This thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for... Show moreThis thesis describes the effects of shortterm fasting on chemotherapy outcome in patients with breast cancer and the IGF-1 and insulin pathway as a target for cancer therapy and as a biomarker for chemotherapy outcome.Preclinical research is evaluated, which shows that short-term fasting during chemotherapy is effective. The effects of short-term fasting in humans is not evident yet. Although the first small clinical studies of short-term fasting as adjunct to chemotherapy are promising in terms of decreased toxicity and enhanced efficacy, the exact mechanism and effects are not established yet. More studies and a longer follow-up are needed to prove this.Insulin-like growth factor 1 (IGF-1) and insulin are members of the IGF-1 pathway, which is involved in cell growth and proliferation. The effects of the IGF-1 pathway on chemotherapy outcome and the pathway itself as target for cancer therapy are described. The disappointing results of clinical studies of IGF-1R inhibitors may be caused by the complexity of the IGF-1R pathway. Lowering both insulin and IGF-1, perhaps with a short-term fasting intervention, serves as a possible target in cancer therapy. Show less
Gal, R.; Monninkhof, E.M.; Gils, C.H. van; Groenwold, R.H.H.; Elias, S.G.; Bongard, D.H.J.G. van den; ... ; May, A.M. 2021
Purpose The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL)... Show morePurpose The Trials within Cohorts (TwiCs) design aims to overcome problems faced in conventional RCTs. We evaluated the TwiCs design when estimating the effect of exercise on quality of life (QoL) and fatigue in inactive breast cancer survivors. Methods UMBRELLA Fit was conducted within the prospective UMBRELLA breast cancer cohort. Patients provided consent for future randomization at cohort entry. We randomized inactive patients 12-18 months after cohort enrollment. The intervention group (n = 130) was offered a 12-week supervised exercise intervention. The control group (n = 130) was not informed and received usual care. Six-month exercise effects on QoL and fatigue as measured in the cohort were analyzed with intention-to-treat (ITT), instrumental variable (IV), and propensity scores (PS) analyses. Results Fifty-two percent (n = 68) of inactive patients accepted the intervention. Physical activity increased in patients in the intervention group, but not in the control group. We found no benefit of exercise for dimensions of QoL (ITT difference global QoL: 0.8, 95% CI = - 2.2; 3.8) and fatigue, except for a small beneficial effect on physical fatigue (ITT difference: - 1.1, 95% CI = - 1.8; - 0.3; IV: - 1.9, 95% CI = - 3.3; - 0.5, PS: - 1.2, 95% CI = - 2.3; - 0.2). Conclusion TwiCs gave insight into exercise intervention acceptance: about half of inactive breast cancer survivors accepted the offer and increased physical activity levels. The offer resulted in no improvement on QoL, and a small beneficial effect on physical fatigue. Show less
Background: Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and... Show moreBackground: Risk-adjusted cancer screening and prevention is a promising and continuously emerging option for improving cancer prevention. It is driven by increasing knowledge of risk factors and the ability to determine them for individual risk prediction. However, there is a knowledge gap between evidence of increased risk and evidence of the effectiveness and efficiency of clinical preventive interventions based on increased risk. This gap is, in particular, aggravated by the extensive availability of genetic risk factor diagnostics, since the question of appropriate preventive measures immediately arises when an increased risk is identified. However, collecting proof of effective preventive measures, ideally by prospective randomized preventive studies, typically requires very long periods of time, while the knowledge about an increased risk immediately creates a high demand for action. Summary: Therefore, we propose a risk-adjusted prevention concept that is based on the best current evidence making needed and appropriate preventive measures available, and which is constantly evaluated through outcome evaluation, and continuously improved based on these results. We further discuss the structural and procedural requirements as well as legal and socioeconomical aspects relevant for the implementation of this concept. Show less
