Background: In the Netherlands, the COVID-19 pandemic resulted in a temporary halt of population screening for cancer and limited hospital capacity for non-COVID care. We aimed to investigate the... Show moreBackground: In the Netherlands, the COVID-19 pandemic resulted in a temporary halt of population screening for cancer and limited hospital capacity for non-COVID care. We aimed to investigate the impact of the pandemic on the in-hospital diagnostic pathway of breast cancer (BC) and colorectal cancer (CRC).Methods: 71,159 BC and 48,900 CRC patients were selected from the Netherlands Cancer Registry. Patients, diagnosed between January 2020 and July 2021, were divided into six periods and compared to the average of patients diagnosed in the same periods in 2017-2019. Diagnostic procedures performed were analysed using logistic regression. Lead time of the diagnostic pathway was analysed using Cox regression. Analyses were stratified for cancer type and corrected for age, sex (only CRC), stage and region.Results: For BC, less mammograms were performed during the first recovery period in 2020. More PET-CTs were performed during the first peak, first recovery and third peak period. For CRC, less ultrasounds and more CT scans and MRIs were performed during the first peak. Lead time decreased the most during the first peak by 2 days (BC) and 8 days (CRC). Significantly fewer patients, mainly in lower stages, were diagnosed with BC (-47%) and CRC (-36%) during the first peak.Conclusion: Significant impact of the COVID-19 pandemic was found on the diagnostic pathway, mainly during the first peak. In 2021, care returned to the same standards as before the pandemic. Long-term effects on patient outcomes are not known yet and will be the subject of future research. Show less
Gruil, N. de; Böhringer, S.; Groot, S. de; Pijl, H.; Kroep, J.R.; Swen, J.J. 2023
Simple Summary: Insulin and insulin-like growth factor 1 (IGF1) are metabolic hormones, which are often upregulated to stimulate proliferation in breast cancer. A fasting mimicking diet (FMD)... Show moreSimple Summary: Insulin and insulin-like growth factor 1 (IGF1) are metabolic hormones, which are often upregulated to stimulate proliferation in breast cancer. A fasting mimicking diet (FMD) targets insulin signaling pathway downregulation to hamper tumor growth. Genes encoding for the insulin receptors on the cell's surface contain genetic variation between patients, which can affect insulin receptor function and cellular response. Therefore, a group of 113 patients with HER2-negative breast cancer receiving neoadjuvant chemotherapy with or without a fasting mimicking diet were investigated. We found that two IGF1 receptor variants were associated with worse pathological response compared to the reference alleles, out of the 17 interrogated common variants. Additionally, two IGF1 receptor variants could interact negatively within the FMD group regarding radiological response. These results emphasize that genetic variation harbors predictive clinical relevance to optimize and personalize cancer therapy. Aim: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. Methods: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. Results: IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). Conclusions: The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD. Show less
Background: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT)... Show moreBackground: Approximately 20% of invasive ductal breast malignancies are human epidermal growth factor receptor 2 (HER2)-positive. These patients receive neoadjuvant systemic therapy (NAT) including HER2-targeting therapies. Up to 65% of patients achieve a pathological complete response (pCR). These patients might not have needed surgery. However, accurate preoperative identification of a pCR remains challenging. A radiologic complete response (rCR) on MRI corresponds to a pCR in only 73% of patients. The current feasibility study investigates if HER2-targeted PET/CT-imaging using Zirconium-89 (89Zr)-radiolabeled trastuzumab can be used for more accurate NAT response evaluation. Methods: HER2-positive breast cancer patients scheduled to undergo NAT and subsequent surgery received a 89Zr-trastuzumab PET/CT both before (PET/CT-1) and after (PET/CT-2) NAT. Qualitative and quantitative response evaluation was performed. Results: Six patients were enrolled. All primary tumors could be identified on PET/CT-1. Four patients had a pCR and two a pathological partial response (pPR) in the primary tumor. Qualitative assessment of PET/CT resulted in an accuracy of 66.7%, compared to 83.3% of the standard-of-care MRI. Quantitative assessment showed a difference between the SUVR on PET/CT-1 and PET/CT-2 (ΔSUVR) in patients with a pPR and pCR of −48% and −90% (p = 0.133), respectively. The difference in tumor-to-blood ratio on PET/CT-1 and PET/CT-2 (ΔTBR) in patients with pPR and pCR was −79% and −94% (p = 0.133), respectively. Three patients had metastatic lymph nodes at diagnosis that were all identified on PET/CT-1. All three patients achieved a nodal pCR. Qualitative assessment of the lymph nodes with PET/CT resulted in an accuracy of 66.7%, compared to 50% of the MRI. Conclusions: NAT response evaluation using 89Zr-trastuzumab PET/CT is feasible. In the current study, qualitative assessment of the PET/CT images is not superior to standard-of-care MRI. Our results suggest that quantitative assessment of 89Zr-trastuzumab PET/CT has potential for a more accurate response evaluation of the primary tumor after NAT in HER2-positive breast cancer. Show less
