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BACKGROUND: Approximately 50% of newly diagnosed breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as Oncotype DX® have identified pts with reduced distant metastasis and without benefit from chemotherapy, freeing patients from excess toxicity. Also, these genomic assays are prognostic of local-regional recurrence (LRR). The de-escalation of therapy is of interest to pts, providers, and payers. Low risk, as identified by Oncotype and Mammaprint®, is associated with low LRR after BCS and breast radiotherapy (RT). METHODS: We hypothesize that BCS alone is non-inferior to BCS plus RT for ipsilateral breast recurrence (IBR) and breast preservation in women intending appropriate endocrine therapy (ET) for stage 1 (ER and/or PR positive, HER2-negative, with an Oncotype DX Recurrence Score [RS] of ≤18) breast cancer. Stratification is by age (< 60; ≥60), tumor size (≤1 cm; >1-2cm), and RS (< 11; 11-18). Pts are randomized post-BCS to Arm 1 with breast RT using standard methods (hypo- or conventional-fractionated whole breast RT with or without boost, APBI) plus 5 years of ET (tamoxifen or AI) or Arm 2 with 5 years of ET (tamoxifen or AI) alone. The specific regimen of ET in both arms is at the treating physician’s discretion. Eligible pts are stage 1: pT1 (2 cm), pN0, age ≥50 to < 70 years, s/p BCS with negative margins (no ink on tumor), s/p axillary nodal staging (SNB or ALND), ER and/or PR positive (ASCO/CAP), HER2-negative (ASCO/CAP), and have an Oncotype DX RS of ≤18 (diagnostic core biopsy or resected specimen). Primary endpoint is IBR. Secondary endpoints are breast conservation rate, invasive in-breast recurrence, recurrence-free interval, distant disease-free survival, overall survival, patient-reported breast pain, patient-reported worry about recurrence, and adherence to ET. We assume a clinically acceptable difference in IBR of 4% at 10 years to judge omission of RT as non-inferior (10-year event-free survival for RT group is 95.6% versus 91.6% for the omission-of-RT group). The study is designed to be able to detect non-inferiority with 80% power and a one-sided α=0.025, and assuming that there would be a ramp-up in accrual in the first two years of the study (leveling off in Years 3-5), 1,670 (835 per arm) patients are required to be randomized. Conservative loss to follow-up is 1% per year. Some of the T1a pts screened will have Oncotype DX scores >18, making them ineligible for the study. In the accrual process, pts will be required to register (1,714 patients) to ensure that our final randomized cohort is 1,670 pts. Accrual as of 6-30-2022 is 169 screened and 147 randomized. Contact information: Protocol: CTSU member website: https://www.ctsu.org. NRG Oncology Pgh Clinical Coordinating Dpt: 1-800-477-7227 or ccdPGH@NRGOncology.org. Support: U10CA180868, -180822, UG1CA189867. NCT04852887. Citation Format: Julia White, Reena S. Cecchini, Eleanor E. Harris, Eleftherios (Terry) Mamounas, Daniel Stover, Patricia A. Ganz, Reshma Jagsi, Carmen Bergom, Valérie Théberge, Mahmoud B. El-Tamer, Richard Zellars, Dean A. Shumway, Guang-Pei Chen, Stewart J. Anderson, Thomas B. Julian, Norman Wolmark, Wendy Rea. A phase III trial evaluating De-escalation of Breast Radiation (DEBRA) following breast-conserving surgery (BCS) of stage 1, HR+, HER2-, RS ≤18 breast cancer: NRG-BR007 [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 OT1-12-01.

Background: The primary aim of the NRG Oncology/NSABP B-52 clinical trial was to test if estrogen deprivation (ED) administered concomitantly with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP), would improve the pCR rate in patients with HER2+/ER+ early breast cancer. A numerical increase in the pCR rate was observed with ED (46.1% v 40.9%), but the difference was not statistically significant. The purposes of this study were to assess the association of sTILs in pretreatment biopsies with pCR in the total population and within the molecular subtypes of breast cancer and to assess changes in sTILs between pre- and on-treatment biopsies. The secondary endpoints of recurrence-free interval (RFI) and overall survival (OS) are currently being analyzed and will be presented along with association of these endpoints with sTILs in pretreatment biopsies in the total cohort and within molecular subtypes. Methods: Scoring of sTILs on routine H&E slides from pre-treatment biopsies with sufficient tumor from 249 of the 315 patients (79%) entered in B-52 were performed by one of two pathologists (SKM, RSM). Both pathologists scored sTILs on a subset of 64 patients to document concordance. Wilcoxon two-sided test, box and whisker plots, and forest plots were used to assess associations with pCR. Molecular subtypes were determined utilizing RNA-seq data and AIMS subtyping method. On-treatment biopsies were available in 46 patients and were scored and compared to paired baseline samples. Results: Good concordance between pathologists was established with an inter-pathologist difference of ˂20% difference between scores in 92% of cases. sTILs in pre-treatment samples were associated with pCR across both arms of the trial (p=0.0074) and in the TCHP+ED arm (p=0.033), but not in the TCHP arm (p=0.093). The distribution of intrinsic subtypes was 34% luminal B, 29% luminal A, 28% HER2E, 5.8% normal, and 2.7% basal, with no significant differences between the arms. Presence of sTILs showed a trend for association with pCR in HER2E pre-treatment samples (p=0.054) but not in non-HER2E (p=0.75). Similarly, sTILs were associated with pCR in non-luminal tumors (p=0.055) but not in luminal tumors (p=0.44). Stratification by treatment arm and menopausal status suggested sTILs are associated with pCR in premenopausal women treated with TCHP (OR: 1.04, 95% CI=1.00-1.09). Interestingly, decreases in the sTIL scores with treatment were associated with pCR in the TCHP+ED arm (p=0.01) but not in the TCHP arm. Analysis of RFI and OS on B-52 is ongoing and will be presented along with associations of sTILs with intrinsic subtypes for RFI and OS. Conclusions: Although a positive correlation between sTILs and pCR was observed, the clinical utility appears limited because of the extensive overlap in the TIL scores between pCR and non-pCR tumors. Significance for a positive association of sTILs with pCR was detected in HER2E but not in luminal tumors. This may be due to the molecular differences of the subtypes, or the make-up of the TILs, or both. The association of a decrease in sTILs with TCHP+ED treatment needs further investigation. The small number of samples is a limitation of the study; however, the B-52 protocol specified that the collection of the B-52 samples was for the purpose of exploratory analysis. Our results highlight the molecular heterogeneity of the HER+/ER+ patient population and suggests that different treatment strategies may be required in future treatment regimens for this patient population. Support: NSABP Foundation; BCRF; 3U10CA180868-03S2, -180822; UG1CA189867; Genentech. Citation Format: Katherine L. Pogue-Geile, Sai K. Maley, Rim S. Kim, Ying Wang, Roberto Salgado, Corey Lipchik, Huichen Feng, Reena S. Cecchini, Samuel A. Jacobs, Ashok Srinivasan, Eleftherios (Terry) Mamounas, Charles E. Geyer Jr, Priya Rastogi, C. Kent Osborne, Soonmyung Paik, Norman Wolmark, Peter C. Lucas, Mothaffar Rimawi. Association of stromal tumor infiltrating lymphocytes (sTILs) in pretreatment biopsies in different molecular subtypes of HER2+/ER+ breast cancer: Assessment of NRG Oncology/NSABP B-52 [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 P1-04-10.

