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Background: OP-1250 is a small molecule oral complete estrogen receptor antagonist (CERAN) that binds the ligand binding domain of the ER and completely blocks ER-driven transcriptional activity. CDK4/6 inhibitors in combination with endocrine therapy have improved progression free survival and overall survival for patients (pts) with metastatic breast cancer (MBC) in the first- and second-line settings. However, most patients will progress and newer combinations such as with OP-1250 may provide improved clinical outcome. OP-1250 potently inactivates both wild-type ER and mutant forms of ER. The latter confers ligand independent activity and is a mechanism of resistance to standard of care endocrine therapies. In preclinical studies, OP-1250 in combination with palbociclib demonstrated synergistic activity in models of wild-type ER and those containing ESR1 activating mutations, and in models of brain metastasis. A Phase 1/2 monotherapy study of OP-1250 is ongoing in MBC subjects who have received 1 or more prior endocrine therapies (NCT04505826). Monotherapy is well tolerated and the recommended phase 2 dose is 120 mg QD. The aim of this combination trial is to define the maximum tolerated dose (MTD), safety, tolerability, and pharmacokinetics (PK) of OP-1250 in combination with palbociclib. Methods: Eligibility criteria include pts with MBC or locally advanced breast cancer who have received no more than 1 prior line of endocrine therapy (prior CDK4/6 inhibitors and one line of chemotherapy are permitted) and measurable or non-measurable disease. Using a 3+3 design, cohorts are sequentially enrolled, and pts receive escalating doses of OP-1250 orally QD continuously in combination with 125 mg of palbociclib orally for 21 of 28 days. Pts are evaluable for dose limiting toxicities (DLTs) if >75% of both treatments were administered within the first 28-day treatment cycle. Blood is collected for PK on cycle 1 days 1, 2 and cycle 2 days 15, 16 for OP-1250 and cycle 1 day 15 for palbociclib. PK profiles, exposure parameters, and drug-drug interactions (DDIs) are assessed. Pts are monitored for adverse events (AE) and tumor assessments (RECIST 1.1) are conducted every two cycles. Results: As of July 7, 2022, 9 pts were evaluable for DLTs after 28 days of treatment in dose levels 30 mg, 60 mg, and 90 mg of OP-1250 in combination with palbociclib. No DLTs occurred at any of the dose levels. As of May 13, 2022, of the 7 pt safety data set, the most common Grade 1/2 treatment emergent adverse events (TEAE), which occurred in 2 patients, were nausea, gastroesophageal reflux, vomiting, and fatigue. Grade 3 neutropenia occurred in 4 pts and all were attributed to palbociclib by the investigator. No Grade 4 events were observed. OP-1250 was highly bioavailable and showed dose proportional exposure in combination with palbociclib. The single and multiple dose exposure of OP-1250 was consistent with that observed in the monotherapy study, indicating an absence of effect of palbociclib on OP-1250 PK. 90 mg steady-state evaluation is ongoing. Palbociclib concentrations at steady state did not demonstrate a meaningful difference from published exposure parameters for the three dose levels evaluated, indicating an absence of DDI. Conclusions: In the first three cohorts of OP-1250 and palbociclib, the combination was well tolerated and no DLTs occurred. There were no clinically significant DDIs observed between OP-1250 and palbociclib at the doses evaluated and exposure of each drug was consistent with observed monotherapy exposure levels. Dose escalation of OP-1250 continues to 120 mg, to be followed by dose expansion. Updated data will be presented. (NCT05266105) Citation Format: Arlene Chan, Daphne Day, Rina Hui, Nicole McCarthy, Rosalind Wilson, Demiana Faltaos, Morena Shaw, Caitlin Murphy. Preliminary data from a Phase 1b dose escalation study of OP-1250, an oral CERAN, in combination with palbociclib in patients with advanced and/or metastatic estrogen receptor (ER)-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-15.

Background: Breast cancer with low HER2 expression (HER2-low) is of high clinical relevance because of new therapeutic options with antibody-drug conjugates. We have recently shown in a large cohort from neoadjuvant clinical trials that HER2-low breast cancer has different molecular characteristics as well as different clinical outcomes compared to HER2-zero. Considering the positive correlation between HER2-low expression and hormone receptor positivity observed consistently in many investigations, we have extended our analysis to HR+ tumors from the post-neoadjuvant PenelopeB trial. In PenelopeB, patients with HR+ breast cancer and residual disease after neoadjuvant chemotherapy (NACT) were randomized to post-neoadjuvant palbociclib versus placebo in addition to endocrine therapy. We evaluated the molecular phenotype and clinical outcomes of HER2-low compared to HER2-zero patients. Methods: A total of 1250 patients were randomized, HER2 status was available for 1151 tumors from pretherapeutic core biopsy, determined mainly by local pathology, and from 1213 tumors from the post-NACT sample, determined as part of central pathology. For 1119 patients a paired HER2-status was both available. HER2-zero was defined as IHC0 and HER2-low-positive was defined as IHC1+ or IHC2+/ISH-. Gene expression analysis of 2549 genes using the HTG oncology biomarker panel was performed in 620 pretherapeutic biopsies and 780 post-NACT residual tumor samples, with 539 paired gene expression samples. Breast cancer subtypes were determined using the AIMS approach. Results: In pretherapeutic biopsies, 695 tumors (60%) were HER2-low and 457 (40%) were HER2-zero. A HER2-low status in the biopsy was significantly linked to improved iDFS (HR 0.76 (0.60-0.96; p=0.02). In residual tumors, 632 tumors (60%) were HER2-low and 581 (40%) were HER2-zero, without any prognostic impact of HER2 low status. In addition, a shift of HER2-low-status comparing core biopsy and residual tumor was observed in 415 (37%) of 1119 tumors. 161 (14%) had a shift from HER2-zero to HER2-low and 254 (23%) shifted from HER2-low to HER2-zero. A shift from HER2-zero to HER2-low in the post-NACT samples was significantly linked to reduced iDFS (HR 1.43 [95%CI 1.01-2.01]), p=0.04), compared to HER2-low group, while a shift from HER2-low to HER2-zero was associated with better iDFS compared to HER2-zero group, although not statistically significant (p=0.17). We did not observe a significant correlation of HER2-low status and AIMS molecular subtypes. In particular, the HER2-enriched (HER2E) subtype was assigned to only 4.3% of HER2-zero and 3.1% of HER2-low tumors. Significant iDFS differences were observed for HER2-low-status in combination with AIMS subtypes (lumB/basal/HER2E vs. lumA/normL; overall p-value < 0.0001) for both pretherapeutic biopsies and residual tumor. Patients with post-NACT HER2-low tumors had an improved survival in the subgroups of aggressive AIMS subtypes (lumB/basal/HER2E), but not in the less aggressive AIMs subtypes (lumA/normL), with a positive test for interaction (p=0.02). For the pre-NACT samples a similar, but non-significant trend was observed. We evaluated a total of 620 core biopsies for differences in gene expression comparing HER2-low and HER2-zero tumors. A total of 417 genes were statistically significantly different, but in a hierarchical clustering there was no clear separation of HER2-low and HER2-zero tumors. Conclusions: In the PenelopeB cohort of HR+ tumors, a HER2-low status in pretherapeutic core biopsies is related to improved disease-free survival, especially for those tumors that have a more aggressive intrinsic subtype. A shift of HER2-low status was observed before and after chemotherapy, indicating an adaptation of the pathway activity to therapy-induced stress, which might become relevant for future diagnostic and therapeutic approaches. Citation Format: Carsten Denkert, Miguel Martín, Michael Untch, Hervé R. Bonnefoi, Erik S. Knudsen, Seock-Ah Im, Angela DeMichele, Agnieszka Witkiewicz, Laura Van ’t Veer, Sung-Bae Kim, Harry D. Bear, Nicole McCarthy, Karen Gelmon, Frederik Marmé, José Ángel García-Sáenz, Nicholas Turner, Federico Rojo, Martin Filipits, Lesley-Ann Martin, Peter A. Fasching, Christian Schem, Catherine M. Kelly, Toralf Reimer, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Yuan Liu, Karsten Weber, Sivaramakrishna Rachakonda, Sibylle Loibl. HER2-06 Outcome analysis of HER2-zero or HER2-low hormone receptor-positive (HR+) breast cancer patients - characterization of the molecular phenotype in combination with molecular subtyping [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr HER2-06.

Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Assess the impact of an implementation intervention on student's physical activity, health-related quality of life (HRQoL) and on-task behaviour.A cluster-randomised controlled trial.Following baseline 61 eligible schools were randomised to a 12-month, implementation intervention to increase teacher scheduling of physical activity, or a waitlist control. Whole school-day and class-time physical activity of students from grades 2 and 3 (~ages 7 to 9) were measured via wrist-worn accelerometers and included: moderate-to-vigorous physical activity, light physical activity, sedentary behaviour and activity counts per minute. Children's health related quality of life (HRQoL) and out-of-school-hours physical activity was measured via parent-proxy surveys. Class level on-task behaviour was measured via teacher self-report surveys. Student and teacher obtained outcomes were measured at baseline and 12-month follow-up. Parent reported outcomes were measured at 12-month follow-up. Linear mixed models compared between group differences in outcomes. Differential effects by sex were explored for student and parent reported outcomes.Data from 2485 students, 1220 parents and500 teachers were analysed. There was no statistically significant between group differences in any of the outcomes, including accelerometer measured physical activity, out-of-school-hours physical activity, HRQoL, and on-task behaviour. A statistically significant differential effect by sex was found for sedentary behaviour across the whole school day (3.16 min, 95% CI: 0.19, 6.13; p = 0.028), with females illustrating a greater difference between groups than males.Only negligible effects on student physical activity were found. Additional strategies including improving the quality of teacher's delivery of physical activity may be required to enhance effects.

Background: In high-risk hormone-receptor (HR)+/HER2- BC patients germline (g) mutations can be found in approximately 14% in BRCA1/2 and in BRCA1/2 and other BC predisposition genes in 20% (Pohl-Rescigno E, et al. JAMA Oncol 2020). In metastatic BC CDK4/6 inhibitors may have greater activity in patients with a BRCA mutation detected in ctDNA (André F, et al. J Clin Oncol 2020). The PENELOPE-B trial did not to show an improved invasive disease-free survival (iDFS) by adding palbociclib to ET in high-risk HR+/HER2- BC (Loibl S, et al. J Clin Oncol 2021). Methods: Blood samples from 898 of 1250 PENELOPE-B patients were available. 445 patients were sampled following a case-cohort design (220 cases defined as patients with any event during follow-up and 225 randomly selected patients without any event [non-cases]) and analyzed for germline variants in BRCA1/2 and 16 non-BRCA1/2 cancer predisposition genes (ATM, BARD1, BRIP1, CDH1, CHEK2, FANCM, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53, XRCC2) by targeted next generation sequencing (NGS). The primary definition of mutational status was the prevalence of a pathogenic mutation (mt) in one or more analyzed BC predisposition genes. Statistical analyses for time-to-event endpoints (iDFS, distant disease-free survival [DDFS], and overall survival [OS]) were based on inverse probability weighting: weighted Cox proportional hazard models and Kaplan-Meier estimates were used. Results: 442 of 445 patients (placebo arm: 104 cases and 105 non-cases; palbociclib arm: 114 cases and 119 non-cases) were successfully analyzed for mutational status. A total of 42 (9.5%) patients (placebo arm: 9.1%; palbociclib arm: 9.9%) carried any mutation. 15 (3.4%) patients had a gBRCA1/2 mt (one of whom carried a gATM mt and one a gCHEK2 mt in addition to gBRCA2 mt) and 29 (6.6%) had mutations in one of the other BC predisposition genes (n=8 CHEK2, n=7 PALB2, n=5 ATM, n=2 RAD50, n=1 for BARD1, FANCM, MRE11A, RAD51C, RAD51D, TP53 and n=1 both RAD51D and BRIP1). The mutational status with respect to all genes analyzed showed no significant correlation to clinical baseline variables. With regard to gBRCA1 and gBRCA2 genes only, the mutational status significantly correlated with age but not with other clinical variables: all 15 (100%) gBRCA mt carriers were younger than 50 years compared to 238 (56%) wildtype (wt) patients (p=0.002). The iDFS rate after 3 years was 80.9% in patients with any mutation and 79.5% in patients without. Mutational status (mt vs. wt) based on all genes analyzed was not prognostic (iDFS: hazard ratio 1.015, 95%CI 0.558-1.784; DDFS: 0.970, 95%CI 0.521-1.758; OS: 0.768, 95%CI 0.274-1.615). Neither the mutated patients had a benefit from palbociclib treatment (palbociclib vs placebo; iDFS: hazard ratio 0.766, 95%CI 0.263-3.022; DDFS: 0.897, 95%CI 0.275-3.489; OS: 0.666, 95%CI 0.063-5.671) nor the wt patients (iDFS: hazard ratio 0.918, 95%CI 0.650-1.303; DDFS: 0.966, 95%CI 0.679-1.393; OS: 0.901, 95%CI 0.573-1.433); interaction tests for treatment arm/mutational status for all time-to-event endpoints were not statistically significant. Analysis in the subgroups of patients by gBRCA1/2 showed similar results but had less statistical power. Conclusions: In this case-cohort analysis of 442 patients enrolled in the PENELOPE-B trial, the detection of BC predisposition genes was lower than expected with 10%. This is probably due to the low rate of gBRCA1/2 carriers (3.4%), which could be influenced by the selection criteria of the trial. Patients with gBRCA1/2 or other BC disposition genes had a comparable outcome to non-carriers in the PENELOPE-B trial. Citation Format: Sibylle Loibl, Jan Hauke, Karen Gelmon, Frederik Marmé, Corinna Ernst, Miguel Martin, Michael Untch, Hervé Bonnefoi, Erik Knudsen, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Sung-Bae Kim, Harry Bear, Nicole McCarthy, Nicholas Turner, Agnieszka Witkiewicz, Federico Rojo, Peter A Fasching, José A García-Sáenz, Catherine M Kelly, Toralf Reimer, Masakazu Toi, Hope S Rugo, Carsten Denkert, Michael Gnant, Andreas Makris, Yuan Liu, Olga Valota, Bärbel Felder, Karsten Weber, Valentina Nekljudova, Eric Hahnen. Germline BRCA1/2 and other predisposition genes in high-risk early-stage HR+/HER2- breast cancer (BC) patients treated with endocrine therapy (ET) with or without palbociclib: A secondary analysis from the PENELOPE-B study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-36.

BackgroundThe cancer genomics field has embraced the advent of precision oncology, and vast volumes of data have been mined for biomarkers of drug actionability. While some cancers, such as lung cancer, have detailed panels of actionable genomic biomarkers, sequencing panels have been less useful in breast cancer given its large number of cancer driver genes mutated at a relatively low frequency. Furthermore, mutation signatures have potential to assist in identifying homologous recombination deficient tumours for targeting with PARP inhibitor therapy.Patients and MethodsTo investigate whether whole genome sequencing could benefit breast cancer patients we initiated the Q-IMPROvE (Queensland-IMplementation of PRecision Oncology in brEast cancer) prospective pilot study. We report the analysis of matched tumour and normal genomes of 28 high-risk breast cancer patients undergoing treatment in the neo-adjuvant setting.ResultsUsing whole genome sequencing, we detected actionable events that would otherwise not have been identified. A quarter of patients demonstrated a defect in homologous recombination DNA repair using the HRDetect and HRD scores. Germline variants of importance (BRCA1, CHEK2) were identified in two patients that did not meet clinical guidelines for germline genetic testing. Somatically,TP53andPIK3CAwere the most commonly mutated breast cancer driver genes.ConclusionsWe have demonstrated the benefit of whole genome sequencing of both the tumour and germline for breast cancer patients otherwise not meeting clinical criteria for genetic health referrals.

