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AIM: Most patients tested by a 44-gene panel for hereditary cancer (HerediGene), even though they had a strong family history, have a negative result or a finding in a low-risk gene. This creates a question about the risk for these individuals to develop breast cancer. The Polygenic Risk Score is a tool used to identify and calculate the lifetime risk of developing breast cancer and thus we are investigating whether it can be used in our cohort of patients to identify this risk. PATIENTS AND METHODS: Among 111 patients analyzed with a 44-gene hereditary cancer panel, we were able to produce the Polygenic Risk Score for 105 of them. All the patients were diagnosed with breast cancer, and they all had a strong family history. We analyzed the ability of the PRS to identify the risk of the patients in combination with the findings of the 44-gene panel. RESULTS: Overall, 74% of patients with a family history had a negative PRS (with a cut-off of 20%). Among the BRCA positive patients all of them had a positive PRS and among all the high-risk gene positive cases, 70% had a positive PRS. On the other hand, among the low-risk genes and the negative cases 18.5% had a positive PRS. There is a positive correlation between the findings from the NGS panel analysis and the PRS. CONCLUSION: Our analysis shows that PRS is correlated to the findings of the 44-gene NGS panel having the majority of the PRS positive patients carry high risk mutations. In addition to this, in 18.5% of the patients with low-risk findings or negative result from the 44-gene panel, the PRS was positive which can explain the outcome of the patient since breast cancer had developed. This is an indication that the combination of PRS with the findings from the 44-gene panel can identify individuals with a higher risk of developing breast cancer. Citation Format: Nikolaos Tsoulos, Konstantinos Agiannitopoulos, Helen Goga, Theodoros Troupis, Christos Markopoulos. Polygenic Risk Score in a cohort of 105 Breast Cancer patients previously tested with a multi gene panel for hereditary 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 P5-12-07.

Background: Women with HR+ breast cancer experience a persistent risk of distant recurrence (DR) even after completion of 5 years of adjuvant endocrine therapy, with more than 50% of DR occurring after 5 years (late DR). The prognostic genomic signatures currently being used in the clinic were not developed or optimized specifically for late DR. We have previously shown that the Breast Cancer Index (BCI) and BCIN+ prognostic models were significantly prognostic for risk of overall (0-10y) and late (5-10y) distant recurrence (DR) in N0 and N1 HR+ patients in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. Here, the prognostic performance of the BCI and BCIN+ models with alternative cut-points optimized for late DR were evaluated in patients from the TEAM trial, who were free from DR for at least 5 years. Methods: BCI testing was performed blinded to clinical outcome. The pre-specified alternative cut-points 4.4 and 1.8 for BCI and BCIN+ models were determined previously from Trans-aTTom and IDEAL studies, respectively (ESMO 2021). Kaplan-Meier analysis and log-rank test were used to evaluate the prognostic significance of BCI/BCIN+ risk groups based on DR. Univariate and multivariate Cox models were used to estimate hazard ratios (HRs) and the associated 95% confidence intervals (CIs). Results: 1285 HR+ N0 (median age 69.2, 54.2% T1, 92.5% G2-3, 21.3% chemotherapy) and 1762 N1 (median age 68.5, 49.7% T1, 80.8% G2-3, 42.6% chemotherapy) patients who remained free from DR at 5 years post randomization were included in the current analysis. For N0 patients, BCI identified 439 (34%) and 846 (66%) patients as low and high-risk with late 10-year DR rates of 3.8% (95% CI: 1.5-6.0%) and 9.1% (95% CI: 6.8-11.4%), respectively (HR: 2.6, 95% CI: 1.4-5.0; p=0.0025). For N1 patients, BCIN+ identified 287 (16%) and 1475 (84%) patients as low and high-risk with late 10-year DR rates of 3.4% (95% CI: 1.2-5.5%) and 12.3% (95% CI: 10.4-14.2%), respectively (HR: 3.5, 95% CI: 1.8-6.9; p< 0.0001). Similar results were observed in the HER2- patients. Notably, BCI/BCIN+ remained a statistically significant prognostic factor in the multivariate analysis after controlling for age, tumor size, grade, treatment. (Table). Conclusions: Compared to the original BCI/BCIN+ models, the optimized BCI and BCIN+ models showed improved prognostic performance for identifying low-risk patients with a very low risk of late DR (< 4%), for both N0 and N1 patients. These results provide further validation of BCI clinical utility as an aid in the decision-making for extended endocrine therapies for HR+ breast cancer, particularly in patients with N1 disease that may be spared extended endocrine treatment. Table Citation Format: John MS Bartlett, Keying Xu, Jenna Wong, Gregory R. Pond, Yi Zhang, Melanie Spears, Ranelle Salunga, Elizabeth Mallon, Karen J. Taylor, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, Cornelis J.H. van de Velde, Daniel Rea, Catherine A. Schnabel, Kai Treuner, Jane Bayani. Validation of the Breast Cancer Index (BCI) prognostic models optimized for late distant recurrence in postmenopausal women with early-stage HR+ breast cancer in the TEAM 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 P2-11-10.

Introduction: Decision making in surgical oncology of the breast has increased its complexity over the last twenty years. This Delphi survey investigates the opinion of an expert panel about the decision making process in surgical procedures on the breast for oncological purposes. Methods: Twenty-seven experts were invited to partake into a Delphi Survey. At the first round they have been asked to provide a list of features involved in the decision making process (patient's characteristics; disease characteristics; surgical techniques, outcomes) and comment on it. Using text-mining techniques we extracted a list of mono-bi-trigrams potentially representative of decision drivers. A technique of “natural language processing” called Word2vec was used to validate changes to texts using synonyms and plesionyms. Word2Vec was also used to test the semantic relevance of n-grams within a corpus of knowledge made up of books edited by panel members. The final list of variables extracted was submitted to the judgement of the panel for final validation at the second round of the Delphi using closed ended questions. Results: 52 features out of 59 have been approved by the panel. The overall consensus was 87.1% Conclusions: Text mining and natural language processing allowed the extraction of a number of decision drivers and outcomes as part of the decision making process in surgical oncology on the breast. This result was obtained transforming narrative texts into structured data. The high level of consensus among experts provided validation to this process.