Lemij, A.A.; Liefers, G.J.; Derks, M.G.M.; Bastiaannet, E.; Fiocco, M.; Lans, T.E.; ... ; Glas, N.A. de 2023
Background A decline in physical activity and the ability to perform activities of daily living (ADL) and instrumental activities of daily living (IADL) could interfere with independent living and... Show moreBackground A decline in physical activity and the ability to perform activities of daily living (ADL) and instrumental activities of daily living (IADL) could interfere with independent living and quality of life in older patients, but may be prevented with tailored interventions. The aim of the current study was to assess changes in physical activity and ADL/IADL in the first 5 years after breast cancer diagnosis in a real-world cohort of older patients and to identify factors associated with physical decline. Methods Patients aged >= 70 years with in situ or stages I-III breast cancer were included in the prospective Climb Every Mountain cohort study. Linear mixed models were used to assess physical activity (according to Metabolic Equivalent of Task (MET) hours per week) and ADL/IADL (according to the Groningen Activity Restriction Scale (GARS)) over time. Secondly, the association with geriatric characteristics, treatment, quality of life, depression, apathy, and loneliness was analyzed. Results A total of 239 patients were included. Physical activity and ADL/IADL changed in the first 5 years after diagnosis (mean change from baseline -11.6 and +4.2, respectively). Geriatric characteristics at baseline were strongly associated with longitudinal change in physical activity and ADL/IADL, whereas breast cancer treatment was not. A better quality of life was associated with better physical activity and preservation of ADL/IADL, while depression and loneliness were negatively associated with these outcomes. Discussion Geriatric characteristics, loneliness, and depressive symptoms were associated with physical decline in older patients with breast cancer, while breast cancer treatment was not.A decline in physical activity and the ability to perform activities of daily living may interfere with quality of life in older patients. This article assessed changes in physical activity and activities of daily living in the first 5 years after breast cancer diagnosis in a real-world cohort of older patients and identified factors associated with physical decline. Show less
BackgroundHodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit... Show moreBackgroundHodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes.MethodsThe authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC-HL) with 5988 age- and calendar year-matched patients with first primary BC (BC-1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment.ResultsCompared to BC-1 patients, BC-HL patients received anthracycline-containing chemotherapy (23.7% vs. 43.8%, p < .001) and breast-conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p < .001) less often. BC treatment considerations were reported for 71% of BC-HL patients. BC-HL patients had a significantly higher risk of 15-year overall mortality than BC-1 patients (61% vs. 23%). Furthermore, risks of BC-specific mortality and nonfatal BC events were significantly increased among BC-HL patients, also when accounting for tumor and treatment characteristics (2.2- to 4.5-fold). BC-HL patients with a screen-detected BC had a significantly reduced (61%) BC-specific mortality. One-third of BC-HL patients had CVD at BC-diagnosis, compared to <0.1% of BC-1 patients. Fifteen-year CVD-specific mortality and CVD incidence were significantly higher in BC-HL patients than in BC-1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment.ConclusionsBC-HL patients experience a higher burden of CVD and worse BC outcomes than BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors. Show less
