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Abstract Purpose To investigate in a feasibility study the combination of [18F]FDG whole-body (WB) positron emission tomography-magnetic resonance (PET-MR), including an integrated breast MR within a single protocol for locoregional and distant staging in breast cancer patients. Methods Consecutive patients with breast cancer diagnoses according to conventional imaging modalities (full-field digital mammography (FFDM) and ultrasound (US)) were prospectively included. All patients underwent [18F]FDG WB PET-MR, including an integrated dedicated breast MR (prone position) and WB PET-MR (supine position) protocol. Results of [18F]FDG WB PET-MR, including integrated breast MR, versus conventional imaging modalities were compared. Results From April 2021–April 2022, 28 patients were included. On conventional imaging, cT1-2 breast cancer was present in 22 (FFDM) and 23 (US) out of 28 patients. With regard to clinical nodal status, eight patients were considered cN0, eighteen cN1 (1-3 suspicious lymph nodes), and two patients were cN2 (four suspicious axillary lymph nodes/internal mammary lymph node metastasis). [18F]FDG WB PET-MR, including an integrated breast MR protocol, upstaged clinical tumor status in two patients and clinical nodal status in nine patients according to both [18F]FDG WB PET-MR and breast MR findings. In addition, distant metastases were detected in three patients (liver/bone), and another patient was diagnosed with a synchronous primary tumor (lung cancer). Conclusion [18F]FDG WB PET-MR, including an integrated breast MR within a single protocol in breast cancer patients, is feasible and provides a promising new approach in breast cancer patients with regard to locoregional and distant staging. Critical relevance statement [18F]FDG whole-body PET-MR, including an integrated breast MR protocol, is feasible and allows locoregional and distant staging within a single imaging exam in breast cancer patients. Key Points [18F]FDG PET-MR allows the combination of breast MR and whole-body staging. Therefore, a single protocol of whole-body [18F]FDG PET-MR, including an integrated breast MRI, is investigated. [18F]FDG PET-MR, including an integrated breast MR is feasible and can be considered in daily clinical practice. Graphical Abstract

Abstract Background 5-Fluorouracil (5-FU) is used as an antineoplastic agent in distinct cancer types. Increasing evidence suggests that the gut microbiota might modulate 5-FU efficacy and toxicity, potentially affecting the patient’s prognosis. The current experimental study investigated 5-FU-induced microbiota alterations, as well as the potential of prebiotic fibre mixtures (M1-M4) to counteract these shifts. Methods A pooled microbial consortium was derived from ten healthy donors, inoculated in an in vitro model of the colon, and treated with 5-FU, with or without prebiotic fibre mixtures for 72 h. Four different prebiotic fibre mixtures were tested: M1 containing short-chain galacto-oligosaccharides (sc GOS), long-chain fructo-oligosaccharides (lcFOS), and low viscosity pectin (lvPect), M2 consisting of arabinoxylan, beta-glucan, pectin, and resistant starch, M3 which was a mixture of scGOS and lcFOS, and M4 containing arabinoxylan, beta-glucan, pectin, resistant starch, and inulin. Results We identified 5-FU-induced changes in gut microbiota composition, but not in microbial diversity. Administration of prebiotic fibre mixtures during 5-FU influenced gut microbiota composition and taxa abundance. Amongst others, prebiotic fibre mixtures successfully stimulated potentially beneficial bacteria (Bifidobacterium, Lactobacillus, Anaerostipes, Weissella, Olsenella, Senegalimassilia) and suppressed the growth of potentially pathogenic bacteria (Klebsiella, Enterobacter) in the presence of 5-FU. The short-chain fatty acid (SCFA) acetate increased slightly during 5-FU, but even more during 5-FU with prebiotic fibre mixtures, while propionate was lower due to 5-FU with or without prebiotic fibre mixtures, compared to control. The SCFA butyrate and valerate did not show differences among all conditions. The branched-chain fatty acids (BCFA) iso-butyrate and iso-valerate were higher in 5-FU, but lower in 5-FU + prebiotics, compared to control. Conclusions These data suggest that prebiotic fibre mixtures represent a promising strategy to modulate 5-FU-induced microbial dysbiosis towards a more favourable microbiota, thereby possibly improving 5-FU efficacy and reducing toxicity, which should be evaluated further in clinical studies.