Introduction: With the introduction of accelerated partial breast irradiation (APBI) and the trend of reducing the number of fractions, the geometric accuracy of treatment delivery becomes critical... Show moreIntroduction: With the introduction of accelerated partial breast irradiation (APBI) and the trend of reducing the number of fractions, the geometric accuracy of treatment delivery becomes critical. APBI patient setup is often based on fiducials, as the seroma is frequently not visible on pretreatment imaging. We assessed the motion of fiducials relative to the tumor bed between planning CT and treatment, and calculated margins to compensate for this motion. Methods: A cohort of seventy patients treated with APBI on a Cyberknife was included. Planning and in room pretreatment CT scans were registered on the tumor bed. Residual motion of the centers of mass of surgical clips and interstitial gold markers was calculated. We calculated the margins required per desired percentage of patients with 100% CTV coverage, and the systematic and random errors for fiducial motion. Results: For a single fraction treatment, a margin of 1.8 mm would ensure 100% CTV coverage in 90% of patients when using surgical clips for patient set-up. When using interstitial markers, the margin should be 2.2 mm. The systematic and random errors were 0.46 mm for surgical clip motion and 0.60 mm for interstitial marker motion. No clinical factors were found predictive for fiducial motion. Conclusions: Fiducial motion relative to the tumor bed between planning CT and APBI treatment is non negligible and should be included in the PTV margin calculation to prevent geographical miss. Systematic and random errors of fiducial motion were combined with other geometric uncertainties to calculate comprehensive PTV margins for different treatment techniques. (c) 2021 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 163 (2021) 1-6 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Plas-Krijgsman, W.G. van der; Boer, A.Z. de; Jong, P. de; Bastiaannet, E.; Bos, F. van den; Mooijaart, S.P.; ... ; Glas, N.A. de 2021
The number of older patients with breast cancer has increased due to the aging of the general population. The use of a geriatric assessment in this population has been advocated in many studies and... Show moreThe number of older patients with breast cancer has increased due to the aging of the general population. The use of a geriatric assessment in this population has been advocated in many studies and guidelines as it can be used to identify high risk populations for early mortality and toxicity. Additionally, geriatric parameters could predict relevant outcome measures. This systematic review summarizes all available evidence on predictive factors for various outcomes (disease-related and survival, toxicity, and patient-reported outcomes), with a special focus on geriatric parameters and patient-reported outcomes, in older patients with breast cancer. Studies were identified through systematic review of the literature published up to September 1st 2019 in the PubMed database and EMBASe. A total of 173 studies were included. Most studies investigated disease-related and survival outcomes (n = 123, 71%). Toxicity was investigated in 40 studies (23%) and a mere 15% (n = 26) investigated patient-reported outcomes. Various measures that can be derived from a geriatric assessment were predictive for survival endpoints. Furthermore, geriatric parameters were among the most frequently found predictors for toxicity and patient-reported outcomes. In conclusion, this study shows that geriatric parameters can predict survival, toxicity, and patient-reported outcomes in older patients with breast cancer. These findings can be used in daily clinical practice to identify patients at risk of early mortality, high risk of treatment toxicity or poor functional outcome after treatment. A minority of studies used relevant outcome measures for older patients, showing the need for studies that are tailored to the older population.(c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Objective Monitoring quality of life (QoL) in patients with cancer can provide insight into functional, psychological and social consequences associated with illness and its treatment. The primary... Show moreObjective Monitoring quality of life (QoL) in patients with cancer can provide insight into functional, psychological and social consequences associated with illness and its treatment. The primary objective of this study is to examine the influence of cultural factors on the communication between the patient and the health care provider and the perceived QoL in women with breast cancer in Japan and the Netherlands. Methods In Japanese and Dutch women with early breast cancer, the number, content and frequency of QoL-related issues discussed at the medical encounter were studied. Patients completed questionnaires regarding QoL and evaluation of communication with the CareNoteBook. Results The total number, frequency and content of QoL-related issues discussed differed between the two countries. Japanese women (n = 134) were significantly more reticent in discussing QoL-issues than the Dutch women (n = 70) (p < .001). Furthermore, Dutch patients perceived the CareNoteBook methodology significantly more positively than the Japanese patients (p < .001). Both groups supported the regular assessment via a CareNoteBook methodology. Conclusions Japanese women are more reluctant in expressing their problems with the illness, its treatment and patient-physician communication than Dutch women. Show less
