The aim of this thesis was to investigate if a text-mining tool is suitable for collecting real-world data from electronic health records to evaluate cancer treatments in clinical practice. By... Show moreThe aim of this thesis was to investigate if a text-mining tool is suitable for collecting real-world data from electronic health records to evaluate cancer treatments in clinical practice. By investigating a range of use cases including treatments of patients with renal cell carcinoma, hepatocellular carcinoma, melanoma, breast cancer, and COVID-19, it showed that the text-mining tool is a suitable method of data needed for the evaluation of treatment patterns, effectiveness, safety, prognostic factors, and guideline adherence. The discussion showed that enhancing the data quality and actively using real-world data for treatment evaluation regarding treatment policies are some of the next steps. Show less
Akdeniz, D.; Barele, M. van; Heemskerk-Gerritsen, B.A.M.; Steyerberg, E.W.; Hauptmann, M.; Beek, I. van de; ... ; HEBON Investigators 2022
Aim: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents... Show moreAim: BRCA1/2 mutation carriers with primary breast cancer (PBC) are at high risk of contralateral breast cancer (CBC). In a nationwide cohort, we investigated the effects of chemotherapeutic agents given for PBC on CBC risk separately in BRCA1 and BRCA2 mutation carriers. Patients and methods: BRCA1 or BRCA2 mutation carriers with an invasive PBC diagnosis from 1990 to 2017 were selected from a Dutch cohort. We estimated cumulative CBC incidence using competing risks analysis. Hazard ratios (HR) for the effect of neo-adjuvant or adjuvant chemotherapy and different chemotherapeutic agents on CBC risk were estimated using Cox regression. Results: We included 1090 BRCA1 and 568 BRCA2 mutation carriers; median follow-up was 8.9 and 8.4 years, respectively. Ten-year cumulative CBC incidence for treatment with and without chemotherapy was 6.7% [95%CI: 5.1-8.6] and 16.7% [95%CI: 10.8-23.7] in BRCA1 and 4.8% [95%CI: 2.7-7.8] and 16.0% [95%CI: 9.3-24.4] in BRCA2 mutation carriers, respectively. Chemotherapy was associated with reduced CBC risk in BRCA1 (multivariable HR: 0.46, 95%CI: 0.29-0.74); a similar trend was observed in BRCA2 mutation carriers (HR: 0.63, 95%CI: 0.29-1.39). In BRCA1, risk reduction was most pronounced in the first 5 years (HR: 0.32, 95%CI: 0.17-0.61). Anthracyclines and the combination of anthracyclines with taxanes were associated with substantial CBC risk reduction in BRCA1 carriers (HR: 0.34, 95%CI: 0.17-0.68 and HR: 0.22, 95%CI: 0.08-0.62, respectively). Conclusion: Risk-reducing effects of chemotherapy are substantial for at least 5 years and may be used in personalised CBC risk prediction in any case for BRCA1 mutation carriers. (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
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
Glas, N. de; Bastiaannet, E.; Boer, A. de; Siesling, S.; Liefers, G.J.; Portielje, J. 2019
PurposeThe number of older patients with breast cancer is rapidly increasing. A previous study showed that between 1990 and 2005, the survival of older patients with breast cancer did not improve... Show morePurposeThe number of older patients with breast cancer is rapidly increasing. A previous study showed that between 1990 and 2005, the survival of older patients with breast cancer did not improve in contrast to younger patients. In recent years, scientific evidence in the older age group has increased and specific guidelines for older women with breast cancer have been developed. The aim of this study was to assess changes in survival outcomes of older patients with breast cancer.Patients and methodsAll patients with breast cancer between 2000 and 2017 were included from the Netherlands cancer registry. We assessed changes in treatments using logistic regression. We calculated changes in relative survival as proxy for breast cancer mortality, stratified by age and stage.ResultsWe included 239,992 patients. Relative survival improved for patients<65 for all stages. In patients aged 65-75 years, relative survival did not improve in stage I-II but did improve in stage III breast cancer (RER 0.98, 95% CI 0.96-1.00, p=0.046). Concurrently, prescription of systemic treatments increased. In patients>75, relative survival did not improve in patients with stage I/II or stage III disease, nor did treatment strategies change.ConclusionsThis study shows that relative survival of patients aged 65-75 years with advanced breast cancer has improved, and concurrently, prescription of systemic treatment increased. To improve survival of patients >75 as well, future studies should focus on individualizing treatments based on concomitant comorbidity, geriatric parameters and the risk of competing mortality and toxicity of treatments. Show less