More diversity is now shown in students gaining admission into universities, many who are ill-equipped for first-year studies and assessment writing. This can result in a failing grade for some, which can impact their success and progression. This study contributes to the student success literature by reporting on the six-step one-on-one targeted intervention strategy devised to support the 33 out of 500 students who were unsuccessful in their first university assessment and its resubmission. The study also details the theoretical framework that underpinned the subject—Carol Dweck’s growth mindset, Mezirow’s transformative learning theory, and the maxim “Your success is our goal”! The study determined that: i) the intervention was successful for the 33 students who each passed the assessment; ii) a pre- and post-intervention writing skills assessment showed an improvement of +0.67 to give an average of 3.48, where 3 is a pass, and iii) at interview, students (76.9%) reported their improved writing abilities and that the intervention support was helpful. The study concluded that failing students can be successful when they are encouraged to use a growth mindset and individually supported to develop their writing skills.

Background: Dose-dense sequential chemotherapy based on anthracyclines and taxanes has achieved an 18% reduction of recurrence risk in the adjuvant setting of early breast cancer (BC). However, the optimal chemotherapy schedule and the preferable interval between cycles are still under investigation. Methods: A total of 990 eligible BC patients were randomized to receive either 3 cycles of epirubicin (E,110 mg/m2) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m2) every 2 weeks followed by 3 cycles of intensified CMF (Control Arm A, E-T-CMF; 333 patients) or three cycles of epirubicin followed by 3 cycles of CMF followed by 9 consecutive weekly cycles of docetaxel (wD) 35 mg/m2 (Experimental Arm B, E-CMF-wD; 331) or 9 consecutive weekly cycles of paclitaxel (wT) 80 mg/m2 (Experimental Arm C, E-CMF-wT; 326). Trastuzumab was administered for HER2-positive disease. The primary endpoint was disease-free survival (DFS). Results: At a median follow-up of 13.3 years, 330 DFS events (33.3%) had been reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus control arm A either in the entire cohort (HR=0.90, p=0.38 and HR=0.85, p=0.20) or among HER2-positive, trastuzumab-treated patients (HR=0.69, p=0.13 and HR=0.67, p=0.13). Thirty-four patients (3.4%) developed secondary neoplasms. Conclusions: Overall, no significant differences in DFS or OS were found amongst the studied regimens after a long-term observational period. Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12610000151033 Citation Format: Flora Zagouri, Georgia-Angeliki Koliou, Foteinos Dimitrakopoulos, Christos Papadimitriou, Ioannis Binas, Angelos Koutras, Pavlos Papakostas, Christos Markopoulos, Vasileios Venizelos, Grigorios Xepapadakis, Charisios Karanikiotis, Amanda Psyrri, Dimitrios Bafaloukos, Paris Kosmidis, Gerasimos Aravantinos, Eleni Res, Davide Mauri, Anna Koumarianou, Kalliopi Petraki, Anna Tsipoura, Dimitrios Pectasides, Helen Gogas, George Fountzilas. Dose-dense sequential adjuvant chemotherapy in the trastuzumab era: Final long-term results of the hellenic cooperative oncology group phase III HE10/05 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 P1-12-01.

Background: Breast cancer is the most frequently diagnosed cancer in women and about 10% of breast cancer cases are hereditary. BRCA1 and BRCA2 are the genes most frequently associated with Hereditary Breast Cancer, although there are numerous other genes, such as PALB2, CHEK2 and ATM, that require to be considered as well. Germline Copy Number Variation (CNV) is one mutation type that is an important contributor to hereditary breast cancer. Nowadays, next-generation sequencing (NGS) technologies has contributed to multi-gene panel analysis used in clinical practice. Methods: In total, 1418 individuals were tested for breast cancer predisposition, using a solution-based capture approach. Targeted NGS was performed with a panel of 36 genes. The capture-based approach allowed for computational analysis of CNVs from NGS data. Results: We investigate the performance of the CNV module of the commercial software suite SeqPilot (JSI Medical Systems) and the non-commercial tool panelcn.MOPS. Both algorithms are specifically developed for CNV analysis of sequencing data reporting 99-100% sensitivity and up to 100% specificity for the prediction of CNVs up to the level of a single gene exon. All CNVs detected with these algorithms were then verified experimentally using the MLPA technique as an orthogonal assay. At least one pathogenic/likely pathogenic variant was identified in 289 samples (20.4%). CNVs accounted for 10.4% (30/289), referring to the deletion of one or more exons of a gene. Interestingly, 50% of deletions were single exon and approximately 36% of CNVs were detected in genes other than BRCA1/2. In specific, of the 30 CNVs detected, 60% occurred in BRCA1, 3.3% in BRCA2, 20% in CHEK2, 6.7% in FANCA, 6.7% in PMS2, and 3.3% in ATM. The majority of CNVs in BRCA1 were deletions of exons 19, 22, and 22-23 whereas deletions of exons 9-10 were the most common deletions in CHEK2. Detailed information of all CNVs detected is provided in Table 1. Conclusions: Our results suggest that CNV analysis should not be restricted to BRCA1/2 due to the significant proportion of CNVs (36%) in additional breast cancer predisposition genes. Furthermore, in silico CNV detection tools provide a cost-effective and feasible methodology for the identification of CNVs from NGS experiments. This outlines the clinical utility of comprehensive genetic testing that includes full sequencing and CNV analysis in hereditary breast cancer facilitating personalized management decisions for patients. Table 1.Pathogenic Copy Number Variations (CNVs) identified in this studyGeneHGVS nomenclatureOther nomenclature# detectedATMNM_000051:c.(-30+1_-29-1)_(331+1_332-1)deldeletion of exons 2-41BRCA1NM_007294:c.(5467+1_5468-1)-(*1_?)deldeletion of exon 237BRCA1NM_007294:c.(5406+1_5407-1)_(*1_?)deldeletion of exons 23-245BRCA1NM_007294:c.(5193+1_5194-1)-(5277+1_5278-1)deldeletion of exon 196BRCA2NM_000059:c.(6841+1_6842-1)_(7007+1_7008-1)deldeletion of exons 12-131CHEK2NM_007194:c.(908+1_909-1)_(1095+1_1096-1)deldeletion of exons 9-104CHEK2NM_007194:c.(792+1_793-1)_(846+1_847-1)deletion of exon 72FANCANM_000135:c.(1626+1_1627-1)_ (2852+1_2853-1)deldeletion of exons 18-291FANCANM_000135:c.(893+1_894-1)_(1359+1_1360-1)deldeletion of exons 11-141PMS2NM_000535: c.(903+1_904-1)_(988+1_989-1)deldeletion of exon 91PMS2NM_000535:c.(705+1_706-1)_(2006+1_2007-1)deldeletion of exons 7-111 Citation Format: Nikolaos Tsoulos, Konstantinos Agiannitopoulos, Georgia Pepe, Eirini Papadopoulou, Georgios N Tsaousis, Despina Apostolopoulou, Angeliki Meintani, Vassileios Venizelos, Christos Markopoulos, Rodoniki Iosifidou, Sofia Karageorgopoulou, Christos Christodoulou, Ioannis Natsiopoulos, Konstantinos Papazisis, Maria Vasilaki-Antonatou, Eleftherios Kabletsas, Amanta Psyrri, Stylianos Giassas, Dimitrios Ziogas, Efthalia Lalla, Anna Koumarianou, Christos Papadimitriou, Vahit Ozmen, Sualp Tansan, Kerim Kaban, Tahsin Ozatlı, Dan Tudor Eniu, Angelica Chiorean, Alexandru Blidaru, George Nasioulas. Different CNVs account for 10.4% of pathogenic variants in 1418 patients referred for hereditary breast cancer testing [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 P2-09-10.

