An Exploration of the Pillars of Leadership in Cancer Education.

Leadership plays a key role in cancer education (CE) and the success of its practices. Leaders in CE must effectively use their leadership skills to be able to communicate, collaborate, and educate their team members. There is a lack of formalized and standardized curriculums for institutions in developing leadership programs, including what themes to focus on in CE. In this article, the authors describe key pillars of leadership in CE that have presented themselves throughout their experience and within the literature. A search was conducted using the Ovid MEDLINE® database and articles were reviewed for eligibility. In this review, thirty articles were selected for their relevance to CE. With this literature search and the authors' reflections, four pillars of leadership in CE were identified: (1) leadership development, (2) collaboration, (3) diversity and equity, and (4) implementation. Within these themes, key areas of importance were discussed further, and barriers to CE leadership were identified. By reflecting upon pillars of leadership in CE, this article may be helpful for developing future leadership programs within CE. It is vital that initiatives continue to be held and barriers are addressed to increase leadership effectiveness within CE.

Treatment and outcomes in breast cancer patients: A cross section study from the EUSOMA breast centre network.

INTRODUCTION: The present study was designed to describe tumour features and treatments for patients with breast cancer. It also aimed at assessing the risk of distant metastases in relation to biological profiles, disease stages and treatment. METHODS: Data were analysed from 81,882 patients in the EUSOMA database (disease stages at diagnosis 0-IV; median age 61 years; range 20-100 years). All patients were treated between January 2016 and December 2021 in 53 Breast Centres within the EUSOMA certification process in 13 European countries. Cases were classified as HR+ /HER2-, HR+ /HER2 + , HR-/HER2 + or HR-/HER2- and data were analysed accordingly. RESULTS: Univariable and multivariable analyses for distant metastases were conducted on a subset of 38,119 cases with information on whether or not they had developed them. Potential determinants included sub-group type, Ki67 value, disease stage, adjuvant systemic therapies and post-operative radiation therapy. In multivariable analysis, the HR-/HER2 + and HR-/HER2- sub-groups were associated with a higher risk of distant metastases than HR+ /HER2-. Ki67 > 20 % and advanced stage disease also carried a high risk. Radiation therapy emerged as a protective factor against distant metastases. CONCLUSIONS: Present results show a large patient database offers an information stream that can be applied to reduce uncertainties in clinical practice. Database parameters need to be updated dynamically for outcome monitoring. Molecular prognostic factors, gene-expression signatures, tumour-infiltrating lymphocytes and circulating tumoral DNA should be added.

The impact of the SARS-COV-2 pandemic on the quality of breast cancer care in EUSOMA-certified breast centres.

AIMS: We analysed the impact of the SARS-CoV-2 pandemic (COVID-19) on the quality of breast cancer care in certified EUSOMA (European Society of Breast Cancer Specialists) breast centres. MATERIALS AND METHODS: The results of the EUSOMA quality indicators were compared, based on pseudonymised individual records, for the periods 1 March 2020 till 30 June 2020 (first COVID-19 peak in most countries in Europe) and 1 March 2019 till 30 June 2019. In addition, a questionnaire was sent to the participating Centres for investigating the impact of the COVID-19 pandemic on the organisation and the quality of breast cancer care. RESULTS: Forty-five centres provided data and 31 (67%) responded to the questionnaire. The total number of new cases dropped by 19% and there was a small significant higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation. Comparing quality indicators (12,736 patients) by multivariable analysis showed mostly non-significant differences. Surgery could be performed in a COVID-free zone in 94% of the centres, COVID testing was performed before surgery in 96% of the centres, and surgical case load was reduced in 55% of the centres. Modifications of the indications for neoadjuvant endocrine therapy, chemotherapy, and targeted therapy were necessary in 23%, 23%, and 10% of the centres; changes in indications for adjuvant endocrine, chemo-, targeted, immune, and radiotherapy in 3%, 19%, 3%, 6%, and 10%, respectively. CONCLUSION: Quality of breast cancer care was well maintained in EUSOMA breast centres during the first wave of the COVID-19 pandemic. A small but significantly higher tumour and lymph node stage at presentation was observed.

Longitudinal Serum Protein Analysis of Women with a High Risk of Developing Breast Cancer Reveals Large Interpatient Versus Small Intrapatient Variations: First Results from the TESTBREAST Study.

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection.

Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers.

BACKGROUND: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. METHODS: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. RESULTS: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. CONCLUSION: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.

Implementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers.

