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Background: To provide a systematic review and meta-analysis that evaluates the diagnostic accuracy of contrast-enhanced mammography (CEM) compared to standard contrast-enhanced breast magnetic resonance imaging (breast MRI). Like breast MRI, CEM enables tumour visualization by contrast accumulation. CEM seems to be a viable substitute for breast MRI.Methods: This systematic search assessed the diagnostic accuracy of these techniques in women with suspicious breast lesions on prior imaging or physical examination, who have undergone both breast MRI and CEM. CEM had to be performed on a commercially available system. The MRI sequence parameters had to be described sufficiently to ensure that standard breast MRI sequence protocols were used. Pooled values of sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR), were estimated using bivariate mixed-effects logistic regression modeling. Hierarchical summary receiver operating characteristic curves for CEM and breast MRI were also constructed.Results: Six studies (607 patients with 775 lesions) met the predefined inclusion criteria. Pooled sensitivity was 96% for CEM and 97% for breast MRI. Pooled specificity was 77% for both modalities. DOR was 79.5 for CEM and 122.9 for breast MRI. Between-study heterogeneity expressed as the I2-index was substantial with values over 80%.Conclusion: Pooled sensitivity was high for both CEM and breast MRI, with moderate specificity. The pooled DOR estimates, however, indicate higher overall diagnostic performance of breast MRI compared to CEM. Nonetheless, current scientific evidence is too limited to prematurely discard CEM as an alternative for breast MRI.

Objectives In approximately 45% of invasive breast cancer (IBC) patients treated with neoadjuvant systemic therapy (NST), ductal carcinoma in situ (DCIS) is present. Recent studies suggest response of DCIS to NST. The aim of this systematic review and meta-analysis was to summarise and examine the current literature on imaging findings for different imaging modalities evaluating DCIS response to NST. More specifically, imaging findings of DCIS pre- and post-NST, and the effect of different pathological complete response (pCR) definitions, will be evaluated on mammography, breast MRI, and contrast-enhanced mammography (CEM). Methods PubMed and Embase databases were searched for studies investigating NST response of IBC, including information on DCIS. Imaging findings and response evaluation of DCIS were assessed for mammography, breast MRI, and CEM. A meta-analysis was conducted per imaging modality to calculate pooled sensitivity and specificity for detecting residual disease between pCR definition no residual invasive disease (ypT0/is) and no residual invasive or in situ disease (ypT0). Results Thirty-one studies were included. Calcifications on mammography are related to DCIS, but can persist despite complete response of DCIS. In 20 breast MRI studies, an average of 57% of residual DCIS showed enhancement. A meta-analysis of 17 breast MRI studies confirmed higher pooled sensitivity (0.86 versus 0.82) and lower pooled specificity (0.61 versus 0.68) for detection of residual disease when DCIS is considered pCR (ypT0/is). Three CEM studies suggest the potential benefit of simultaneous evaluation of calcifications and enhancement. Conclusions and Clinical Relevance Calcifications on mammography can remain despite complete response of DCIS, and residual DCIS does not always show enhancement on breast MRI and CEM. Moreover, pCR definition effects diagnostic performance of breast MRI. Given the lack of evidence on imaging findings of response of the DCIS component to NST, further research is demanded. Key Points • Ductal carcinoma in situ has shown to be responsive to neoadjuvant systemic therapy, but imaging studies mainly focus on response of the invasive tumour. • The 31 included studies demonstrate that after neoadjuvant systemic therapy, calcifications on mammography can remain despite complete response of DCIS and residual DCIS does not always show enhancement on MRI and contrast-enhanced mammography. • The definition of pCR has impact on the diagnostic performance of MRI in detecting residual disease,and when DCIS is considered pCR, pooled sensitivity was slightly higher and pooled specificity slightly lower.

Background Gut bacteria-derived short-chain fatty acids (SCFA) and branched-chain fatty acids (BCFA) are considered to have beneficial metabolic, anti-inflammatory as well as anti-carcinogenic effects. Previous preclinical studies indicated bidirectional interactions between gut bacteria and the chemotherapeutic capecitabine or its metabolite 5-FU. This study investigated the effect of three cycles of capecitabine on fecal SCFA and BCFA levels and their associations with tumor response, nutritional status, physical performance, chemotherapy-induced toxicity, systemic inflammation and bacterial abundances in patients with colorectal cancer (CRC). Methods Forty-four patients with metastatic or unresectable CRC, scheduled for treatment with capecitabine (± bevacizumab), were prospectively enrolled. Patients collected a fecal sample and completed a questionnaire before (T1), during (T2) and after (T3) three cycles of capecitabine. Tumor response (CT/MRI scans), nutritional status (MUST score), physical performance (Karnofsky Performance Score) and chemotherapy-induced toxicity (CTCAE) were recorded. Additional data on clinical characteristics, treatment regimen, medical history and blood inflammatory parameters were collected. Fecal SCFA and BCFA concentrations were determined by gas chromatography–mass spectrometry (GC–MS). Gut microbiota composition was assessed using 16S rRNA amplicon sequencing. Results Fecal levels of the SCFA valerate and caproate decreased significantly during three cycles of capecitabine. Furthermore, baseline levels of the BCFA iso-butyrate were associated with tumor response. Nutritional status, physical performance and chemotherapy-induced toxicity were not significantly associated with SCFA or BCFA. Baseline SCFA correlated positively with blood neutrophil counts. At all time points, we identified associations between SCFA and BCFA and the relative abundance of bacterial taxa on family level. Conclusions The present study provided first indications for a potential role of SCFA and BCFA during capecitabine treatment as well as implications for further research. Trial registration The current study was registered in the Dutch Trial Register (NTR6957) on 17/01/2018 and can be consulted via the International Clinical Trial Registry Platform (ICTRP).

Background Intestinal microbiota might interact with capecitabine and vice versa. Patients and methods 33 mCRC patients collected faecal samples before, during, and after three cycles capecitabine. Results Intestinal microbiota were not affected by capecitabine and not different between responders and non-responders. Conclusions Our study provides insights into challenges and points of attention for the design of upcoming clinical microbiota studies. Background Previous pre-clinical research has indicated that the intestinal microbiota can potentiate anti-tumour efficacy of capecitabine and that capecitabine treatment impacts intestinal microbiota composition and diversity. Using a longitudinal design, this study explores the associations between the intestinal microbiota and treatment response in patients with metastatic colorectal cancer (mCRC) during capecitabine treatment. Patients and methods Patients with mCRC treated with capecitabine were prospectively enrolled in a multicentre cohort study. Patients collected a faecal sample and completed a questionnaire before, during, and after three cycles of capecitabine. Several clinical characteristics, including tumour response, toxicity and antibiotic use were recorded. Intestinal microbiota were analysed by amplicon sequencing of the 16S rRNA V4 gene-region. Results 33 patients were included. After three cycles of capecitabine, six patients (18%) achieved a partial response, 25 (76%) showed stable disease, and one (3%) experienced progressive disease. 90 faecal samples were collected. Microbial diversity (α-diversity), community structure (β-diversity), and bacterial abundance on phylum and genus level were not significantly different between responders and non-responders and were not significantly affected by three cycles of capecitabine. Conclusions This is the first clinical study with longitudinal intestinal microbiota sampling in mCRC patients that explores the role of the intestinal microbiota during treatment with capecitabine. Intestinal microbiota composition and diversity before, during, and after three cycles of capecitabine were not associated with response in this study population. Capecitabine did not induce significant changes in the microbiota composition and diversity during the treatment period. Individual effects of antibiotics during capecitabine treatment were observed.

Purpose The hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the main parameters in guiding systemic treatment choices in breast cancer, but can change during the disease course. This study aims to evaluate the biopsy rate and receptor subtype discordance rate in patients diagnosed with advanced breast cancer (ABC). Methods Patients diagnosed with ABC in seven hospitals in 2007–2018 were selected from the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Multivariable logistic regression analyses were performed to identify factors influencing biopsy and discordance rates. Results Overall, 60% of 2854 patients had a biopsy of a metastatic site at diagnosis. One of the factors associated with a reduced biopsy rate was the HR + /HER2 + primary tumor subtype (versus HR + /HER2- subtype: OR = 0.68; 95% CI: 0.51–0.90). Among the 748 patients with a biopsy of the primary tumor and a metastatic site, the overall receptor discordance rate was 18%. This was the highest for the HR + /HER2 + primary tumor subtype, with 55%. In 624 patients with metachronous metastases, the HR + /HER2 + subtype remained the only predictor significantly related to a higher discordance rate, irrespective of prior (neo-)adjuvant therapies (OR = 7.49; 95% CI: 3.69–15.20). Conclusion The HR + /HER2 + subtype has the highest discordance rate, but the lowest biopsy rate of all four receptor subtypes. Prior systemic therapy was not independently related to subtype discordance. This study highlights the importance of obtaining a biopsy of metastatic disease, especially in the HR + /HER2 + subtype to determine the most optimal treatment strategy.