Background: The presence of a DCIS component accompanying invasive breast cancer (IBC) is associated with a higher rate of primary mastectomy compared to IBC without DCIS. After neoadjuvant systemic therapy (NST), HER2+ IBC patients show high response rates, allowing for increasing breast-conserving surgery rates. The aim of this study was to examine surgical trends after NST in a Dutch nationwide HER2+ cohort, and the influence of a DCIS component on mastectomy rate. Methods: Women with HER2+ IBC, diagnosed between 2010 and 2019 and treated with NST and surgery were included from the Netherlands Cancer Registry. Mastectomy rate was examined over the years, and compared between patients with and without a DCIS component in the pre-NST biopsy. Multivariable logistic regression analysis was used to investigate the association of the DCIS component with mastectomy rate and likelihood of achieving ypT0. Results: In total, 5289 patients were included. Over 10 years, mastectomy rate significantly decreased from 62.6 % in 2010 to 35.1 % in 2019. Patients with IBC+DCIS more often underwent mastectomy, with a rate of 48.4 % in 2019, compared to 30.0 % in IBC only (p

IntroductionSentinel lymph node (SLN) metastasis is an important predictor of prognosis in breast cancer (BC) patients, guiding treatment decisions. However, patients with the same BC subtype and tumor negative SLN (SLNneg) can have different survival outcomes. We hypothesized that the host anti-tumor immune reaction in SLNneg is important and results in morphometrically measurable changes in SLN size or shape which are related to patient prognosis.MethodsSurface area, circumference, long axis and short axis were histologically measured in 694 SLNneg from 356 cases of invasive BC and 67 ductal carcinoma in situ cases. The area occupied by fat was categorized as less or more than 50%. The long to short axis (L/S) ratio was calculated. The relationship between SLNneg morphometries and clinicopathological variables like tumor-infiltrating lymphocytes (TILs) within the primary tumor, as well as prognosis at 10 years follow up were analyzed.ResultsThe mean SLNneg surface area was 78.7mm2, circumference 40.3mm, long axis 13.1mm, short axis 8.2mm and L/S ratio 1.7. Larger surface area, long axis and short axis, including age >55 years were associated with higher body mass index (BMI) and SLN fat over 50% (p

Abstract Background To quantify the relationship between [18F]FDG uptake of the primary tumour measured by PET-imaging with immunohistochemical (IHC) expression of ER, PR, HER2, Ki-67, and clinical subtypes based on these markers in breast cancer patients. Methods PubMed and Embase were searched for studies that compared SUVmax between breast cancer patients negative and positive for IHC expression of ER, PR, HER2, Ki-67, and clinical subtypes based on these markers. Two reviewers independently screened the studies and extracted the data. Standardized mean differences (SMD) and 95% confidence intervals (CIs) were estimated by using DerSimonian-Laird random-effects models. P values less than or equal to 5% indicated statistically significant results. Results Fifty studies were included in the final analysis. SUVmax is significantly higher in ER-negative (31 studies, SMD 0.66, 0.56–0.77, P

Abstract This clinical study explored the associations between the intestinal microbiota, chemotherapy toxicity, and treatment response in postmenopausal oestrogen receptor positive breast cancer patients.Oestrogen receptor positive postmenopausal breast cancer patients were prospectively enroled in a multicentre cohort study and treated with 4 cycles of (neo)adjuvant adriamycin, cyclophosphamide (AC) followed by 4 cycles of docetaxel (D). Patients collected a faecal sample and completed a questionnaire before treatment, during AC, during D, and after completing AC-D. Chemotherapy toxicity and tumour response were determined. Intestinal microbiota was analysed by amplicon sequencing of the 16 S rRNA V4 gene-region. In total, 44 patients, including 18 neoadjuvant patients, were included, and 153 faecal samples were collected before AC-D (n = 44), during AC (n = 43), during D (n = 29), and after AC-D treatment (n = 37), 28 participants provided all four samples. In the whole group, observed species richness reduced during treatment (p = 0.042). The abundance of Proteobacteria, unclassified Enterobacterales, Lactobacillus, Ruminococcaceae NK4A214 group, Marvinbryantia, Christensenellaceae R7 group, and Ruminococcaceae UCG-005 changed significantly over time. Patients with any grade diarrhoea during docetaxel treatment had a significantly lower observed species richness compared to patients without diarrhoea. In the small group neoadjuvant treated patients, pathologic response was unrelated to baseline intestinal microbiota richness, diversity and composition. While the baseline microbiota was not predictive for pathologic response in a rather small group of neoadjuvant treated patients in our study, subsequent shifts in microbial richness, as well as the abundance of specific bacterial taxa, were observed during AC-D treatment in the whole group and the neoadjuvant group.