BackgroundThe cardiotoxic effects of doxorubicin, trastuzumab, and other anticancer agents are well known, but molecular genetic testing is lacking for the early identification of patients at risk for therapy-related cardiac toxicity.MethodsUsing the Agena Bioscience MassARRAY system, we genotyped TRPC6 rs77679196, BRINP1 rs62568637, LDB2 rs55756123, RAB22A rs707557, intergenic rs4305714, LINC01060 rs7698718, and CBR3 rs1056892 (V244M) (previously associated with either doxorubicin or trastuzumab-related cardiotoxicity in the NCCTG N9831 trial of anthracycline-based chemotherapy ± trastuzumab) in 993 patients with HER2+ early breast cancer from the NSABP B-31 trial of adjuvant anthracycline-based chemotherapy ± trastuzumab. Association analyses were performed with outcomes of congestive heart failure (N = 29) and maximum decline in left ventricular ejection fraction (LVEF) using logistic and linear regression models, respectively, under an additive model with age, baseline LVEF, and previous use of hypertensive medications as covariates.ResultsAssociations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, TRPC6 rs77679196 and CBR3 rs1056892 were significantly associated with congestive heart failure, p < 0.05, with stronger associations observed in patients treated with chemotherapy only (no trastuzumab) or in the combined analysis of all patients relative to those patients treated with chemotherapy + trastuzumab.ConclusionsTRPC6 rs77679196 and CBR3 rs1056892 (V244M) are associated with doxorubicin-induced cardiac events in both NCCTG N9831 and NSABP B-31. Other variants previously associated with trastuzumab-related decline in LVEF failed to replicate between these studies.

Perspective on This Article from Body Mass Index and the Risk for Developing Invasive Breast Cancer among High-Risk Women in NSABP P-1 and STAR Breast Cancer Prevention Trials

Perspectives on this Article from Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer

High body mass index (BMI) has been associated with an increased risk for breast cancer among postmenopausal women. However, the relationship between BMI and breast cancer risk in premenopausal women has remained unclear. Data from two large prevention trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) were used to explore the relationship between baseline BMI and breast cancer risk. The analyses included 12,243 participants with 253 invasive breast cancer events from the Breast Cancer Prevention Trial (P-1) and 19,488 participants with 557 events from the Study of Tamoxifen and Raloxifene (STAR). Both studies enrolled high-risk women (Gail score ≥ 1.66) with no breast cancer history. Women in P-1 were pre- and postmenopausal, whereas women in STAR (P-2) were all postmenopausal at entry. Using Cox proportional hazards regression, we found slight but nonsignificant increased risks of invasive breast cancer among overweight and obese postmenopausal participants in STAR and P-1. Among premenopausal participants, an increased risk of invasive breast cancer was significantly associated with higher BMI (P = 0.01). Compared with BMI less than 25, adjusted HRs for premenopausal women were 1.59 for BMI 25 to 29.9 and 1.70 for BMI 30 or more. Our investigation among annually screened, high-risk participants in randomized, breast cancer chemoprevention trials showed that higher levels of BMI were significantly associated with increased breast cancer risk in premenopausal women older than 35 years, but not postmenopausal women. Cancer Prev Res; 5(4); 583–92. ©2012 AACR.

Background: The NRG Oncology/NSABP B-52 neoadjuvant clinical trial was conducted to test if the addition of estrogen deprivation (ED) would improve the pCR rate in HER2+/ER+ breast cancer patients (pts) treated with docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP). A numerical increase in pCR rate was observed with ED (46.1% v 40.9%), but the difference was not statistically significant. We have previously quantitated T cells (CD8, FOXP3), macrophages (CD68), and immune checkpoint proteins (PD-1, PD-L1) with multiplex immunofluorescence in B-52 and shown that CD68 and FOXP3 cells were associated with pCR but not CD8 cells. Our purpose was to determine the associations of FCGR genotypes and immune cells with pCR. Methods: A single baseline, pre-treatment FFFPE tissue section per case (N=181) was used to perform a 7-plex multiplex immunofluorescence procedure using opal fluorophores for staining. The Vectra Pathology System and inForm analysis software (Akoya Biosciences) was used for imaging and quantitation of CD8, CD68, FOXP3, PD-1, and PD-L1 cells in both the tumoral and stromal regions. Stromal data is reported here. Favorable- and unfavorable- FcGγR genotypes for FCGR2A-131H/R and FCGR3A-158V/F alleles were determined via the Sequenom MassARRAY iPLEX platform. Rates of pCR with pts with 1 or 2 favorable alleles was compared to pts who were homozygous for the unfavorable allele. Within each genotype, Wilcoxon rank sum test was used to test the association of markers with pCR and within each treatment. Results: No significant association of FCGR2A and 3A alleles with pCR was detected in the entire B-52 cohort, however, among pts with favorable FCGR genotypes (FCGR2A-131-HH, or H/R, FCGR3A-158- VV, or VF HR) the median value of the % CD68 cells was significantly higher in tumors that achieved pCR v those that did not (p=0.0004, p=0.0006), respectively. In pts who were homozygous for the FCGR2A or FCGR3A unfavorable alleles, there was no significant difference in the median values of the % of CD68 cells between pCR and no-pCR tumors. Further stratification of tumors by treatment showed that pts with an FCGR2A or FCGR3A favorable genotype and whose tumors achieved pCR had a higher median value of CD68 only in the TCHP + ED arm (p=0.0007, p=0.0003), respectively and not in the TCHP arm (p=0.059; p=0.21). Higher levels of PD-L1 were associated with pCR in pts with FCGR3A- favorable genotypes, but higher levels of FOXP3 were associated with pCR regardless of genotype. In contrast to the other cell types, higher PD-1 or CD8 cells showed no association with genotypes. Conclusions: This is an exploratory study examining the potential role of ADCP in HER2+/ER+ breast cancer and supports the notion that ADCP may be one mechanism that promotes the elimination of tumor cells in a subset of pts in the neoadjuvant setting. Tumors that achieve pCR have higher % of CD68 cells, in pts with favorable FCGR2A and 3A genotypes than pts who do not. However, in pts with unfavorable FCGR3A or FCGR2A genotypes there was no difference in the median CD68 levels in pCR v no-pCR tumors. When tumors were further stratified by CD68 levels, FCGR3A genotypes, and treatment, the association of pCR in tumors with high CD68 and FCGR3A favorable genotypes was seen only in the TCHP+ED arm. This may indicate that ED may improve pCR rates in some tumors with more macrophages and favorable genotypes. Macrophages are known to have estrogen receptors, and estrogen has been shown to promote the alternative activation of macrophages, potentially dampening down the immune response. Thus, one could speculate that ED may block the estrogen-induced alternative activation of macrophages, allowing the classically activated macrophages to phagocytize tumor cells. Support: BCRF, U10CA180868 & Admin Sup, U24CA196067, Genentech, NSABP Foun. Citation Format: Katherine L Pogue-Geile, Ying Wang, Huichen Feng, Corey Lipchick, Patrick Gavin, Rim S Kim, Reena S Cecchini, Samuel A Jacobs, Ashok Srinivasan, Sandra M Swain, Eleftherios Mamounas, Charles E Geyer, Jr, Priya Rastogi, Peter C Lucas, C. Kent Osborne, Soonmyung Paik, Norman Wolmark, Mothaffar F Rimawi. Potential role of the antibody-dependent cellular phagocytosis (ADCP) in tumors achieving pCR in NRG Oncology/NSABP B-52 [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 P1-07-04.