In node positive breast cancer patients who are treated with neoadjuvant systemic therapy, axillary staging and treatment is still a topic of debate. This multicenter study will contribute to evidence-based guidelines with regard to the oncologic safety and impact on quality of life of less vs. more invasive axillary staging and treatment strategies.Background: Node positive breast cancer (cN+) patients with an axillary pathologic complete response after neoadjuvant systemic therapy (NST) are not expected to benefit from axillary lymph node dissection (ALND). Therefore, less invasive axillary staging procedures have been introduced to establish response-guided treatment. However, evidence is lacking with regard to their oncologic safety and impact on quality of life (QoL). We hypothesize that if response-guided treatment is given, less invasive staging procedures are non-inferior to standard ALND in terms of oncologic safety, and superior to standard ALND in terms of QoL. Patients and Methods: MINIMAX is a Dutch multicenter registry study that includes patients with cN1-3M0 unilateral invasive breast cancer, who receive NST, followed by axillary staging and treatment according to local protocols. In a retrospective registry of +/- 4000 patients, the primar y endpoint is oncologic safety at 5 and 10 years (disease-free, breast-cancer-specific and overall survival, and axillary recurrence rate). In a prospective multicenter registry, the primar y endpoints are QoL at 1 and 5 years, and we aim to verify the 5-year oncologic safety. With an estimated 5-year disease-free survival of 72.5% and anticipated loss to follow-up of 10%, a sample size of 549 is needed to have 80% power to detect non-infer iority (with a 10% margin) of less invasive staging procedures. Conclusion: In cN+ patients treated with NST, less invasive axillary staging procedures are already implemented globally. Evidence is needed to support the assumed oncologic safety and superior QoL of such procedures. This study will contribute to evidence-based guidelines. (C) 2021 The Authors. Published by Elsevier Inc.

INTRODUCTION: Neoadjuvant systemic therapy (NST) is increasingly applied in breast cancer to improve surgical and oncological outcome. Approximately 21% of patients receiving NST achieve pathological complete response (pCR) of the breast. There is disagreement on the definition of pCR with respect to residual DCIS (ypT0 versus ypT0/is). The aim of this retrospective study was to determine the percentage of breast pCR (ypT0) and residual DCIS (ypTis), and its association with clinicopathological variables, in patients treated with NST and surgery.MATERIALS AND METHODS: Patients with invasive breast cancer treated with neoadjuvant chemotherapy, with or without targeted therapy, in the period of 2010-2019 were selected from the Netherlands Cancer Registry (NCR). Descriptive statistics and multivariable logistic regression analyses were used to analyse the percentage of ypT0 and ypTis and its association with clinicopathological variables.RESULTS: From the NCR database, 20495 patients were included, of whom 5847 (28.5%) achieved breast pCR (ypT0) and 881 (4.3%) showed residual DCIS (ypTis). The percentage of ypTis was highest in HER2+ tumour subtypes (ER+HER2+ 7.9%, ER-HER2+ 9.8%, ER+HER2- 2.1%, triple negative 3.3%, p < 0.001). Multivariable logistic regression analyses demonstrated high tumour grade (OR 2.00, p = 0.003) and HER2+ tumour subtype (ER+HER2+ OR 3.58, ER-HER2+ OR 4.37, p < 0.001) as independent predictors for ypTis.CONCLUSION: pCR (ypT0) was achieved in 5847 (28.5%) patients receiving NST and residual DCIS (ypTis) was found in 881 (4.3%) patients. Consequently, the rate of pCR may be affected by ypTis when not excluded from the definition. The percentage of ypTis is highest in HER2+ subtypes.

Simple Summary Neoadjuvant chemo(targeted) therapy (NCT) can downstage disease burden in breast cancer, allowing less invasive surgery. The ability of sequential hybrid [18F]FDG PET/MRI to predict the final pathologic primary tumour response to NCT in breast cancer was investigated. In addition, the value of sequential hybrid [18F]FDG PET/MRI in predicting axillary response was investigated separately in clinically node-positive breast cancer patients. In this study, final pathologic primary tumour and axillary lymph node response prediction with qualitative or quantitative [18F]FDG PET/MRI after NCT is not reliable. However, combining the relative decrease in [18F]FDG PET and MR imaging variables halfway through NCT improved diagnostic performance, especially in predicting the final pathologic axillary lymph node response. These findings suggest that sequential hybrid [18F]FDG PET/MRI could have complementary value in the early prediction of the final pathologic response to NCT in breast cancer. Background: The aim of this study was to investigate whether sequential hybrid [18F]FDG PET/MRI can predict the final pathologic response to neoadjuvant chemo(targeted) therapy (NCT) in breast cancer. Methods: Sequential [18F]FDG PET/MRI was performed before, halfway through and after NCT, followed by surgery. Qualitative response evaluation was assessed after NCT. Quantitatively, the SUVmax obtained by [18F]FDG PET and signal enhancement ratio (SER) obtained by MRI were determined sequentially on the primary tumour. For the response of axillary lymph node metastases (ALNMs), SUVmax was determined sequentially on the most [18F]FDG-avid ALN. ROC curves were generated to determine the optimal cut-off values for the absolute and percentage change in quantitative variables in predicting response. Diagnostic performance in predicting primary tumour response was assessed with AUC. Similar analyses were performed in clinically node-positive (cN+) patients for ALNM response. Results: Forty-one breast cancer patients with forty-two primary tumours and twenty-six cases of pathologically proven cN+ disease were prospectively included. Pathologic complete response (pCR) of the primary tumour occurred in 16 patients and pCR of the ALNMs in 14 cN+ patients. The AUC of the qualitative evaluation after NCT was 0.71 for primary tumours and 0.54 for ALNM responses. For primary tumour response, combining the percentage decrease in SUVmax and SER halfway through NCT achieved an AUC of 0.78. The AUC for ALNM response prediction increased to 0.92 by combining the absolute and the percentage decrease in SUVmax halfway through NCT. Conclusions: Qualitative PET/MRI after NCT can predict the final pathologic primary tumour response, but not the ALNM response. Combining quantitative variables halfway through NCT can improve the diagnostic accuracy for final pathologic ALNM response prediction.

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.

Background: Data on effectiveness and optimal use of neoadjuvant endocrine therapy (NET) in clinically biopsy-proven node-positive breast cancer is lacking. This study examined the incidence of axillary pathological complete response (pCR) on NET in clinically biopsy-proven node-positive breast cancer patients. Secondary, patient and tumour characteristics, as well as the optimal duration of NET in relation to the occurrence of axillary pCR were investigated.Material and methods: Patients diagnosed with primary hormone receptor positive, HER2 negative breast cancer between 2014 and 2019, with at least one positive axillary lymph node (pathologically proven), treated with NET were selected from the Netherlands Cancer Registry. The incidence of axillary pCR in combination with patient, tumour and treatment characteristics was analysed.Results: In a population of 561 patients, an axillary pCR of 7.3% on NET was observed. Median length of treatment was 8.1 months in the patients without vs. 8.8 months in those with axillary pCR, with no statistically significant difference. A p-value

Background: Regional recurrence (RR), also known as lymph node recurrence, is an endpoint in several trials concerning reducing axillary treatment in cT1-2N0 breast cancer patients. The risk of RR may decrease with each subsequent event-free year, affecting the yield and consequently usefulness of long (er) follow-up. The aim of this study is to determine the risk of RR as a first event within five years after diagnosis in subtypes of breast cancer, conditional to being event-free for one, two, three and four years.Methods: From the Netherlands Cancer Registry, cT1-2N0 breast cancer patients diagnosed from 2005 to 2008 were analyzed. Subgroup analysis was performed for pT1-2N+(sn) patients. RR risk was calculated with Kaplan-Meier analysis. Conditional RR (assuming x event-free years) was determined by selecting patients without an event at x years, and calculating the remaining risk for RR within five years after diagnosis.Results: A total of 18,009 cT1-2N0 (all pN stages) breast cancer patients were included. RR occurred in 1.3% of cT1-2N0 and 1.5% of pT1-2N+(sn) patients. The risk of RR varied between subtypes; it was highest for triple negative tumors and lowest for ER + PR + Her2-and ER + Her2+ tumors. After event-free years, the risk of RR decreased subsequently in both groups and in all subtypes. After two event-free years, the risk of RR was 0.8%.Conclusion: The absolute yield of follow-up to detect RR beyond two years is low; for every 125 event-free patients, one RR can be expected until five years. This suggests that follow-up longer than two years is of limited value for detecting RR in both clinical and research setting.(c) 2020 Published by Elsevier Ltd.