Cancer patients’ quality of life (QoL) and distress are affected by dispositional factors such as attachment anxiety or avoidance. In this review, we aimed to provide a thorough overview of the relationship between attachment dimensions and QoL and distress among early-stage breast cancer patients. Following PRISMA guidelines, we conducted a systematic search using PubMed, PsycINFO, Scopus, Cinahl, Google Scholar, and PMC Europe. We reviewed 8 eligible studies describing 1180 patients. Insecure attachment appeared to be related to poorer QoL and higher distress levels. Avoidant attachment was more frequent and was more often associated with more negative outcomes. Healthcare providers should consider investigating modifiable personality traits in the immediate post diagnosis period to identify patients more vulnerable to mental health problems, deliver personalized care, and reduce emotional burden.

Multiparametric assays for risk stratification are widely used in the management of both node negative and node positive hormone receptor positive invasive breast cancer. Recent data from multiple sources suggests that different tests may provide different risk estimates at the individual patient level. The TEAM pathology study consists of 3284 postmenopausal ER+ve breast cancers treated with endocrine therapy Using genes comprising the following multi-parametric tests OncotypeDx®, Prosigna™ and MammaPrint® signatures were trained to recapitulate true assay results. Patients were then classified into risk groups and survival assessed. Whilst likelihood χ2 ratios suggested limited value for combining tests, Kaplan–Meier and LogRank tests within risk groups suggested combinations of tests provided statistically significant stratification of potential clinical value. Paradoxically whilst Prosigna-trained results stratified Oncotype-trained subgroups across low and intermediate risk categories, only intermediate risk Prosigna-trained cases were further stratified by Oncotype-trained results. Both Oncotype-trained and Prosigna-trained results further stratified MammaPrint-trained low risk cases, and MammaPrint-trained results also stratified Oncotype-trained low and intermediate risk groups but not Prosigna-trained results. Comparisons between existing multiparametric tests are challenging, and evidence on discordance between tests in risk stratification presents further dilemmas. Detailed analysis of the TEAM pathology study suggests a complex inter-relationship between test results in the same patient cohorts which requires careful evaluation regarding test utility. Further prognostic improvement appears both desirable and achievable.

Background Classification of splicing variants (SVs) in genes associated with hereditary cancer is often challenging. The aim of this study was to investigate the occurrence of SVs in hereditary cancer genes and the clinical utility of RNA analysis. Material and methods 1518 individuals were tested for cancer predisposition, using a Next Generation Sequencing (NGS) panel of 36 genes. Splicing variant analysis was performed using RT-PCR and Sanger Sequencing. Results In total, 34 different SVs were identified, 53% of which were classified as pathogenic or likely pathogenic. The remaining 16 variants were initially classified as Variant of Uncertain Significance (VUS). RNA analysis was performed for 3 novel variants. Conclusion The RNA analysis assisted in the reclassification of 20% of splicing variants from VUS to pathogenic. RNA analysis is essential in the case of uncharacterized splicing variants, for proper classification and personalized management of these patients.

Formative assessment is a crucial aspect of teaching and learning in the classroom, but there is evidence that there has been a lack of effective implementation of formative assessment in practice. In response, this article outlines the design and development of a formative assessment framework that can be implemented as a consistent whole-school approach to embedding practice that is owned and developed by teachers. The approach outlined in the framework, therefore, is designed to integrate formative assessment practices within a school system context, providing advice and support to school leaders and teachers. The framework in practice should act to enable teachers and students to develop new understandings and perspectives about each other and the nature of teaching and learning, as well as ways to implement new practices of teaching and learning supported by reflective modes of active participation.