Roughly 50% of newly diagnosed breast cancer is stage 1, the majority being ER/PR positive, HER2- negative. Genomic assays such as Oncotype DX® have identified patients with reduced distant metastasis and lack of chemotherapy benefit, allowing patients to avoid excess toxicity. These genomic assays have been shown to be prognostic for local-regional recurrence (LRR). The de-escalation of therapy is of interest to patients, providers, and payers. Low risk, as identified by both the use of Oncotype and Mammaprint® is associated with low LRR after lumpectomy and breast radiotherapy. TRIAL DESIGN: In the DEBRA trial, we hypothesized that breast-conserving surgery (BCS) alone is non-inferior to BCS plus radiotherapy for in-breast cancer control and breast preservation in women intending appropriate endocrine therapy for stage 1 (ER and/or PR-positive, HER2-negative, and Oncotype DX Recurrence Score [RS] low) breast cancer. Stratification is by age (1-2 cm), and RS 18, making them ineligible for the study. An extra step in the accrual process will require us to register 1,714 patients to ensure our final randomized cohort is 1,670 patients. Accrual: Screen 1,714 to randomize 1,670 into the study. Contact information: Protocol: CTSU member website: https://www.ctsu.org. NRG Oncology Pgh Clinical Coordinating Dpt: 1-800-477-7227 or ccd@nsabp.org. Support: U10CA180868, U10CA180822. NCT04852887. Citation Format: Julia White, Stewart J Anderson, Eleanor ER Harris, Eleftherios P Mamounas, Daniel G Stover, Patricia A Ganz, Reshma Jagsi, Reena S Cecchini, Carmen Bergom, Valerie Theberge, Mahmoud El-Tamer, Rich C Zellars, Dean A Shumway, Guang-Pei Chen, Thomas B Julian, Norman Wolmark. Evaluating de-escalation of breast radiation (DEBRA) following lumpectomy for breast conservative treatment of stage 1, hr+, HER2-, RS ≤18 breast cancer: NRG-BR007 a phase III trial [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 P3-18-04.

Adjuvant chemotherapy improves breast cancer survival but is associated with bothersome short- and long-term toxicity. Factors associated with toxicity, especially subacute toxicity up to 2 years following chemotherapy, have not been fully elucidated. The NRG Oncology/NSABP B-30 clinical trial compared 3 different doxorubicin-, cyclophosphamide-, and docetaxel-based chemotherapy regimens given over 3–6 months. Patients with hormone receptor-positive breast cancer received subsequent adjuvant endocrine therapy. From baseline through 24 months, 2156 patients completed questionnaires serially. We used multivariable probabilistic index models to identify factors associated with acute (>0–12 months) and subacute (>12–24 months) difficulties with pain, cognition, vasomotor symptoms, and vaginal symptoms. For all symptom domains, presence of symptoms prior to chemotherapy initiation were associated with symptoms in the subacute period (all p

Issue Infodemics (i.e., overflow of information in physical and digital spaces that makes it difficult for people to make good health decisions) can undermine emergency response, but capacity for infodemic management has been limited in countries thus far. Specifically, there is a need to build capacities in the field with practical and scalable tools. Description of the problem WHO has developed tools and trainings to quickly build and enhance infodemic management (IM) capacity at the country-level, such as tools for rapid generation of IM insights and a framework for conducting landscape analyses to establish sustainable IM capacities. These were developed in collaboration with multidisciplinary experts who provided feedback. We sought to create tools that can be a basis for introducing evidence-generation in health information systems to inform emergency preparedness and response, and mainstream methods into routine infodemic diagnostics activities. Results The tools and trainings provide a comprehensive framework for diagnosing and addressing infodemics, such as a public health taxonomy to guide digital intelligence analysis and integrated analysis methods for generation of actionable insights. Additionally, the landscape analysis framework outlines steps for assessing strategic needs and assets for routinizing IM functions as part of existing public health systems and programs. Lessons The tools and trainings will be deployed in the field to evaluate utility. Feedback from users in the global WHO infodemic manager community will be systematically captured. Key messages • Field responders need practical tools and trainings that guide quick infodemic response during health emergencies. • These tools and trainings can be used to diagnose and intervene on infodemics, even in settings where infodemic insights units are not yet established.

An Acoustic Doppler Current Profiler (ADCP) moored at the deep-sea ANTARES neutrino telescope site near Toulon, France, measured downward vertical currents of amplitudes up to 0.03 m s−1 in spring 2006. The currents were accompanied by enhanced levels of acoustic reflection by a factor of about 10 and by horizontal currents reaching 0.35 m s−1. These observations coincided with high levels of bioluminescence detected by the telescope. Although during winter 2006 deep dense-water formation occurred in this area, episodes of high levels of suspended particles and large vertical currents continuing into the summer are not direct evidence of this process. It is hypothesized that the main process allowing for particles to be moved across the entire water column (2500 m) within a few days, is local convection, triggered by small-mesoscale phenomena, such as meanders including a bipolar vortex, linked with boundary current instabilities.

The ENUBET project intends to reduce the flux related systematics in an accelerator neutrino beam to the 1% level by monitoring associated charged leptons produced in a narrow band meson beam. Large angle leptons from kaon decays are measured in an instrumented decay tunnel, while low angle muons from pions can be monitored after the hadron dump. A key element of the project is the design of a meson transfer line with conventional magnets that maximizes the yield of K+ and π+, while minimizing the total length to reduce meson decays in the not instrumented region. The transfer line is optimized for 8.5 GeV/c mesons with a momentum bite of 5-10%, considering various proton drivers and target designs and it is based on conventional quadrupoles and dipoles and provides a large bending angle that can ensure a reduced background from the untagged neutrino component at the neutrino detector. The ENUBET Collaboration presented at NuFact2021 the latest design of the hadron beam line, the performance of the positron tagger prototypes tested at CERN beamlines, a full simulation of the positron reconstruction chain and the expected physics reach.