Palbociclib was approved in the United States in 2015 to treat estrogen receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). This study evaluated outcomes and safety in patients treated with palbociclib in Australia and India with hormone receptor-positive (HR+)/HER2- ABC before palbociclib became commercially available.Postmenopausal women (≥18 years) with HR+/HER2- ABC who were appropriate candidates for letrozole therapy received palbociclib 125 mg once daily for 21 days followed by 7 days off, and letrozole 2.5 mg once daily (continuous). Safety, tumor response, and patient-reported outcomes (Australian cohort) were evaluated.In total, 252 patients received palbociclib plus letrozole (Australia, n = 152; India, n = 100). More patients in the Australian versus Indian cohort had received prior chemotherapy (advanced/metastatic setting: 45.9% vs. 32.0%), endocrine therapy (advanced/metastatic setting: 63.2% vs. 54.3%), and advanced/metastatic therapies (61.8% vs. 31.0%). The most frequently reported all-grade palbociclib-related treatment-emergent adverse events were neutropenia (66.7%), fatigue (35.3%), and stomatitis (26.6%); grade 3/4 neutropenia was reported as palbociclib-related in 62.7% of patients. Febrile neutropenia was reported in six patients (2.4%). Eight patients (3.2%) discontinued because of an adverse event. The objective response rate was 19.4% (95% CI, 14.7%-24.9%) overall and 2.3% in Australian patients with ≥2 lines of prior therapy for metastatic disease. Patient-reported quality of life scores were maintained throughout the study.In an expanded access setting in Australia and India, palbociclib plus letrozole was well tolerated in patients with HR+/HER2- ABC, with a safety profile consistent with previous reports.

Background: Molecular plasticity of breast cancer is crucial for the development of therapy-resistant disease. In this investigation, we studied changes in molecular signatures between pretherapeutic (pre-Tx) and post-therapeutic (post-NACT) tumor samples from patients included in the PENELOPE-B (NCT01864746) trial. The phase III PENELOPE-B study did not show a significant benefit from palbociclib in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy (NACT) and at high-risk of relapse (CPS-EG score ≥3 or 2 and ypN+) (Loibl et al. JCO 2021). However, first translational investigations showed that a small number of patients with a luminal-B tumor subtype, based on absolute intrinsic molecular subtyping (AIMS, Paquet & Hallet, JNCI 2014) subtyping after NACT, had a numerical benefit from post-NACT palbociclib. We have therefore extended the analysis and included a cohort of paired pre-Tx and post-NACT samples. Methods: We investigated gene expression in pre-Tx (n=259) tumor tissue samples using the HTG EdgeSeq Oncology Biomarker Panel including 2549 genes (HTG Molecular Diagnostics Inc.); for the same patients the same panel on post-NACT residual tumor samples were available. The paired samples were selected based on a case-cohort approach. Based on 91 genes of this panel, the AIMS subtype was calculated. In addition, we performed exploratory biomarker analyses to identify genes and gene signatures with prognostic and predictive relevance. After completion of NACT, PENELOPE-B patients were randomized to palbociclib versus placebo in addition to standard endocrine therapy. Results: The prevalence of AIMS subtypes, in particular LumA vs LumB, changed in pre-Tx and post-NACT tumors. In the pre-Tx samples, 115 (44%) and 123 (47%) of tumors had LumA and LumB subtypes, respectively, as expected from a high-risk cohort. However, in the post-NACT samples, LumA tumors were predominant (n=183, 71%) over LumB (n=30; 12%). 78 (30%) and 6 (2%) tumors switched their subtype from LumB to LumA and LumA to LumB, respectively. For further analyses, we compared the groups of low proliferating (LumA and NormL) and high proliferating subtypes (LumB, BasalL and HER2E). In bivariable Cox regression analysis, the grouped pre-Tx and post-NACT AIMS subtypes were independent prognostic factors for iDFS: HR=1.85 (1.16-2.98, p=0.011) for pre-Tx LumB/BasalL/HER2E vs LumA/NormL and HR=2.18 (1.24-3.84, p=0.007) for post-NACT. Similar results were found when adjusted for prognostic clinical factors and for DDFS and OS endpoints although the pre-Tx subtype did not reach significance. These and further Cox models investigating interaction effects show that patients with tumors developing from high (pre-Tx) to low proliferation (post-NACT) had a higher iDFS risk compared to stable low proliferating tumors but a lower iDFS risk compared to stable high proliferating tumors. Neither in the pre-Tx LumB/BasalL/HER2E nor in the pre-Tx LumA/NormL subgroup a benefit from palbociclib was observed. Based on the results of the AIMS subtyping, we extended the exploratory analysis to identify genes that might be involved in the prognostic and predictive effects as well as genes driving the subtype switch. The analysis is ongoing and the relevant genes will be presented at the conference. Conclusions: Our findings show that the switch from high-risk molecular subtypes (in particular LumB) to low-risk subtypes (in particular LumA) is common in neoadjuvant therapy of luminal tumors. The adaptation of luminal high-risk tumors to therapy-induced stress is crucial for the clinical outcome and the results suggest that molecular defined tumor subtypes might not be as stable as originally thought. Citation Format: Carsten Denkert, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Agnieszka Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Nicole McCarthy, Thorsten Stiewe, Karen A. Gelmon, José A. García-Sáenz, Catherine M. Kelly, Toralf Reimer, Erik Knudsen, Nicholas Turner, Federico Rojo, Peter A. Fasching, Julia Teply-Szymanski, Yuan Liu, Masakazu Toi, Hope S. Rugo, Michael Gnant, Andreas Makris, Bärbel Felder, Karsten Weber, Sibylle Loibl. Molecular plasticity of luminal breast cancer and response to CDK 4/6 inhibition - The biomarker program of the PENELOPE-B trial investigating post-neoadjuvant palbociclib [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD2-04.

BACKGROUND To determine if a school-based physical activity (PA) intervention that supported primary school teachers to schedule PA during school hours impacted their own PA. METHODS A 2x2 factorial group cluster-randomised controlled trial was undertaken in 12 Australian primary schools. The nine-month intervention supported classroom teachers to increase scheduled weekly PA for their class via physical education, sport, Energisers and integrated lessons. Teachers' PA (n = 76) was measured at follow-up only using accelerometers (Actigraph GT3X or GT9X). Linear mixed models were used to estimate between-group differences in teachers' mean minutes of sedentary, light, moderate-to-vigorous-intensity physical activity (MVPA) across the school day and during class-time. RESULTS At follow-up, there were non-significant between-group differences favouring intervention teachers, compared to controls, for light PA (4.9 minutes, 95% CI: -6.3, 16.0; P = .33) and MVPA (0.4 minutes, 95% CI: -10.9, 11.6; P = .94) across the school day; although not favouring the intervention for sedentary behaviour (5.1 minutes, 95% CI: -11.4, 21.7; P = .48). Similar patterns were seen during class-time for light PA and sedentary time, but not for MVPA. CONCLUSIONS Supporting teachers with the scheduling of PA for their class may impact on their own PA. Fully powered studies are needed to better understand the impact of the intervention on teachers' PA. TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12616001228471 (http://www.anzctr.org.au/).

Aim: To assess the impact of a multistrategy intervention designed to improve teachers’ implementation of a school physical activity (PA) policy on student PA levels. Methods: A cluster-randomized controlled trial was conducted in 12 elementary schools. Policy implementation required schools to deliver 150 minutes of organized PA for students each week via physical education, sport, or class-based activities such as energizers. Schools received implementation support designed using the theoretical domains framework to help them implement the current policy. Results: A total of 1,502 children in kindergarten to grade 6 participated. At follow-up compared with control, students attending intervention schools had, measured via accelerometer, significantly greater increases in school day counts per minute (97.5; 95% confidence interval [CI], 64.5 to 130.4; P P P = .02) per school day. Teachers in intervention schools delivered significantly more minutes (36.6 min) of PA to their students at follow-up (95% CI, 2.7–70.5, P = .04). Conclusions: Supporting teachers to implement a PA policy improves student PA. Additional strategies may be needed to support teachers to implement activities that result in larger gains in student MVPA.