Background In line with the paradigm to minimize surgical morbidity in patients with primary breast cancer, there is increasing evidence for the safety of a repeat breast-conserving treatment (BCT) of an ipsilateral breast tumour recurrence (IBTR) in selected patients. The conditions for the feasibility of a repeat BCT vary widely in literature. In clinical practice, many physicians have ongoing concerns about the oncological safety and possible toxicity of repeat BCT. Aim To investigate the attitude of Dutch breast surgeons and radiation oncologists towards repeat BCT and to report on their experiences with, objections against and perceived requirements to consider a repeat BCT in case of IBTR. Patients and methods An online survey consisting of a maximum of 26 open and multiple-choice questions about repeat BCT for IBTR was distributed amongst Dutch breast surgeons and radiation oncologists. Results Forty-nine surgeons representing 49% of Dutch hospitals and 20 radiation oncologists representing 70% of Dutch radiation oncology centres responded. A repeat BCT was considered feasible in selected cases by 28.7% of breast surgeons and 55% of radiation oncologists. The most important factors to consider a repeat BCT for both groups were the patient’s preference to preserve the breast and surgical feasibility of a second lumpectomy. Arguments against a repeat BCT were based on the perceived unacceptable toxicity and cosmesis of a second course of radiotherapy. The technique of preference for re-irradiation would be partial breast irradiation (PBI) according to all radiation oncologists. Differentiating between new primary tumours (NPT) and true recurrences (TR) was reported to be done by 57.1% of breast surgeons and 60% of radiation oncologists. The most important reason to differentiate between NPT and TR was to establish prognosis and to consider whether a repeat BCT would be feasible. Conclusion An increasing number of Dutch breast cancer specialists is considering a repeat BCT feasible in selected cases, at the patient’s preference and with partial breast re-irradiation.

Background The ACOSOG Z0011 trial showed that completion axillary lymph node dissection (cALND) can be safely omitted for some patients with T1-2 clinically node-negative breast cancer with one to two involved sentinel lymph nodes (SLNs) treated with breast-conserving therapy (BCT). There is little evidence for the safety of omitting cALND for mastectomy-treated patients. Consequently, cALND is often recommended for sentinel node-positive patients treated with mastectomy. The aim of this study is to determine the proportion of patients who could avoid cALND by choosing BCT instead of mastectomy at a tertiary cancer center. Patients and Methods All T1-2 clinically node-negative breast cancer patients treated with BCT or mastectomy between 2012 and 2017 with metastases in the SLN(s) were selected from a prospectively maintained database. Clinical factors and outcomes were evaluated between the two groups. Differences were compared using Wilcoxon rank-sum test, chi-square test or Fisher's exact test as appropriate. Significance was set at the 0.05 level for all analyses. Results A total of 306 patients were included, 199 (65.0%) of whom were treated with BCT and 107 (35.0%) with mastectomy. Patients treated with mastectomy were more often treated with cALND compared with those treated with BCT (71.0% versus 26.6%, p < 0.0001). Overall, 52 of the mastectomy patients (68.4%) could have avoided cALND if they had chosen BCT. Conclusions Patients treated with mastectomy are more likely to receive cALND than those treated with BCT. Axillary management should be addressed during discussion of primary tumor therapy, and cALND may be avoided when patients choose BCT instead of mastectomy.

Background The onset of the COVID-19 pandemic forced the Dutch national screening program to a halt and increased the burden on health care services, necessitating the introduction of specific breast cancer treatment recommendations from week 12 of 2020. We aimed to investigate the impact of COVID-19 on the diagnosis, stage and initial treatment of breast cancer. Methods Women included in the Netherlands Cancer Registry and diagnosed during four periods in weeks 2–17 of 2020 were compared with reference data from 2018/2019 (averaged). Weekly incidence was calculated by age group and tumor stage. The number of women receiving initial treatment within 3 months of diagnosis was calculated by period, initial treatment, age, and stage. Initial treatment, stratified by tumor behavior (ductal carcinoma in situ [DCIS] or invasive), was analyzed by logistic regression and adjusted for age, socioeconomic status, stage, subtype, and region. Factors influencing time to treatment were analyzed by Cox regression. Results Incidence declined across all age groups and tumor stages (except stage IV) from 2018/2019 to 2020, particularly for DCIS and stage I disease (p wks2–8: 2.04, ORwks9–11: 2.18). Invasive tumors were less likely to be treated initially by mastectomy with immediate reconstruction (ORwks12–13: 0.52) or by breast conserving surgery (ORwks14–17: 0.75). Chemotherapy was less likely for tumors diagnosed in the beginning of the study period (ORwks9–11: 0.59, ORwks12–13: 0.66), but more likely for those diagnosed at the end (ORwks14–17: 1.31). Primary hormonal treatment was more common (ORwks2–8: 1.23, ORwks9–11: 1.92, ORwks12–13: 3.01). Only women diagnosed in weeks 2–8 of 2020 experienced treatment delays. Conclusion The incidence of breast cancer fell in early 2020, and treatment approaches adapted rapidly. Clarification is needed on how this has affected stage migration and outcomes.

Objective: The purpose of this study was to perform a systematic review and meta-analysis to determine the diagnostic performance of current noninvasive imaging modalities for assessment of axillary response after neoadjuvant systemic therapy (NST) in clinically node-positive breast cancer patients. Summary of Background Data: NST can lead to downstaging of axillary lymph node disease. Imaging can potentially provide information about the axillary response to NST and, consequently, tailor the surgical management. Methods: PubMed and Embase were searched for studies that compared noninvasive imaging after NST with axillary surgery outcome to identify axillary response in patients with initial pathologically proven axillary lymph node metastasis. Two reviewers independently screened the studies and extracted the data. A meta-analysis was performed by computing the pooled sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Thirteen studies describing 2380 patients were included for final analysis. Of these patients, 1322 had undergone axillary ultrasound, 849 breast MRI, and 209 whole-body F-18-FDG PET-CT. The overall axillary pathologic complete response rate was 39.5% (941/2380). For axillary ultrasound, the pooled sensitivity, specificity, PPV, and NPV were 65%, 69%, 77%, 50%, respectively. For breast MRI, the pooled sensitivity, specificity, PPV, and NPV were 60%, 76%, 78%, 58%, respectively. For whole-body F-18-FDG PET-CT, the pooled sensitivity, specificity, PPV, and NPV were 38%, 86%, 78%, 49%, respectively. Conclusions: The diagnostic performance of current noninvasive imaging modalities is limited to accurately assess axillary response after NST in clinically node-positive breast cancer patients.

Introduction: Postoperative complications impact morbidity and mortality of colon cancer patients. Emerging evidence suggests that intestinal microbiota might play a critical role in the development of postoperative complications after gastrointestinal surgery. Here, we studied changes in fecal microbiota composition comparing samples collected before and after colon cancer surgery. Moreover, we examined whether the microbiota composition before surgery was associated with postoperative complications, and we explored potential determinants of the preoperative microbiota in colon cancer patients. Methods: For this study, two fecal samples were provided by 78 patients with colon cancer. The first (preoperative) sample was collected shortly after diagnosis and before (median and interquartile (IQR) range of 4 (2-6) days) colon cancer surgery. The second (postoperative) sample was collected approximately 6 weeks (median and IQR of 42 (37-47) days) after surgery and before start of adjuvant chemotherapy (whenever applicable). Based on 16S ribosomal RNA gene amplicon sequencing, the fecal microbiota diversity and composition were determined. Preoperative microbiota composition of patients who developed postoperative complications in the 30 days following surgery (n=18, 23%) was compared to those who did not (n=60, 77%) using univariate and multivariate analyses. Explorative random forest analyses were conducted to identify predictors of complication status, with relative abundance of the core genera, sex, age, fecal calprotectin levels, dietary fiber intake, body mass index, smoking status, ASA classification, cancer stage and tumor location being considered as potential predictors. Results: After surgery, microbial alpha diversity was reduced compared to the preoperative situation, whereas compositional changes over time only reached statistical significance for Lachnospiraceae NK4A136 and Coprococcus 1, which both decreased in relative abundance after surgery. Already before the start of surgery, relative abundance of the genera Bacteroides (10% vs 6%) and Lachnoclostridium (0.6% vs 0.2%) appeared to be higher in patients with complications versus those with uncomplicated recovery. In a prediction analysis, current smoking and relative abundance of Lachnoclostridium were identified as most profound predictors of complication status. Fecal calprotectin levels and current smoking status explained most (together 6%) of the overall variation in microbiota composition before surgery. Conclusion: In this study, higher relative abundances of the genera Bacteroides and Lachnoclostridium before surgery were associated with postoperative complications in patients with colon cancer. Future studies should expand on the potential causal and pathogenic routes underlying these observations. Citation Format: Dieuwertje E. Kok, Jannigje G. Kers, Hendriek C. Boshuizen, Niels Klaassen, Henk K. van Halteren, Flip M. Kruyt, Marjolein L. Smidt, Johannes H. De Wilt, Annemarie Boleij, Ellen Kampman, Erwin G. Zoetendal. Pre- and postoperative fecal microbiota and its association with complications after surgery in colon cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4380.