Introduction The main hormonal treatment of estrogen sensitive breast cancer includes the use of selective estrogen receptor modulators, aromatase inhibitors and GnRH-Analogs. It has been observed that administering aromatase inhibitor to breast cancer patients not only impairs their glucose metabolism but it can even cause frank diabetes mellitus. Moreover, it has been hypothesized that aromatase inhibitors may have an impact on glucose metabolism by their effect on estrogen levels. Therefore, we designed an experiment in order to assess the effect of estrogens on insulin secretion from rat beta pancreatic insulinoma INS-1 cells. Methods Experiments were conducted on an INS-1 cell line, a rodent beta cell line derived from a rat insulinoma induced by X-ray irradiation, which displays high insulin content, production of both proinsulin I and II and responsiveness to glucose and hormones. INS-1 cells were routinely cultured in 75cm2 flasks (T75) containing 10ml of appropriate culture media and then were transferred into 6-well plates and treated with 17β-E2. Proliferation, as well as insulin expression in the 17β-E2 treated cells in mRNA and protein level was then investigated. Cell cultures were treated with 12.5mM, 25mM, 50mM, 100mM and 200mM estradiol. After 24 hours, RNA as well as protein extraction was carried out. Gene expression was examined in mRNA and protein level, by real time quantitative reverse transcriptase PCR and by western blotting, respectively. Extraction of total RNA was achieved with the use of NucleoZOL (Macherey-Nagel, Duren, Germany). Protein concentration of samples was measured by using the bicinchoninic acid (BCA) assay and bovine serum albumin (BSA) as the standard (Thermo Scientific TM Pierce TM BCA Protein Assay Kit, USA). Results Real time PCR showed a dose-dependent up regulation of insulin gene expression by estradiol. The findings were consistent with the results from western blot, although the estradiol dose-dependent increase in gene expression was not so clear. Finally, both protein and mRNA expression of insulin increased in a dose dependent manner, with mRNA reaching a plateau at 100nM estradiol treatment. Conclusion The experimental data suggest that there might be a direct effect of estrogen on beta cells and insulin secretion.

This article outlines the rationale for, and development of an online support system (OSS) for teachers of mathematics in regional, rural and remote (RRR) Australia as part of an ongoing longitudinal project, Regional Teachers of Mathematics Networks (RTMN). The OSS is designed to assist development of interconnected collaborative networks for teachers of mathematics in order to help them develop their professional identity. The article builds on the logic of the broader RTMN project, arguing that the development of a teacher of mathematics identity (ToMI) framework through participation in networked communities of practice (CoPs) is integral to improved practice and teacher retention. Theoretical considerations, framed within the overarching conceptual umbrella of cultural accumulation theory, are provided and relate mathematics CoPs to professional development and its role in the development of a localised teacher of mathematics identity. This framing outlines the importance of an OSS that supports both face-to-face and online (virtual) CoP functions for teachers of mathematics. The article also states the case for a design-based implementation research approach that allows stakeholders to sustain ongoing evaluation and updating of the OSS platform for professional learning exchanges within the ToMI framework.

Background/Objective: Sentinel lymph node biopsy (SLNB) is not routine in DCIS. Guidelines suggest SLNB when there is high risk for underlying invasion (large size, high grade, symptomatic lesion) ...

BACKGROUND: Dose-dense sequential chemotherapy with anthracyclines and taxanes achieved an 18% reduction of recurrence risk in early breast cancer (BC). The optimal chemotherapy schedule and interval between cycles remain under investigation. METHODS: Overall, 990 patients were randomised to receive either three cycles of epirubicin (E, 110 mg/m(2)) every 2 weeks followed by 3 cycles of paclitaxel (T, 200 mg/m(2)) every 2 weeks followed by three cycles of intensified CMF (Control Arm A, E-T-CMF) that was previously used in BC or three cycles of epirubicin followed by three cycles of CMF followed by nine consecutive weekly cycles of docetaxel (wD) 35 mg/m(2) (Arm B, E-CMF-wD) or nine consecutive weekly cycles of paclitaxel (wT) 80 mg/m(2) (Arm C, E-CMF-wT). Trastuzumab was administered for HER2-positive disease. RESULTS: At a median follow-up of 13.3 years, 330 disease-free survival (DFS) events (33.3%) were reported. DFS and overall survival (OS) did not differ between patients in the combined B and C arms versus arm A either in the entire cohort (HR = 0.90, P = 0.38 and HR = 0.85, P = 0.20) or among trastuzumab-treated patients (HR = 0.69, P = 0.13 and HR = 0.67, P = 0.13). Thirty-four patients (3.4%) developed secondary neoplasms. CONCLUSIONS: Overall, no significant differences in survival were found amongst the studied regimens after a long-term observational period. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12610000151033.

Background/Aim: The use of multi-gene panels for germline testing in breast cancer enables the estimation of cancer risk and guides risk-reducing management options. The aim of this study was to present data that demonstrate the different levels of actionability for multi-gene panels used in genetic testing of breast cancer patients and their family members. Materials and Methods: We performed an analysis in our clinical database to identify breast cancer patients undergoing genetic testing. We reviewed positive results in respect of risk estimation and management, cascade family testing, secondary findings and information for treatment decision-making. Results: A total of 415 positive test reports were identified with 57.1%, 18.1%, 10.8% and 13.5% of individuals having pathogenic/likely pathogenic variants in high, moderate, low and with insufficient evidence for breast cancer risk genes, respectively. Six point seven percent of individuals were double heterozygotes. Conclusion: Germline findings in 92% of individuals are linked to evidence-based treatment information and risk estimates for predisposition to breast and/or other cancer types. The use of germline findings for treatment decision making expands the indication of genetic testing to include individuals that could benefit from targeted treatments.

The clinical management of invasive breast cancer has changed during the last decade with the use of molecular-based multigene assays (MGAs).They are increasingly used to gain additional prognostic and predictive information and guide adjuvant treatment decisions. Since 2004, several MGAs have become available but, four of them are the most widely used in clinical practice: the OncotypeDX® Breast Recurrence Score, the 70-gene signature MammaPrint®, the Prosigna® (PAM50) and the EndoPredict® (EP/EPclin Scores) assay. However, MGAs are not all the same and they do not provide interchangeable information. They differ in terms of the technological platform used for their development, the number and specific genes assessed, and the patient populations in which they were validated. Furthermore, although they are all validated for providing prognostic information, not all of them are supported with data from prospective randomised trials confirming the clinical value of their use in chemotherapy treatment decisions in certain groups of breast cancer patients; in this regard, so far there are published data only for OncotypeDX and MammaPrint, whilst PAM-50 (Prosigna) and EndoPredict assays are currently not supported by entirely prospective randomized trials evaluating their predictive value of chemotherapy benefit. As such, inclusion of these MGAs in major international treatment guidelines differs in indications for their use in clinical practice as prognosticators only or as predictors of chemotherapy benefit as well. Use of MGAs in clinical decision making can lead to de-escalation of chemotherapy recommendations and thus save a large number of patients from unnecessary side effects and decrease the cost of breast cancer treatment to National Health systems. This review provides an overview of the four most widely used MGAs in clinical practice, including basic information on their development and validation, as well as recent data on the information they can provide.