Background: To determine Australian primary school principals’, teachers’, and parents’ attitudes to changing school uniform policies to allow students to wear sports uniforms every day and to assess associations between participant characteristics and their attitudes. A secondary aim was to identify principals’ and teachers’ perceived barriers to uniform changes. Methods: Cross-sectional surveys of principals, teachers, and parents of children in grades 2 to 3 (age 7–10 y) from 62 Australian primary schools (Oct 2017–Mar 2018) were undertaken. Mixed logistic regression analyses assessed the associations between participant characteristics and attitudes toward uniform changes. Results: In total, 73% of the principals (38/52) who responded reported that their school only allowed children to wear a sports uniform on sports days. Overall, 38% of the principals (18/47), 63% of the teachers (334/579), and 78% of the parents (965/1231) reported they would support a policy that allowed children to wear daily sports uniforms. The most commonly reported barrier was the perception that sports uniforms were not appropriate for formal occasions. Conclusions: Although the majority of the principals were not supportive of a change to a daily sports uniform, the majority of the teachers and parents were. Strategies to improve principal support may be required if broader adoption of physical activity–supporting uniforms is to be achieved.

Background: The Penelope-B trial did not show improvement in invasive disease-free survival (iDFS) with the addition of palbociclib to endocrine therapy (ET) in patients with high-risk early breast cancer (BC) after neoadjuvant chemotherapy (NACT). Biomarkers may be able to identify subgroups of patients deriving benefit from Palbociclib and guide future studies. Estrogen-receptor (ER), progesterone-receptor (PgR) and Ki-67 might be helpful in identifying patients benefiting from palbociclib. Concordantly, tumors with elevated expression of Cyclin D1 and phosphorylated retinoblastoma protein (phospho-RB) may harbor more dependency on CDK4/6 and thus higher sensitivity to palbociclib. Methods: The percentage of positive ER and PgR cells and Ki-67 assessed in surgical specimens after NACT were combined to obtain the immunohistochemical score 3 (IHC3, Cuzick et al JCO 2011, low vs high based on the median IHC3 value). Cyclin D1 and phospho-RB Ser 807/811 immunoreactive (phospho-RB) scores were analyzed in residual tumors after NACT (range 0-12 each). Proportional hazard regression model was used to assess the predictive and prognostic value of IHC3 and treatment on iDFS. Subgroup analysis was performed according to BC intrinsic subtypes (luminal-A/normal-like, luminal-B/HER2-enriched/basal) and HER2-status (HER2 0, HER2 low). Cox/Fine-Gray regression was used to define the predictive and prognostic value of CyclinD1 (≤1, >1), phospho-RB (≤2, >2) as dichotomized and continuous variables on iDFS, distant DFS (DDFS), locoregional invasive recurrence-free interval (LRRFI) and overall survival (OS). Multivariate analyses (MVA) were adjusted for age (≤50 vs >50), Ki-67 (≤15 vs >15), region (non-Asian vs Asian), ypN (ypN0-1 vs ypN2-3), risk status (CPS-EG=2 ypN+ vs ≥3), cT (cT1-2 vs cT3-4), ypT (ypT0-2 vs ypT3-4), and grade (G1-2 vs G3). The MVA for IHC3 includes all the covariates above except Ki-67. p< 0.05 was defined as statistically significant. Results: Data for ER, PgR, Ki-67, HER2, Cyclin D1 and phospho-RB were available for 1250 patients. Overall, 98.9% of the patients had ER+ tumors, 75.0% PgR+, 52.2% had HER2 low, 25.5% Ki-67>15, 50% had IHC3 score higher than median, 93.9% had Cyclin D1 >1, 57.8% had phospho-RB >2. Patients with IHC3 score high had a worse iDFS compared to patients with IHC3 score low (MVA HR 2.28 95%CI (1.78-2.91), p< 0.0001). Patients with luminal-A/normal-like tumors and IHC3 low had an improved iDFS with the addition of palbociclib to ET (MVA HR 0.35 95%CI (0.14-0.90), test for interaction p=0.01). No difference was observed according to HER2 status. Cyclin D1>1 has no predictive value but is prognostic for better iDFS (MVA HR 0.62 95%CI (0.41-0.94), p=0.023), LRRFI (MVA HR 0.30 95%CI (0.15-0.63), p=0.001) and OS (MVA HR 0.50 95%CI (0.28-0.89), p=0.019). Similar results were obtained when Cyclin D1 was analysed as a continuous variable. Phospho-RB had neither predictive nor prognostic value. Phospho-RB highly correlates with Ki-67 (p< 0.001, Spearman correlation 0.248). Conclusions: Patients with high Cyclin D1 expression had a favorable prognosis independent of treatment arm, but patients with luminal-A/normal-like tumors and IHC3 low after NACT had an improved outcome when receiving palbociclib in addition to adjuvant ET. Theses exploratory studies suggest specific signatures/phenotypes could predict benefit from Palbociclib in high-risk early breast cancer. Citation Format: Erik S. Knudsen, Sivaramakrishna Rachakonda, Frederik Marmé, Miguel Martín, Michael Untch, Hervé R. Bonnefoi, Wolfgang D. Schmitt, Sung-Bae Kim, Harry D. Bear, Agnieszka Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Nicole McCarthy, Bruno V. Sinn, Karen Gelmon, José Ángel García-Sáenz, Catherine M. Kelly, Toralf Reimer, Nicholas Turner, Federico Rojo, Martin Filipits, Peter A. Fasching, Christian Schem, Lesley-Ann Martin, Yuan Liu, Masakazu Toi, Hope Rugo, Michael Gnant, Andreas Makris, Jenny Furlanetto, Karsten Weber, Carsten Denkert, Sibylle Loibl. Immunohistochemical markers and determinants of clinical response in the Penelope-B trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-06.

Limited evidence exists on the effects of weight loss on chronic disease risk and patient-reported outcomes in breast cancer survivors. Breast cancer survivors (stage I-III, body mass index 25–45 kg/m2) were randomized to a 12-month, remotely delivered (22 telephone calls, mailed material, optional text messages) weight loss (diet and physical activity) intervention (n = 79) or usual care (n = 80). Weight loss (primary outcome), body composition, metabolic syndrome risk score and components, quality of life, fatigue, musculoskeletal pain, menopausal symptoms, fear of recurrence, and body image were assessed at baseline, 6 months, 12 months (primary endpoint), and 18 months. Participants were 55 ± 9 years and 10.7 ± 5.0 months post-diagnosis, retention was 81.8% (12 months) and 80.5% (18 months). At 12-months, intervention participants had significantly greater improvements in weight (−4.5% [95%CI: −6.5,−2.5], p &lt, 0.001), fat mass (−3.3 kg [−4.8,−1.9], 0.001), metabolic syndrome risk score (−0.19 [−0.32,−0.05], p = 0.006), waist circumference (−3.2 cm [−5.5,−0.9], p = 0.007), fasting plasma glucose (−0.23 mmol/L [−0.44,−0.02], p = 0.032), physical quality of life (2.7 [0.7,4.6], p = 0.007, Cohen’s effect size (d) = 0.40), musculoskeletal pain (−0.5 [−0.8,−0.2], p = 0.003, d = 0.49), and body image (−0.2 [−0.4,−0.0], p = 0.030, d = 0.31) than usual care. At 18 months, effects on weight, adiposity, and metabolic syndrome risk scores were sustained, however, significant reductions in lean mass were observed (−1.1 kg [−1.7,−0.4], 0.001). This intervention led to sustained improvements in adiposity and metabolic syndrome risk.