Background After breast cancer treatment, follow-up consists of physical examination and mammography for at least 5 years, to detect local and regional recurrence. The risk of recurrence may decrease after event-free time. This study aims to determine the risk of local recurrence (LR) as a first event until 5 years after diagnosis, conditional on being event-free for 1, 2, 3 and 4 years. Methods From the Netherlands Cancer Registry, all M0 breast cancers diagnosed between 2005 and 2008 were included. LR risk was calculated with Kaplan–Meier analysis, overall and for different subtypes. Conditional LR (assuming x event-free years) was determined by selecting event-free patients at x years, and calculating their LR risk within 5 years after diagnosis. Results Five-year follow-up was available for 34,453 patients. Overall, five-year LR as a first event occurred in 3.0%. This risk varied for different subtypes and was highest for triple negative (6.8%) and lowest for ER+PR+Her2− (2.2%) tumors. After 1, 2, 3 and 4 event-free years, the average risk of LR before 5 years after diagnosis decreased from 3.0 to 2.4, 1.6, 1.0, and 0.6%. The risk decreased in all subtypes, the effect was most pronounced in subtypes with the highest baseline risk (ER−Her2+ and triple negative breast cancer). After three event-free years, LR risk in the next 2 years was 1% or less in all subtypes except triple negative (1.6%). Conclusion The risk of 5-year LR as a first event was low and decreased with the number of event-free years. After three event-free years, the overall risk was 1%. This is reassuring to patients and also suggests that follow-up beyond 3 years may produce low yield of LR, both for individual patients and studies using LR as primary outcome. This can be used as a starting point to tailor follow-up to individual needs.

Rationale and research objective: As a result of neoadjuvant chemotherapy (NAC), approximately 1/3 of clinically node positive (cN+) breast cancer patients convert to a pathologic complete response (pCR) of the axilla. Targeted Axillary Dissection appears to be most accurate to evaluate axillary treatment-response, but evidence to support this is limited. The RISAS trial was set up to determine the accuracy of sentinel lymph node biopsy (SLNB) combined with excision of the pretreatment marked positive lymph node for axillary staging after NAC in cN+ patients. Methods: This prospective, multicenter trial included cT1-4N1,2,3b patients treated with NAC. Prior to NAC, an iodine seed was placed in the pathologically confirmed positive lymph node. After NAC, all patients underwent SLNB together with excision of the marked lymph node (RISAS-procedure) followed by axillary lymph node dissection (ALND). The identification rate and the accuracy (i.e. false negative rate (FNR) and negative predictive value (NPV)) were calculated for the RISAS procedure. Assuming an FNR of 2%, a prevalence of a positive ALND of 64% and a 10% drop-out rate, a sample size of 248 patients was needed to determine non-inferiority. The NULL hypothesis of inferiority would be rejected at a significance level of 5% if the upper bound of the two-sided 90% Clopper-Pearson confidence interval of the observed FNR would be below the non-inferiority margin of 6.25%. Secondary objectives included the accuracy of the SLNB and excision of the marked lymph node separately. Results: A total of 252 pathologically proven cN+ patients provided informed consent of whom 227 underwent the RISAS procedure/Targeted Axillary Dissection (SLNB combined with excision of the marked positive lymph node). The identification rate of the RISAS procedure is 98% (223/227). Preliminary analysis shows a false negative rate of approximately 5% and a negative predictive value of approximately 91%. Furthermore, by combining SLNB with excision of the marked lymph node, both the identification rate and the accuracy are improved compared to either the SLNB alone or the excision of the marked lymph node alone. Conclusion: This prospective multicenter validation trial shows that the RISAS procedure/Targeted Axillary Dissection is most suitable in terms of identification rate and accuracy to replace ALND for axillary staging after NAC in cN+ patients. The trial was funded by the Dutch Cancer Society (KWF, grant number 2015-8023). Citation Format: Janine Simons, Thiemo JA v Nijnatten, Linetta B Koppert, Carmen C van der Pol, Paul J v Diest, Agnes Jager, David v Klaveren, Boen LR Kam, Marc BI Lobbes, Maaike de Boer, Cees Verhoef, Paul RA Sars, Harold J Heijmans, Els RM van Haaren, Wouter J Vles, Caroline ME Contant, Marian BE Menke, Leonie HM Smit, Wendy Kelder, Marike Boskamp, Ingeborg Mares-Engelberts, Ernest JT Luiten, Marjolein L Smidt. Radioactive Iodine Seed placement in the Axilla with Sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer: Results of the prospective multicenter RISAS trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS1-10.

Introduction The COVID-19 pandemic led to a significant drop in the incidence of cancer diagnoses in the Netherlands, partially due to the suspension of all national cancer screening programs on 16th March 2020 (week 12). Hospitals were forced to focus on care for COVID-19 patients resulting in limited capacity and down scaling of health care for non-COVID-19 patients. Specific recommendations for breast cancer treatment strategies, such as alterations in sequence, type, and/or frequency, were temporarily implemented from week 12 onwards. The aim of this study was to investigate the impact of the first outbreak on the initial treatment of breast cancer patients. Methods Women older than 18 years, treated within three months following their breast cancer diagnosis during weeks 2-17 2018-2019 (reference period) or weeks 2-17 2020 (COVID-19 period), were selected from the Netherlands Cancer Registry. Weeks 2-17 2020 were split up in four periods, based on the number of breast cancer diagnoses: weeks 2-8, weeks 9-11, weeks 12-13, and weeks 14-17. Average number of breast conserving surgeries (BCS), mastectomies with direct reconstruction (DR), mastectomies without DR, chemotherapy, endocrine therapy or other therapies, given as initial treatment per week, were calculated, stratified by period and by tumor stage. Treatments given to patients diagnosed in the reference period were compared with treatments given to patients diagnosed in the COVID-19 period, using a Mantel-Haenszel test, adjusting for age. Results A total of 16,553 patients were included in the current study. Of these patients 5,504 received their initial treatment in weeks 2-17 2018, 5,641 in weeks 2-17 2019 and 5,408 in weeks 2-17 2020. An increase in the use of endocrine therapy was seen in weeks 12-13 and 14-17 2020 compared to weeks 2-17 2018/2019, especially for patients with stage I cancer (12.3% and 7.7% vs 4.8%) and stage II cancer (25.4% and 17.4% vs 13.4%). In addition, a lower proportion of patients with stage II breast cancer received chemotherapy as first treatment in weeks 12-13 (21.1%) and 14-17 2020 (20.1%) compared to weeks 2-17 2018/2019 (29.8%) (Table). Discussion The COVID-19 pandemic led to a major increase in the use of endocrine therapy following the recommendations, which was mainly used to enable postponing surgery. The lower use of chemotherapy was probably related to the thought to limit hospital visits and the expected higher risk of developing COVID-19 complications due to chemotherapy. Possible long-term effects of changes in initial treatments will be monitored. Foodnote by table: Weeks 2-17 2020 (the COVID-19 period) were compared to the same weeks in 2018-2019, adjusted for age (74). A statistically significant: ↑ higher proportion of patients received this therapy, corrected for age; ↓ lower proportion of patients received this therapy, corrected for age; a: lower proportion of patients aged between 50 and 64 years received BCS; b: higher proportion of patients aged 39 or younger received mastectomy without DR; c: higher proportion of patients aged 39 or younger, or aged between 50 and 75 years received endocrine therapy; d: higher proportion of patients aged between 40 and 74 years received endocrine therapy; e: higher proportion of patients aged 74 or younger received endocrine therapy; f: higher proportion of patients aged 39 or younger received chemotherapy; g: higher proportion of patients aged 75 years or older received BCS Average number (percentage) initial treatments per week, stratified by stage and periodTotalBreast conserving surgeryMastectomy with direct reconstructionMastectomy without direct reconstructionChemotherapyEndocrine therapyTotalDCISWeek 2-17 2018/201940.629.5 (72.7)4.9 (12.0)5.7 (13.9)0.1 (0.2)0.3 (0.8)0.1 (0.2)Week 2-8 202043.730.9 (70.6)5.0 (11.4)7.3 (16.7)0.4 (1.0)0.1 (0.3)0.0 (0.0)Week 9-11 202038.027.0 (71.1)4.0 (10.5)7.0 (18.4)0.0 (0.0)0.0 (0.0)0.0 (0.0)Week 12-13 202048.031.5 (65.6)7.0 (14.6)7.0 (14.6)0.0 (0.0)2.5 (5.2) ↑0.0 (0.0)Week 14-17 202028.319.0 (67.3)3.0 (10.6)5.8 (20.4) ↑0.0 (0.0)0.5 (1.8)0.0 (0.0)Stage IWeek 2-17 2018/2019146.2104.5 (71.5)10.0 (6.8)17.8 (12.2)6.2 (4.3)7.0 (4.8)0.7 (0.5)Week 2-8 2020148.4107.9 (72.7)7.0 (4.7) ↓15.3 (10.3)10.0 (6.7) ↑7.4 (5.0)0.9 (0.6)Week 9-11 2020131.793.7 (71.1)8.0 (6.1)14.3 (10.9)6.3 (4.8)8.0 (6.1)1.3 (1.0)Week 12-13 2020163.0107.5 (66.0)a10.0 (6.1)20.0 (12.3)b4.5 (2.8)20.0 (12.3)c1.0 (0.6)Week 14-17 2020117.377.0 (65.7) ↓10.8 (9.2)16.8 (14.3)3.3 (2.8)9.0 (7.7) ↑0.5 (0.4)Stage IIWeek 2-17 2018/2019114.937.0 (32.2)5.0 (4.3)20.8 (18.1)34.3 (29.8)15.4 (13.4)2.5 (2.2)Week 2-8 2020116.133.4 (28.8) ↓4.1 (3.6)18.4 (15.9)38.4 (33.1) ↑18.3 (15.7)3.4 (3.0)Week 9-11 2020118.735.7 (30.1)5.7 (4.8)19.0 (16.0)36.0 (30.3)20.0 (16.9)2.3 (2.0)Week 12-13 2020142.042.5 (29.9)5.5 (3.9)26.5 (18.7)30.0 (21.1) ↓36.0 (25.4)d1.5 (1.1)Week 14-17 202083.327.5 (33.0)5.5 (6.6)16.0 (19.2)16.8 (20.1) ↓14.5 (17.4)e3.0 (3.6)Stage IIIWeek 2-17 2018/201931.12.0 (6.3)0.5 (1.7)5.8 (18.5)16.0 (51.5)5.3 (17.0)1.6 (5.0)Week 2-8 202027.92.4 (8.7)0.6 (2.1)5.0 (17.9)14.3 (51.3)4.7 (16.9)0.9 (3.1)Week 9-11 202026.72.0 (7.5)0.3 (1.3)5.7 (21.3)12.7 (47.5)f5.7 (21.3)0.3 (1.3)Week 12-13 202038.52.0 (5.2)0.5 (1.3)7.5 (19.5)19.0 (49.4)8.5 (22.1)1.0 (2.6)Week 14-17 202020.81.5 (7.2)1.3 (6.0) ↑4.5 (21.7)8.0 (38.6)4.5 (21.7)1.0 (4.8)Stage IVWeek 2-17 2018/201915.00.3 (2.3)0.0 (0.2)0.6 (4.0)5.3 (34.9)6.8 (44.9)2.1 (13.7)Week 2-8 202014.60.6 (3.9)0.0 (0.0)0.4 (2.9)4.7 (32.4)6.7 (46.1)2.1 (14.7)Week 9-11 202012.00.0 (0.0)0.0 (0.0)0.0 (0.0)3.3 (27.8)7.0 (58.3)1.3 (11.1)Week 12-13 202019.51.5 (7.7)0.0 (0.0)2.5 (12.8) ↑6.0 (30.8)7.5 (38.5)2.0 (10.3)Week 14-17 202013.80.3 (1.8)g0.0 (0.0)0.3 (1.8)3.8 (27.3)8.3 (60.0) ↑1.3 (9.1) Citation Format: Anouk H Eijkelboom, Linda de Munck, Marie-Jeanne Vrancken Peeters, Marjolein Smidt, Mireille Broeders, Monique Bos, Marjanka K Schmidt, Maud Bessems, Luc Strobbe, Desirée van den Bongard, Aafke Honkoop, Janneke Verloop, Cristina Guerrero Paez, Marc Lobbes, Sabine Linn, Pieter Westenend, Catharina W Menke-van der Houven van Oordt, Jelle Wesseling, Vivianne Tjan Heijnen, Sabine Siesling, On behalve of the NABON COVID-19 consortium. Effect of the COVID-19 pandemic on the initial treatment of breast cancer in the Netherlands: A population-based study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-88.