Background Hospital report cards (HRCs) are usually presented in a textual and factual format, likely hampering information processing. Objective This study aimed to investigate the effects of... Show moreBackground Hospital report cards (HRCs) are usually presented in a textual and factual format, likely hampering information processing. Objective This study aimed to investigate the effects of audiovisual and narrative information in HRCs on user responses, and to test differences between older and younger women. Design A 2 (modality [textual vs. audiovisual]) x 3 (narration style [factual vs. process narrative vs. experience narrative]) online experiment was conducted. Information about breast cancer care was used as a case example. Age (younger [<65] vs. older [>= 65]) was included as a potential effect modifier. Setting and Participants A total of 631 disease-naive women (M-age = 56.06) completed an online survey. The outcomes were perceived cognitive load, satisfaction, comprehension, information recall and decisional conflict. Data were analysed using AN(C)OVAs. Results Audiovisual (vs. textual) information resulted in higher information satisfaction across age groups, but was associated with lower comprehension in older women. An experience narrative (vs. factual information) increased satisfaction with attractiveness and emotional support of the information only in older women. A three-way interaction effect was found, suggesting that older women were most satisfied with the comprehensibility of audiovisual factual or textual process narrative information. Younger women were most satisfied with the comprehensibility of audiovisual process narrative or textual factual information. Discussion and Conclusion Audiovisual and narrative information in an HRC showed beneficial effects on satisfaction measures. In particular, audiovisual information could be incorporated into HRCs to increase satisfaction with information. Public Contribution Lay persons helped in optimizing the visuals used in the stimulus materials by checking for clarity. Show less
The molecular mechanisms that instigate a healthy cell to become malignant are fueled by (epi)genetic alterations in so-called driver genes. While the Holy Grail of precision medicine is to... Show moreThe molecular mechanisms that instigate a healthy cell to become malignant are fueled by (epi)genetic alterations in so-called driver genes. While the Holy Grail of precision medicine is to identify these genetic dependencies and to target them with specific compounds in a personalized fashion, this has proven a daunting task, as tumors are exquisitely characterized by genetic instability and a mutator phenotype. Genetically engineered mouse models (GEMMs) are uniquely suited for functional in vivo validation of genotype-phenotype relationships, as they enable in vivo assessment of de novo tumorigenesis in a mammalian organism with intact immune and stromal compartments upon perturbation of (combinations of) oncogenes and/or tumor suppressor genes. Somatic modeling of cancer using CRISPR technology in vivo proved to be a true game-changing tool, allowing for rapid functional validation of candidate cancer genes enrolling from forward genetic screens and catalogs of alterations in human tumors. In this work, I showed how CRISPR approaches were deployed to precisely engineer tumorigenic events in the mouse mammary gland for dissecting oncogenic cascades, unraveling new therapeutic vulnerabilities and mechanisms of therapy resistance in different breast cancer subtypes. Show less
To improve cancer treatments, personalized medicine approaches have aimed to identify exactly which mutations are driving tumor development in a given patient and specifically target these... Show moreTo improve cancer treatments, personalized medicine approaches have aimed to identify exactly which mutations are driving tumor development in a given patient and specifically target these mutations using precision therapies. However, one of the main challenges of this approach is identifying which mutations are true drivers, as tumors typically contain many additional passenger mutations that do not actually contribute to tumor development. Besides this, many patients often relapse after prolonged treatment due to the emergence of acquired resistance, limiting the clinical effectiveness of targeted treatments. In this thesis, we focussed on using genetically engineered mouse models to identify candidate cancer genes and therapy resistance mechanisms in two different breast cancers: invasive lobular carcinoma (ILC) and triple-negative breast cancer (TNBC). For ILC, we used transposon-based insertional mutagenesis (TIM) to uncover several novel cancer genes driving ILC development. Besides this, we also developed a novel computational approach (IM-Fusion) for improving the discovery of cancer genes from TIM screens and explored mechanisms of resistance in Fgfr2-driven ILC. For TNBC, we used CRISPR-based iterative mouse modeling combined with comparative oncogenomics to identify novel drivers of BRCA1-deficient TNBC. Finally, using combined in-vivo/in-vitro screens, we identified Parg as a driver of treatment resistance in BRCA2-deficient TNBC. Show less
Vries, S. de; Schaapveld, M.; Kardaun, J.W.P.F.; Bruin, K.H. de; Krol, A.D.G.; Lugtenburg, P.J.; ... ; Leeuwen, F.E. van 2018
