a recent meta-analysis as potent markers of anthracycline sensitivity (Bartlett et al JCO 2015). The ROSCO study has been designed to prospectively test the utility of these markers to select anthracycline or taxane based chemotherapy in the neoadjuvant setting. Key entry criteria: Confirmed invasive breast cancer; centrally confirmed CEP17 duplication and TOP2A status; primary tumouru003e2cms or documented axillary node metastasis Exclusion criteria include breast cancer with good risk features i.e. Grade 1/2 ER PR rich (Q score 7/8), HER2 negative tumours. Study treatment: Patients will undergo central testing for CEP-17 and TOP2A and be randomised to 4 cycles of FEC100 (5-Flourouracil 500mg/m2 Epirubicin 100mg/m2 cyclophosphamide 600mg/m2) or 4 cycles of TC (Docetaxel 75mg/m2 Cyclophosphamide 600 mg/m2). Following chemotherapy patients will undergo surgical resection, (Institutional standard). Patients with residual invasive cancer will receive 4 cycles of the alternative chemotherapy to that received in the neoadjuvant setting. HER2 positive patients will receive concurrent trastuzumab and continue standard adjuvant trastuzumab. . Patients with biopsy proven axillary node metastases will undergo combined blue dye and radioisotope tracer guided sentinel lymph node biopsy (SLNB) and axillary lymph node clearance as a single procedure during breast surgery. Adjuvant endocrine and radiation therapy will be Institutional standard Endpoints: The primary endpoint is pathological complete response (no invasive disease in breast or axilla (pCR)). Secondary endpoints include: clinical and radiological response; rate of breast conservation; patient reported outcomes; safety, tolerability and long term outcomes. In patients with proven nodal involvement the false negative rate of a negative post treatment SLNB compared to axillary node clearance will be reported. Sample size and stratification: 1050 patients will be randomised in a 1:1 ratio stratified by nodal status, ER, HER2, and biomarker status (CEP-17 amplified or TOP2A amplified/deleted) vs normal (CEP-17 normal TOP2A normal). Analysis: The primary analysis will assess the interaction between the treatment effect and CEP17/TOP2A status to determine if a differential treatment effect exists between CEP17/TOP2A Normal and CEP17/TOP2A Abnormal patients. pCR will be analysed using a logistic regression model including co-variates for treatment, CEP17/TOP2A status and an interaction term of the two effects Sample size is based on the ability to detect an absolute improvement in pCR in the biomarker abnormal group from 21% in the TC treated group to 30% in the FEC treated group. With 90% power at 10% significance level. Contact Information: the ROSCO Trial Office ROSCO@trials.bham.ac.uk. Citation Format: Rea DW, Haywood L, Francis AM, Bowden SJ, Brookes CM, MacKenzie M, Cameron D, Stein R, Earl HM, Thomas J, Abraham J, Stanley A, Starczinski J, McGoldrick T, Treharne-Jones P, Billingham L, Bartlett JM. ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-02.