We aimed to compare (1) treatments and time intervals between treatments of breast cancer patients diagnosed during and before the COVID-19 pandemic, and (2) the number of treatments started during and before the pandemic.Women were selected from the Netherlands Cancer Registry. For aim one, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the treatment of women diagnosed within four periods of 2020: pre-COVID (weeks 1-8), transition (weeks 9-12), lockdown (weeks 13-17), and care restart (weeks 18-26), with data from 2018/2019 as reference. Wilcoxon rank-sums test was used to compare treatment intervals, using a two-sided p-value 0.05. For aim two, number of treatments started per week in 2020 was compared with 2018/2019.We selected 34,097 women for aim one. Compared to 2018/2019, neo-adjuvant chemotherapy was less likely for stage I (OR 0.24, 95%CI 0.11-0.53), stage II (OR 0.63, 95%CI 0.47-0.86), and hormone receptor+/HER2- tumors (OR 0.55, 95%CI 0.41-0.75) diagnosed during transition. Time between diagnosis and first treatment decreased for patients diagnosed during lockdown with a stage I (p 0.01), II (p 0.01) or III tumor (p = 0.01). We selected 30,002 women for aim two. The number of neo-adjuvant endocrine therapies and surgeries starting in week 14, 2020, increased by 339% and 18%, respectively. The number of adjuvant chemotherapies decreased by 42% in week 15 and increased by 44% in week 22.The pandemic and subsequently altered treatment recommendations affected multiple aspects of the breast cancer treatment strategy and the number of treatments started per week.

Background After 5 years of annual follow‐up following breast cancer, Dutch guidelines are age based: annual follow‐up for women 75 years. We determined how the risk of recurrence corresponds to these consensus‐based recommendations and to the risk of primary breast cancer in the general screening population. Subjects, Materials, and Methods Women with early‐stage breast cancer in 2003/2005 were selected from the Netherlands Cancer Registry (n = 18,568). Cumulative incidence functions were estimated for follow‐up years 5–10 for locoregional recurrences (LRRs) and second primary tumors (SPs). Risks were compared with the screening population without history of breast cancer. Alternative cutoffs for age were determined by log‐rank tests. Results The cumulative risk for LRR/SP was lower in women 69 revealed better risk differentiation and would provide more risk‐based schedules. Still, other factors, including systemic treatments, had an even greater impact on recurrence risks. Conclusion The current consensus‐based recommendations use suboptimal age cutoffs. The proposed alternative cutoffs will lead to a more balanced risk‐based follow‐up and thereby more efficient allocation of resources. However, more factors should be taken into account for truly individualizing follow‐up based on risk for recurrence. Implications for Practice The current age‐based recommendations for breast cancer follow‐up after 5 years are suboptimal and do not reflect the actual risk of recurrent disease. This results in situations in which women with higher risks actually receive less follow‐up than those with a lower risk of recurrence. Alternative cutoffs could be a start toward risk‐based follow‐up and thereby more efficient allocation of resources. However, age, or any single risk factor, is not able to capture the risk differences and therefore is not sufficient for determining follow‐up. More risk factors should be taken into account for truly individualizing follow‐up based on the risk for recurrence., Actual survival benefits related to the intensive follow‐up recommendations of current guidelines for patients with breast cancer are unclear. This article analyses long‐term breast cancer recurrence patterns to determine how the current age‐based recommendations on follow‐up schedules after 5 years correspond to the actual risk of locoregional recurrence and second primary breast cancer. Alternative guidelines are proposed.

Objectives To investigate whether breast MRI has comparable diagnostic performance as dedicated axillary MRI regarding assessment of node-negative and node-positive breast cancer. Methods Forty-seven patients were included. All had undergone both breast MRI and dedicated axillary MRI, followed by surgery. All included breast MRI exams had complete field of view (FOV) of the axillary region. First, unenhanced T2-weighted (T2W) and subsequent diffusion-weighted (DW) images of both MRI exams were independently analyzed by two breast radiologists using a confidence scale and compared to histopathology. ADC values were measured by two researchers independently. Diagnostic performance parameters were calculated on a patient-by-patient basis. Results T2W breast MRI had the following diagnostic performance: sensitivity of 50.0% and 62.5%, specificity of 92.3%, PPV of 57.1% and 62.5%, NPV of 90.0% and 92.3%, and AUC of 0.72 for reader 1 and 0.78 for reader 2. T2W dedicated axillary MRI had the following diagnostic performance: sensitivity of 37.5% and 62.5%, specificity of 82.1% and 92.3%, PPV of 44.6% and 50.0%, NPV of 87.8% and 91.4%, and AUC of 0.65 for reader 1 and 0.73 for reader 2. In both evaluations, addition of DW images resulted in comparable diagnostic performance. For both breast MRI and dedicated axillary MRI, there was no significant difference between mean ADC values of benign and malignant lymph nodes. Conclusions T2W breast MRI with complete FOV of the axillary region has comparable diagnostic performance as T2W dedicated axillary MRI regarding assessment of node-negative and node-positive breast cancer. Optimization of T2W breast MRI protocol by including a complete FOV of the axillary region can, therefore, be recommended in clinical practice. Key Points • Breast MRI with complete field of view of the axillary region has comparable diagnostic performance as dedicated axillary MRI regarding assessment of node-negative and node-positive breast cancer. • Optimization of breast MRI protocol by including a complete field of view of the axillary region is recommended in clinical practice. • For both breast MRI and dedicated axillary MRI, DW imaging (including ADC measurements) is of no added value.

