Women from families in which many individuals have developed breast and/or ovarian cancer may request for DNA-testing. A DNA-test result may disclose their own risks to develop cancer (again),... Show moreWomen from families in which many individuals have developed breast and/or ovarian cancer may request for DNA-testing. A DNA-test result may disclose their own risks to develop cancer (again), their relatives__ risks and subsequent options for medical surveillance. This thesis describes several multicenter studies in the Netherlands about the psychological and medical impact of DNA-testing on the lives of these women and their relatives. Despite their accurate understanding of the global meaning of DNA-test result, many participants interpreted the result differently from what the genetic-counselor had actually communicated. Like in a children__s whisper game, their relatives also misinterpreted the information communicated by the first messenger. The messengers__ misinterpretation was not only related to their inaccurate thoughts about heredity and cancer in general, but also to their feelings, and especially to their unfulfilled need for certainty, sense of self and unresolved existential issues. The presence of misinterpretations predicted the extent of the counselees' distress and the medical decisions after DNA-test result disclosure. The study results are described in their historical and theoretical context, followed by practical clinical suggestions for genetic-counselors and psychologists. For instance, we suggest that genetic-counselor try to avoid the communication of ambiguous DNA-test results that do not have medical consequences. Show less
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
Topolnjak, R.; Sonke, J.J.; Nijkamp, J.; Rasch, C.; Minkema, D.; Remeijer, P.; Vliet-Vroegindeweij, C. van 2010
Purpose: To quantify the differences in setup errors measured with the cone-beam computed tomography (CBCT) and electronic portal image devices (EPID) in breast cancer patients.Methods and... Show morePurpose: To quantify the differences in setup errors measured with the cone-beam computed tomography (CBCT) and electronic portal image devices (EPID) in breast cancer patients.Methods and Materials: Repeat CBCT scan were acquired for routine offline setup verification in 20 breast cancer patients. During the CBCT imaging fractions, EPID images of the treatment beams were recorded. Registrations of the bony anatomy for CBCT to planning CT and EPID to digitally reconstructed-radiographs (DRRs) were compared. In addition, similar measurements of an anthropomorphic thorax phantom were acquired. Bland-Altman and linear regression analysis were performed for clinical and phantom registrations. Systematic and random setup errors were quantified for CBCT and EPID-driven correction protocols in the EPID coordinate system (U, V), with V parallel to the cranial-caudal axis and U perpendicular to V and the central beam axis.Results: Bland-Altman analysis of clinical EPID and CBCT registrations yielded 4 to 6-mm limits of agreement, indicating that both methods were not compatible. The EPID-based setup errors were smaller than the CBCT-based setup errors. Phantom measurements showed that CBCT accurately measures setup error whereas EPID underestimates setup errors in the cranial caudal direction. In the clinical measurements, the residual bony anatomy setup errors after offline CBCT-based corrections were Sigma(U) = 1.4 mm, Sigma(V) = 1.7 mm, and sigma(U) = 2.6 mm, sigma(V) = 3.1 mm. Residual setup errors of EPID driven corrections corrected for underestimation were estimated at Sigma(U) = 2.2mm, Sigma(V) = 3.3 mm, and sigma(U) = 2.9 mm, sigma(V) = 2.9 mm.Conclusion: EPID registration underestimated the actual bony anatomy setup error in breast cancer patients by 20% to 50%. Using CBCT decreased setup uncertainties significantly. (C) 2010 Elsevier Inc. Show less
In het proefschrift van Martine van Miltenburg wordt het onderzoek naar de rol van FAK en annexine A1 in borstkankerontwikkeling en uitzaaiing (metastasering) beschreven. E__n van de... Show moreIn het proefschrift van Martine van Miltenburg wordt het onderzoek naar de rol van FAK en annexine A1 in borstkankerontwikkeling en uitzaaiing (metastasering) beschreven. E__n van de sleutelprocessen bij de metastasering is de verandering van het rustige fenotype van kankercellen naar het beweeglijke fenotype. Een belangrijke ontdekking is dat het eiwit annexine A1 een belangrijke rol speelt in metastasering van basale borstkanker. Verhoogde expressie van annexine A1 draagt bij aan beweeglijkheid en daarmee agressief gedrag van tumorcellen. Hoe hoger de expressie van annexine A1, hoe meer uitzaaiingen, simpel gezegd. Wanneer annexine A1 wordt uitgeschakeld in deze cellen verandert de cel van het agressieve gedrag naar een ___rustige___ tumorcel, en ontstaan er beduidend minder uitzaaiingen. Ondanks de veelbelovende resultaten is het geen optie om remming van annexine A1 als anti-kanker therapie te gebruiken omdat annexine A1 ook in gezonde lichaamscellen een belangrijke functie heeft. Maar de onderzoekers denken wel dat annexine A1 een ___marker___ voor basale borstkanker kan worden. Doordat annexine A1 specifiek in basale borstkanker verhoogd tot expressie komt zou het als marker wellicht goed gebruikt kunnen worden om dit relatief agressieve type borstkanker type te bepalen bij pati__nten. Show less
The skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible... Show moreThe skeleton is one of the most common organs to be affected by metastatic disease. However, only a restricted number of solid cancers, especially those of the breast and prostate, are responsible for the majority of the bone metastases. Bone metastases are a major cause of morbidity, characterized by severe pain and high incidence of fractures, spinal cord compression and bone marrow aplasia requiring hospitalization. Despite the high frequency of skeletal metastases, the molecular mechanisms underlying the predisposition for tumors to colonize bone are poorly understood and treatment options are often unsatisfactory. The focus of this thesis was to better understand the processes that contribute to the formation of distant metastasis (chapter 2), particularly to bone (chapter 4__7), as well as to explore new treatment strategies with conventional (chapter 4 and 5) and novel therapeutic molecules (chapter 6 and 7) using optical imaging to sensitively monitor growth, dissemination and metastasis in mouse models (chapter 3__7). Show less
Le, Dévédec S.E.; Roosmalen, W.P.E. van; Maria, N.; Grimbergen, M.; Pont, C.M.; Lalai, R.A.; Water, B. van de 2009
This thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1... Show moreThis thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1 and BRCA2 breast cancer susceptibility genes. For the remaining families the genetic etiology is unknown. It is still possible that other high-penetrant genes play a role. Although a polygenic model with multiple low-penetrant genes acting additive or multiplicative will probable explain most of the BRCA1/2 negative families. Linkage in an international set of 150 high-risk breast cancer families couldn__t identify high-risk genes. However when limiting the linkage analysis to Dutch families only, we identified 9q21-22 as a putative breast cancer susceptibility locus 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
The cumulative lifetime risk of developing breast cancer for a Dutch woman is about 12%. In some families breast cancer seems to occur even more frequently or women fall ill at a relatively young... Show moreThe cumulative lifetime risk of developing breast cancer for a Dutch woman is about 12%. In some families breast cancer seems to occur even more frequently or women fall ill at a relatively young age. Such families may have a genetic susceptibility towards breast cancer. To learn more about the likelihood of this susceptibility actually being present, members of such families may request genetic counselling and DNA-testing. The main purpose of this thesis is to provide more insight into some effects of genetic counselling and DNA testing for breast cancer. We address effects on: (a) risk perception; (b) psychological distress; and (c) intentions for risk-management behaviour. Regarding the effects of DNA testing, special attention is paid to women who receive a so-called uninformative DNA-test result. The data of this thesis do not provide support for one of the two hypotheses which has been postulated about the impact of an uninformative result. They suggest that, as a group, women seem to be reassured upon learning their uninformative result, but to a lesser extent than women who received a true negative result. Only a small minority of women with an uninformative result incorrectly concluded that the chance of a mutation being present was non-existent. 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
Cortactine wordt gecodeerd door het gen EMS1 dat op het chromosoom 11q13 ligt. Het 11q13 gebied is geamplificeerd in een deel van de borsttumoren dat geassocieerd is met cortactine overexpressie en... Show moreCortactine wordt gecodeerd door het gen EMS1 dat op het chromosoom 11q13 ligt. Het 11q13 gebied is geamplificeerd in een deel van de borsttumoren dat geassocieerd is met cortactine overexpressie en de aanwezigheid van lymfeklier metastasen en een verhoogde sterfte. Cortactine is een F-actine bindend eiwit dat betrokken is bij de regulatie van het actine cytoskelet, dat belangrijk is bij cel migratie. Agnes van Rossum onderzocht de rol van cortactine (over)expressie op cel biologische processen die betrokken zijn bij de ontwikkeling en/of het gedrag van borstkanker. Zij ontdekte onder meer dat er cortactine varianten zijn die de cel migratie beïnvloeden. Verder lijkt cortactine een rol te spelen bij intercellulaire cel adhesie en cel spreiding. Een studie met cortactine transgene muizen toonde aan dat cortactine geen oorzakelijke rol heeft in het ontstaan van borstkanker. Van Rossum vermoedt dat cortactine de binding tussen cellen en hun omgeving dusdanig kan beïnvloeden dat deze gemakkelijker uit de oorspronkelijke tumor kunnen ontsnappen en gaan migreren. 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