Background: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation... Show moreBackground: Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines.Methods: For 425 cancer-free women with cancer FH (mean age 40.6 years, range 21-74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS306) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. >= 20 % and >= 30 % eLTR, or >= 5 % e10YR were determined.Findings: Of the women with non-informative PV status, including PRS306 and NGRFs changed clinical recommendations for 31.0 %, (57/184, 20 % eLTR), 15.8 % (29/184, 30 % eLTR) and 22.4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16.7 % (25/150), 1.3 % (2/150) and 9.5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2 , PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed. Interpretation: For women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age.Funding: Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Koln Fortune. Show less
A deeper understanding of the parameters driving response and resistance to immunotherapy is needed to improve the low response rates observed in breast cancer patients. Research into immunotherapy... Show moreA deeper understanding of the parameters driving response and resistance to immunotherapy is needed to improve the low response rates observed in breast cancer patients. Research into immunotherapy response has predominantly focused on T cells, however effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. By combining profiling of blood and tumors from metastatic breast cancer patients with mechanistic studies in mouse models, we uncovered the critical role of eosinophils in immunotherapy response, and we provide proof-of-principle for eosinophil engagement to enhance immunotherapy efficacy. Focusing on resistance mechanisms to immunotherapy, we demonstrate that neoadjuvant immunotherapy triggers persistent and systemic regulatory T cell activation which blunts therapeutic efficacy against metastatic spread of breast tumors. In addition, we demonstrate that neutrophils in the tumor microenvironment pose a barrier to immunotherapy response through T cell suppression. Lastly, we demonstrate that combining the immunomodulatory agent PD1-IL2v with cisplatin is a powerful approach to induce a broad activation of systemic and intratumoral adaptive and innate immunity, resulting in effective immunotherapy responses. Overall, this work identifies several key players and their interconnectivities in anti-tumor immunity and tumor-induced immunosuppression that may be therapeutically exploited to improve immunotherapy responses for breast cancer patients. Show less
Due to a shorter remaining life expectancy, the risk of recurrence in older patients with low risk breast cancer is often reduced and the benefit of treatments may be very limited, especially with... Show moreDue to a shorter remaining life expectancy, the risk of recurrence in older patients with low risk breast cancer is often reduced and the benefit of treatments may be very limited, especially with adjuvant treatments. In the first part of this thesis, we studied the interplay between breast cancer mortality and other-cause mortality. In the second part of this thesis, we investigated the effect of surgery and radiotherapy in subsets of the older population of patients with breast cancer in which the actual treatment effect is questionable. Show less
Introduction: In older patients with breast cancer, the risk of dying from other causes than breast cancer strongly increases after the age of 70. The aim of this study was to assess contributions... Show moreIntroduction: In older patients with breast cancer, the risk of dying from other causes than breast cancer strongly increases after the age of 70. The aim of this study was to assess contributions of breast cancer mortality versus other-cause mortality after locoregio-nal or distant recurrence in a population-based cohort of older patients analysed by multi-state models. Methods: Surgically treated patients >70 years diagnosed with stage I-III breast cancer in 2003-2009 were selected from the Netherlands Cancer Registry. A novel multi-state model with locoregional and distant recurrence that incorporates relative survival was fitted. Other-cause and breast cancer mortality were indicated as population and excess mortality. Results: Overall, 18,419 patients were included. Ten-year cumulative incidences of locoregio-nal and distant recurrence were 2.8% (95%CI 2.6-3.1%) and 12.5% (95%CI 11.9-13.1%). Other-cause mortality increased from 23.9% (95%CI 23.7-24.2%) in patients 70-74 years to 73.8% (95%CI 72.2-75.4%) in those >80 years. Ten-year probabilities of locoregional or distant recurrence with subsequent breast cancer death were 0.4-1.3% and 10.2-14.6%, respectively. For patients with a distant recurrence in the first two years after diagnosis, breast cancer death probabilities were 95.3% (95%CI 94.2-96.4%), 93.1% (95%CI 91.6-94.6%), and 88.6% (95%CI 86.5-90.8%) in patients 70-74, 75-79, and >80 years. Conclusion: In older patients without recurrence, prognosis is driven by other-cause mortality. Although locoregional recurrence is a predictor for worse outcome, given its low incidence it contributes little to breast cancer mortality after diagnosis. For patients who develop a distant recurrence, breast cancer remains the dominant cause of death, even at old age.