AIM: The majority of invasive lobular carcinomas (ILC) of the breast are luminal A tumors of good prognosis, having a low or intermediate OncotypeDX Recurrence Score (RS). They are usually treated with hormonal therapy only and some have doubted the relevance of the RS for patients with ILC. However, in a number of ILC cases a high RS can be found, indicating chemotherapy benefit. The aim of the present analysis was to explore in our database of lobular carcinomas analyzed with OncotypeDX, the percentage of tumors with a RS >25 and test the hypothesis if Progesterone Receptor (PgR) and/or Ki-67 expression could be an indicator to have patients evaluated with OncotypeDX. PATIENTS AND METHODS: Among 2.946 patients analyzed with Oncotype DX, we found 397 patients with pure lobular carcinomas (13.47%). Ki-67 expression was obtained from 315 patients and 13 of them (4%) had a high Ki-67 value of >30%. PgR expression was negative in 56 out of 397 patients (14%). We analyzed the possible relationship of RS values with PgR levels and Ki-67 expression. RESULTS: Overall, 94% of patients with ILC had a Recurrence Score ≤25 and only 6% (24/397) had a RS ≥26. There was a wide distribution of RS among patients with different values of PgR; however, there was a negative trend of Recurrence Score values and PgR expression levels. This trend was more obvious in the 56 patients with negative PgR expression. Although there were high RS values across all levels of Ki-67 expression, there was a trend towards high RS with higher Ki-67 expression; 5 out of 13 patients (38%) with ki-67 >30% had a RS ≥26. CONCLUSION: Our analysis shows that the majority of lobular carcinomas of the breast have a low OncotypeDX RS, suggesting that can be treated only with hormonal therapy. However, negative or low PgR levels and high Ki-67 expression might predict a high RS and thus chemotherapy benefit and those two parameters could be used as indicators for OncotypeDX evaluation of lobular carcinomas of the breast. Citation Format: Christos Markopoulos, Mahi Sariyanni, Asimina Karamargiou, Zoi Antonopoulou, Nikolaos Tsoulos. PgR levels and Ki67 expression of Lobular Carcinomas of the Breast might indicate OncotypeDX testing to evaluate Chemotherapy benefit [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 P6-01-30.

This paper describes a design-based implementation research (DBIR) approach to the development and trialling of a new generation massive open online course (ngMOOC) situated in an instructional setting of undergraduate mathematics at a regional Australian university. This process is underscored by two important innovations: (a) a basis in a well-established human cognitive architecture in terms of cognitive load theory; and (b) point-of-contact feedback based in a well-tested online system dedicated to enhancing the learning process. Analysis of preliminary trials suggests that the DBIR approach to the ngMOOC construction and development supports theoretical standpoints that argue for an understanding of how design for optimal learning can utilise conditions, such as differing online or blended educational contexts, in order to be effective and scalable. The ngMOOC development described in this paper marks the adoption of a cognitive architecture in conjunction with feedback systems, offering the groundwork for use of adaptive systems that cater for learner expertise. This approach seems especially useful in constructing and developing online learning that is self-paced and curriculum-based.

A measure of teacher identity specific to teachers of mathematics was developed and assessed, the teacher of mathematics identity (ToMI) scale. A sample of teachers was recruited from a state-based mathematics association to complete an online survey including items based on the theories of Mead, Erikson, and Wenger. The subscales of belonging to a mathematics community, self-efficacy as a teacher of mathematics, and enthusiasm to be a teacher of mathematics were derived using exploratory factor analysis (n = 301) and then confirmed with confirmatory factor analysis (n = 311) with randomly allocated independent subsamples. These subscales were related and, when combined to form a single factor, explained a substantial proportion of the variance in the data, suggesting that the ToMI scale can be used as three separate subscales or combined to form a single overarching construct. Overall, ToMI and subscale scores were used in the validation process. Tests of validity were run in the two randomly allocated subsamples independently, allowing for replication of findings. As predicted based on the literature, the ToMI scale and subscales were related to the number of years teaching mathematics, the size of teacher of mathematics network accessed by teachers, and participation in mathematics-specific self-directed professional learning and wellbeing while teaching mathematics. These results reveal this initial iteration of the ToMI scale as valid concerning the underlying teacher identity theory, providing an important research avenue to pursue our understanding and development of effective teachers of mathematics.

Sentinel lymph node biopsy (SLNB) remains the gold standard for regional axillary staging in early, clinically and radiologically node-negative breast cancer. The technique of SLNB has been refined since its initial conception, and currently SLNB is a milestone of breast cancer surgical management. Cumulative evidence from randomized trials suggests that SLNB is accurate and safe in patients with early, clinically and radiologically node-negative disease. As a result, axillary node clearance (axillary lymph node dissection, ALND) has been abandoned as a staging procedure and is reserved for local control in certain cases of node-positive breast cancer. In recent years, emerging data from landmark trials have extended the use of SLNB beyond its well-established scope, for instance in patients with node-positive breast cancer who receive primary systemic therapy. Moreover, modern data suggest that SLNB may be adequate as a means of staging as well as of local control (i.e. leading to omission of ALND) in breast cancers with low axillary nodal burden. In this chapter, we elaborate on the current concept of SLNB and review its extended indications. We also explore the data relevant to complete omission of SLNB in selected invasive breast cancer cases, in line with very recent randomised trials currently underway.