PURPOSE The US National Cancer Institute Moonshot initiative calls for improving analysis and reporting of toxicity to inform treatment tolerability. We used existing clinician-reported adverse event (AE) and patient-reported outcome (PRO) questionnaire data from the randomized, double-blind NSABP B-35 clinical trial to explore reasons for anastrozole and tamoxifen discontinuation. METHODS Postmenopausal women with ductal carcinoma in situ treated with breast-conserving therapy were randomly assigned to anastrozole or tamoxifen for 5 years. The primary outcome for this analysis was time to treatment discontinuation. AEs were collected every 6 months post–random assignment from all 3,104 participants and summarized using the Toxicity Index (TI). PRO data were collected at baseline and every 6 months from 1,194 participants. Univariate and multivariable analyses of time to treatment discontinuation were performed using Cox regression models with TIs and PROs as time-dependent covariates. RESULTS Of 3,046 analyzed participants, 869 (28.5%) discontinued treatment prematurely. In multivariable analysis, when both baseline PROs and on-treatment AEs were considered, thrombosis and arthralgia AEs were associated with discontinuation of both tamoxifen and anastrozole; additional AEs associated with discontinuation varied by drug. In addition, baseline pain interference, hot flashes, and unhappiness were associated with tamoxifen discontinuation (n = 589; overall Harrell's C-statistic 0.686 [95% CI, 0.640 to 0.732]); no baseline PROs were associated with anastrozole discontinuation (n = 589; overall Harrell's C-statistic 0.656 [95% CI, 0.630 to 0.681]). When only baseline PROs were examined, pain interference, hot flashes, and unhappiness were associated with shorter time to discontinuation of tamoxifen; only hot flashes were associated with discontinuation of anastrozole. CONCLUSION Analysis of AEs using the TI yielded important insights into reasons for discontinuation of endocrine therapy that was enhanced by the addition of PRO baseline and treatment-emergent symptoms.

Background. Several randomized trials demonstrated aromatase inhibitors (AI) superiority in terms of disease-free survival (DFS) compared to tamoxifen treatment for postmenopausal hormone receptor-positive breast cancer (BC) patients. Anyway, AI toxicity profile is a concern due to estrogen suppression. Pivotal trials demonstrated a significant bone mineral density (BMD) loss due to AI, with a consistent 5-year risk of bone fractures, thus impacting on patients' quality of life. Bisphosphonates represent an effective treatment in postmenopausal osteoporosis fractures prevention. However, an adequate patient's selection for adjuvant bisphosphonates treatment during AI endocrine therapy is still a challenge. Final results of BONADIUV trial presented at San Antonio Breast cancer Symposium in 2016 showed that treatment with ibandronate, as compared to placebo, significantly improved BMD change in osteopenic women treated with adjuvant AI, and consistently protected patients' bone loss. We present the secondary 5-year analysis on survival outcomes of the trial. Patients and methods. The BONADIUV trial is a single-blind, randomized, placebo-controlled phase 2 study designed to evaluate the impact of ibandronate treatment on BMD in osteopenic women taking AI. Between January 2011 and May 2014, 171 osteopenic patients (lumbar spine [LS] and/or trochanter -1< T-score Results. At the database cutoff time for the present analysis on May 4, 2018, median follow up was 63.3 months (mean 61.2; range 2.7-87.3) for whole series, 64.9 months (range 33.8-84.0) for the placebo arm, and 62.2 months (range 24.2-87.3) for the ibandronate arm. Ten patients in the placebo group and 17 patients in the ibandronate group withdrew the allocated arm before any follow up data collection, and so were excluded from the analysis, performed on 144 patients (72 patients per arm). At the database cutoff time, the OS rate was 97.2% in the placebo group and 100% in the ibandronate arm. We observed four loco-regional relapse (three in the placebo arm, one in the ibandronate arm; p=0.33), three distant metastases (none in the placebo arm, three in the ibandronate arm; p=0.075), and three contralateral BC (one in the placebo arm, two in the ibandronate arm; p=0.65). The number of iDFS events did not differ between groups: four in the placebo group and six in the ibandronate group (p=0.56). Up to data cutoff, two deaths have occurred; none in the placebo arm and two in the ibandronate arm (p=0.15). The OS rate did not differ between arms. Conclusions. The secondary analysis of survival outcomes showed no difference between arms in terms of OS and iDFS rates. Further large investigations and mature follow-up from the published ones are awaited. Citation Format: Meattini I, Scotti V, Desideri I, Saieva C, Visani L, Salvestrini V, Cecchini S, De Feo ML, Mariotti M, Olmetto E, Delli Paoli C, Francolini G, Bernini M, Orzalesi L, Sanchez L, Nori J, Bianchi S, Livi L. Oral ibandronate for osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: secondary 5-year survival outcomes analysis of the single-center phase 2 BONADIUV trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-16-04.

TPS613 Background: Approximately 50% of newly diagnosed breast cancers are stage 1, with the majority being ER/PR-positive, HER2-negative. Genomic assays such as the Oncotype DX® have identified patients (pts) with reduced risk of distant metastasis and without benefit from chemotherapy added to endocrine therapy, freeing them from excess toxicity. Genomic assays are also recognized as prognostic for in-breast recurrence (IBR) after BCS and could similarly allow de-escalation of adjuvant radiotherapy (RT). Reducing overtreatment is of interest to pts, providers, and payers. Methods: We hypothesize that BCS alone is non-inferior to BCS plus RT for in-breast recurrence and breast preservation in women intending endocrine therapy (ET) for stage 1 breast cancer (ER &/or PR positive, HER2-negative with an Oncotype DX Recurrence Score [RS] of ≤18). Stratification is by age (1-2cm), & (RS 18, making them ineligible for the study. In the accrual process, pts will be required to register (1,714 pts) to ensure that our final randomized cohort is 1,670 pts. Current accrual (2-2-2022) is 52 screened and 45 randomized. Support: U10CA180868, -180822, NCT04852887. Clinical trial information: NCT04852887.

The NRG Oncology/NSABP B-47 menstrual history (MH) study examined trastuzumab effects on menstrual status and associated circulating reproductive hormones. MH was evaluated by questions related to hysterectomy, oophorectomy, and reported menstrual changes. Pre/perimenopausal women were assessed at entry, 3, 6, 12, 18, 24, 30, and 36 months. Consenting women had estradiol and FSH measurement at entry, 3, 6, 12, 18, and 24 months. Logistic regression determined predictors of amenorrhea and hormone levels at 12, 24, and 36 months. Between 2/8/2011 and 2/10/2015, 3270 women with node-positive/high-risk node-negative HER2-low breast cancer were enrolled. There were 1,458 women enrolled in the MH study; 1231 consented to baseline blood samples. Trastuzumab did not contribute to a higher amenorrhea rate. Amenorrhea predictors were consistent with earlier studies; however, to our knowledge, this is the largest prospective study to include serial reproductive hormone measurements to 24 months and clinical amenorrhea reports to 36 months. These data can help to counsel patients regarding premature menopause risk.