Background To maximise their potential health benefits, school-based physical activity policies need to be implemented at scale. This paper describes the third in a sequence of trials that sought to optimise an effective strategy (PACE) to assist schools’ implementation of a physical activity policy. Specifically, it aimed to determine the probability that a multi-strategy intervention adapted to reduce in-person contact (Adapted PACE) was “as good as” the original intervention (PACE) in increasing the weekly minutes of structured physical activity implemented by classroom teachers. Methods A noninferiority cluster randomised controlled trial was undertaken with 48 primary schools in New South Wales, Australia. Schools were randomised to receive PACE or a model with adaptations made to the delivery modes (Adapted PACE). Teachers’ scheduled minutes of weekly physical activity was assessed at baseline (Oct 2018-Feb 2019) and 12-month follow-up (Oct-Dec 2019). The noninferiority margin was set at − 16.4 minutes based on previous data and decision panel consensus. A linear mixed model analysed within a Bayesian framework was used to explore noninferiority between the two PACE models. A cost minimisation analysis was conducted from the health service provider perspective, using the Australian dollar (AUD). Results The posterior estimate for the between group difference at follow-up was − 2.3 minutes (95% credible interval = − 18.02, 14.45 minutes). There was an estimated 96% probability of Adapted PACE being considered noninferior (only 4% of the posterior samples crossed the noninferiority margin of − 16.4 minutes). That is, the minutes of physical activity implemented by teachers at Adapted PACE schools was not meaningfully less than the minutes of physical activity implemented by teachers at PACE schools. The mean total cost was AUD$25,375 (95% uncertainty interval = $21,499, $29,106) for PACE and AUD$16,421 (95% uncertainty interval = $13,974, $19,656) for Adapted PACE; an estimated reduction of AUD$373 (95% uncertainty interval = $173, $560) per school. Conclusions It is highly probable that Adapted PACE is noninferior to the original model. It is a cost-efficient alternative also likely to be a more suitable approach to supporting large scale implementation of school physical activity policies. Trial registration Retrospectively registered with the Australian New Zealand Clinical Trials Registry (ACTRN12619001229167).

IntroductionMulticomponent school-based physical activity (PA) interventions can improve students’ cardiorespiratory fitness (CRF) and PA. Due to the complex nature of such interventions when delivered at scale their effect sizes markedly reduce. Modifying student school uniforms, so that they are more PA enabling, may be a simple intervention that could enhance student health. The primary aim of this trial is to assess the effectiveness of an activity enabling uniform intervention (shorts, polo shirt and sports shoes) in improving children’s CRF.Methods and analysisA cluster randomised controlled trial will be conducted in 24 primary schools in New South Wales (NSW), Australia. Schools will be randomly allocated to either intervention or usual practice following baseline data collection. Active WeAR Everyday intervention schools will allow students in grades 4–6 (aged approx. 9–12 years) to wear their existing sports uniform (shorts, polo shirt and sports shoes) every day. To avoid any financial cost to students they will be provided with two additional sports shirts and one pair of shorts. Study outcomes will be assessed at baseline and 9 months postbaseline. The primary outcome is students’ CRF measured using the 20 m multistage fitness test. Secondary outcomes include students’: mean daily steps and steps/minute measured via accelerometer, quality of life, mental well-being and perceived PA self-efficacy. The acceptability, feasibility and cost of the intervention will be assessed. Analyses will be performed using an intention-to-treat framework. Linear mixed effects regression models will be used to assess intervention effects on the primary outcome at follow-up. Planned exploratory analyses will examine effects by subgroups (eg, gender).Ethics and disseminationThis study has received approval from Hunter New England Local Health District Human Ethics Committee (2020/ETHO2602) the University of Newcastle, Human Research Ethics Committee (H-2021-0013), NSW Department of Education (SERAP: 2020387) and Catholic School Offices.Trial registration numberACTRN12621000201875.

ObjectivesTo assess if a multi-strategy intervention effectively increased weekly minutes of structured physical activity (PA) implemented by classroom teachers at 12 months and 18 months.MethodsA cluster randomised controlled trial with 61 primary schools in New South Wales Australia. The 12-month multi-strategy intervention included; centralised technical assistance, ongoing consultation, principal’s mandated change, identifying and preparing school champions, development of implementation plans, educational outreach visits and provision of educational materials. Control schools received usual support (guidelines for policy development via education department website and telephone support). Weekly minutes of structured PA implemented by classroom teachers (primary outcome) was measured via teacher completion of a daily log-book at baseline (October–December 2017), 12-month (October–December 2018) and 18-month (April–June 2019). Data were analysed using linear mixed effects regression models.ResultsOverall, 400 class teachers at baseline, 403 at 12 months follow-up and 391 at 18 months follow-up provided valid primary outcome data. From baseline to 12-month follow-up, teachers at intervention schools recorded a greater increase in weekly minutes of PA implemented than teachers assigned to the control schools by approximately 44.2 min (95% CI 32.8 to 55.7; pConclusionA multi-strategy intervention increased mandatory PA policy implementation. Some, but not all of this improvement was maintained after implementation support concluded. Further research should assess the impact of scale-up strategies on the sustainability of PA policy implementation over longer time periods.Trial registration numberAustralian New Zealand Clinical Trials Registry (ACTRN12617001265369).

Background Many school-based physical activity (PA) interventions are complex and have modest effects when delivered in real world contexts. A commonly reported barrier to students’ PA, particularly among girls, are uniforms that are impractical (e.g. tunic/dress and black leather shoes). Modifying student uniforms may represent a simple intervention to enhance student PA. The primary aim of this trial was to assess the impact of a PA enabling uniform intervention (shorts, polo shirt and sports shoes) on girls’ moderate-to-vigorous physical activity (MVPA) and total PA i.e. counts per minute (cpm). Methods A cluster randomized controlled trial was undertaken in 42 primary schools in New South Wales, Australia. Schools were randomized on one school day to the intervention group, where students wore a PA enabling uniform (their sports uniform) or a control group, where students wore their usual traditional uniform. Student PA was measured using wrist-worn Actigraph GT3X and GT9X accelerometers. Linear mixed models controlling for student characteristics were used to examine the effects of the intervention.. Results Of the 3351 eligible students, 2315 (69.1%) had parental consent and 2180 of these consenting students participated (94.2%) of which 1847 (84.7%) were included in the analysis. For the primary aim the study found no significant differences between girls at schools allocated to the intervention relative to the control on change in MVPA (0.76 min, 95% CI − 0.47 to 1.99, p = 0.22) or cpm (36.99, 95% CI − 13.88 to 87.86, p = 0.15). Exploratory analysis revealed small effects for a number of findings, including significant reduction in sedentary activity (− 1.77, 95% CI − 3.40 to − 0.14, p = 0.035) among all students at schools allocated to the intervention, and non-significant improvements in girls’ light intensity PA (1.47 min, 95% CI − 0.06 to 3.00, p = 0.059) and sedentary activity (− 2.23 min; 95% CI − 4.49 to 0.02, p = 0.052). Conclusion The findings suggests that the intervention may yield small improvements in some measure of PA and require substantiation in a larger RCT with longer-term follow-up. The inclusion of additional intervention components may be required to achieve more meaningful effects. Trial registration The trial was prospectively registered with Australian New Zealand Clinical Trials Register ACTRN12617001266358 1st September 2017.

Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma, is associated with a low 5-year survival and harsh treatment side effects, underscoring an urgent need for therapy. The unfolded protein response (UPR) is activated in response to endoplasmic reticulum (ER) stress, where three ER stress receptors, IRE1, PERK and ATF6, aim to restore cellular homeostasis. The UPR is pro-tumourigenic in many cancers. In this study, we investigate basal UPR activity in RMS. Basal activation of IRE1 and PERK was observed in RMS cell lines, which was diminished upon addition of the IRE1 RNase inhibitor, MKC8866, or PERK inhibitor, AMGEN44. UPR inhibition caused a reduction in cell viability, cell proliferation and inhibition of long-term colony formation in both subtypes of RMS. Alveolar RMS (ARMS) subtype was highly sensitive to IRE1 inhibition, whereas embryonal RMS (ERMS) subtypes responded more markedly to PERK inhibition. Further investigation revealed a robust activation of senescence upon UPR inhibition. For the first time, the UPR is implicated in RMS biology and phenotype, and inhibition of UPR signalling reduces cell growth, suggesting that the UPR may be a promising target in RMS.