During the last decade, the emerging field of molecular fluorescence imaging has led to the development of tumor-specific fluorescent tracers and an increase in early-phase clinical trials without having consensus on a standard methodology for evaluating an optical tracer. By combining multiple complementary state-of-the-art clinical optical imaging techniques, we propose a novel analytical framework for the clinical translation and evaluation of tumor-targeted fluorescent tracers for molecular fluorescence imaging which can be used for a range of tumor types and with different optical tracers. Here we report the implementation of this analytical framework and demonstrate the tumor-specific targeting of escalating doses of the near-infrared fluorescent tracer bevacizumab-800CW on a macroscopic and microscopic level. We subsequently demonstrate an 88% increase in the intraoperative detection rate of tumor-involved margins in primary breast cancer patients, indicating the clinical feasibility and support of future studies to evaluate the definitive clinical impact of fluorescence-guided surgery.

Micro-computed tomography (micro-CT) for intraoperative surgical margin assessment of breast cancer: A feasibility study in breast conserving surgery.

PURPOSE: Around 15%-30% of patients receiving breast-conserving surgery (BCS) for invasive breast carcinoma or ductal carcinoma in situ (DCIS) need a reoperation due to tumor-positive margins at final histopathology. Currently available intraoperative surgical margin assessment modalities all have specific limitations. Therefore, we aimed to assess the feasibility and accuracy of micro-computed tomography (micro-CT) as a novel method for intraoperative margin assessment in BCS. METHODS: Lumpectomy specimens from 30 consecutive patients diagnosed with invasive breast cancer or DCIS were imaged using a micro-CT. Margin status was assessed on micro-CT images by two investigators who were blinded to the final histopathological margin status. The micro-CT margin status was compared with the histopathological margin status. RESULTS: The margin status could be assessed by micro-CT in 29 out of 30 patients. Of these, nine patients had a positive tumor margin and 20 a negative tumor margin at final histopathology. Margin status evaluation by micro-CT took always less than 15 min. The margin status in 25 patients was correctly predicted by micro-CT. There were four false-negative predictions. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of micro-CT in margin status prediction were 86%, 56%, 100%, 100% and 83%, respectively. With micro-CT, the positive margin rate could potentially have been reduced from 31% to 14%. CONCLUSIONS: Whole lumpectomy specimen micro-CT scanning is a promising technique for intraoperative margin assessment in BCS. Intraoperative quick feedback on the margin status could potentially lead to a reduction in the number of reoperations.

Evolution in sentinel lymph node biopsy in breast cancer.

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in clinically node-negative (cN0) breast cancer patients without neoadjuvant chemotherapy (NAC). The application of SLNB in patients receiving NAC has also been explored. Evidence supports its use after NAC in pretreatment cN0 patients. Nonetheless, its routine use in all the pretreatment node-positive patients who become cN0 after NAC is unjustified due to the unacceptably high false-negative rate, which can be improved in a subset of patients. Axillary surgery omission in selected patients with a low risk of ALN metastasis has gained more and more research interest because the SLNs are tumor-free in more than 70% of all patients. To avoid drawbacks of conventional mapping methods, novel techniques for SLN detection have been developed and shown to be highly accurate in patients with early breast cancer. This article reviews the progress in SLNB in patients with breast cancer.

The Impact of Curriculum Design in the Acquisition of Knowledge of Oncology: Comparison Among Four Medical Schools.

Over the past 5 years, cancer has replaced coronary heart disease as the leading cause of death in the Netherlands. It is thus paramount that medical doctors acquire a knowledge of cancer, since most of them will face many patients with cancer. Studies, however, have indicated that there is a deficit in knowledge of oncology among medical students, which may be due not only to the content but also to the structure of the curriculum. In this study, we compared students' knowledge acquisition in four different undergraduate medical programs. Further, we investigated possible factors that might influence students' knowledge growth as related to oncology. The participants comprised 1440 medical students distributed over four universities in the Netherlands. To measure students' knowledge of oncology, we used their progress test results from 2007 to 2013. The progress test consists of 200 multiple-choice questions; this test is taken simultaneously four times a year by all students. All questions regarding oncology were selected. We first compared the growth of knowledge of oncology using mixed models. Then, we interviewed the oncology coordinator of each university to arrive at a better insight of each curriculum. Two schools showed similar patterns of knowledge growth, with a slight decrease in the growth rate for one of them in year 6. The third school had a faster initial growth with a faster decrease over time compared to other medical schools. The fourth school showed a steep decrease in knowledge growth during years 5 and 6. The interviews showed that the two higher-scoring schools had a more focused semester on oncology, whereas in the others, oncology was scattered throughout the curriculum. Furthermore, the absence of a pre-internship training program seemed to hinder knowledge growth in one school. Our findings suggest that curricula have an influence on students' knowledge acquisition. A focused semester on oncology and a pre-internship preparatory training program are likely to have a positive impact on students' progress in terms of knowledge of oncology.