The ENUBET ERC project, also included in the CERN Neutrino Platform as NP06/ENUBET, is developing a new neutrino beam based on conventional techniques in which the flux and the flavor composition are known with unprecedented precision (O (1%)). Such a goal is accomplished monitoring the associated charged leptons produced in the decay region of the ENUBET facility. Positrons and muons from kaon decays are measured by a segmented calorimeter instrumenting the walls of the decay tunnel, while muon stations after the hadron dump can be used to monitor the neutrino component from pion decays. Furthermore, the narrow momentum width (O (10%)) of the neutrino energy on an event by event basis, thanks to its correlation with the radial position of the interaction at the neutrino detector. ENUBET is therefore an ideal facility for a high precision neutrino cross-section measurement at the GeV scale, that could enhance the discovery potential of the next-generation of long baseline experiments. It is also a powerful tool for testing the sterile neutrino hypothesis and to investigate possible non-standard interactions.

Pesticides are frequently applied to agricultural activities to improve harvest, in terms of yield and product quality. Useful tools for ecotoxicological studies of marine ecosystems are based on biomarker application on bioindicator key fish species. The main aim of the present study was to detect the potential presence of pesticides in a polluted coastal marine environment, namely Milazzo Gulf, situated in the north eastern coast of Sicily (Italy), by measuring the enzymatic activities of the ecotoxicological biomarkers acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in brain and blood samples of Chelon labrosus. Also, Marinello Reserve was selected as a reference site. The data showed a significant inhibition in AChE (81%) and BChE (71%) activities in fish from Milazzo Gulf in respect to those from the reference site. The esterase inhibition is primarily due to the presence of organophosphorus insecticides and carbamates that resulted, in Milazzo Gulf, higher in concentration in respect to the reference quality standard decree (D.M. 260, 2010). The results obtained in this study confirm the suspected presence of insecticides in waters and fish from Milazzo Gulf, which may lead to a considerable hazard to humans. This study confirms the relevant advantages of the biomarker approach on fish species in the ecotoxicological evaluation of marine environments.

Antimullerian hormone (AMH) is a promising biomarker for ovarian reserve. In this study, we assessed AMH before and 1 year after initiation of adjuvant chemotherapy on National Surgical Adjuvant Breast and Bowel Project (NSABP)/NRG Oncology B-47 in female participants aged 42 years and younger (median age = 39 years). At baseline, median AMH was 1.2 ng/mL; 13 (4.7%) values were less than 0.1 ng/mL (the threshold for detectable levels, in the perimenopause and menopause range), and 57 values (20.6%) were less than 0.5 ng/mL. At 1 year, 215 (77.6%) were less than 0.1 ng/mL, and 264 (95.3%) were less than 0.5 ng/mL. Postchemotherapy menses were reported by 46.2% of participants. Multivariable logistic regression found that the odds of having postchemotherapy menses increased with younger age, higher body mass index, and higher prechemotherapy AMH, but not by trastuzumab administration or by the choice of chemotherapy (doxorubicin-cyclophosphamide followed by paclitaxel vs docetaxel-cyclophosphamide). We conclude that higher prechemotherapy AMH predicts a lower risk of chemotherapy-induced amenorrhea and that AMH 1 year after chemotherapy initiation is not informative in this setting because it is likely to be very low.

The MoEDAL trapping detector, consists of approximately 800 kg of aluminium volumes. It was exposed during Run-2 of the LHC program to 6.46 fb^-1 of 13 TeV proton-proton collisions at the LHCb interaction point. Evidence for dyons (particles with electric and magnetic charge) captured in the trapping detector was sought by passing the aluminium volumes comprising the detector through a SQUID magnetometer. The presence of a trapped dyon would be signalled by a persistent current induced in the SQUID magnetometer. On the basis of a Drell-Yan production model, we exclude dyons with a magnetic charge ranging up to 5 Dirac charges, and an electric charge up to 200 times the fundamental electric charge for mass limits in the range 790 - 3130 GeV., arXiv admin note: text overlap with arXiv:1903.08491

A tracking detector composed of scintillator bars with a triangular cross-section read out by silicon photomultipliers in analog mode was developed. The tracker was designed to instrument a low density spectrometer for neutrino experiments. The performance of the system has been studied by exposing it to charged particle beams at the CERN-PS. The tests have shown that the position resolution in reconstructing charged particles’ tracks is within 2.2 mm over the momentum range 0.5–10 GeV/c.

The ENUBET ERC project (2016–2021) is studying a narrow band neutrino beam where lepton production can be monitored at single particle level. For this purpose, the decay tunnel is instrumented with longitudinally segmented calorimeters. Three different specialized calorimeters have been designed and tested, two of which based on the shashlik calorimetric concept with a compact readout while the third is a less compact version with a lateral readout. All of the prototypes are composed of thick steel absorbers coupled to plastic scintillators. Regarding the shashlik modules, a matrix of 3 × 3 fibers runs transversely with a density of one fiber/cm2. The fibers are coupled individually to silicon photomultipliers mounted on a custom PCB allowing to reduce the dead zones between adjacent modules to an extremely small level compared to the “fiber bundling” configurations. This setup allows a very effective longitudinal segmentation and hence e / π separation. The second shashlik module is based on polysiloxane scintillators which come in liquid form, are poured around the fiber arrays and finally made solid with a thermal treatment. Finally, the lateral readout module, light is collected from both sides of each scintillator tile and the 10 fibers from the same UCM are bundled to a single SiPM. Here are discussed the results of test beams performed in 2016–2018 at the CERN-PS East Area and the characterization of SiPMs of different cell size ( 12 μ m and 15 μ m ) before and after being exposed to neutron fluxes up to 1012/cm2 at the INFN-LNL CN accelerator facility.

A prototype for the instrumented decay tunnel of ENUBET was tested in 2018 at the CERN East Area facility with charged particles up to 5 GeV. This detector is a longitudinal sampling calorimeter with lateral scintillation light readout. The calorimeter was equipped by an additional "$t_0$-layer" for timing and photon discrimination. The performance of this detector in terms of electron energy resolution, linearity, response to muons and hadron showers are presented in this paper and compared with simulation. The $t_0$-layer was studied both in standalone mode using pion charge exchange and in combined mode with the calorimeter to assess the light yield and the 1 mip/2 mip separation capability. We demonstrate that this system fulfills the requirements for neutrino physics applications and discuss performance and additional improvements., Comment: 23 pages, 20 figures, to appear in JINST

The goal of the ENUBET project is to demonstrate that a precision of ∼ 1 % on measurement of the absolute neutrino cross section at GeV scale can be achieved by monitoring the positron production in the decay tunnel coming from the three-body semileptonic decays of kaons. The baseline option for the tunnel instrumentation employs a fine-grained shashlik calorimeter with a 4.3 X0 longitudinal segmentation to separate positrons and pions coming from other decay modes of kaons. The system is complemented by rings of plastic scintillator doublets below the calorimeter acting as a photon veto to suppress the π 0 background and to provide timing informations. SiPMs instrumenting the detector will be exposed to sizeble amounts of neutrons arising in hadronic showers. In order to reproduce such a working environment, SiPMs with different cell size (from 12 to 20 μ m ) were irradiated at the INFN-LNL CN Van Der Graaf with neutron fluences up to 2 × 10 11 n/cm2 (1 MeV-eq.). The exposed light sensors were characterized in terms of I–V curves at different irradiation levels, and their response tested by exposing a prototype on beam at CERN. In this contribution we will report the results of the described tests on SiPMs, together with the advances in their integration with the ENUBET detectors.