The Kolliker-Fuse Nucleus (KF) has been widely investigated for its contribution to "inspiratory off-switch" while more recent studies showed that activation of the Parabrachial Nucleus (PBN) shortened expiratory duration. This study used an adult, in vivo, decerebrate rabbit model to delineate the contribution of each site to inspiratory and expiratory duration through sequential block of glutamatergic excitation with the receptor antagonists 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX) and d(-)-2-amino-5-phosphonopentanoic acid (AP5). Glutamatergic disfacilitation caused large increases in inspiratory and expiratory duration and minor decrease in peak phrenic activity (PPA). Hypoxia only partially reversed respiratory rate depression but PPA was increased to >200 % of control. The contribution of PBN activity to inspiratory and expiratory duration was equal while block of the KF affected inspiratory duration more than expiratory. We conclude that in the in vivo preparation respiratory rate greatly depends on PBN/KF activity, which contributes to the "inspiratory on- "and "off-switch", but is of minor importance for the magnitude of phrenic motor output.

The aim of the current study was to examine the association between Australian primary school children’s objectively measured in-school-hours weekly physical activity (PA) and their health-related quality of life (HRQoL). A cross-sectional study of 1128 Grade 2 and 3 children, aged 7–9 years, from 62 primary schools was conducted in New South Wales, Australia between October 2017 and April 2018. Children’s PA was assessed via an accelerometer worn for five days during school hours. Their parents completed a telephone interview, answering demographic, child HRQoL and out-of-school-hours PA questions. Children’s in-school-hours PA was classified as total PA and moderate-to-vigorous PA (MVPA). HRQoL scores were aggregated and reported at the high construct level domains (Total Quality of Life (Total HRQoL), Physical and Psychosocial Health Summary Scores). Multiple linear mixed regression analyses accounting for clustering were conducted to evaluate the association between children’s in-school-hours weekly PA and their HRQoL. After adjusting for potential confounders, significant positive associations were found between children’s in-school-hours weekly total PA and Total HRQoL (0.62 units, 95% CI: 0.29; 0.94, p < 0.001), Physical (0.71 units, 95% CI: 0.38; 1.04, p ≤ 0.001) and Psychosocial (0.58 units, 95% CI: 0.19; 0.97, p = 0.004) scores, with a stronger association observed between average weekly MVPA than average weekly total PA. There were also positive associations between PA and HRQoL for each sex when analysed separately. Our findings demonstrate a positive association between children’s objectively-measured in-school-hours PA and parent-reported child HRQoL, strengthening evidence supporting the continued implementation of school-based PA programs for broader health outcomes.

Cyclin-dependent kinase (CDK4/6) inhibitors in combination with endocrine therapy are currently the optimal first line treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) non-amplified metastatic breast cancer (MBC). However, not all patients benefit from this treatment and all patients will inevitably progress. Identifying therapeutic strategies in this setting is therefore of immediate clinical importance. We present an overview of the mechanisms of resistance to CDK4/6 inhibitors and review potential biomarkers that may guide therapy selection. We also discuss the use of CDK4/6 inhibitors in the context of non-HR-positive/HER2-non-amplified breast cancer and in combination with therapies other than endocrine therapy.

Resistance to endocrine therapy is a significant therapeutic challenge in the treatment of women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy have been shown to improve progression free survival, overall response rate and clinical benefit rate in women with HR+ HER2- metastatic breast cancer compared with endocrine therapy alone. This review examines the clinical evidence to support the use of CDK4/6 inhibitors in first and second line settings. Practical guidance is provided for the use of CDK4/6 inhibitors, including tolerability data, monitoring requirements and management of key toxicities for each of the available agents.

Objectives Industry-supported decision impact studies demonstrate that Oncotype Dx (ODX) changes treatment recommendations (TR) in 24-40% of hormone receptor+/HER2- patients. ODX is not reimbursed by third-party payers in Australia, potentially resulting in more selective use. We sought to evaluate the impact of self-funded ODX on TRs. Methods Data collected included demographics, tumor characteristics, indication for ODX and pre- and post-recurrence score (RS) TR. Primary endpoint was frequency of TR change and associations with TR change were sought. Results Eighteen physicians contributed 382 patients (median age 54). A total of 232 (61%) of tumors were T1 and were grade 1, 2 and 3 in 49 (13%), 252 (66%) and 79 (21%). A total of 257 (67%) were node negative. Assay indications were: confirm need for chemotherapy (CT) (36%), confirm omission of CT (40%) and genuine equipoise (24%). RS was low (≤17) in 55%, intermediate (18-31) in 36% and high (≥32) in 9%. Thirty-eight percent of patients had TR change post-ODX. Sixty-five percent of patients recommended CT pre-ODX changed to hormone therapy alone (HT)-more likely if lower grade and if ER and/or PR > 10%. Fourteen percent of patients with pre-ODX TR for HT added CT-more likely if ER and/or PR ≤10% and if Ki67 > 15% Overall, TR for CT decreased from 47% to 24%. Conclusion Patient-funded ODX changed TRs in 38% of patients, de-escalating 65% from CT to HT and adding CT to 14% of those recommended HT. These changes were greater than an industry-funded study suggesting that physicians can identify situations where the assay may influence decisions.

Research consistently indicates that schools fail to implement mandatory physical activity policies. This review aimed to describe factors (barriers and facilitators) that may influence the implementation of school physical activity policies which specify the time or intensity that physical activity should be implemented and to map these factors to a theoretical framework. A systematic search was undertaken in six databases for quantitative or qualitative studies published between 1995-March 2016 that examined teachers', principals' or school administrators' reported barriers and/or facilitators to implementing mandated school physical activity policies. Two independent reviewers screened texts, extracted and coded data from identified articles using the Theoretical Domains Framework (TDF). Of the 10,346 articles identified, 17 studies met the inclusion criteria (8 quantitative, 9 qualitative). Barriers and facilitators identified in qualitative studies covered 9 and 10 TDF domains respectively. Barriers and facilitators reported in quantitative studies covered 8 TDF domains each. The most common domains identified were: ‘environmental context and resources’ (e.g., availability of equipment, time or staff), ‘goals’ (e.g., the perceived priority of the policy in the school), ‘social influences’ (e.g., support from school boards), and ‘skills’ (e.g., teachers' ability to implement the policy). Implementation support strategies that target these factors may represent promising means to improve implementation of physical activity policies and increase physical activity among school-aged children. Future studies assessing factors that influence school implementation of physical activity policies would benefit from using a comprehensive framework to help identify if any domains have been overlooked in the current literature. Registration This review was prospectively registered with PROSPERO (CRD42016051649) on the 8th December 2016.

Despite the benefits of factorial designs in quantifying the relative benefits of different school-based approaches to prevent unhealthy weight gain among students, few have been undertaken. The aims of this 2 × 2 cluster randomized factorial trial was to evaluate the impact of a physical activity and nutrition intervention on child weight status and quality of life. Twelve primary schools in New South Wales, Australia randomly allocated to one of four groups: (i.) physical activity (150 min of planned in-school physical activity); (ii.) nutrition (a healthy school lunch-box); (iii.) combined physical activity and nutrition; or (iv.) control. Outcome data assessing child weight and quality of life were collected at baseline and 9-months post-baseline. Within Grades 4–6 in participating schools, 742 students participated in anthropometric measurements, including child body mass index (BMI) and waist circumference, at baseline and follow-up. Findings indicated that students that received the nutrition intervention had higher odds of being classified in the BMI category of underweight/healthy weight (OR 1.64 95%CI 1.07, 2.50; p = 0.0220), while those who received the physical activity intervention reported a lower waist circumference (mean difference − 1.86 95%CI -3.55, −0.18; p = 0.030). There were no significant effects of the nutrition or physical activity intervention on child BMI scores or child quality of life, and no significant synergistic effects of the two interventions combined. Future research assessing the longer-term impact of both intervention strategies, alone and combined, is warranted to better understand their potential impact on child health. Trial registration Australian Clinical Trials Registry ACTRN: ACTRN12616001228471.