Supplemental Digital Content is available in the text., Objective To provide a systematic review regarding the diagnostic performance of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) and diffusion-weighted imaging (DWI) compared to 18F-FDG PET/computed tomography (CT) focused on nodal and distant staging in breast cancer patients. Methods The PubMed and Embase databases were searched for relevant publications until April 2020. Two independent reviewers searched for eligible articles based on predefined in- and exclusion criteria, assessed quality and extracted data. Results Eleven eligible studies were selected from 561 publications identified by the search. In seven studies, PET/CT was compared with PET/MRI, and in five, PET/CT with DWI. Significantly higher sensitivity for PET/MRI compared to PET/CT in a lesion-based analysis was reported for all lesions together (77% versus 89%) in one study, osseous metastases (69–99% versus 92–98%) in two studies and hepatic metastases (70–75% versus 80–100%) in one study. Moreover, PET/MRI revealed a significantly higher amount of osseous metastases (90 versus 141) than PET/CT. PET/CT is associated with a statistically higher specificity than PET/MRI in the lesion detection of all lesions together (98% versus 96%) and of osseous metastases (100% versus 95%), both in one study. None of the reviewed studies reported significant differences between PET/CT and DWI for any of the evaluated sites. There is a trend toward higher specificity for PET/CT. Conclusion In general, there is a trend toward higher sensitivity and lower specificity of PET/MRI when compared to PET/CT. Results on the diagnostic performance of DWI are conflicting. Rather than evaluating it separate, it seems to have complementary value when combined with other MR sequences.

Objective: The aim was to investigate whether pathologic complete response (pCR) in the breast is correlated with absence of axillary lymph node metastases at final pathology (ypN0) in patients treated with neoadjuvant systemic therapy (NST) for different breast cancer subtypes. Background: Pathologic complete response rates have improved on account of more effective systemic treatment regimens. Promising results in feasibility trials with percutaneous image-guided tissue sampling for the identification of breast pCR after NST raise the question whether breast surgery is a redundant procedure. Thereby, the need for axillary surgery should be reconsidered as well. Methods: Patients diagnosed with cT1-3N0-1 breast cancer and treated with NST, followed by surgery between 2010 and 2016, were selected from the Netherlands Cancer Registry. Patients were compared according to the pathologic response of the primary tumor with associated pathologic axillary outcome. Multivariable analysis was performed to determine clinicopathological variables correlated with ypN0. Results: A total of 4084 patients were included for analyses, of whom 986 (24.1%) achieved breast pCR. In clinically node negative patients (cN0), 97.7% (432/442) with breast pCR had ypN0 compared with 71.6% (882/1232) without breast pCR (P

Introduction: Various options for axillary staging after neoadjuvant systemic therapy (NST) are available for breast cancer patients with a clinically positive axillary node (cN+). This survey assessed current practices amongst breast cancer specialists.Materials and methods: A survey was performed amongst members of the European Society of Surgical Oncology and two UK-based Associations: the Association of Breast Surgery and the British Association of Surgical Oncology. The survey included 3 parts: 1. general information, 2, diagnostic work-up and 3. axillary staging after NST.Results: A total of 310 responses were collected: parts 1, 2 and 3 were fully completed by 282 (91%), 270 (87.1%) and 225 (72.6%) respondents respectively. After NST, 153/267 (57.3%) respondents currently perform ALND routinely and 114 (42.7%) respondents perform less invasive restaging of the axilla with possible omission of ALND. In the latter group, 85% does and 15% does not use nodal response seen on imaging to guide the axillary restaging procedure. Regarding respondents that do use imaging: 95% would perform a less invasive staging procedure in case of complete nodal response on imaging (63% sentinel lymph node biopsy (SLNB), excision of a previously marked positive node with SLNB (21%) and without SLNB (11%)). In case of no nodal response on imaging 77% would perform ALND.Conclusion: Current axillary staging and management practices in cN + patients after NST vary widely. To determine optimal axillary staging and management in terms of quality of life and oncologic safety, breast specialists are encouraged to include patients in clinical trials prospective registries. (C) 2019 Elsevier Ltd, BASO - The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Simple Summary Besides the already known factors that increase the risk of breast cancer, like hormonal treatment, heredity, and obesity, growing evidence exists that intestinal microbiota can influence breast cancer carcinogenesis. Current clinical information into the role of the intestinal microbiota in breast cancer patients is limited. This study aimed to see whether there are differences in intestinal microbiota richness, diversity, and composition between oestrogen receptor positive breast cancer patients and controls. We concluded that the intestinal microbiota richness, diversity, and composition were not different between breast cancer patients and postmenopausal controls. An increased relative abundance of Dialister and Veillonellaceae was observed in breast cancer patients scheduled for adjuvant treatment, which might be caused by a relative decrease in other bacteria due to surgery associated factors rather than an absolute increase. For future studies, we strongly advise a more homogeneous group of breast cancer patients of preferably treatment-naive patients. Abstract Background: Previous preclinical and clinical research has investigated the role of intestinal microbiota in carcinogenesis. Growing evidence exists that intestinal microbiota can influence breast cancer carcinogenesis. However, the role of intestinal microbiota in breast cancer needs to be further investigated. This study aimed to identify the microbiota differences between postmenopausal breast cancer patients and controls. Patients and methods: This prospective cohort study compared the intestinal microbiota richness, diversity, and composition in postmenopausal histologically proven ER+/HER2- breast cancer patients and postmenopausal controls. Patients scheduled for (neo)adjuvant adriamycin, cyclophosphamide (AC), and docetaxel (D), or endocrine therapy (tamoxifen) were prospectively enrolled in a multicentre cohort study in the Netherlands. Patients collected a faecal sample and completed a questionnaire before starting systemic cancer treatment. Controls, enrolled from the National Dutch Breast Cancer Screening Programme, also collected a faecal sample and completed a questionnaire. Intestinal microbiota was analysed by amplicon sequencing of the 16S rRNA V4 gene region. Results: In total, 81 postmenopausal ER+/HER2- breast cancer patients and 67 postmenopausal controls were included, resulting in 148 faecal samples. Observed species richness, Shannon index, and overall microbial community structure were not significantly different between breast cancer patients and controls. There was a significant difference in overall microbial community structure between breast cancer patients scheduled for adjuvant treatment, neoadjuvant treatment, and controls at the phylum (p = 0.042) and genus levels (p = 0.015). Dialister (p = 0.001) and its corresponding family Veillonellaceae (p = 0.001) were higher in patients scheduled for adjuvant treatment, compared to patients scheduled for neoadjuvant treatment. Additional sensitivity analysis to correct for the potential confounding effect of prophylactic antibiotic use, indicated no differences in microbial community structure between patients scheduled for neoadjuvant systemic treatment, adjuvant systemic treatment, and controls at the phylum (p = 0.471) and genus levels (p = 0.124). Conclusions: Intestinal microbiota richness, diversity, and composition are not different between postmenopausal breast cancer patients and controls. The increased relative abundance of Dialister and Veillonellaceae was observed in breast cancer patients scheduled for adjuvant treatment, which might be caused by a relative decrease in other bacteria due to prophylactic antibiotic administration rather than an absolute increase.

Background Neoadjuvant systemic therapy (NST) is a widely accepted initial treatment modality that can lead to pathologic downstaging of the axillary disease burden in breast cancer patients. Axillary response as well as baseline 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography with computed tomography (PET/CT) differ between breast cancer subtypes. The value of baseline 18F-FDG PET/CT in predicting axillary response to NST is not yet established, possibly since breast cancer subtype was not taken into account. The purpose of this study was to investigate the value of baseline 18F-FDG PET/CT in predicting axillary response to NST with a specific emphasis on subtype. Methods PET-parameters derived from the primary tumor as well as the most FDG-avid axillary lymph node were measured on baseline 18F-FDG PET/CT. Overall imaging findings were compared with the gold standard of histopathology of the axillary surgery specimen. Analyses for ER-positive/HER2-negative were performed separately from HER2-positive and TN patients. In addition, separate analyses for clinically node-positive patients were performed. Results Sixty-six patients with 69 primary tumors were included in this study. Thirty-three axillae contained ER-positive/HER2-negative, 16 HER2-positive, and 20 TN breast cancer. No significant difference in PET-parameters between patients with axillary residual disease and axillary pathologic complete response were found for ER-positive/HER2-negative breast cancer. In the combined HER2-positive/TN subgroup, the SUVmax was significantly lower in patients without residual axillary disease in both the entire cohort and in patients with clinically node-positive disease. In this combined subgroup, a cut-off of 4.89 SUVmax measured on the most FDG-avid axillary lymph node could predict residual axillary disease with a sensitivity, specificity, PPV, and NPV of 90%, 69%, 53%, and 95%, respectively. Conclusions Predicting axillary response following NST with baseline 18F-FDG PET/CT can be performed when focusing on breast cancer subtypes. The easily computed PET-parameter SUVmax can predict axillary response in HER2-positive and TN breast cancer. This study adds to the accumulating evidence that studies investigating the value of 18F-FDG PET/CT in breast cancer should always take subtypes into account.