The knowledge of the initial flux, energy and flavor of current neutrino beams is the main limitation for a precise measurement of neutrino cross-sections. The ENUBET ERC project is studying a facility based on a narrow-band neutrino beam capable of constraining the neutrino fluxes normalization through the monitoring of the associated charged leptons in an instrumented decay tunnel. In ENUBET, the identification of large-angle positrons from [Formula: see text] decays at single particle level can potentially reduce the [Formula: see text] flux uncertainty at the level of 1%. This setup would allow for an unprecedented measurement of the [Formula: see text] cross-section at the GeV scale. This input would be highly beneficial to reduce the budget of systematic uncertainties in the next long baseline oscillation projects. Furthermore, in narrow-band beams, the transverse position of the neutrino interaction at the detector can be exploited to determine a priori with significant precision the neutrino energy spectrum without relying on the final state reconstruction. This contribution will present the advances in the design and simulation of the hadronic beam line. Special emphasis will be given to a static focusing system of secondary mesons that can be coupled to a slow extraction proton scheme. The consequent reduction of particle rates and pile-up effects makes the determination of the [Formula: see text] flux through a direct monitoring of muons after the hadron dump viable, and paves the way to a time-tagged neutrino beam. Time-coincidences among the lepton at the source and the neutrino at the detector would enable an unprecedented purity and the possibility to reconstruct the neutrino kinematics at source on an event-by-event basis. We will also present the performance of positron tagger prototypes tested at CERN beamlines, a full simulation of the positron reconstruction chain and the expected physics reach of ENUBET.

We present the first application of polysiloxane-based scintillators as active medium in a shashlik sampling calorimeter. These results were obtained from a testbeam campaign of a $\sim$6$\times$6$\times$45 cm$^3$ (13 $X_0$ depth) prototype. A Wavelength Shifting fiber array of 36 elements runs perpendicularly to the stack of iron (15 mm) and polysiloxane scintillator (15 mm) tiles with a density of about one over cm$^2$. Unlike shashlik calorimeters based on plastic organic scintillators, here fibers are optically matched with the scintillator without any intermediate air gap. The prototype features a compact light readout based on Silicon Photo-Multipliers embedded in the bulk of the detector. The detector was tested with electrons, pions and muons with energies ranging from 1 to 7 GeV at the CERN-PS. This solution offers a highly radiation hard detector to instrument the decay region of a neutrino beam, providing an event-by-event measurement of high-angle decay products associated with neutrino production (ENUBET, Enhanced NeUtrino BEams from kaon Tagging, ERC project). The results in terms of light yield, uniformity and energy resolution, are compared to a similar calorimeter built with ordinary plastic scintillators., Comment: 28 pages, 16 figures. To appear in NIM-A

Background: Chemotherapy-induced toxicities are prevalent in patients treated with adjuvant chemotherapy and often impact on activities of daily living and other aspects of function and well-being. Understanding which patients are more likely to experience long-term chemotherapy-induced peripheral neuropathy (CIPN) and hot flashes may help tailor treatment recommendations. Methods: Patients enrolled in the NRG Oncology/NSABP B-30 clinical trial were randomized to doxorubicin and docetaxel (AT), doxorubicin, docetaxel, and cyclophosphamide (ATC), or doxorubicin and cyclophosphamide followed by docetaxel (AC-T) (with increasing docetaxel doses across regimens). 1840 patients completed patient-reported outcomes (PRO) questionnaires including a symptom checklist asking about bother due to “numbness or tingling in hands or feet” and “hot flashes” as well as the FACT-General question 5 (GP5; “I am bothered by side effects of treatment”), assessed using a 5 category response scale. We examined the impact of pre-treatment host factors (demographic and clinical) on development and persistence of CIPN and hot flashes in NSABP B-30 patients. Analyses were performed using the Toxicity Index (TI), which summarizes the severity and frequency of toxicities over time. Univariate and multivariable probabilistic index models, a rank-based method that is a more general version of the Kruskal-Wallis test, for the cumulative TI of toxicity in the acute period (cycle 4 day 1 through 12 months post-randomization) and long-term follow-up (18 and 24 months post-randomization) were performed, and included baseline demographic, clinical, and PRO data. Results: Multivariable analysis revealed a higher probability of CIPN in the acute period for patients randomized to the AC-T treatment regimen and those with pre-existing numbness, higher GP5 at baseline, Black race, and obesity. In the long-term follow-up period, all the above factors except race were statistically significant. Older age at surgery and mastectomy were also associated with persistence of CIPN. GP5 at 12 months was significantly associated with the probability of CIPN in the longer-term period (0.577, p Multivariable probabilistic index models for cumulative TIsVariableComparison A Citation Format: N. Lynn Henry, Sungjin Kim, Ron D. Hays, Marcio A. Diniz, Michael Luu, Mourad Tighiouart, Reena S. Cecchini, Greg Yothers, Andre Rogatko, Patricia A. Ganz. Risk factors for long-term adjuvant chemotherapy toxicity using pre-treatment host factors and self-rated treatment bother (GP5) in a clinical trial population [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 PD5-04.

PURPOSE Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2–overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.

Introduction Cancer clinical trials (CCT) provide much of the evidence for clinical guidelines and standards of care. But low levels of CCT participation are well documented, especially for minorities. Methods and materials We conducted an online survey of 556 recruitment practices across the NRG Oncology network. Survey aims were 1) to learn how sites recruit minority/underserved populations; 2) to better understand the catchment areas of the NRG institutions; and 3) to aid in planning education programs for accrual of minority/underserved populations. Results The survey response rate was 34.9%. The most effective methods reported for recruiting minority/underserved participants were patient navigators (44.4%) and translators (38.9%). All institutions reported using a mechanism for eligibility screening and 71% of institutions reported using a screening/enrollment tracking system. CCT training was required at 78.1% and cultural competency training was required at 47.5% of responding institutions. Only 19.9% of sites used community partners to assist with minority recruitment and just 37.1% of respondents reported a defined catchment area. Sites reported very little race and ethnicity data. Conclusion This NRG Oncology online survey provides useful data for improvements in trial enrollment and training to recruit minority/underserved populations to CCT. Areas for further investigation include web-based methods for recruitment and tracking, cultural competency training, definition of catchment areas, use of patient navigators, and community partnerships. The survey results will guide recruitment training programs.