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Purpose Chemotherapy-induced febrile neutropenia (FN) is a life-threatening and chemotherapy dose-limiting adverse event. FN can be prevented with granulocyte-colony stimulating factors (G-CSFs).... Show morePurpose Chemotherapy-induced febrile neutropenia (FN) is a life-threatening and chemotherapy dose-limiting adverse event. FN can be prevented with granulocyte-colony stimulating factors (G-CSFs). Guidelines recommend primary G-CSF use for patients receiving either high (> 20%) FN risk (HR) chemotherapy, or intermediate (10-20%) FN risk (IR) chemotherapy if the overall risk with additional patient-related risk factors exceeds 20%. In this study, we applied an EHR text-mining tool for real-world G-CSF treatment evaluation in breast cancer patients. Methods Breast cancer patients receiving IR or HR chemotherapy treatments between January 2015 and February 2021 at LUMC, the Netherlands, were included. We retrospectively collected data from EHR with a text-mining tool and assessed G-CSF use, risk factors, and the FN and neutropenia (grades 3-4) and incidence. Results A total of 190 female patients were included, who received 77 HR and 113 IR treatments. In 88.3% of the HR regimens, G-CSF was administered; 7.3% of these patients developed FN vs. 33.3% without G-CSF. Although most IR regimen patients had >= 2 risk factors, only 4% received G-CSF, of which none developed neutropenia. However, without G-CSF, 11.9% developed FN and 31.2% severe neutropenia. Conclusions Our text-mining study shows high G-CSF use among HR regimen patients, and low use among IR regimen patients, although most had >= 2 risk factors. Therefore, current practice is not completely in accordance with the guidelines. This shows the need for increased awareness and clarity regarding risk factors. Also, text-mining can effectively be implemented for the evaluation of patient care. Show less
The majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after... Show moreThe majority of breast cancer patients is treated with breast-conserving surgery (BCS) combined with adjuvant radiation therapy. Up to 40% of patients has a tumor-positive resection margin after BCS, which necessitates re-resection or additional boost radiation. Cathepsin-targeted near-infrared fluorescence imaging during BCS could be used to detect residual cancer in the surgical cavity and guide additional resection, thereby preventing tumor-positive resection margins and associated mutilating treatments. The cysteine cathepsins are a family of proteases that play a major role in normal cellular physiology and neoplastic transformation. In breast cancer, the increased enzymatic activity and aberrant localization of many of the cysteine cathepsins drive tumor progression, proliferation, invasion, and metastasis. The upregulation of cysteine cathepsins in breast cancer cells indicates their potential as a target for intraoperative fluorescence imaging. This review provides a summary of the current knowledge on the role and expression of the most important cysteine cathepsins in breast cancer to better understand their potential as a target for fluorescence-guided surgery (FGS). In addition, it gives an overview of the cathepsin-targeted fluorescent probes that have been investigated preclinically and in breast cancer patients. The current review underscores that cysteine cathepsins are highly suitable molecular targets for FGS because of favorable expression and activity patterns in virtually all breast cancer subtypes. This is confirmed by cathepsin-targeted fluorescent probes that have been shown to facilitate in vivo breast cancer visualization and tumor resection in mouse models and breast cancer patients. These findings indicate that cathepsin-targeted FGS has potential to improve treatment outcomes in breast cancer patients. Show less
This thesis describes the steps necessary for the addition of the tumor-stroma ratio (TSR) into clinical practice as high-risk factor besides the TNM classification. The route from laboratory... Show moreThis thesis describes the steps necessary for the addition of the tumor-stroma ratio (TSR) into clinical practice as high-risk factor besides the TNM classification. The route from laboratory biomarker development to clinical implementation is followed. During this process, the relationship of the TSR to other available biomarkers for prognostic information for breast and colon cancer patients is investigated. Additionally, the prognostic value of the TSR in lung cancer is studied. Show less