My PhD studies focused on understanding the role of macrophages, a type of immune cells which are abundantly present in several tumor types, in breast cancer progression and therapy response.In the... Show moreMy PhD studies focused on understanding the role of macrophages, a type of immune cells which are abundantly present in several tumor types, in breast cancer progression and therapy response.In the first part of my thesis, I describe how macrophages can acquire different functional characteristics in different types of breast cancer. Next, I focused on understanding the interplay between macrophages and cancer therapies. In particular, I revealed that macrophages counteract the efficacy of conventional chemotherapy drugs. I showed that eliminating macrophages with an antibody that targets CSF-1 receptor (CSF-1R) enhances the anti-cancer efficacy of platinum-based chemotherapeutic agents in breast cancer. I mechanistically discovered that CSF-1R inhibition stimulates intratumoral type I interferon signaling which is essential for the therapeutic synergy between cisplatin and CSF-1R blockade. I also uncovered that further elimination of immunosuppressive neutrophils, another type of immune cells, was required to engage an efficacious anti-tumor immunity. Show less
Rossum, A.G.J. van; Kok, M.; Werkhoven, E. van; Opdam, M.; Mandjes, I.A.M.; Leeuwen-Stok, A.E. van; ... ; MATADOR Trialists' Grp 2018
This thesis was divided in two parts. Part I demonstrated benefit of zoledronic acid addition to chemotherapy in terms of pathological response in postmenopausal women. Part II is all about... Show moreThis thesis was divided in two parts. Part I demonstrated benefit of zoledronic acid addition to chemotherapy in terms of pathological response in postmenopausal women. Part II is all about neoadjuvant endocrine therapy, and discusses the optimal duration of this treatment and the information on treatment efficacy that aromatase-inhibitor specific adverse events may provide. Show less
Aaldriks, A.A.; Giltay, E.J.; Cessie, S. le; Geest, L.G.M. van der; Portielje, J.E.A.; Tanis, B.C.; ... ; Maartense, E. 2013
Despite major advances in breast cancer diagnostics and treatment over the years, the disease is still a leading cause of death in women worldwide. Primary breast tumors can be treated relatively... Show moreDespite major advances in breast cancer diagnostics and treatment over the years, the disease is still a leading cause of death in women worldwide. Primary breast tumors can be treated relatively well with radiation, surgery, chemotherapy or a combination of these treatments. The occurrence of distant metastases derived from the primary tumor however, results in a considerable decrease in disease prognosis. Metastasis formation occurs through a series of distinct cell biological steps (outlined above). Understanding the molecular mechanisms that underlie each of these steps will help in the development of more successful anti-metastasis treatments. In this thesis, both in vitro and in vivo studies are described that aim at unraveling some of the processes involved in metastasis formation: signaling by components of the focal adhesions and cell migration. Show less