Breast cancer is the most prevalent cancer in women. Early detection of this disease improves survival and therefore population screenings, based on mammography, are performed. However, the... Show moreBreast cancer is the most prevalent cancer in women. Early detection of this disease improves survival and therefore population screenings, based on mammography, are performed. However, the sensitivity of this screening modality is not optimal and new screening methods, such as blood tests, are being explored. Most of the analyses that aim for early detection focus on proteins in the bloodstream. In this study, the biomarker potential of total serum N-glycosylation analysis was explored with regard to detection of breast cancer. In an age-matched case-control setup serum protein N-glycan profiles from 145 breast cancer patients were compared to those from 171 healthy individuals. N-glycans were enzymatically released, chemically derivatized to preserve linkage-specificity of sialic acids and characterized by high resolution mass spectrometry. Logistic regression analysis was used to evaluate associations of specific N-glycan structures as well as N-glycosylation traits with breast cancer. In a case-control comparison three associations were found, namely a lower level of a two triantennary glycans and a higher level of one tetraantennary glycan in cancer patients. Of note, various other N-glycomic signatures that had previously been reported were not replicated in the current cohort. It was further evaluated whether the lack of replication of breast cancer N-glycomic signatures could be partly explained by the heterogenous character of the disease since the studies performed so far were based on cohorts that included diverging subtypes in different numbers. It was found that serum N-glycan profiles differed for the various cancer subtypes that were analyzed in this study. Show less
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... Show moreBackground 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 < 0.05). DCIS was less likely to be treated within 3 months (odds ratio [OR](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. Show less
Introduction: As the prognosis of early-stage breast cancer patients is excellent, prevention of radiation induced toxicity has become crucial. Reduction of margins compensating for intrafraction... Show moreIntroduction: As the prognosis of early-stage breast cancer patients is excellent, prevention of radiation induced toxicity has become crucial. Reduction of margins compensating for intrafraction motion reduces non-target dose. We assessed motion of the tumor bed throughout APBI treatment fractions and calculated CTV-PTV margins for breathing and drift.Methods: This prospective clinical trial included patients treated with APBI on a Cyberknife with fiducial tracking. Paired orthogonal kV images made throughout the entire fraction were used to extract the tumor bed position. The images used for breathing modelling were used to calculate breathing amplitudes. The margins needed to compensate for breathing and drift were calculated according to Engelsman and Van Herk respectively.Results: Twenty-two patients, 110 fractions and 5087 image pairs were analyzed. The margins needed for breathing were 0.3-0.6 mm. The margin for drift increased with time after the first imaging for positioning. For a total fraction duration up to 8 min, a margin of 1.0 mm is sufficient. For a fraction of 32 min, 2.5 mm is needed. Techniques that account for breathing motion can reduce the margin by 0.1 mm. There was a systematic trend in the drift in the caudal, medial and posterior direction. To compensate for this, 0.7 mm could be added to the margins.Conclusions: The margin needed to compensate for intrafraction motion increased with longer fraction duration due to drifting of the target. It doubled for a fraction of 24 min compared to 8 min. Breathing motion has a limited effect.