The Impact of Massed and Spaced-Out Curriculum in Oncology Knowledge Acquisition.

Starting in 2009, cancer has been the leading cause of death in the Netherlands. Oncology is therefore an important part of the medical curriculum in undergraduate education. It is crucial that medical students know about cancer, since doctors will encounter many cases of oncology. We have compared the influence that teaching oncology has when spread over a 3-year curriculum versus concentrated in one semester. The participants comprised 525 medical students from one medical school with comprehensive integrated curricula. Of those, 436 followed the massed curriculum, with oncology concentrated in one semester. The remaining 89 students followed a spaced-out curriculum, in which oncology was spread out over 3 years. To measure students' knowledge, we used their progress test results from 2009 to 2012. All questions about oncology were categorized and selected. Because of our unbalanced sample and missing data and to reduce the chances for a type II error, we compared the growth of oncology questions using mixed effect models. A cubic growth model with an unstructured covariance matrix fitted our data best. At the start, students in the spaced-out curriculum scored higher on oncology questions. The initial growth was faster for the spaced-out curriculum students, whereas the acceleration over time was slower compared to the massed curriculum students. At the end of the growth curve, the knowledge of the massed curriculum students increased faster. In the last test, the massed curriculum students outperformed those in the spaced-out curriculum. The way students acquired and applied their knowledge was similar in both curricula. It seems, however, that students benefitted more from massed than spaced-out education, which may be due to the comprehensive integrated teaching involved.

Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study.

Purpose: To provide proof of principle of safety, breast tumor-specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer.Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.Conclusions: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730-41. ©2016 AACR.

Threshold Analysis and Biodistribution of Fluorescently Labeled Bevacizumab in Human Breast Cancer.

In vivo tumor labeling with fluorescent agents may assist endoscopic and surgical guidance for cancer therapy as well as create opportunities to directly observe cancer biology in patients. However, malignant and nonmalignant tissues are usually distinguished on fluorescence images by applying empirically determined fluorescence intensity thresholds. Here, we report the development of fSTREAM, a set of analytic methods designed to streamline the analysis of surgically excised breast tissues by collecting and statistically processing hybrid multiscale fluorescence, color, and histology readouts toward precision fluorescence imaging. fSTREAM addresses core questions of how to relate fluorescence intensity to tumor tissue and how to quantitatively assign a normalized threshold that sufficiently differentiates tumor tissue from healthy tissue. Using fSTREAM we assessed human breast tumors stained in vivo with fluorescent bevacizumab at microdose levels. Showing that detection of such levels is achievable, we validated fSTREAM for high-resolution mapping of the spatial pattern of labeled antibody and its relation to the underlying cancer pathophysiology and tumor border on a per patient basis. We demonstrated a 98% sensitivity and 79% specificity when using labeled bevacizumab to outline the tumor mass. Overall, our results illustrate a quantitative approach to relate fluorescence signals to malignant tissues and improve the theranostic application of fluorescence molecular imaging. Cancer Res; 77(3); 623-31. ©2016 AACR.

Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers.

PURPOSE: Recommendations for treating patients who carry a BRCA1/2 gene are mainly based on cumulative lifetime risks (CLTRs) of breast cancer determined from retrospective cohorts. These risks vary widely (27% to 88%), and it is important to understand why. We analyzed the effects of methods of risk estimation and bias correction and of population factors on CLTRs in this retrospective clinical cohort of BRCA1/2 carriers. PATIENTS AND METHODS: The following methods to estimate the breast cancer risk of BRCA1/2 carriers were identified from the literature: Kaplan-Meier, frailty, and modified segregation analyses with bias correction consisting of including or excluding index patients combined with including or excluding first-degree relatives (FDRs) or different conditional likelihoods. These were applied to clinical data of BRCA1/2 families derived from our family cancer clinic for whom a simulation was also performed to evaluate the methods. CLTRs and 95% CIs were estimated and compared with the reference CLTRs. RESULTS: CLTRs ranged from 35% to 83% for BRCA1 and 41% to 86% for BRCA2 carriers at age 70 years width of 95% CIs: 10% to 35% and 13% to 46%, respectively). Relative bias varied from -38% to +16%. Bias correction with inclusion of index patients and untested FDRs gave the smallest bias: +2% (SD, 2%) in BRCA1 and +0.9% (SD, 3.6%) in BRCA2. CONCLUSION: Much of the variation in breast cancer CLTRs in retrospective clinical BRCA1/2 cohorts is due to the bias-correction method, whereas a smaller part is due to population differences. Kaplan-Meier analyses with bias correction that includes index patients and a proportion of untested FDRs provide suitable CLTRs for carriers counseled in the clinic.