Major achievements in the field of immune oncology have demonstrated the ability of the immune system to induce a response against cancer. The prognostic impact of pre-existing immunity in several... Show moreMajor achievements in the field of immune oncology have demonstrated the ability of the immune system to induce a response against cancer. The prognostic impact of pre-existing immunity in several cancer types, including breast and colon cancer, demonstrates the influence of the immune system on disease progression. At the same time, immunotherapeutic approaches that aim to enhance antitumor immune reactions have significantly improved the clinical outcome for a subset of patients. However, a large proportion of patients (60-80%) do not respond to immunotherapeutic treatments. To extend the benefit of immunotherapeutic strategies to a larger number of patients, it is imperative to understand the mechanisms associated with immune responsiveness. Different variables have been described to influence the development of antitumor immunity in cancer patients, including the tumor’s genetic program, the genetic makeup of the patients, and environmental factors such as the microbiome. These factors likely act in concert to modulate antitumor immune responses. This thesis aimed to dissect the molecular determinants of cancer immune responsiveness in human tumors. A systems biology approach was used to define underlying factors that shape the tumor microenvironment and reveal potential mechanisms of immune escape. Show less
The main objective of work presented in this thesis was to explore the clinical utility of the Polygenic Risk Score (PRS) based on breast cancer associated common low risk variants, which explain ... Show moreThe main objective of work presented in this thesis was to explore the clinical utility of the Polygenic Risk Score (PRS) based on breast cancer associated common low risk variants, which explain ~18% of the familial relative risk, for individual breast cancer risk prediction. It did so by generating knowledge about the PRS in the Dutch general population and in clinic-based breast cancer families, as well as in a large international population of BRCA1/2 pathogenic variant carriers. We have validated the association of the PRS with breast cancer for women in both the Dutch population and breast cancer families and showed a better risk-discrimination by adding the PRS to family-based risk prediction. Secondly, we have shown that addition of the PRS to family-based risk prediction has an impact on screening recommendations for many non-carriers and carriers of a pathogenic variant in a moderate breast cancer gene. The results will support implementation of comprehensive risk prediction in the clinic, and may help women to make more informed choices about their optimal clinical management. Show less
Background: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are... Show moreBackground: Protein truncating variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain. Methods: We analyzed data on 59,639 breast cancer cases and 53,165 controls from studies participating in the Breast Cancer Association Consortium BRIDGES project. We sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1146 training variants), BRCA1 (644), BRCA2 (1425), CHEK2 (325), and PALB2 (472). We evaluated breast cancer risks according to five in silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated. Results: The most predictive in silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1, and BRCA2, data were compatible with small subsets (approximately 7%, 2%, and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set. Conclusions: These results will inform risk prediction models and the selection of candidate variants for functional assays and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility. Show less
Purpose Intensive screening in BRCA1/2 mutation carriers aims to improve breast cancer (BC) prognosis. Our aim is to clarify the prognostic impact of tumor size in BRCA mutation carriers with a pT1... Show morePurpose Intensive screening in BRCA1/2 mutation carriers aims to improve breast cancer (BC) prognosis. Our aim is to clarify the prognostic impact of tumor size in BRCA mutation carriers with a pT1 BC, which is currently unclear. We are especially interested in differences between pT1a, pT1b, and pT1c regarding the prognosis of node-negative breast cancer, the effect of chemotherapy, and the prevalence of lymph node involvement. Methods For this study, BRCA1/2-associated BC patients were selected from a nationwide cohort. Primary outcomes were 10-year overall survival (OS) per pT1a-b-c group and the effect of chemotherapy on prognosis of node-negative BC, using Kaplan-Meier and Cox models. Finally, we evaluated lymph node involvement per pT1a-b-c group. Results 963 women with pT1 BRCA1/2-associated BC diagnosed between 1990 and 2017 were included, of which 679 had pN0 BC. After a median follow-up of 10.5 years, 10-year OS in patients without chemotherapy was 77.1% in pT1cN0 and lower than for pT1aN0 (91.4%, p = 0.119) and pT1bN0 (90.8%, p = 0.024). OS was better with than without chemotherapy for pT1cN0 (91.6% vs. 77.1%, p = 0.001; hazard ratio (HR) 0.56, 95% confidence interval (CI): 0.21-1.48). Lymph node involvement was 24.9% in pT1c, 18.8% in pT1b, and 8.6% in pT1a. Conclusion Smaller tumor size is associated with better OS and less lymph node involvement in pT1 BRCA1/2-associated BC patients. The results suggest that early detection in BRCA1/2 mutation carriers of pT1a/b BC may reduce mortality and the need for systemic therapy. Show less