(c) 2021 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 159 (2021) 176-182 This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Invasive lobular carcinoma (ILC) is the second most common type of breast cancer. Hallmarks of ILC include disruption of adherens junctions and hyperactivation of phosphoinositide 3-kinase (PI3K)... Show moreInvasive lobular carcinoma (ILC) is the second most common type of breast cancer. Hallmarks of ILC include disruption of adherens junctions and hyperactivation of phosphoinositide 3-kinase (PI3K)-mTOR signaling. The tumor suppressor PTEN regulates PI3K signaling. We present a preclinical mouse model of ILC metastasis, based on inactivation of the adherens junction protein E-cadherin and the tumor suppressor p53 and surgical excision of primary tumors. In this model, pharmacological mTOR inhibition blocks growth of primary tumors as well as metastatic disease, and this response is partially dependent on the adaptive immune system. Loss of E-cadherin mouse mammary epithelium leads to apoptosis, and PTEN activation alone results in squamous metaplastic mammary tumors, but a combination of these events leads to ILC formation, indicating a causal role of PI3K signaling together with E-cadherin loss in ILC. Combined somatic loss of the adherens junction molecule p120 and p53 in the mouse mammary gland leads to metaplastic mammary tumors, and loss of p120 in breast cancer cell lines promotes anoikis resistance through hypersensitization of growth factor receptor (GFR) signaling. Combined inactivation of E-cadherin, p120 and p53 induces basal-like tumors, with an epithelial-to- mesenchymal-transition (EMT) phenotype, and no ILC formation. Show less
Since cancer survival rates are rising, there is growing attention for longterm side effects of cancer and its treatment. A common side effect is the negative impact of treatment on sexuality of... Show moreSince cancer survival rates are rising, there is growing attention for longterm side effects of cancer and its treatment. A common side effect is the negative impact of treatment on sexuality of patients and their partners. Patient and partners as well as healthcare professionals experience several barriers to discuss this topic, like lack of time and lack of knowlegde. Two-thirds of the cancer patients reported to be in need of information regarding sexual health; especially those who were younger, who reported a negative impact of cancer on sexuality and those who were diagnosed less than two years ago. Patients and partners reported to prefer to discuss sexual health with nurse practitioners throughout the treatment proces. Besides, satisfaction with sexual life after treatment is related to satisfaction before treatment, not only with current sexual function.Widely available information and defining responsibility within the oncology treatment team would be helpful to improve communication around sexual health in cancer care. Additionally, specialized clinics would tackle soms frequently reported barriers of discussing sexuality. More reseach is needed on the implementation of sexual healthcare in oncology practice to deliver continuum of care, which will ultimately improve patient care. Show less
Tumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances... Show moreTumors are complex ecosystems containing not just cancer cells, but a large variety of cell types, including immune cells. Moreover, tumors have a systemic influence: they can signal long distances using soluble molecules and hijack non-neoplastic cells (such as immune cells) in distant organs for their own benefit, thus maximising their metastatic potential. The phenotype of immune cells in tumors and in systemic environments is therefore a key determinant of cancer progression and response to therapy.This thesis aims to understand what governs the tumor-immune ecosystem. We argue that cancer-intrinsic genetic aberrations have a dominant role in determining the tumor immune contexture, as well as systemic inflammatory activation. Understanding the intricate connection between the genetics of breast cancer and anti-tumor immune responses will help develop personalised immune intervention strategies for cancer, tailored to the genetic makeup of a patient’s tumor. Furthermore, we examine in detail the role of neutrophils in cancer-induced systemic inflammation, and how they influence the progression and spread of breast cancer. While tumors can be highly heterogeneous in nature, we show that neutrophils themselves also have a tremendous phenotypic diversity. Mapping this heterogeneity in neutrophil phenotypes may help to utilise these cells in cancer immunotherapy. Show less