In order to form a distant metastasis, a cancer cell has to migrate out of the primary tumor, intravasate into a blood or a lymphatic vessel, subsequently survive in the absence of cell-cell and... Show moreIn order to form a distant metastasis, a cancer cell has to migrate out of the primary tumor, intravasate into a blood or a lymphatic vessel, subsequently survive in the absence of cell-cell and cell-matrix interactions, extravasate the blood or lymphatic vessel, migrate through the target organ and finally proliferate to grow out into a full metastasis. During all of these processes, specific kinases are involved in the concerted activation of distinct signaling pathways. We hypothesised that the protein tyrosine kinase FAK plays a crucial role in one or multiple of the processes involved in the formation of metastases. Therefore, the overall aim of the studies described in this thesis was to investigate the role of the non-receptor protein tyrosine kinase FAK in the distinct processes involved in tumorigenesis and metastasis and to unravel the involved downstream signaling pathways. Moreover, the potential of a combined therapy of the inhibition of FAK and exposure to the cytostatic doxorubicin was tested, as well as dissection of the intracellular events downstream of FAK. Show less
Dit proefschrift behelst een aantal klinische studies met betrekking tot de behandeling van borstkanker. Zowel aspecten van de locoregionale behandeling, d.w.z. chirurgie en bestraling, als van de... Show moreDit proefschrift behelst een aantal klinische studies met betrekking tot de behandeling van borstkanker. Zowel aspecten van de locoregionale behandeling, d.w.z. chirurgie en bestraling, als van de systemische behandeling, d.w.z. chemotherapie en hormonale therapie, worden belicht. Het proefschrift bestaat uit drie delen. Het eerste deel behelst de rol van de timing van chemotherapie t.o.v. de operatie bij de behandeling van borstkanker. Hieruit blijkt onder meer dat het geven van chemotherapie voorafgaand aan de operatie leidt tot "krimpen" van het gezwel en derhalve tot een stijging in het aantal borstsparende behandelingen. In deel twee wordt de rol van de locoregionale behandeling, d.w.z. chirurgie en bestraling, bij borstkanker bestudeerd. Tevens worden potenti_le voorspellende factoren voor het optreden van een lokaal recidief bestudeerd. Met name jonge vrouwen die borstsparende therapie ondergaan blijken een verhoogd risico te hebben op het optreden van een lokaal recidief. Het optreden van het lokale recidief lijkt voorspeld te kunnen worden door overexpressie van de tumorcel marker, genaamd PS6K. In deel drie wordt dieper ingegaan op vrouwen jonger dan veertig jaar met borstkanker. Deze groep vrouwen heeft een slechte prognose vergeleken met oudere vrouwen en de oorzaak hiervoor is onduidelijk. Derhalve wordt op dit moment geadviseerd om iedere vrouw jonger dan 35 jaar met borstkanker te behandelen met chemotherapie. In deel 3 wordt aangetoond dat er wel degelijk jonge vrouwen te identificeren zijn met een goede prognose waarbij de vraag gesteld kan worden of het geven van chemotherapie bij deze vrouwen wel noodzakelijk is. Show less
Prognostic factors are used for making treatment decisions regarding adjuvant systemic therapy. The major prognostic variables that are used in clinical practice are the number of positive axillary... Show morePrognostic factors are used for making treatment decisions regarding adjuvant systemic therapy. The major prognostic variables that are used in clinical practice are the number of positive axillary lymph nodes and tumour size. A number of other variables are associated with disease recurrence and survival as well. In particular UPA and PAI-1 appear to be strong prognostic variables. No differences in prognostic value of oestrogen receptor and progesterone receptor detected by immunocytochemical assay or enzyme immuno assay were found. In the study presented no significant association between mitotic counts and disease recurrence or survival was found, which was explained by the favourable tumour characteristics of the group of patients and the associated low number of events. Several tools have been developed to make individualised estimates of baseline prognosis and absolute survival benefit of adjuvant systemic therapy. Two of these tools, Adjuvant! and Numeracy, were compared. Adjuvant! was the preferred prognostic model. The administration of adjuvant chemotherapy concurrently with radiotherapy appeared too toxic. As anthracyclin-containing regimens have become standard for adjuvant chemotherapy in early breast cancer which are considered more toxic than the regimens studied the concurrent administration of adjuvant chemotherapy and radiotherapy is dissuaded. Show less