Abstract Background: Patients with high risk early breast cancer undergoing chemotherapy are frequently treated with both anthracycline and taxane-based chemotherapy exposing patients to multiple toxicities. Molecular predictors of response to specific chemotherapy agents are emerging. Abnormal duplication of the centromeric region of chromosome 17 (CEP17) and either Topoisomerase 2A (TOP2A) gene amplification or deletion, have been identified in a recent meta-analysis as potent markers of anthracycline sensitivity (Bartlett et al JCO 2015). The ROSCO study has been designed to prospectively test the utility of these markers to select anthracycline or taxane based chemotherapy in the neoadjuvant setting. Key entry criteria: Confirmed invasive breast cancer; centrally confirmed CEP17 duplication and TOP2A status; primary tumour>2cms or documented axillary node metastasis Exclusion criteria include breast cancer with good risk features i.e. Grade 1/2 ER PR rich (Q score 7/8), HER2 negative tumours. Study treatment: Patients will undergo central testing for CEP-17 and TOP2A and be randomised to 4 cycles of FEC100 (5-Flourouracil 500mg/m2 Epirubicin 100mg/m2 cyclophosphamide 600mg/m2) or 4 cycles of TC (Docetaxel 75mg/m2 Cyclophosphamide 600 mg/m2). Following chemotherapy patients will undergo surgical resection, (Institutional standard). Patients with residual invasive cancer will receive 4 cycles of the alternative chemotherapy to that received in the neoadjuvant setting. HER2 positive patients will receive concurrent trastuzumab and continue standard adjuvant trastuzumab. . Patients with biopsy proven axillary node metastases will undergo combined blue dye and radioisotope tracer guided sentinel lymph node biopsy (SLNB) and axillary lymph node clearance as a single procedure during breast surgery. Adjuvant endocrine and radiation therapy will be Institutional standard Endpoints: The primary endpoint is pathological complete response (no invasive disease in breast or axilla (pCR)). Secondary endpoints include: clinical and radiological response; rate of breast conservation; patient reported outcomes; safety, tolerability and long term outcomes. In patients with proven nodal involvement the false negative rate of a negative post treatment SLNB compared to axillary node clearance will be reported. Sample size and stratification: 1050 patients will be randomised in a 1:1 ratio stratified by nodal status, ER, HER2, and biomarker status (CEP-17 amplified or TOP2A amplified/deleted) vs normal (CEP-17 normal TOP2A normal). Analysis: The primary analysis will assess the interaction between the treatment effect and CEP17/TOP2A status to determine if a differential treatment effect exists between CEP17/TOP2A Normal and CEP17/TOP2A Abnormal patients. pCR will be analysed using a logistic regression model including co-variates for treatment, CEP17/TOP2A status and an interaction term of the two effects Sample size is based on the ability to detect an absolute improvement in pCR in the biomarker abnormal group from 21% in the TC treated group to 30% in the FEC treated group. With 90% power at 10% significance level. Contact Information: the ROSCO Trial Office ROSCO@trials.bham.ac.uk. Citation Format: Rea DW, Haywood L, Francis AM, Bowden SJ, Brookes CM, MacKenzie M, Cameron D, Stein R, Earl HM, Thomas J, Abraham J, Stanley A, Starczinski J, McGoldrick T, Treharne-Jones P, Billingham L, Bartlett JM. ROSCO: A randomised phase III, stratified CEP17/TOP2A biomarker trial of neo-adjuvant 5-flourouracil, epirubicin and cyclophosphamide vs docetaxel and cyclophosphamide chemotherapy. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT3-02-02.

Background: Neo-tAnGo, a National Cancer Research Network (NCRN) multicentre randomised neoadjuvant chemotherapy trial in early breast cancer, enroled 831 patients in the United Kingdom. We report a central review of post-chemotherapy histopathology reports-on the surgical specimens, to assess the presence and degree of response.Methods: A central independent two-reader review (EP and HME) of histopathology reports from post-treatment surgical specimens was performed. The quality and completeness of pathology reporting across all centres was assessed. The reviews included pathological response to chemotherapy (pathological complete response (pCR); minimal residual disease (MRD); and lesser degrees of response), laterality, the number of axillary metastases and axillary nodes, and the type of surgery. A consensus was reached after discussion.Results: In all, 825 surgical reports from 816 patients were available for review. Out of 4125 data items there were 347 discrepant results (8.4% of classifications), which involved 281 patients. These involved grading of breast response (169 but only 9 involving pCR vs MRD); laterality (6); presence of axillary metastasis (35); lymph node counts (108); and type of axillary surgery (29). Excluding cases with pCR, only 45% of reports included any comment regarding response in the breast and 30% in the axillary lymph nodes.Conclusion: We found considerable variability in the completeness of reporting of surgical specimens within this national neoadjuvant breast cancer trial. This highlights the need for consensus guidelines among trial groups on histopathology reporting, and the participation of histopathologists throughout the development and analysis of neoadjuvant trials.