Over a century ago, the systematic evaluation of medical treatment outcomes was first described by Ernest Codman. At that time a too progressive thought, while the value of measuring the quality of... Show moreOver a century ago, the systematic evaluation of medical treatment outcomes was first described by Ernest Codman. At that time a too progressive thought, while the value of measuring the quality of care is seen nowadays.The NABON Breast Cancer Audit (NBCA) provides insight into the various care processes that are part of the complex multidisciplinary treatment of patients diagnosed with breast cancer. Results of the NBCA show a good and still improving quality of care for patients diagnosed with breast cancer. In addition, this thesis provides insight into a sub-area where variation between hospitals is found; the performance of an immediate breast reconstruction in patients undergoing mastectomy. Many factors influence this hospital variation, such as patient and tumour factors, hospital factors and differences in indications for immediate breast reconstruction between surgeons and plastic surgeons. Physicians should inform patients about the various breast cancer treatment options. Informing a patient about immediate breast reconstruction results in a 14 times higher chance of actually undergoing a breast reconstruction after mastectomy.These factors should to be evaluated and improved as quality of life is higher for patients with immediate breast reconstruction than with mastectomy alone. By continuously measuring, providing feedback and acting on the data found at both a national level and in the consultation room, Ernest Codman's heritage will certainly be realized. Show less
Jong, G. de; Bartels, L.; Kedde, M.; Verdegaal, E.M.E.; Gillissen, M.A.; Levie, S.E.; ... ; Wagner, K. 2020
Targeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form... Show moreTargeted cancer therapy with monoclonal antibodies has proven successful for different cancer types but is limited by the availability of suitable antibody targets. CD43s, a unique sialylated form of CD43 expressed by hematologic malignancies, is a recently identified target and antibodies interacting with CD43s may have therapeutic potential against acute myeloid leukemia (AML) and myelodysplastic syndrome. CD43s is recognized by the human antibody AT1413, that was derived from a high-risk AML patient who successfully cleared leukemia after allogeneic stem cell transplantation. Here we observed that AT1413 binds also to certain non-hematopoietic tumor cells, particularly melanoma and breast cancer. AT1413 immune precipitated CD43s from melanoma cells confirming that it recognizes the same target on melanoma as on AML. AT1413 induced antibody-dependent cellular cytotoxicity against short-term cultured patient-derived melanoma samples. However, AT1413 was unable to affect the growth of melanoma cells in vivo. To increase the efficacy of AT1413 as a therapeutic antibody, we generated two different formats of bispecific T-cell engaging antibodies (TCEs): one binding bivalently (bTCE) and the other monovalently (knob-in-hole; KiH) to both CD43s and CD3 epsilon. In vitro, these TCEs redirected T-cell cytotoxicity against melanoma cells with differences in potencies. To investigate their effects in vivo, we grafted mice that harbor a human immune system with the melanoma cell line A375. Treatment with both AT1413 bTCE and AT1413 KiH significantly reduced tumor outgrowth in these mice. These data indicate a broad therapeutic potential of AT1413 that includes AML and CD43s-expressing solid tumors that originate from CD43-negative tissues. Show less
Lugtenberg, R.T.; Groot, S. de; Kaptein, A.A.; Fischer, M.J.; Kranenbarg, E.M.K.; Duijm-de Carpentier, M.; ... ; Dutch Breast Canc Res Grp BOOG 2020
Purpose In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness... Show morePurpose In the phase II DIRECT study a fasting mimicking diet (FMD) improved the clinical response to neoadjuvant chemotherapy as compared to a regular diet. Quality of Life (QoL) and illness perceptions regarding the possible side effects of chemotherapy and the FMD were secondary outcomes of the trial. Methods 131 patients with HER2-negative stage II/III breast cancer were recruited, of whom 129 were randomly assigned (1:1) to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and the day of neoadjuvant chemotherapy. The European Organisation for Research and Treatment of Cancer (EORTC) questionnaires EORTC-QLQ-C30 and EORTC-QLQ-BR23; the Brief Illness Perception Questionnaire (BIPQ) and the Distress Thermometer were used to assess these outcomes at baseline, halfway chemotherapy, before the last cycle of chemotherapy and 6 months after surgery. Results Overall QoL and distress scores declined during treatment in both arms and returned to baseline values 6 months after