This study aimed to quantify, and examine grade level (Grade Kindergarten-2 vs. 3–6) and sex differences in the daily minutes of moderate-to-vigorous physical activity (MVPA) of primary school children, and the proportion of children meeting MVPA recommendations, across the school day and in break times. Consenting children in Kindergarten to Grade 6 from 12 Catholic primary schools within the Hunter region of New South Wales, Australia (February-April 2017) wore accelerometers during school hours (approx. 9am-3 pm) for five school days. Differences in student physical activity by Grade (Kindergarten-2; Grade 3–6) and sex were analysed using regression mixed modelling for the whole school day, during class time and break time. Valid data was available for 1862 students. Mean (SD) minutes of MVPA were consistently higher for Grade K-2 compared to Grade 3–6 students respectively, 37.02 (12.4) and 32.6 (12.2) across the school day; 20.4 (8.4) and 15.3 (7.6) minutes within breaks. Over the whole school day 69.7% of Grade K-2 and 54.1% of Grade 3–6 met the recommended 30 min of MVPA. Boys had higher MVPA than girls and a higher proportion of boys met MVPA recommendations than girls with 68.9% and 52.4% over whole school day and 6.43% and 0.98% respectively during break times. A large percentage of Australian children are not meeting physical activity guidelines whilst at school, with declining levels of physical activity from Grade K-2 to Grade 3–6 especially evident in girls.

Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics.

Background Pertuzumab combined with trastuzumab and docetaxel is the standard first-line therapy for HER2-positive metastatic breast cancer, based on results from the phase III CLEOPATRA trial. PERUSE was designed to assess the safety and efficacy of investigator-selected taxane with pertuzumab and trastuzumab in this setting. Patients and methods In the ongoing multicentre single-arm phase IIIb PERUSE study, patients with inoperable HER2-positive advanced breast cancer (locally recurrent/metastatic) (LR/MBC) and no prior systemic therapy for LR/MBC (except endocrine therapy) received docetaxel, paclitaxel or nab-paclitaxel with trastuzumab [8mg/kg loading dose, then 6mg/kg every 3weeks (q3w)] and pertuzumab (840mg loading dose, then 420mg q3w) until disease progression or unacceptable toxicity. The primary end point was safety. Secondary end points included overall response rate (ORR) and progression-free survival (PFS). Results Overall, 1436 patients received at least one treatment dose (initially docetaxel in 775 patients, paclitaxel in 589, nab-paclitaxel in 65; 7 discontinued before starting taxane). Median age was 54years; 29% had received prior trastuzumab. Median treatment duration was 16months for pertuzumab and trastuzumab and 4months for taxane. Compared with docetaxel-containing therapy, paclitaxel-containing therapy was associated with more neuropathy (all-grade peripheral neuropathy 31% versus 16%) but less febrile neutropenia (1% versus 11%) and mucositis (14% versus 25%). At this preliminary analysis (52 months' median follow-up), median PFS was 20.6 [95% confidence interval (CI) 18.9–22.7] months overall (19.6, 23.0 and 18.1months with docetaxel, paclitaxel and nab-paclitaxel, respectively). ORR was 80% (95% CI 78%–82%) overall (docetaxel 79%, paclitaxel 83%, nab-paclitaxel 77%). Conclusions Preliminary findings from PERUSE suggest that the safety and efficacy of first-line pertuzumab, trastuzumab and taxane for HER2-positive LR/MBC are consistent with results from CLEOPATRA. Paclitaxel appears to be a valid alternative taxane backbone to docetaxel, offering similar PFS and ORR with a predictable safety profile. ClinicalTrials.gov NCT01572038.

Since Inhibitor of Apoptosis (IAP) proteins have been implicated in cellular adaptation to endoplasmic reticulum (ER) stress, we investigated the regulation of ER stress-induced apoptosis by small-molecule second mitochondria-derived activator of caspase (Smac) mimetics that antagonize IAP proteins. Here, we discover that Smac mimetic suppresses tunicamycin (TM)-induced apoptosis via resolution of the unfolded protein response (UPR) and ER stress. Smac mimetics such as BV6 selectively inhibit apoptosis triggered by pharmacological or genetic inhibition of protein N-glycosylation using TM or knockdown of DPAGT1, the enzyme that catalyzes the first step of protein N-glycosylation. In contrast, BV6 does not rescue cell death induced by other typical ER stressors (i.e., thapsigargin (TG), dithiothreitol, brefeldin A, bortezomib, or 2-deoxyglucose). The protection from TM-triggered apoptosis is found for structurally different Smac mimetics and for genetic knockdown of cellular IAP (cIAP) proteins in several cancer types, underlining the broader relevance. Interestingly, lectin microarray profiling reveals that BV6 counteracts TM-imposed inhibition of protein glycosylation. BV6 consistently abolishes TM-stimulated accumulation of ER stress markers such as glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) and reduces protein kinase RNA-like ER kinase (PERK) phosphorylation and X box-binding protein 1 (XBP1) splicing upon TM treatment. BV6-stimulated activation of nuclear factor-κB (NF-κB) contributes to the resolution of ER stress, since NF-κB inhibition by overexpression of dominant-negative IκBα superrepressor counteracts the suppression of TM-stimulated transcriptional activation of CHOP and GRP78 by BV6. Thus, our study is the first to show that Smac mimetic protects from TM-triggered apoptosis by resolving the UPR and ER stress. This provides new insights into the regulation of cellular stress responses by Smac mimetics. ispartof: CELL DEATH & DISEASE vol:10 issue:3 ispartof: location:England status: published

In an attempt to improve children’s physical activity levels governments have introduced policies specifying the minimum time schools are to schedule physical activity each week. Despite this, the majority of schools in many jurisdictions fail to implement these policies. This study will assess the effectiveness of a multi-component implementation strategy on increasing the minutes of planned physical activity scheduled by primary school teachers each week. A cluster randomised controlled trial will be conducted in 62 primary schools in the Hunter New England region of New South Wales, Australia. Schools will be randomly allocated to receive either a multi-component implementation strategy that includes; obtaining executive support, training in-school champions, provision of tools and resources, implementation prompts, reminders and feedback; or usual practice. The study will employ an effectiveness-implementation hybrid design, assessing both policy implementation and individual (student) behavioural outcomes. The primary trial outcome of mean minutes of physical activity scheduled by classroom teachers across the school week will be measured via teacher log-book at baseline and approximately 12 and 18 months post baseline. A nested evaluation of the impact of policy implementation on child physical activity will be undertaken of students in Grades 2 and 3. Analyses will be performed using an intention to treat framework. Linear mixed effects regression models will be used to assess intervention effects on the primary outcome at both follow-up periods. This study will be the one of the first well powered randomised trials internationally to examine the impact of an implementation strategy for a physical activity policy in primary schools and will address a fundamental research translation gap. Given the dearth of research, the findings will be important in informing future implementation efforts in this setting. ANZCTR ACTRN12617001265369 version 1 registered 1st September 2017.

Smac mimetics that deplete cellular inhibitor of apoptosis (cIAP) proteins have been shown to activate Nuclear Factor-kappa B (NF-κB). Here, we report that Smac mimetic-mediated activation of NF-κB contributes to the rescue of cancer cells from tunicamycin (TM)-triggered apoptosis. The prototypic Smac mimetic BV6 activates non-canonical and canonical NF-κB pathways, while TM has little effect on NF-κB signaling. Importantly, ectopic expression of dominant-negative IκBα superrepressor (IκBα-SR), which inhibits canonical and non-canonical NF-κB activation, significantly reversed this BV6-imposed protection against TM. Similarly, transient or stable knockdown of NF-κB-inducing kinase, which accumulated upon exposure to BV6 alone and in combination with TM, significantly counteracted BV6-mediated inhibition of TM-induced apoptosis. Interestingly, while cIAP2 was initially degraded upon BV6 treatment, it was subsequently upregulated in an NF-κB-dependent manner, as this restoration of cIAP2 expression was abolished in IκBα-SR-overexpressing cells. Interestingly, upon exposure to TM/BV6 apoptosis was significantly increased in cIAP2 knockdown cells. Furthermore, NF-κB inhibition partially prevented BV6-stimulated expression of Mcl-1 upon TM treatment. Consistently, Mcl-1 silencing significantly inhibited BV6-mediated protection from TM-induced apoptosis. Thus, NF-κB activation by Smac mimetic contributes to Smac mimetic-mediated protection against TM-induced apoptosis.

