Purpose: To compare health-related quality of life (HRQL) in elderly breast cancer patients between two types of Accelerated Partial Breast Irradiation: intraoperative radiotherapy (IORT) and... Show morePurpose: To compare health-related quality of life (HRQL) in elderly breast cancer patients between two types of Accelerated Partial Breast Irradiation: intraoperative radiotherapy (IORT) and external beam APBI (EB-APBI).Methods: Between 2011 and 2016 women >= 60 years undergoing breast conserving therapy for early stage breast cancer were included in a prospective multi-centre cohort study. Patients were treated with electron IORT (1 x 23.3 Gy) or photon EB-APBI (10 x 3.85 Gy daily). HRQL was measured by the EORTC-QLQ C30 and BR23 questionnaires before surgery and at several time points until 1 year.Results: HRQoL data was available of 204 IORT and 158 EB-APBI patients. In longitudinal analyses emotional functioning and future perspective were significantly, but not clinically relevantly, worse in IORT-treated patients, and improved significantly during follow-up in both groups. All other aspects of HRQL slightly worsened after treatment and recovered within 3 months with an improvement until 1 year. Cross-sectional analysis showed that postoperatively fatigue and role functioning were significantly worse in IORT patients compared to EB-APBI patients who were not yet irradiated, but the difference was not clinically relevant. At other timepoints there were no significant differences. Multivariable analysis at 1 year identified comorbidity and systemic therapy as risk factors for a worse global health score (GHS).Conclusions: EB-APBI and IORT were well tolerated. Despite a temporary deterioration after treatment, all HRQL scales recovered within 3 months resulting in no clinically relevant differences until 1 year between groups nor compared to baseline levels. (C) 2019 Elsevier Ltd. All rights reserved. Show less
Paxillin is a well-known multidomain scaffold protein that is involved in the regulation of cell-matrix adhesiondynamics, a process required for the tumor cell migration and invasion.... Show morePaxillin is a well-known multidomain scaffold protein that is involved in the regulation of cell-matrix adhesiondynamics, a process required for the tumor cell migration and invasion. Phosphorylation of the serine residue 178requires c-Jun NH2-terminal kinase (JNK) activation, which occurs downstream of epidermal growth factor receptor (EGFR)-mediated signaling and drives cell migration. In this study, we investigated the significance of paxillin Ser178 phosphorylation in breast cancer progression.We employed the rat mammary carcinoma MTLn3 cell line with which we established stabile variants of both wild type and mutant GFP-paxillin constructs. With those, we next performed several in vitro assays including cell proliferation, migration and focal adhesion dynamics. Finally, we monitored the metastatic spread of both cell line variants in an othrotopic mouse model for breast cancer.Here we show that expression of the phospho-defective mutant paxillinS178A in the metastatic mammary adenocarcinoma MTLn3 cell-line significantly decreased EGF-induced cell migration, which was correlated with impaired focal adhesion dynamics. Moreover, paxillinS178A attenuated lung metastasis formation in an orthotopic in vivo mammary gland tumor/metastasis model, demonstrating the importance of JNK-mediated paxillin phosphorylation in breast cancer progression. Expression of paxillinS178A caused a decrease in EGFR expression while re-expression of EGFR in MTLn3-paxillinS178A cells fully restored EGF-driven cell motility and focal adhesion dynamics. Furthermore, re-expression of EGFR in MTLn3-paxillinS178A rescued spontaneous metastasis from breast to lung.Overall our data show an important role for JNK-mediated paxillin Ser178 phosphorylation in the regulation of EGFR expression and thereby, in EGF-driven cell migration and metastasis formation. Show less
Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the... Show moreBackground: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer. Show less
Lakeman, I.M.M.; Schmidt, M.K.; Asperen, C.J. van; Devilee, P. 2019
Purpose of ReviewBreast cancer is the most common cancer among females in developed countries. Strategies such as early detection by breast cancer screening can reduce the burden of disease but... Show morePurpose of ReviewBreast cancer is the most common cancer among females in developed countries. Strategies such as early detection by breast cancer screening can reduce the burden of disease but have disadvantages including overdiagnosis and increased cost. Stratification of women according to the risk of developing breast cancer, based on genetic and lifestyle risk factors, could improve risk-reduction and screening strategies by targeting those most likely to benefit.Recent FindingsBreast cancer risk is partly determined by genetic factors including rare pathogenic variants in susceptibility genes and common low-risk variants. Other risk factors include alcohol use, smoking, reproductive factors, hormonal factors, family history, mammographic density, BMI, and body height. Ideally, all risk factors are combined into an individual breast cancer lifetime risk score, but this requires knowledge about their interactions as well as accurate effect sizes. A few risk models seem to be sufficiently developed to inform clinical risk management to minimise cancer risk of those at increased risk and avoid overtreatment of those at decreased risk.SummaryIn this review, we briefly summarise the breast cancer susceptibility factors and discuss avenues towards combining all these factors to create individual risk scores. Show less
This thesis is about clinical quality audits, used to measure and improve the quality of health care; focusing on the quality of breast cancer care (see: the NBCA) and on the quality of breast... Show moreThis thesis is about clinical quality audits, used to measure and improve the quality of health care; focusing on the quality of breast cancer care (see: the NBCA) and on the quality of breast implant surgery (see: the DBIR) in the Netherlands. Show less
Koedoot, E.; Smid, M.; Foekens, J.A.; Martens, J.W.M.; Le Dévédec, S.E.; Water, B. van de 2019