Background Cancer cachexia is characterized by a negative energy balance, muscle and adipose tissue wasting, insulin resistance, and systemic inflammation. Because of its strong negative impact on prognosis and its multifactorial nature that is still not fully understood, cachexia remains an important challenge in the field of cancer treatment. Recent animal studies indicate that the gut microbiota is involved in the pathogenesis and manifestation of cancer cachexia, but human data are lacking. The present study investigates gut microbiota composition, short-chain fatty acids (SCFA), and inflammatory parameters in human cancer cachexia. Methods Faecal samples were prospectively collected in patients (N = 107) with pancreatic cancer, lung cancer, breast cancer, or ovarian cancer. Household partners (N = 76) of the patients were included as healthy controls with similar diet and environmental conditions. Patients were classified as cachectic if they lost >5% body weight in the last 6 months. Gut microbiota composition was analysed by sequencing of the 16S rRNA V4 gene region. Faecal SCFA levels were quantified by gas chromatography. Faecal calprotectin was assessed with enzyme-linked immunosorbent assay. Serum C-reactive protein and leucocyte counts were retrieved from medical records. Results Cachexia prevalence was highest in pancreatic cancer (66.7%), followed by ovarian cancer (25%), lung cancer (20.8%), and breast cancer (17.3%). Microbial alpha-diversity was not significantly different between cachectic cancer patients (N = 33), non-cachectic cancer patients (N = 74), or healthy controls (N = 76) (species richness P = 0.31; Shannon effective index P = 0.46). Community structure (beta-diversity) tended to differ between these groups (P = 0.053), although overall differences were subtle and no clear clustering of samples was observed. Proteobacteria (P < 0.001), an unknown genus from the Enterobacteriaceae family (P < 0.01), and Veillonella (P < 0.001) were more abundant among cachectic cancer patients. Megamonas (P < 0.05) and Peptococcus (P < 0.001) also showed differential abundance. Faecal levels of all SCFA tended to be lower in cachectic cancer patients, but only acetate concentrations were significantly reduced (P < 0.05). Faecal calprotectin levels were positively correlated with the abundance of Peptococcus, unknown Enterobacteriaceae, and Veillonella. We also identified several correlations and interactions between clinical and microbial parameters. Conclusions This clinical study provided the first insights into the alterations of gut microbiota composition and SCFA levels that occur in cachectic cancer patients and how they are related to inflammatory parameters. These results pave the way for further research examining the role of the gut microbiota in cancer cachexia and its potential use as therapeutic target.

Background Neoadjuvant systemic therapy (NST) is a widely accepted initial treatment modality that can lead to pathologic downstaging of the axillary disease burden in breast cancer patients. Axillary response as well as baseline 18F-fluorodeoxyglucose (18F-FDG) uptake on positron emission tomography with computed tomography (PET/CT) differ between breast cancer subtypes. The value of baseline 18F-FDG PET/CT in predicting axillary response to NST is not yet established, possibly since breast cancer subtype was not taken into account. The purpose of this study was to investigate the value of baseline 18F-FDG PET/CT in predicting axillary response to NST with a specific emphasis on subtype. Methods PET-parameters derived from the primary tumor as well as the most FDG-avid axillary lymph node were measured on baseline 18F-FDG PET/CT. Overall imaging findings were compared with the gold standard of histopathology of the axillary surgery specimen. Analyses for ER-positive/HER2-negative were performed separately from HER2-positive and TN patients. In addition, separate analyses for clinically node-positive patients were performed. Results Sixty-six patients with 69 primary tumors were included in this study. Thirty-three axillae contained ER-positive/HER2-negative, 16 HER2-positive, and 20 TN breast cancer. No significant difference in PET-parameters between patients with axillary residual disease and axillary pathologic complete response were found for ER-positive/HER2-negative breast cancer. In the combined HER2-positive/TN subgroup, the SUVmax was significantly lower in patients without residual axillary disease in both the entire cohort and in patients with clinically node-positive disease. In this combined subgroup, a cut-off of 4.89 SUVmax measured on the most FDG-avid axillary lymph node could predict residual axillary disease with a sensitivity, specificity, PPV, and NPV of 90%, 69%, 53%, and 95%, respectively. Conclusions Predicting axillary response following NST with baseline 18F-FDG PET/CT can be performed when focusing on breast cancer subtypes. The easily computed PET-parameter SUVmax can predict axillary response in HER2-positive and TN breast cancer. This study adds to the accumulating evidence that studies investigating the value of 18F-FDG PET/CT in breast cancer should always take subtypes into account. Supplementary Information The online version contains supplementary material available at 10.1186/s13550-021-00861-z.

Simple Summary Natural killer (NK) cells are potent killers of tumor cells. Many tumors, including breast cancers, develop mechanisms to suppress anti-tumor immune responses, requiring the development of strategies to overcome suppression. Here, we tested a combination therapy that aims to (1) enhance NK cell activation and (2) reduce NK cell inhibition mediated by suppressive factors in tumors or in the tumor microenvironment. We cultured cell lines under hypoxia to mimic the tumor microenvironment or used patient-derived breast cancer cells that were primed by the patient’s tumor environment. Our results demonstrated that cytokine-activated NK cells remained active under hypoxia and that tumor-targeting antibodies enhanced the NK cell anti-breast cancer response. Moreover, we observed that NK cell suppression by inhibitory ligands on the tumor cells can be reduced by the selection of NK cell donors with NK receptors that are incompatible with these ligands. Collectively, we present two powerful strategies to enhance the NK cell responses against breast cancer. Abstract Natural killer (NK)-cell-based immunotherapies are an attractive treatment option for cancer. We previously showed that alloreactive mouse NK cells cured mice of 4T1 breast cancer. However, the tumor microenvironment can inhibit immune responses, and these suppressive factors must be overcome to unfold the NK cells’ full anti-tumor potential. Here, we investigated the combination of antibody-dependent cellular cytotoxicity (ADDC) and the selection of KIR-HLA-ligand mismatched NK cells to enhance NK cell anti-breast cancer responses in clinically relevant settings. Donor-derived and IL-2-activated NK cells were co-cultured with patient-derived breast cancer cells or cell lines MCF7 or SKBR3 together with the anti-HER2 antibody trastuzumab. NK cells mediated anti-breast cancer cytotoxicity under normoxic and hypoxic conditions. Under both conditions, trastuzumab vigorously enhanced NK cell degranulation (CD107a) against HER2-overexpressing SKBR3 cells, but we observed a discrepancy between highly degranulating NK cells and a rather modest increase in cytotoxicity of SKBR3. Against patient-derived breast cancer cells, the anti-tumor efficacy was rather limited, and HLA class I expression seemed to contribute to inhibited NK cell functionality. KIR-ligand-mismatched NK cells degranulated stronger compared to the matched NK cells, further highlighting the role of HLA. In summary, trastuzumab and KIR-ligand-mismatched NK cells could be two strategies to potently enhance NK cell responses to breast cancer.

Background Detecting pathological breast calcifications remains challenging. Based on recent studies, contrast-enhanced spectral mammography (CESM) was shown to be superior compared to full-field digital mammography (FFDM). Purpose To evaluate the diagnostic accuracy of CESM in suspicious breast calcifications and its impact on surgical decision-making. Material and Methods All screening recalled patients with suspicious calcifications that underwent CESM in the period October 2012 until September 2015 were included. One experienced radiologist provided a BI-RADS classification for the FFDM images only. The evaluation was repeated for the CESM exam. In a simulated tumor board meeting, two breast surgeons decided on the preferred surgical treatment (breast conservation therapy [BCT] versus mastectomy) for all malignant cases. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated defining BI-RADS >= 4 as being malignant. In addition, differences in surgical decision-making were analyzed and compared using McNemar's test. Results In total, 147 women were included in this study (mean age = 61 years; age range = 49-75 years). Pathology showed 82 benign and 65 malignant lesions, of which 33 were ductal carcinomas in situ and 32 were invasive lesions. Diagnostic performances of CESM (differences compared to FFDM in brackets) were: sensitivity 93.8% (+3%), specificity 36.6% (-2.5%), PPV 54% (0%), and NPV 88.2% (+4%). Based on low-energy images, surgeons suggested BCT in 89% of the cases. Based on the CESM exam, no statistical changes in decisions were observed (86% BCT, P = 0.453). Conclusion CESM only slightly improves the diagnostic accuracy of the evaluation of breast calcifications. It is not of added value compared to FFDM in guiding surgical decision-making.