PURPOSE Most distant recurrences (DRs) in women with hormone receptor–positive breast cancer occur after 5 years from diagnosis. The Clinical Treatment Score post-5 years (CTS5) estimates DRs after 5 years of adjuvant endocrine therapy (AET). The aim of this study was to externally validate the CTS5 as a prognostic/predictive tool. METHODS The CTS5 categorizes patients who have been disease free for 5 years into low, intermediate, and high risk and calculates an absolute risk for developing DRs between 5 and 10 years. Discrimination and calibration were assessed using data from the TEAM and IDEAL trials. The predictive value of the CTS5 was tested with data from the IDEAL trial. RESULTS A total of 5,895 patients from the TEAM trial and 1,591 patients from the IDEAL trial were included. When assessing the CTS5 discrimination, significantly more DRs were found at 10 years after diagnosis in the CTS5 high- and intermediate-risk groups than in the low-risk group (hazard ratio, 5.7 [95% CI, 3.6 to 8.8] and 2.8 [95% CI, 1.7 to 4.4], respectively). In low- and intermediate-risk patients, the CTS5-predicted DR rates were higher, although not statistically significantly so, than observed rates. However, in high-risk patients, the CTS5-predicted DR rates were significantly higher than observed rates (29% v 19%, respectively; P < .001). The CTS5 was not predictive for extended AET duration. CONCLUSION The CTS5 score as applied to patients treated in the TEAM and IDEAL cohorts discriminates between risk categories but overestimates the risk of late DRs in high-risk patients. Therefore, the numerical risk assessment from the CTS5 calculator in its current form should be interpreted with caution when used in daily clinical practice, particularly in high-risk patients.

Background: EUSOMA undertook the commitment of defining the requirements for a specialist breast centre, which has become the reference document for the implementation of breast centres. Summary: The EUSOMA requirements for a specialist breast centre give clear indications regarding the requisite caseload, dedicated team composition (core and non-core team), organisation, availability of services and equipment throughout the patient pathway, quality control, and application of a multidisciplinary approach. The minimum number of cases is 150 newly diagnosed breast cancer cases per year. Based on the EUSOMA requirements, a voluntary and accredited certification scheme has been developed. In Europe, other voluntary certification schemes are available, such as those developed by the German Cancer Society and German Society for Breast Disease, the National Cancer Peer Review Programme in the UK, and the “label de qualité” established by the Swiss Anticancer League and the Swiss Senology Society. The European Commission Initiative on Breast Cancer (ECIBC) has overseen the development of a European Quality Assurance Scheme. Key Messages: Nearly 20 years after the initial publication of the EUSOMA requirements, ensuring that all breast cancer patients in Europe are treated only in certified breast centres should be considered a high priority and eventually achieved through collaborative efforts.

The emerging concept of generative dialogue is accompanied by strong claims for its benefit. A literature review identified six dominant models of generative dialogue across the range of disciplines of education, business studies, counselling and psychology. Through the analysis, commonalities and differences between the different models are identified, with an ultimate goal of providing an overarching description of those crucial attributes that make generative dialogue and its implementation beneficial as a management tool in education.

BACKGROUND: Prevention of bone metastases is a major issue for breast cancer patients, as it would improve quality of life in a population where long survival is anticipated. PATIENTS AND METHODS: Early breast cancer patients, who had been treated with anthracycline-based chemotherapy within two randomized trials, were included in the study. We evaluated, by quantitative reverse transcription–polymerase chain reaction, 819 formalin-fixed paraffin-embedded tumor tissue samples for mRNA expression of RANK, OPG, and RANKL, as well as their ratios, for potential prognostic significance for the development of bone metastases and also for disease-free survival (DFS) and overall survival. RESULTS: Median age was 52.7 years, whereas 54.2% of the patients were postmenopausal and 78.3% estrogen receptor/progesterone receptor positive. After a median follow-up of 119.9 months, 226 patients (27.6%) had died and 291 patients (35.5%) had disease progression. Low mRNA expression of RANKL was associated with postmenopausal status and greater number of positive lymph nodes (P = .002 and P

Breast cancer (BC) has historically been treated as a single disease entity; however, in the last decade, insights into its molecular heterogeneity have underpinned the development/commercialisation of several genomic tools whose goal is to guide patient management in early BC. These include the Oncotype DX® Breast Recurrence Score™ assay, MammaPrint®, Prosigna®, and EndoPredict®. Although these assays are similar in that they are all multigene assays reflecting risk of recurrence, they differ substantially in the technological platform used to measure gene expression; the number and identity of genes assessed; the patient populations used for development and validation; and the level of evidence supporting clinical utility. They also differ in the amount of evidence demonstrating their impact on treatment decisions and cost effectiveness in different countries. This review discusses these 4 assays, highlighting the clinical evidence that supports each of them, while focussing on the Recurrence Score assay. This assay has the greatest body of evidence supporting its clinical utility and decision impact/effectiveness, and currently is the only one validated as a predictor of response to adjuvant chemotherapy in hormone-receptor positive early BC patients treated with endocrine therapy and to be included as such in international/national BC treatment guidelines. The review also discusses ongoing prospective trials investigating the 4 assays, recent outcome studies, as well as analyses comparing different assays on the same tumour blocks.

The Breast Surgery theoretical and practical knowledge curriculum comprehensively describes the knowledge and skills expected of a fully trained breast surgeon practicing in the European Union and European Economic Area (EEA). It forms part of a range of factors that contribute to the delivery of high quality cancer care. It has been developed by a panel of experts from across Europe and has been validated by professional breast surgery societies in Europe. The curriculum maps closely to the syllabus of the Union of European Medical Specialists (UEMS) Breast Surgery Exam, the UK FRCS (breast specialist interest) curriculum and other professional standards across Europe and globally (USA Society of Surgical Oncology, SSO). It is envisioned that this will serve as the basis for breast surgery training, examination and accreditation across Europe to harmonise and raise standards as breast surgery develops as a separate discipline from its parent specialties (general surgery, gynaecology, surgical oncology and plastic surgery). The curriculum is not static but will be revised and updated by the curriculum development group of the European Breast Surgical Oncology Certification group (BRESO) every 2 years.

The primary treatment modality for breast cancer is surgery, which is a craft specialty requiring lengthy, high-quality training to achieve competency. This is especially true in an era of complex multidisciplinary oncology regimes and oncoplastic and reconstructive surgeries. Globally, training in breast surgery is highly variable in length, content, and quality, contributing to significant variation in the quality of care and outcomes. This chapter reviews training and its assessment and validation globally.