Splicing factors (SFs) act in dynamic macromolecular complexes to modulate RNA processing. To understand the complex role of SFs in cancer progression, we performed a systemic analysis of the co... Show moreSplicing factors (SFs) act in dynamic macromolecular complexes to modulate RNA processing. To understand the complex role of SFs in cancer progression, we performed a systemic analysis of the co-regulation of SFs using primary tumor RNA sequencing data. Co-regulated SFs were associated with aggressive breast cancer phenotypes and enhanced metastasis formation, resulting in the classification of Enhancer- (21 genes) and Suppressor-SFs (64 genes). High Enhancer-SF levels were related to distinct splicing patterns and expression of known oncogenic pathways such as respiratory electron transport, DNA damage and cell cycle regulation. Importantly, largely identical SF co-regulation was observed in almost all major cancer types, including lung, pancreas and prostate cancer. In conclusion, we identified cancer-associated co-regulated expression of SFs that are associated with aggressive phenotypes. This study increases the global understanding of the role of the spliceosome in cancer progression and also contributes to the development of strategies to cure cancer patients. Show less
Early-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast... Show moreEarly-onset breast cancer may be due to Li-Fraumeni Syndrome (LFS). Current national and international guidelines recommend that TP53 genetic testing should be considered for women with breast cancer diagnosed before the age of 31years. However, large studies investigating TP53 mutation prevalence in this population are scarce. We collected nationwide laboratory records for all young breast cancer patients tested for TP53 mutations in the Netherlands. Between 2005 and 2016, 370 women diagnosed with breast cancer younger than 30years of age were tested for TP53 germline mutations, and eight (2.2%) were found to carry a (likely) pathogenic TP53 sequence variant. Among BRCA1/BRCA2 mutation negative women without a family history suggestive of LFS or a personal history of multiple LFS-related tumours, the TP53 mutation frequency was <1% (2/233). Taking into consideration that TP53 mutation prevalence was comparable or even higher in some studies selecting patients with breast cancer onset at older ages or HER2-positive breast cancers, raises the question of whether a very early age of onset is an appropriate single TP53 genetic testing criterion. Show less
This thesis describes the preferences of both older patients with breast cancer and clinicians to optimize the current care of this patient group. The significant increase in the number of breast... Show moreThis thesis describes the preferences of both older patients with breast cancer and clinicians to optimize the current care of this patient group. The significant increase in the number of breast cancer patients above the age of 65 years necessitates insight into their preferences. Decision-making regarding treatment of early breast cancer is often difficult as decisions need to be made between two surgical options and about the addition of systemic therapy. Like younger patients, older patients are faced with these difficult decisions (together with their clinician). However, treatments for early breast cancer differ substantially between younger and older patients, which possibly can be explained by the preferences of older patients or their clinicians. Currently, little is known about the preferences of older patients, while this knowledge is particularly of great value. To assess how the current care of older patients and the treatment-decision-making process with this patient group can be optimised, we explore the preferences and motivations of older patients with early breast cancer; if and how their preferences for treatment and participation in decision-making differ from those of younger patients; and the treatment preferences of breast cancer specialists with regard to treatment of older patients. 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
In this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a... Show moreIn this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a transcription factor than can drive tumor cell proliferation and approximately 70% off all breast tumors is thought to be dependent on the activity of this hormone-mediated transcription factor. After stimulation of ERα a wild variety of co-factors are recruited, leading to the assembly of a transcriptional complex. Although there are multiple ways of targeting the action of ERα and thereby inhibiting tumor growth, still a significant proportion of patients develop a recurrence. Cross-resistance between the different endocrine therapy options can occur, but a proportion of patients that relapse on one type of therapy can still benefit from a different treatment modality, illustrating the existence of multiple resistance mechanisms which can be treatment selective. A better understanding of ERα-biology and the development of endocrine therapy resistance, can lead the way to the discovery of novel biomarkers and potential drug targets, that can further increase patient survival. Show less
Hoekstra, N.; Fleury, E.; Lara, T.R.M.; Baan, P. van der; Bahnerth, A.; Struik, G.; ... ; Pignol, J.P. 2018
Introduction: For early stage breast cancer patients, non-breast cancer mortality including secondary cancers and cardiac events can overshadow the benefit of adjuvant radiotherapy. This study... Show moreIntroduction: For early stage breast cancer patients, non-breast cancer mortality including secondary cancers and cardiac events can overshadow the benefit of adjuvant radiotherapy. This study evaluates the excess risk of secondary cancer for various breast radiotherapy techniques including accelerated partial breast irradiation (APBI).Methods: Secondary cancers Lifetime Attributable Risks (LAR) were calculated using a modified BEIR-VII formalism to account for the specific survival of breast cancer patients. Those survivals were extracted from the SEER database. Doses scattered to various organs were measured into a Rando phantom with custom-made breast phantoms. Treatments delivered typical doses of brachytherapy APBI (34 Gy in 10 fractions), external beam APBI (38.5 Gy in 10 fractions) using 3D-conformal, Cyberknife stereotactic (CK), or VMAT, as well as whole breast irradiation (WBI) delivering 42.5 Gy in 16 fractions.Results: WBI resulted in the highest total LAR, with 4.3% excess risk of secondary cancer for a patient treated at age 50 years. Lung cancers accounted for 75-97% of secondary malignancies. For a typical early stage patient irradiated at 50, the excess risks of secondary lung cancer were 1.1% for multicatheter HDR, between 2.2% and 2.5% for 3D-CRT or CK, 3.5% for VMAT APBI, and 3.8% for WBI.Conclusions: APBI reduces the risk of secondary cancer 2-4 fold compared to WBI. These techniques are well suited for long-living early stage breast cancer patients. HDR brachytherapy and 3D-conformal APBI achieve mean lung doses between 1 and 1.5 Gy, which could serve as reference. (C) 2018 Elsevier B.V. All rights reserved. Show less