Background. Several randomized trials demonstrated aromatase inhibitors (AI) superiority in terms of disease-free survival compared to tamoxifen treatment for postmenopausal hormone receptor-positive breast cancer (BC) patients. Anyway AI toxicity profile due to estrogen suppression is a concern. Pivotal trials demonstrated a significant bone mineral density (BMD) loss due to AI, with a consistent risk of fractures, thus impacting on patients' quality of life. Bisphosphonates represent an effective treatment in postmenopausal osteoporosis fractures prevention. Several studies demonstrated that upfront bisphosphonates therapy prevents bone loss in postmenopausal women receiving adjuvant AI for early-stage BC. However an adequate patients selection for adjuvant bisphosphonates treatment during AI endocrine therapy is still a challenge. We present the final results of the BONADIUV trial, a single-blind, randomized, placebo-controlled phase 2 study designed to evaluate the impact of ibandronate treatment on BMD in osteopenic women taking AI. Methods. Between January 2011 and May 2014, 561 patients underwent a baseline BMD assessment before starting AI as planned adjuvant treatment. Overall 171 osteopenic patients (lumbar spine [LS] and/or trochanter -1< T-score Results. A total of 171 patients were randomized in the study. Overall 27 patients (15.8%) withdrew the protocol (17 ibandronate vs 10 placebo arm): the final analysis was performed on 144 patients (72 patients per arm). P-value from Wilcoxon test showed no significant difference between arms at baseline both for LS (p=0.94) and trochanter (p=0.83). At 2-year, osteopenic patients treated with ibandronate gained +18.7% and +15.5% at the LS and trochanter BMD, respectively. Patients treated with placebo lost -13.3% at the LS, and gained +2.9% at the trochanter. Trochanter p-value from covariance analysis showed a mean BMD change significantly in favor of ibandronate arm at 1-year (p=0.012), and borderline at 2-year (p=0.087). Concerning LS, the mean BMD change was significantly in favor of ibandronate arm both at 1-year (p=0.002) and 2-year (p Conclusions. Final results of our study showed that treatment with ibandronate, as compared to placebo, improved BMD change in osteopenic women treated with adjuvant AI, and consistently protected patients' bone loss. Citation Format: Livi L, Saieva C, Desideri I, Scotti V, De Luca Cardillo C, Carta G, Cecchini S, Orzalesi L, Sanchez LJ, Casella D, Bernini M, Nori J, Bianchi S, De Feo ML, Meattini I. A single-blind, randomized, placebo-controlled phase II study to evaluate the impact of oral ibandronate on bone mineral density in osteopenic breast cancer patients receiving adjuvant aromatase inhibitors: Final results of the single-center BONADIUV trial [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 P2-09-12.

Background: Preclinical evidence has shown that in xenograft models with estrogen receptor (ER)+/HER2+ breast cancer, signaling through the ER pathway can be enhanced in the presence of anti-HER2 treatment and lead to treatment resistance. Concurrent targeting of ER and HER2 has led to enhanced treatment efficacy and complete tumor disappearance. We hypothesized that targeting ER with endocrine therapy concurrently with chemotherapy plus dual HER2 inhibition will not be antagonistic and can overcome ER-mediated resistance and result in higher pCR as neoadjuvant treatment of ER+/HER2+ breast cancer. NRG Oncology/NSABP B-52 is a phase III, multicenter, randomized neoadjuvant therapy trial designed to determine whether the addition of estrogen deprivation to neoadjuvant therapy consisting of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP+Est-Dep) yields a greater rate of pCR (breast and nodes) than TCHP alone. Methods: A total of 315 patients (pts) were randomly assigned between January 15, 2014 and March 17, 2016 to receive neoadjuvant therapy consisting of TCHP with or without estrogen deprivation therapy. Pts with locally advanced, hormone receptor-positive, HER2+ invasive breast cancer with no evidence of metastatic disease were eligible. Premenopausal women randomized to estrogen deprivation therapy received ovarian function suppression with goserelin (LHRH agonist) or equivalent plus an aromatase inhibitor (AI). Postmenopausal women received an AI. The determination of pCR (breast and nodes) was defined as the absence of any invasive component in the resected breast specimen and all resected lymph nodes following completion of neoadjuvant therapy. Following the intent-to-treat principle, the difference between the rates of pCR (breast and nodes) was tested using the binomial test for the difference between two proportions. The study was designed to have a statistical power of 80% to detect an increase in the pCR rate from 45% in the TCHP alone group to 60% in the TCHP+Est-Dep group. Results: The groups were balanced, with 57% clinically node positive and 50% premenopausal. Assessments for pCR were available from 308 of 315 randomized patients. The pCR (breast and nodes) for TCHP alone and TCHP+Est-Dep were 40.9% and 46.1%, respectively (p=0.36). The pCR (breast) were 44.2% and 47.4%, respectively (p=0.57). Grade 3/4 toxicities included diarrhea (23%, Conclusion: The addition of estrogen deprivation to neoadjuvant chemotherapy is not antagonistic. It improved pCR rates numerically, but the improvement was not statistically significant. The combination did not increase toxicity and may be a reasonable approach since all patients will receive endocrine therapy after neoadjuvant therapy. Correlative science studies including evaluation of residual cancer burden (RCB) and long-term outcomes will help define the role of estrogen deprivation in the treatment of HER2+ early breast cancer. Support: U10CA180868, -180822; UG1CA189867, Genentech. Citation Format: Rimawi MF, Cecchini RS, Rastogi P, Geyer, Jr CE, Fehrenbacher L, Stella PJ, Dayao Z, Rabinovitch R, Dyar SH, Flynn PJ, Baez-Diaz L, Paik S, Swain SM, Mamounas EP, Osborne CK, Wolmark N. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52 [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 S3-06.

The uncertainty in the initial neutrino flux is the main limitation for a precise determination of the absolute neutrino cross section. The ERC funded ENUBET project (2016-2021) is studying a facility based on a narrow band beam to produce an intense source of electron neutrinos with a ten-fold improvement in accuracy. Since March 2019 ENUBET is also a Neutrino Platform experiment at CERN: NP06/ENUBET. A key element of the project is the instrumentation of the decay tunnel to monitor large angle positrons produced together with $\nu_e$ in the three body decays of kaons ($K_{e3}$) and to discriminate them from neutral and charged pions. The need for an efficient and high purity e/$\pi$ separation over a length of several meters, and the requirements for fast response and radiation hardness imposed by the harsh beam environment, suggested the implementation of a longitudinally segmented Fe/scintillator calorimeter with a readout based on WLS fibers and SiPM detectors. An extensive experimental program through several test beam campaigns at the CERN-PS T9 beam line has been pursued on calorimeter prototypes, both with a shashlik and a lateral readout configuration. The latter, in which fibers collect the light from the side of the scintillator tiles, allows to place the light sensors away from the core of the calorimeter, thus reducing possible irradiation damages with respect to the shashlik design. This contribution will present the achievements of the prototyping activities carried out, together with irradiation tests made on the Silicon Photo-Multipliers. The results achieved so far pin down the technology of choice for the construction of the 3 m long demonstrator that will take data in 2021., Comment: Talk presented at the "15th Topical Seminar on Innovative Particle and Radiation Detectors (IPRD19)", 14-17 October 2019. Siena, Italy. 9 pages, 7 figures