Ductal cancer in situ (DCIS) is mainly a screen-detected disease and although the risk for breast cancer is age-dependent, most screening programs do not include women over the age of 75 years. Older women are usually excluded from clinical trials and treatment practices are largely based on observational studies or extrapolation of trial results from younger patients, leading to either over- or under-treatment of this population. We systematically reviewed available electronic databases for DCIS treatment patterns and outcomes in older patients 15 years. Inclusion criteria allowed for randomised controlled trials, cohort studies, case-control and cross-sectional studies, as well as meta-analyses, systematic reviews and position papers. Results showed that, although elderly are not necessarily frail, they are generally treated as such by physicians, aiming to de-escalate therapeutic interventions. After adjusting for frailty, age seems to be a significant factor for less surgery; however, older women with DCIS are more probable to receive surgery than their counterparts with early invasive cancer. DCIS biology and subtypes are independent risk factors for local recurrence or progression to invasive carcinoma, if DCIS is under-treated. The end-benefit of surgery, radio- and endocrine-therapy depend on additional parameters, such as life expectancy, co-morbidities and competing risks of death. Screen-detected DCIS in older women is a challenging clinical problem, mainly due to the lack of high-level data. Therapeutic strategies should be tailored to life expectancy and performance status, DCIS features and patient preference, aiming at combining optimal oncological outcomes with maintenance of quality of life.

Tumor-infiltrating lymphocytes (TILs) and their subsets contribute to breast cancer prognosis. We investigated the prognostic impact of CD3+, CD8+ and FOXP3+ TILs in patients with early intermediate/high-risk breast cancer treated with adjuvant anthracycline-based chemotherapy within two randomized trials conducted by our Group. We examined 1011 patients (median follow-up 130.9 months) and their tumors for total, stromal (s) and intratumoral (i) CD3, CD8 and FOXP3 lymphocyte density (counts/mm2) on tissue-microarray cores by immunohistochemistry. Morphological sTIL density on whole H&E-stained sections was also evaluated. The majority of TILs were CD3+. Total CD3 and CD8, sCD3 and sCD8, iCD3 and iCD8, sFOXP3 and iFOXP3 were strongly correlated (Spearman’s rho values > 0.6). High individual lymphocytic subsets and sTIL density were strongly associated with high tumor grade, higher proliferation and HER2-positive and triple-negative tumors (all p values

This article outlines an approach to bridging the gap between the theory and practice of differentiated instruction. Differentiated instruction has long been suggested as a pedagogical approach to cater for student individuality and diversity, particularly in mixed-ability classrooms. Although the theory of differentiated instruction has been applied widely, such instruction has not been taken up widely in teaching practice. The first part of the article explores the relationship of theory and practice of differentiated instruction in relation to pedagogical content knowledge, teacher efficacy, formative assessment, teacher confidence and competence and professional learning. This exploration uses exemplar cases from mathematics teaching to pave the way for an outline, in the second part of the article, of how differentiated instruction could be implemented for the mixed-ability groupings increasingly engaged in the Australian secondary mathematics classroom. A protype practice framework for teachers is presented as part of a project being conducted in regional Australia, with the overall aim of assisting teachers in developing and implementing strategies for differentiated instruction in secondary mathematics classrooms.

Summary Background After 5 years of median follow-up, the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial reported no difference in disease-free survival between exemestane monotherapy and a sequential scheme of tamoxifen followed by exemestane in postmenopausal patients with early-stage, hormone receptor-positive breast cancer. As recurrence risk in hormone receptor-positive breast cancer remains linear beyond 5 years after diagnosis, we analysed long-term follow-up outcomes of this trial. Methods The TEAM trial, a multicentre, open-label, randomised, controlled, phase 3 trial, included postmenopausal patients with early-stage hormone receptor-positive breast cancer from nine countries. Patients were randomly allocated (1:1) by a computer-generated random permuted block method (block sizes 4–8) to either 5 years of oral exemestane monotherapy (25 mg once a day) or a sequential scheme of oral tamoxifen (20 mg once a day) followed by exemestane for a total duration of 5 years. After the publication of the IES trial, the protocol was amended (Dec 13, 2004). Patients assigned to tamoxifen were switched after 2·5–3·0 years to exemestane therapy for a total duration of 5·0 years of treatment. Randomisation was done centrally in each country. Long-term follow-up data for disease recurrence and survival was collected in six participating countries and analysed by intention to treat. The primary endpoint was disease-free survival at 10 years of follow-up. The trial is registered with ClinicalTrials.gov, numbers NCT00279448 and NCT00032136; with Netherlands Trial Register, number NTR 267; and the Ethics Commission Trial, number 27/2001. Findings 6120 patients of the original 9776 patients in the TEAM trial were included in the current intention-to-treat analysis. Median follow-up was 9·8 years (IQR 8·0–10·3). During follow-up, 921 (30%) of 3075 patients in the exemestane group and 929 (31%) of 3045 patients in the sequential group had a disease-free survival event. Disease-free survival at 10 years was 67% (95% CI 65–69) for the exemestane group and 67% (65–69) for the sequential group (hazard ratio 0·96, 0·88–1·05; p=0·39). Interpretation The long-term findings of the TEAM trial confirm that both exemestane alone and sequential treatment with tamoxifen followed by exemestane are reasonable options as adjuvant endocrine therapy in postmenopausal patients with hormone receptor-positive early breast cancer. These results suggest that the opportunity to individualise adjuvant endocrine strategy accordingly, based on patient preferences, comorbidities, and tolerability might be possible. Funding Pfizer, Dutch Cancer Foundation.

Student mathematics performance and the need for work-ready graduates to be mathematics-competent is a core issue for many universities. While both student and teacher are responsible for learning outcomes, there is a need to explicitly acknowledge the weak mathematics foundation of many university students. A systematic literature review was undertaken of identified innovations and/or interventions that may lead to improvement in student outcomes for university mathematics-based units of study. The review revealed the importance of understanding the foundations of student performance in higher education mathematics learning, especially in first year. Pre-university mathematics skills were identified as significant in student retention and mathematics success at university, and a specific focus on student pre-university mathematics skill level was found to be more effective in providing help, rather than simply focusing on a particular at-risk group. Diagnostics tools were found to be important in...