surgery. However, patients' perceptions differed slightly over time. In particular, patients receiving the FMD were less concerned and had better understanding of the possible adverse effects of their treatment in comparison with patients on a regular diet. Per-protocol analyses yielded better emotional, physical, role, cognitive and social functioning scores as well as lower fatigue, nausea and insomnia symptom scores for patients adherent to the FMD in comparison with non-adherent patients and patients on their regular diet. Conclusions FMD as an adjunct to neoadjuvant chemotherapy appears to improve certain QoL and illness perception domains in patients with HER2-negative breast cancer. Trialregister ClinicalTrials.gov Identifier: NCT02126449. Show less
Background Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with... Show moreBackground Breast cancer survivors (BCS) may have increased risk of hypothyroidism, but risk according to treatment modality is unclear. We estimated the incidence of hypothyroidism in women with breast cancer, and according to cancer treatment. Methods Using nationwide registries, we identified all Danish women aged >= 35 years diagnosed with non-metastatic breast cancer (1996-2009). We matched up to five cancer-free women (controls) for each BCS. We excluded women with prevalent thyroid disease. Cancer treatment was chemotherapy with or without radiotherapy (RT) targeting the breast/chest wall only, or also the lymph nodes (RTn). We identified hypothyroidism using diagnostic codes, and/or levothyroxine prescriptions. We calculated the cumulative incidence, incidence rates (IR) per 1000 person-years, and used Cox regression to estimate hazard ratios (HR) and associated 95% confidence intervals (CIs) of hypothyroidism, adjusting for comorbidities. Results We included 44,574 BCS and 203,306 matched controls with 2,631,488 person-years of follow-up. BCS had a slightly higher incidence of hypothyroidism than controls [5-year cumulative incidence, 1.8% (95%CI = 1.7-1.9) and 1.6% (95%CI = 1.5-1.6), respectively]. The overall IR was 4.45 (95%CI = 4.25-4.67) and 3.81 (95%CI = 3.73-3.90), corresponding to an adjusted HR = 1.17 (95%CI = 1.11-1.24). BCS who received RTn with chemotherapy (HR = 1.74, 95%CI = 1.50-2.02) or without chemotherapy (HR = 1.31, 95%CI = 1.14-1.51) had an elevated risk of hypothyroidism compared with matched controls and compared with BCS who underwent surgery alone [HR = 1.71, 95%CI = 1.45-2.01 and HR = 1.36, 95%CI = 1.17-1.58, respectively]. Conclusions BCS have an excess risk of hypothyroidism compared with age-matched controls. BCS and those working in cancer survivorship settings ought to be aware that this risk is highest in women treated with radiation therapy to the lymph nodes and chemotherapy. Show less
The objective of this study was to investigate the expression and function of GRHL2 in different breast cancer subtypes. In Chapter 2, we focused on the expression of GRHL2 in human breast cancer... Show moreThe objective of this study was to investigate the expression and function of GRHL2 in different breast cancer subtypes. In Chapter 2, we focused on the expression of GRHL2 in human breast cancer and the distinct effects of GRHL2 knockout on aspects of growth versus migration in basal A and luminal-like subtypes. In Chapter 3, ChIP-seq was used to explore the genomic landscape of GRHL2 binding sites in basal A and luminal-like subtypes of breast cancer and this data was used to predict shared and distinct GRHL2 target genes. In Chapter 4, based on a conditional GRHL2 knockout system, we determined the dynamic changes in genome-wide DNA transcription triggered by loss of GRHL2 in luminal-like breast cancer cells and used the data to predict affected pathways. In Chapter 5, ChIP-seq and BrU-seq data were integrated to identify genes whose transcription is controlled by GRHL2 and establish gene expression networks regulated by GRHL2 in luminal-like breast cancer. Show less
Therapy resistance is a known problem in breast cancer and is associated with a variety of mechanisms. The role of the tumor microenvironment in cancer development and resistance mechanisms is... Show moreTherapy resistance is a known problem in breast cancer and is associated with a variety of mechanisms. The role of the tumor microenvironment in cancer development and resistance mechanisms is becoming increasingly understood. Tumor-stroma is the main component of the tumor microenvironment. Stromal cells like cancer-associated fibroblasts (CAFs) are believed to contribute to chemotherapy resistance via the production of several secreted factors like cytokines and chemokines. CAFs are found to influence disease progression; patients with primary