The ENUBET project is studying a narrow band neutrino beam where lepton production can be monitored at single particle level in an instrumented decay tunnel and that could provide a 1% measurement of the neutrino flux at source. The three body semi-leptonic decay of kaons monitored by large angle positron production offers a fully controlled $\nu_{e}$ source at the GeV scale for a new generation of short baseline experiments. The ENUBET Collaboration presented at NuFact2018 the first end-to-end simulation of the beamline, the physics performance and the results of the test beam performed on the positron tagger. We reported ENUBET expected fluxes for $\nu_{e}$ and $\nu_{\mu}$

Summary Background Whole-breast irradiation after breast-conserving surgery for patients with early-stage breast cancer decreases ipsilateral breast-tumour recurrence (IBTR), yielding comparable results to mastectomy. It is unknown whether accelerated partial breast irradiation (APBI) to only the tumour-bearing quadrant, which shortens treatment duration, is equally effective. In our trial, we investigated whether APBI provides equivalent local tumour control after lumpectomy compared with whole-breast irradiation. Methods We did this randomised, phase 3, equivalence trial (NSABP B-39/RTOG 0413) in 154 clinical centres in the USA, Canada, Ireland, and Israel. Adult women (>18 years) with early-stage (0, I, or II; no evidence of distant metastases, but up to three axillary nodes could be positive) breast cancer (tumour size ≤3 cm; including all histologies and multifocal breast cancers), who had had lumpectomy with negative (ie, no detectable cancer cells) surgical margins, were randomly assigned (1:1) using a biased-coin-based minimisation algorithm to receive either whole-breast irradiation (whole-breast irradiation group) or APBI (APBI group). Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with or without a supplemental boost to the tumour bed, and APBI was delivered as 34 Gy of brachytherapy or 38·5 Gy of external bream radiation therapy in 10 fractions, over 5 treatment days within an 8-day period. Randomisation was stratified by disease stage, menopausal status, hormone-receptor status, and intention to receive chemotherapy. Patients, investigators, and statisticians could not be masked to treatment allocation. The primary outcome of invasive and non-invasive IBTR as a first recurrence was analysed in the intention-to-treat population, excluding those patients who were lost to follow-up, with an equivalency test on the basis of a 50% margin increase in the hazard ratio (90% CI for the observed HR between 0·667 and 1·5 for equivalence) and a Cox proportional hazard model. Survival was assessed by intention to treat, and sensitivity analyses were done in the per-protocol population. This trial is registered with ClinicalTrials.gov , NCT00103181 . Findings Between March 21, 2005, and April 16, 2013, 4216 women were enrolled. 2109 were assigned to the whole-breast irradiation group and 2107 were assigned to the APBI group. 70 patients from the whole-breast irradiation group and 14 from the APBI group withdrew consent or were lost to follow-up at this stage, so 2039 and 2093 patients respectively were available for survival analysis. Further, three and four patients respectively were lost to clinical follow-up (ie, survival status was assessed by phone but no physical examination was done), leaving 2036 patients in the whole-breast irradiation group and 2089 in the APBI group evaluable for the primary outcome. At a median follow-up of 10·2 years (IQR 7·5–11·5), 90 (4%) of 2089 women eligible for the primary outcome in the APBI group and 71 (3%) of 2036 women in the whole-breast irradiation group had an IBTR (HR 1·22, 90% CI 0·94–1·58). The 10-year cumulative incidence of IBTR was 4·6% (95% CI 3·7–5·7) in the APBI group versus 3·9% (3·1–5·0) in the whole-breast irradiation group. 44 (2%) of 2039 patients in the whole-breast irradiation group and 49 (2%) of 2093 patients in the APBI group died from recurring breast cancer. There were no treatment-related deaths. Second cancers and treatment-related toxicities were similar between the two groups. 2020 patients in the whole-breast irradiation group and 2089 in APBI group had available data on adverse events. The highest toxicity grade reported was: grade 1 in 845 (40%), grade 2 in 921 (44%), and grade 3 in 201 (10%) patients in the APBI group, compared with grade 1 in 626 (31%), grade 2 in 1193 (59%), and grade 3 in 143 (7%) in the whole-breast irradiation group. Interpretation APBI did not meet the criteria for equivalence to whole-breast irradiation in controlling IBTR for breast-conserving therapy. Our trial had broad eligibility criteria, leading to a large, heterogeneous pool of patients and sufficient power to detect treatment equivalence, but was not designed to test equivalence in patient subgroups or outcomes from different APBI techniques. For patients with early-stage breast cancer, our findings support whole-breast irradiation following lumpectomy; however, with an absolute difference of less than 1% in the 10-year cumulative incidence of IBTR, APBI might be an acceptable alternative for some women. Funding National Cancer Institute, US Department of Health and Human Services.

International audience; Shashlik calorimeters equipped with a compact readout based on Silicon PhotoMultipliers can be longitudinally segmented by directly coupling the WLS fibers with the photosensors thus embedding the readout in the bulk of the calorimeter. Results on energy resolution and particle identification for such calorimeters are presented. The SiPMs for the readout have also been characterized after being exposed to neutron fluences up to 2×10$^{11}$ n/cm$^2$ (1 MeV eq.). Alternative options for the active material were also investigated; we studied in particular polysiloxane as a substitute for plastic scintillator.

Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity. This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study. A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10 years (119.2–137.2 months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF 25, age ≥ 60 and, non-Caucasian ethnicity. One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.

Silicon Photomultipliers with cell-pitch ranging from 12 $\mu$m to 20 $\mu$m were tested against neutron irradiation at moderate fluences to study their performance for calorimetric applications. The photosensors were developed by FBK employing the RGB-HD technology. We performed irradiation tests up to $2 \times 10^{11}$ n/cm$^2$ (1 MeV eq.) at the INFN-LNL Irradiation Test facility. The SiPMs were characterized on-site (dark current and photoelectron response) during and after irradiations at different fluences. The irradiated SiPMs were installed in the ENUBET compact calorimetric modules and characterized with muons and electrons at the CERN East Area facility. The tests demonstrate that both the electromagnetic response and the sensitivity to minimum ionizing particles are retained after irradiation. Gain compensation can be achieved increasing the bias voltage well within the operation range of the SiPMs. The sensitivity to single photoelectrons is lost at $\sim 10^{10}$ n/cm$^2$ due to the increase of the dark current., Comment: 14 pages, 13 figures. To appear in JINST