The aim of the study is to compare the efficacy of SPIO as a tracer in sentinel node biopsy (SNB) in breast cancer with Tc and patent blue in a multicentre prospective study and perform a meta-analysis of all published studies. It also aims to follow skin discoloration after SPIO injection and describe when and how it resolves. Totally 206 patients with early breast cancer were recruited. Tc and patent blue were administered in standard fashion. Patients were injected with SPIO (Sienna+) preoperatively. SNB was performed and detection rates were recorded for both methods. Skin discoloration was followed and documented postoperatively. Data extraction and subsequent meta-analysis of all previous studies were also performed. SN detection rates were similar between standard technique succeeded and SPIO both per patient (97.1 vs. 97.6 %, p = 0.76) as well as per node (91.3 vs. 93.3 %, p = 0.34), something which was not affected by the presence of malignancy. Concordance rates were also consistently high (98.0 % per patient and 95.9 % per node). Discoloring was present in 35.5 % of patients postoperatively, almost exclusively in breast conservation. It fades slowly and is still detectable in 8.6 % of patients after 15 months. Meta-analysis depicted similar detection rates (p = 0.71) and concordance rates (p = 0.82) per patient. However, it seems that SPIO is characterized by higher nodal retrieval (p < 0.001). SPIO is an effective method for the detection of SN in patients with breast cancer. It is comparable to the standard technique and seems to simplify logistics. Potential skin discoloration is something of consideration in patients planned for breast conservation.

e12534 Background: The purpose of this analysis is to evaluate how many patients previously treated according to OncotypeDX Recurrence Score (RS) could have been spared of Chemotherapy if the TAILORx RS data had been taken into account in the clinical treatment decisions. Methods: A series of 182 patients, 34-74 years of age with early breast cancer, treated in our Breast Unit during the last 10 years, for whom treatment decisions were based on OncotypeDX RS. The Recurrence Scores of all these patients were obtained and the actual treatment decisions that were made based on the pre-TAILORx cut-offs of RS 18 and 31 were recorded. These decisions were then re-evaluated based on the after TAILORx cut-off scores, by taking also into consideration the patients’ age. Descriptive statistics were used as well as logistic regression models to estimate the potential change in treatment decisions based on the new Oncotype Dx cut-offs. Results: In the cohort of patients we analyzed that underwent Oncotype Dx testing, 34.1% (62/182) received Chemotherapy, based on the initial pre-TAILORX cut-offs of the RS. When utilizing the new cut-offs (after TAILORx results) in combination with age, we have estimated that, for the patients > 50 years of age, a 12.7% was potentially over-treated and for those ≤50 years old, 9.1% was potentially over-treated since they have received chemotherapy with a RS below 16; additionally, 30.8% of the patients of that age that have RS between 16 and 20 have received chemotherapy even though the average chemotherapy benefit for this group is 1.6% and can go up to 6.7% if they have a high clinical risk as it was defined by the investigators of the TAILORx trial. Finally, 84,6% of patients ≤50 years old with RS between 21-25 received chemotherapy with a 6.5% potential benefit demonstrated in the TAILORx trial. Conclusions: Our analysis suggests that, by using the cut-offs of TAILORx trial, adjuvant chemotherapy could had been omitted in at least a further 11.5% of patients with early breast cancer, reassuring their quality of life without declining their prognosis.

Several studies support an important role of angiogenesis in breast cancer growth and metastasis. The main objectives of the study were to investigate the immunohistochemical expression of vascular endothelial growth factor (VEGF) family ligands (VEGF-A and VEGF-C) and receptors (VEGFR1, VEGFR2 and VEGFR3) in breast cancer and their associations with clinicopathological parameters, cancer subtypes/subgroups and patient outcome. Formalin-fixed paraffin-embedded tumor tissue samples were collected from early-stage breast cancer patients treated with anthracycline-based chemotherapy within a randomized trial. Immunohistochemistry was performed on serial 2.5 μm thick tissue sections from tissue microarray blocks. High VEGF-A, VEGF-C, VEGFR1, VEGFR2 and VEGFR3 protein expression was observed in 11.8% (N = 87), 80.8% (N = 585), 28.1% (N = 202), 64.6% (N = 359) and 71.8% (N = 517) of the cases, respectively. Significant associations were observed among all proteins (all p-values

Background:\ud Aromatase inhibitors improve disease-free survival compared with tamoxifen in postmenopausal women with hormone receptor–positive breast cancer. The Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial compared exemestane monotherapy with sequential therapy of tamoxifen followed by exemestane. The trial failed to show a statistically significant difference between treatment arms. A robust translational program was established to investigate predictive biomarkers.\ud \ud Methods:\ud A tissue microarray was retrospectively constructed using a subset of patient tissues (n = 4631) from the TEAM trial (n = 9766). Immunohistochemistry was performed for biomarkers, classed into three groups: MAPK pathway, NF-kappa B pathway, and estrogen receptor (ER) phosphorylation. Expression was analyzed for association with relapse-free survival (RFS) at 2.5 and 10 years and treatment regimen using Kaplan-Meier curves and log-rank analysis. All statistical tests were two-sided.\ud \ud Results:\ud In univariate analysis, ER167 (hazard ratio [HR] = 0.71, 95% confidence interval [CI] = 0.59 to 0.85, P < .001), IKKα (HR = 0.74, 95% CI = 0.60 to 0.92, P = .005), Raf-1338 (HR = 0.64, 95% CI = 0.52 to 0.80, P < .001), and p44/42 MAPK202/204 (HR = 0.77, 95% CI = 0.64 to 0.92, P = .004) were statistically significantly associated with improved RFS at 10 years in patients receiving sequential therapy. Associations were strengthened when IKKα, Raf-1338, and ER167 were combined into a cumulative prognostic score (HR = 0.64, 95% CI = 0.52 to 0.77, P