Background. Residual axillary lymph node involvement after neoadjuvant systemic therapy (NST) is the determining factor for postmastectomy radiation therapy (PMRT). Preoperative identification of patients needing PMRT is essential to enable shared decision-making when choosing the optimal timing of breast reconstruction. We determined the risk of positive sentinel lymph node (SLN) after NST in clinically node-negative (cN0) breast cancer.Methods. All cT1-3N0 patients treated with NST followed by mastectomy and SLNB between 2010 and 2016 were identified from the Netherlands Cancer Registry. Rate of positive SLN for different breast cancer subtypes was determined. Logistic regression analysis was performed to determine correlated clinicopathological variables with positive SLN.Results. In total 788 patients were included, of whom 25.0% (197/788) had positive SLN. cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+, and cT1-2N0 triple-negative patients had the lowest rate of positive SLN: 7.2-11.5%, 0-6.3%, and 2.9-6.2%, respectively. cT1-3N0 ER+HER2- and cT3N0 triple-negative patients had the highest rate of positive SLN: 23.8-41.7% and 30.4%, respectively. Multivariable regression analysis showed that cT2 (odds ratio [OR] 1.93; 95% confidence interval [CI] 1.01-3.96), cT3 (OR 2.56; 95% CI 1.30-5.38), grade 3 (OR 0.44; 95% CI 0.21-0.91), and ER+HER2- subtype (OR 3.94; 95% CI 1.77-8.74) were correlated with positive SLN.Conclusions. In cT1-3N0 ER+HER2+, cT1-3N0 ER-HER2+, and cT1-2N0 triple-negative patients treated with NST, immediate reconstruction can be considered an acceptable option due to low risk of positive SLN. In cT1-3N0 ER+HER2- and cT3N0 triple-negative patients treated with NST, risks and benefits of immediate reconstruction should be discussed with patients due to the relatively high risk of positive SLN.

Introduction: Imaging findings can be affected by histopathological characteristics, such as breast cancer subtypes. The aim was to determine whether the diagnostic performance, in particular negative predictive value (NPV), of axillary US differs per subtype of breast cancer.Methods: All patients diagnosed between 2008 and 2016 in our hospital with primary invasive breast cancer and an axillary US prior to axillary surgery were included. Histopathology of axillary surgery specimens served as gold standard. The NPV, sensitivity, specificity, positive predictive value (PPV) and accuracy of the axillary US were determined for the overall population and for each subtype (ER+/PR+HER2-,HER2+, triple negative tumors). The Chi-square test was used to determine the difference in diagnostic performance parameters between the subtypes.Results: A total of 1094 breast cancer patients were included. Of these, 35 were diagnosed with bilateral breast cancer, resulting in 1129 cancer cases. Most common subtype was ER+/PR+HER2- in 858 cases (76.0%), followed by 150 cases of HER2+ tumors (13.3%) and 121 cases of triple negative tumors (10.7%). Sensitivity, specificity and accuracy of axillary US did not significantly differ between the subtypes. There was a significant difference for NPV between triple negative tumors and HER2+ tumors (90.3% vs. 80.2%, p = 0.05) and between HER2+ and ER/PR+HER2- tumors (80.2% vs. 87.2%, p = 0.04).Conclusion: There was no significant difference in the diagnostic performance of axillary US between the subtypes, except for NPV. This was highest in triple negative subtype and lowest in HER2+ tumors. This can be explained by the difference in prevalence of axillary lymph node metastases in our cohort. (C) 2019 Published by Elsevier Ltd.

Background Survival estimates valid at the time of diagnosis are of limited value for (ex-)breast cancer patients who survived several years, as it includes information on already deceased patients. This study analyzed the 10-year conditional risk of recurrent breast cancer in specific prognostic subgroups according to T and N stage and breast cancer subtypes. Secondly, we investigated 10-year conditional overall (OS) and relative survival (RS), adjusted for confounding. Patients and methods We selected all women diagnosed in 2005 with operated T1-2N0-1 breast cancer from the Netherlands Cancer Registry. Patients were classified into T1N0, T1N1, T2N0 and T2N1 stage. Ten-year conditional recurrence rates were calculated for every year from diagnosis for patients without an event (local (LR), regional recurrence (RR), distant metastasis (DM) or death). Ten-year conditional OS was calculated using multivariable Cox regression. RS was estimated by dividing patient survival rates by those of the general Dutch population. Results We included 7,969 patients: 52.3% had T1N0, 15.3% T1N1, 19.9% T2N0 and 12.5% T2N1 stage. For T1N0, 10-year LR rates changed from 4.6% at diagnosis to 0.5% in year 10. RR rates decreased from 2.3% to 0.2% and DM rates decreased from 7.8% to 0.6%. For T2N1 stage, the LR, RR and DM rates decreased from 6.2% to 0.8%, 5.2% to 0.4% and 19.6% to 1.5%, respectively. Of all patients, 1,702 patients (21.4%) had an unknown breast cancer subtype and were consequently excluded from the analyses according to subtype. Of the remaining 6,267 patients, 3,774 (60.2%) had luminal A, 1,465 (23.4%) had luminal B, 314 (5.0%) had HER2 positive and 714 (11.4%) had triple negative disease For the luminal A subtype, LR, RR and DM rates ranged from 3.9% to 0.4%, 1.7% to 0.5% and 7.3% to 1.1%, while for triple negative these rates ranged between 5.6% to 0.7%, 4.9% to 0.2% and 16.7% to 0%, respectively. Differences between subgroups attenuated over time and all recurrence rates became ≤1.5% in year 10. Ten-year OS and RS, adjusted for confounding, showed diminishing risk differences between subgroups over time. Conclusion Differences in recurrence rates, OS and RS between prognostic subgroups decreased as years passed by. These results highlight the importance of taking into account disease-free years to more accurately predict (ex-)breast cancer patients' prognosis over time. Citation Format: van Maaren MC, Strobbe LJ, Smidt ML, Moossdorff M, Poortmans PM, Siesling S. 10-year conditional recurrence risks, overall and relative survival for breast cancer patients in the Netherlands: Taking account of event-free years [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 P1-08-19.

PURPOSE: Although most of the clinicians in breast cancer care seem to approve of shared decision making (SDM), actual implementation is limited. The aim of this study was to explore the experiences, issues and concerns of early-adopter professionals with regards to shared decision making.METHODS: This qualitative descriptive study was part of a pilot study aimed at implementing SDM in breast cancer teams. We interviewed 27 clinicians; 9 breast cancer surgeons, 11 nurse practitioners and 7 nurses. The teams were exposed to a multifaceted implementation programme, among others: a patient decision aid (PtDA), a procedure to disseminate the PtDA and advice on redesigning the clinical pathway.RESULTS: Participants considered SDM, including the delivery of the PtDA, to be a team effort, in which every professional should take responsibility. Most clinicians primarily focused on the first steps of SDM ignoring preference and decision talk. The remaining steps, like the uptake of the PtDA in the clinical pathway, were regarded as challenging, with surgeons, intentionally or unconsciously, delegating this responsibility to nurses. One barrier to successfully implementing SDM seems to lie in the fact that clinicians were unaware of their lack of competency regarding SDM.CONCLUSIONS: A deeper understanding is needed among clinicians of what SDM actually is and how a PtDA contributes to this process. Nurses play an important role in the delivery of the PtDA, but their role is not clearly defined. Teams should consider a clear realignment of tasks between surgeons and nurses, which implies redesign of the pathway.

Contrast-enhanced mammography (CEM) has shown to be superior to full-field digital mammography (FFDM), but current results are dominated by studies performed on systems by one vendor. Information on diagnostic accuracy of other CEM systems is limited. Therefore, we aimed to evaluate the diagnostic performance of CEM on an alternative vendor’s system. We included all patients who underwent CEM in one hospital in 2019, except those with missing data or in whom CEM was used as response monitoring tool. Three experienced breast radiologists scored the low-energy images using the BI-RADS classification. Next, the complete CEM exams were scored similarly. Histopathological results or a minimum of one year follow-up were used as reference standard. Diagnostic performance and AUC were calculated and compared between low-energy images and the complete CEM examination, for all readers independently as well as combined. Breast cancer was diagnosed in 23.0% of the patients (35/152). Compared to low-energy images, overall CEM sensitivity increased from 74.3 to 87.6% (p p = 0.0146). AUC increased from 0.872 to 0.957 (p = 0.0001). Performing CEM on the system tested, showed that, similar to earlier studies mainly performed on another vendor’s systems, both sensitivity and specificity improved when compared to FFDM.