[A woman with a red nipple with purulent discharge]. / Een vrouw met een rode tepel met purulent vocht.

We describe a 49-year-old woman who presented to the surgeon with recurring complaints of her right nipple, such as redness, pain, swelling and purulent discharge from the areolar margin. The diagnosis 'Zuska's disease' should be distinguished from breast cancer, Paget's and Mondor's disease. Treatment is surgical with a microdochectomy.

Genetic testing and familial implications in breast-ovarian cancer families.

DNA-testing for BRCA1 and BRCA2 has become incorporated in the diagnostic procedure of patients with breast and/or ovarian cancer. Since 1994 an immense amount of information has been gathered on mutation spectra, mutation risk assessment, cancer risks for mutation carriers, factors that modify these risks, unclassified DNA variants, surveillance strategies and preventive options. For the patient and family the main determinator still is whether a mutation is found or not. When a pathogenic mutation is detected in an index case, relatives can opt for pre-symptomatic DNA testing. However in the vast majority no mutation, or only unclear mutations are detectable yet. This means that a hereditary cause cannot be excluded, but pre-symptomatic DNA-testing is still unavailable for relatives. Surveillance for both index cases and relatives is based of the family history of cancer. Next generation genetic testing may help to elucidate genetic causes in these families.

Risk-reducing mastectomy in BRCA1/2 mutation carriers: factors influencing uptake and timing.

INTRODUCTION: Strategies in case of high risk of breast cancer in BRCA1/2 mutation carriers are either intensive breast cancer screening or risk-reducing mastectomy (RRM). Both options have a high physical and psychosexual impact. The aim of this study is to investigate who chooses when to undergo RRM. METHODS: BRCA1/2 mutation carriers have been prospectively registered at the family cancer clinic between 1994 and 2011. Analyses were performed to assess the relation between characteristics of the BRCA1/2 mutation carriers and an earlier decision for RRM. RESULTS: A cumulative percentage of 35.6% of all women chose to undergo RRM within the first five years after disclosure of DNA test results. Women needed less time to choose for RRM measured from the first visit, if they were younger than 50 years of age (hazard ratio (HR)=2.67, 95% confidence interval (CI)=1.30-5.48) or had a mother who had had breast cancer (HR=1.51 95% CI=1.04-2.18). Also, women needed less time to choose for RRM in case of a previous breast cancer (HR=2.25, 95% CI=1.55-3.27). After a previous unilateral therapeutic mastectomy as a treatment for breast cancer, women needed less time to choose for RRM of the contralateral breast (HR=2.69, 95% CI=1.29-5.62) compared to women who had had breast-conserving therapy. CONCLUSION: BRCA1/2 mutation carriers aged under 50, having a mother with breast cancer, who had previous unilateral breast cancer and previous unilateral therapeutic mastectomy chose more often and earlier for RRM.

89Zr-bevacizumab PET imaging in primary breast cancer.

UNLABELLED: Vascular endothelial growth factor (VEGF)-A is overexpressed in most malignant and premalignant breast lesions. VEGF-A can be visualized noninvasively with PET imaging and using the tracer (89)Zr-labeled bevacizumab. In this clinical feasibility study, we assessed whether VEGF-A in primary breast cancer can be visualized by (89)Zr-bevacizumab PET. METHODS: Before surgery, breast cancer patients underwent a PET/CT scan of the breasts and axillary regions 4 d after intravenous administration of 37 MBq of (89)Zr-bevacizumab per 5 mg. PET images were compared with standard imaging modalities. (89)Zr-bevacizumab uptake was quantified as the maximum standardized uptake value (SUV max). VEGF-A levels in tumor and normal breast tissues were assessed with enzyme-linked immunosorbent assay. Data are presented as mean ± SD. RESULTS: Twenty-five of 26 breast tumors (mean size ± SD, 25.1 ± 19.8 mm; range, 4-80 mm) in 23 patients were visualized. SUV max was higher in tumors (1.85 ± 1.22; range, 0.52-5.64) than in normal breasts (0.59 ± 0.37; range, 0.27-1.69; P < 0.001). The only tumor not detected on PET was 10 mm in diameter. Lymph node metastases were present in 10 axillary regions; 4 could be detected with PET (SUV max, 2.66 ± 2.03; range, 1.32-5.68). VEGF-A levels in the 17 assessable tumors were higher than in normal breast tissue in all cases (VEGF-A/mg protein, 184 ± 169 pg vs. 10 ± 21 pg; P = 0.001), whereas (89)Zr-bevacizumab tumor uptake correlated with VEGF-A tumor levels (r = 0.49). CONCLUSION: VEGF-A in primary breast cancer can be visualized by means of (89)Zr-bevacizumab PET.