Aim Obesity is associated with poor prognosis and risk of treatment side-effects in breast cancer survivors. This pilot study assessed the feasibility, acceptability, safety and efficacy of a telephone-delivered weight loss intervention, among women (BMI 25–40 kg/m2) following treatment for stage I–III breast cancer, on weight loss (primary outcome), quality of life and treatment-related side-effects (vs usual care). Methods Ninety women (mean ± SD age: 55.3 ± 8.7years; BMI: 31.0 ± 4.3 kg/m2; 15.9 ± 2.9 months postdiagnosis), recruited from a state-based cancer registry, were randomized to a weight loss (diet and physical activity) intervention (n = 45) or usual care (n = 45). Data collected at baseline and 6 months included weight, body composition, quality of life, fatigue and body image. Acceptability and satisfaction were assessed in intervention participants. Results Oncologists provided consent to contact 82.6% of patients, with 84.1% of those women contacted and eligible consenting to participate. Compared with usual care, mean weight loss was significantly greater in the intervention arm (−3.1 kg [95% CI, −5.4 to −0.7]; −3.7% baseline weight [95% CI, −6.6 to −0.9]), as were reductions in fat mass (−2.1 kg [95% CI, −4.2 to −0.1]) and waist circumference (−4.0 cm [95% CI, −6.6 to −1.3]). No other statistically significant intervention effects were observed. Participants were highly satisfied with the intervention overall and it is timing in relation to diagnosis/treatment. One reported adverse event (musculoskeletal injury) was attributable to the intervention. Conclusions This weight loss intervention was feasible, acceptable, safe and effective for women 1–2 years after a breast cancer diagnosis. The effect of weight loss on quality of life and treatment-related side-effects should be examined further in fully-powered studies.

Endocrine therapy for the treatment of hormone receptor positive, HER2 negative, metastatic breast cancer is continually evolving. We systematically reviewed phase 2 and 3 randomized controlled trials (RCTs) of agents used in this setting to assess the effectiveness and safety of these agents for postmenopausal women. Across the 32 studies in more than 10,000 patients, the greatest improvement in progression-free survival (PFS) was seen with the addition of a cyclin-dependent kinase (CDK)4/6 inhibitor to standard endocrine therapy. Treatment with a mammalian target of rapamycin (mTOR) inhibitor, phosphoinositol-3-kinase (Pi3K) inhibitor, vascular endothelial growth factor (VEGF) inhibitor and with a selective estrogen receptor degrader (SERD) also showed benefit in PFS for selected trials. Overall survival (OS) improved with the use of mTOR inhibitors and a SERD; however, studies were not powered for an OS endpoint. Encouraging results from early studies of histone deacetylase (HDAC) and B-cell lymphoma (BCL2) inhibitors are yet to be confirmed in phase III clinical trials. Study discontinuation rates and toxicity-related deaths were highest with VEGF inhibitors in combination with endocrine therapy, limiting their use in hormone receptor positive breast cancer. CDK4/6 inhibitors and mTOR inhibitors appeared to have activity in both first and second line settings, but required additional monitoring for common toxicities. The activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors was limited to the first-line setting and treatment discontinuation rates were higher than with mTOR inhibitors and SERDs. Overall, PFS benefit appears to be greatest when agents acting on CDK4/6, mTOR and Pi3K pathways, and SERDs are added to standard endocrine therapy. If these early results persist in further studies, these data are likely to change the way we treat hormone receptor positive, HER2 negative metastatic breast cancer. In the follow-up article to this review, we will consider the potential future treatment options for these patients.

Endocrine therapy is an established and effective treatment strategy for hormone receptor positive metastatic breast cancer. The clinical utility of endocrine therapy is lost over time due to evolving changes in tumor biology and the development of endocrine resistance. Many agents targeting the intracellular signaling pathways associated with endocrine resistance are in development. Encouraging early results have been seen for agents which directly target the estrogen receptor (ER), inhibitors of co-signaling pathways, inhibitors of ER chaperones, ER antagonists able to inhibit mutated or otherwise activated ERs, and modulators of histone acetylation restoring synthesis of ER signaling components. Following our systematic review of treatments with established benefits in this supplement, we review some of the more promising new strategies for overcoming endocrine resistance, looking at the impact on disease control and quality of life for women with hormone receptor positive, HER2 negative breast cancer. We also examine the biomarkers that may guide selection of the best therapy for the individual.

Background: An Australian industry-funded decision impact study demonstrated that Oncotype Dx (ODX) changed treatment recommendations (TR) in 24% of hormone receptor+/HER2- patients. ODX is available in Australia, but is self-funded by patients (∼USD 4175), so its use is limited. We sought to evaluate the impact of self-funded ODX on TRs. A high proportion of TR changes would imply a benefit to the broader community if ODX testing were available to all appropriately selected patients. Methods: All Australian physicians who had ordered >5 ODX were invited to participate. Data collected included demographics, tumor characteristics, indication for ODX (confirm need for chemotherapy (CT), confirm omission of CT, or genuine equipoise). Pre- and post Recurrence Score (RS) TRs (CT recommended versus hormone therapy alone (HT)) were also collected. The primary endpoint was the frequency and predictors of TR change. Relationships between categorical variables were assessed using Chi2 test and logistic regression analysis determined factors associated with TR change post-ODX. Results: 382 patients with median age 54 (range 31-76) were included. 18 physicians contributed a median of 17 (5-87) patients. Tumor characteristics were: T1 232 (61%); ≥T2 150 (39%); grade 1 49 (13%), grade 2 252 (66%) and grade 3 79 (21%) and Ki67>15% in 131/231 (49%). 257 (67%) were node negative (N0). Assay indications were: confirm need for CT in 36%, confirm omission of CT in 40% and genuine equipoise in 24%. RS was low in 55%, intermediate in 36% and high in 9%. Of 355 patients with a TR recorded pre-ODX, 38% had TR change post-ODX. 109/168 patients (65%) recommended CT pre-ODX changed to HT alone, and this was more likely if lower grade (82.1% vs 50.8% p15% (27.5% vs 9.8% p=0.015). Overall, TR for CT decreased from 47% to 24%. Influence of adverse prognostic factors (defined as ≥T2, grade 3, ER and/or PR Number of "adverse factors"01234N0 (n=234)Number of patients90116244 RS median (range)16 (0-40)17 (0-41)26 (5-52)31 (22-40) TR change19/90 (21%)45/116 (39%)6/24 (25%)2/4 HT to CT7/71 (10%)10/61 (16%)2/11 (18%)1/2 CT to HT12/19 (63%)35/55 (64%)4/13 (31%)1/2 N+ (n=114)Number of patients22424181 RS median (range)14 (5-34)16 (0-38)14 (0-32)24 (12-50)39 TR change11/22 (50%)21/42 (50%)25/41 (42%)3/8 (38%)0/1 HT to CT3/13 (23%)3/14 (21%)0/12NANA CT to HT8/9 (89%)18/28 (64%)25/29 (86%)3/7 (43%)0/1 Conclusions: Patient self-funded ODX changed TRs in 38%. 65% who would have been recommended CT pre-ODX were spared CT post-ODX, suggesting that traditional histopathological indications for CT in ER+ patients has led to many receiving CT unnecessarily. Where the pre ODX TR was HT alone, only 14% changed to adding CT, suggesting that the indication was reassurance that CT could be omitted. Consideration could be made for third party funding in select patient groups. Citation Format: Chin-Lenn L, Segelov E, De Boer R, Marx G, Hughes TM, McCarthy N, White S, Foo S, Rutovitz J, Della Fiorentina S, Jennens R, Antill Y, Tsoi D, Cronk M, Lombard J, Kiely BE, Chirgwin J, Gorelik A, Mann GB. Indications for, and impact of oncotype DX on adjuvant treatment recommendations when third party funding is unavailable. [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 P5-15-02.