Abstract Background Quality of life (QoL) is an important patient-reported outcome that has been studied extensively as an endpoint. There is a growing interest in factors that may influence QoL, such as personality. This descriptive systematic review examined the relationship between personality and QoL in women with non-metastatic breast cancer. Methods On November 24th, 2020, with a update on March 7th, 2022, PubMed, PsycINFO, CINAHL, Web of Science and Embase were systematically searched for studies that assessed the direct relationship between personality traits and QoL among adult women diagnosed with non-metastatic breast cancer. The National Institutes of Health Study Quality Assessment Tool was used to assess the quality and risk of bias of the included studies. Three reviewers independently extracted data regarding objectives, population, setting, design, method, outcome measurements and key results. The results are descriptively reported. Results Twelve studies (6 cohort studies and 6 cross-sectional studies) were included. Three studies were rated as poor, one study was rated as good, and the remaining studies were rated as moderate. There was a small to moderate effect of personality on QoL as correlation coefficients ranged from 0.10 to 0.77, and the explained variance ranged from 4 to 43%. The (strength of the) relationship depended on the personality trait and QoL domain that was measured and was most apparent for the personality traits ‘optimism’ and ‘trait anxiety’ on psychosocial QoL domains. The results for the personality traits (unmitigated) agency, agreeableness, conscientiousness, novelty seeking, and self-efficacy indicated a smaller but statistically significant correlation between these personality traits and QoL. Conclusions The results confirm that personality affects QoL in women with non-metastatic breast cancer and thus provides evidence that personality traits are indeed important influential factors of QoL. It is therefore strongly recommended for all future QoL research to measure personality traits and use these variables as predictive factors, as they are needed to accurately interpret QoL. Information regarding personality traits provide physicians and patients with an interpretation of low or deterioration of QoL, which could guide physicians to improve their patients’ health outcomes and subsequently QoL using psycho-oncological support or treatment.

Abstract 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 α‐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 (β‐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

Abstract 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.

Abstract 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

Abstract Background The main purpose was to investigate the correlation between magnetic resonance imaging (MRI)-based response patterns halfway through neoadjuvant chemotherapy and immunotherapy (NAC) and pathological tumor response in patients with breast cancer. Secondary purposes were to compare the predictive value of MRI-based response patterns measured halfway through NAC and after NAC and to measure interobserver variability. Methods All consecutive patients treated with NAC for primary invasive breast cancer from 2012 to 2015 and who underwent breast MRI before, halfway through (and after) NAC were included. All breast tumors were reassessed on MRI by two experienced breast radiologists and classified into six patterns: type 0 (complete radiologic response); type 1 (concentric shrinkage); type 2 (crumbling); type 3 (diffuse enhancement); type 4 (stable disease); type 5 (progressive disease). Percentages of tumors showing pathological complete response (pCR), > 50% tumor reduction and > 50% tumor diameter reduction per MRI-based response pattern were calculated. Correlation between MRI-based response patterns and pathological tumor reduction was studied with Pearson’s correlation coefficient, and interobserver agreement was tested with Cohen’s Kappa. Results Patients (n = 76; mean age 53, range 29–72 years) with 80 tumors (4 bilateral) were included. There was significant correlation between these MRI-based response patterns halfway through NAC and tumor reduction on pathology assessment (reader 1 r = 0.33; p = 0.003 and reader 2 r = 0.45; p 50% tumor reduction in 90%, 78% and 65% of cases, respectively. In 83% of tumors with type 0 halfway through NAC, pathology assessment showed pCR. There was no significant correlation between MRI-based response patterns after NAC and tumor reduction rates on pathology assessment (reader 1 r = − 0.17; p = 0.145 and reader 2 r = − 0.17; p = 0.146). In 41% of tumors with type 0 after NAC, pathology assessment showed pCR. Conclusion MRI-based response patterns halfway through NAC can predict pathologic response more accurately than MRI-based response patterns after NAC. Complete radiological response halfway NAC is associated with 83% pCR, while complete radiological response after NAC seems to be correct in only 41% of cases.

Breast cancer is the second most common malignancy, worldwide. Treatment decisions are based on tumor stage, histological subtype, and receptor expression and include combinations of surgery, radiotherapy, and systemic treatment. These, together with earlier diagnosis, have resulted in increased survival. However, initial treatment efficacy cannot be guaranteed upfront, and these treatments may come with (long-term) serious adverse effects, negatively affecting a patient's quality of life. Gene expression-based tests can accurately estimate the risk of recurrence in early stage breast cancers. Disease recurrence correlates with treatment resistance, creating a major need to resensitize tumors to treatment. Notch signaling is frequently deregulated in cancer and is involved in treatment resistance. Preclinical research has already identified many combinatory therapeutic options where Notch involvement enhances the effectiveness of radiotherapy, chemotherapy or targeted therapies for breast cancer. However, the benefit of targeting Notch has remained clinically inconclusive. In this review, we summarize the current knowledge on targeting the Notch pathway to enhance current treatments for breast cancer and to combat treatment resistance. Furthermore, we propose mechanisms to further exploit Notch-based therapeutics in the treatment of breast cancer.