12 Background: Breast cancer can be classified into molecular subtypes that have distinct survival patterns. The purpose of this study was i) to evaluate the prognostic significance of breast cancer subtypes in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing CMF with ECMF, and ii) to evaluate whether the subtypes were predictive of the added benefit of epirubicin in these trials. Methods: Tumor tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumors into six intrinsic subtypes (1). We used Cox regression to compare overall survival (OS), breast cancer specific survival (BSS) and relapse free survival (RFS) in the different subgroups. We also compared the effect of ECMF with CMF by subgroup. Results: IHC data were available for 1725 cases of whom 805 were Luminal 1-basal negative, 153 were Luminal 1-basal positive, 174 were Luminal 2, 192 were HER2-like, 230 were core basal phenotype and 171 were 5-negative phenotype. Median follow-up time was 7 years. The prognostic effects of the subtypes were similar to those reported for unselected breast cancer cases irrespective of adjuvant therapy (Blows FM, et al. PLoS Med 2010;75:e1000279.). In particular, the luminal 1-basal negative tumors were associated with the best prognosis in five years after surgery and the HER2-like tumors were associated with the poorest prognosis. ECMF has previously shown to be associated with a 33% relative risk reduction for OS compared to CMF (Poole CJ et al. N Engl J Med 2006;35518:1851-62.). There was little evidence for significant heterogeneity of effect by tumor subtype for any end point (OS P= 0.40, BSS P=0.53 RFS P=0.50). However, there was an observed trend towards the largest additional benefit from ECMF being in women with tumors of the 5-negative phenotype (OS HR=0.39 95% CI 0.21-0.73) and the smallest being in Luminal 1-basal negative tumors (OS HR=0.86 95% CI 0.64-1.16). Conclusions: In a clinical trial in which all patients received chemotherapy, we confirmed that breast cancer subtypes show distinct behaviour with differences in short and long term survival. The benefit of ECMF over CMF was statistically similar in all disease subtypes.

International organizations increasingly require estimates of forest parameters to monitor the state of and changes in forest resources, the sustainability of forest practices and the role of forests in the carbon cycle. Most countries rely on data from their national forest inventories (NFI) to produce these estimates. However, because NFI survey years may not match the required reporting years, techniques for updating NFI-based estimates are necessary.The main aim was to develop an unbiased method to update NFI estimates of mean growing stock volume (m3/ha) using models to predict annual plot-level volume change, and to estimate the associated uncertainties. Because the final large area volume estimates were based on plot-level model predictions rather than field observations, hybrid inference was necessary to accommodate both model prediction uncertainty and sampling variation. Specific objectives were to compare modelling approaches, to assess the utility of Landsat data for increasing model prediction accuracy, to select the most accurate method, and to compare model-based and design-based uncertainty components. For four monospecific forest types, data from the 2nd and 3rd Spanish NFI surveys together with site variables and Landsat images were used to construct models to predict NFI information for the year of the 4th NFI survey. Data from the 3rd and 4th surveys were used to assess the accuracy of the model predictions at both plot-level and large area spatial scales.The most accurate method used a set of three models: one to predict the probability of volume removals, one to predict the amount of removed volume, and one to predict gross annual volume. Incorporation of Landsat-based variables in the models increased prediction accuracy. Differences between large area estimates based on plot-level field observations for the 4th NFI survey and estimates based on the model predictions were minimal for all four forest types. Further, the standard errors of the estimates based on the model predictions were only slightly greater than standard errors based on the field observations. Thus, model predictions of plot-level growing stock volume based on field and satellite image data as auxiliary information can be used to update large area NFI estimates for reporting years for which spectral data are available but field observations are not. Finally, variances of means are under-estimated unless hybrid inferential methods are used to incorporate both model prediction uncertainty and sampling variation. For the two forest types for which the two sources of uncertainty were of the same order of magnitude, the under-estimation was non-negligible.