tumors with a high amount of tumor-stroma have a significantly worse outcome. Therefore the role of CAFs resistance mechanisms makes them a promising target in anti-cancer therapy. An overview of recent advances in strategies to target breast cancer stroma is given and the current literature regarding these stromal targets is discussed. CAF-specific proteins as well as secreted molecules involved in tumor-stroma interactions provide possibilities for stroma-specific therapy. The development of stroma-specific therapy is still in its infancy and the available literature is limited. Within the scope of personalized treatment, biomarkers based on the tumor-stroma have future potential for the improvement of treatment via image-guided surgery (IGS) and PET scanning. Show less
Boer, A.Z. de; Water, W. van de; Bastiaannet, E.; Glas, N.A. de; Kiderlen, M.; Portielje, J.E.A.; Extermann, M. 2020
Introduction Since older patients with breast cancer are underrepresented in clinical trials, an oncogeriatric approach is advocated to guide treatment decisions. However, the effect on outcomes is... Show moreIntroduction Since older patients with breast cancer are underrepresented in clinical trials, an oncogeriatric approach is advocated to guide treatment decisions. However, the effect on outcomes is unclear. The aim of this study was to compare treatments and outcomes between patients treated in an oncogeriatric and a standard care setting. Methods Patients aged >= 70 years with early stage breast cancer were included. Theoncogeriatric cohortcomprised unselected patients from the Moffitt Cancer Center, and thestandard cohortpatients from a Dutch population-based cohort. Cox models were used to characterize the influence of care setting on recurrence risk and overall mortality. Results Overall, 268 patients were included in the oncogeriatric and 1932 patients in the standard cohort. Patients in the oncogeriatric cohort were slightly younger, had more comorbidity, and received more adjuvant endocrine therapy and chemotherapy. Oncogeriatric care was associated with a lower risk of recurrence, which remained significant after adjustment for patient and tumour characteristics [hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.44-0.99]. Oncogeriatric care was also associated with a lower overall mortality, which also remained significant after adjustment for patient and tumour characteristics (HR 0.69, 95% CI 0.55-0.87). Conclusions Patients treated in the oncogeriatric care setting had a lower risk of recurrence, which may be explained by more systemic treatment. Overall mortality was also lower, but other explanations besides care setting could not be ruled out as the cohorts had different patient profiles. Future studies need to clarify the impact of an oncogeriatric approach on outcomes. Show less
Background Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea-active ingredient epigallocatechin-3-gallate (EGCG)-is one of the most... Show moreBackground Many cancer patients use additional herbs or supplements in combination with their anti-cancer therapy. Green tea-active ingredient epigallocatechin-3-gallate (EGCG)-is one of the most commonly used dietary supplements among breast cancer patients. EGCG may alter the metabolism of tamoxifen. Therefore, the aim of this study was to investigate the influence of green tea supplements on the pharmacokinetics of endoxifen; the most relevant active metabolite of tamoxifen. Methods In this single-center, randomized cross-over trial, effects of green tea capsules on endoxifen levels were evaluated. Patients treated with tamoxifen for at least 3 months were eligible for this study. After inclusion, patients were consecutively treated with tamoxifen monotherapy for 28 days and in combination with green tea supplements (1 g twice daily; containing 300 mg EGCG) for 14 days (or vice versa). Blood samples were collected on the last day of monotherapy or combination therapy. Area under the curve (AUC(0-24h)), maximum concentration (C-max) and minimum concentration (C-trough) were obtained from individual plasma concentration-time curves. Results No difference was found in geometric mean endoxifen AUC(0-24h)in the period with green tea versus tamoxifen monotherapy (- 0.4%; 95% CI - 8.6 to 8.5%;p = 0.92). Furthermore, no differences inC(max)(- 2.8%; - 10.6 to 5.6%;p = 0.47) norC(trough)(1.2%; - 7.3 to 10.5%;p = 0.77) were found. Moreover, no severe toxicity was reported during the whole study period. Conclusions This study demonstrated the absence of a pharmacokinetic interaction between green tea supplements and tamoxifen. Therefore, the use of green tea by patients with tamoxifen does not have to be discouraged. Show less