Purpose: Side effects are the main reason for discontinuation of adjuvant endocrine therapy in older adults. The aim of this study was to examine geriatric predictors of treatment discontinuation... Show morePurpose: Side effects are the main reason for discontinuation of adjuvant endocrine therapy in older adults. The aim of this study was to examine geriatric predictors of treatment discontinuation of adjuvant endocrine therapy within the first 2 years after initiation, and to study the association between early discontinuation and functional status and quality of life (QoL). Methods: Patients aged >= 70 years with stage I-III breast cancer who received adjuvant endocrine therapy were included. The primary endpoint was discontinuation of endocrine therapy within 2 years. Risk factors for discontinuation were assessed using univariate logistic regression models. Linear mixed models were used to assess QoL and functional status over time. Results: Overall, 258 patients were included, of whom 36% discontinued therapy within 2 years after initiation. No geriatric predictive factors for treatment discontinuation were found. Tumour stage was inversely associated with early discontinuation. Patients who discontinued had a worse breast cancer-specific QoL (b = - 4.37; 95% CI - 7.96 to - 0.78; p = 0.017) over the first 2 years, in particular on the future perspective subscale (b = - 11.10; 95% CI - 18.80 to - 3.40; p = 0.005), which did not recover after discontinuation. Treatment discontinuation was not associated with functional improvement. Conclusion: A large proportion of older patients discontinue adjuvant endocrine treatment within 2 years after initiation, but geriatric characteristics are not predictive of early discontinuation of treatment. Discontinuation of adjuvant endocrine therapy did not positively affect QoL and functional status, which implies that the observed poorer QoL in this group is probably not caused by adverse effects of endocrine therapy. Show less
Purpose The tumor-stroma ratio (TSR) has repeatedly proven to be correlated with patient outcomes in breast cancer using large retrospective cohorts. However, studies validating the TSR often show... Show morePurpose The tumor-stroma ratio (TSR) has repeatedly proven to be correlated with patient outcomes in breast cancer using large retrospective cohorts. However, studies validating the TSR often show variability in methodology, thereby hampering comparisons and uniform outcomes. Method This paper provides a detailed description of a simple and uniform TSR scoring method using Hematoxylin and Eosin (H&E)-stained core biopsies and resection tissue, specifically focused on breast cancer. Possible histological challenges that can be encountered during scoring including suggestions to overcome them are reported. Moreover, the procedure for TSR estimation in lymph nodes, scoring on digital images and the automatic assessment of the TSR using artificial intelligence are described. Conclusion Digitized scoring of tumor biopsies and resection material offers interesting future perspectives to determine patient prognosis and response to therapy. The fact that the TSR method is relatively easy, quick, and cheap, offers great potential for its implementation in routine diagnostics, but this requires high quality validation studies. Show less
Background Radiotherapy (RT) is part of the curative treatment of approximately 70% of breast cancer (BC) patients. Wide practice variation has been reported in RT dose, fractionation and its... Show moreBackground Radiotherapy (RT) is part of the curative treatment of approximately 70% of breast cancer (BC) patients. Wide practice variation has been reported in RT dose, fractionation and its treatment planning for BC. To decrease this practice variation, it is essential to first gain insight into the current variation in RT treatment between institutes. This paper describes the development of the NABON Breast Cancer Audit-Radiotherapy (NBCA-R), a structural nationwide registry of BC RT data of all BC patients treated with at least surgery and RT. Methods A working group consisting of representatives of the BC Platform of the Dutch Radiotherapy Society selected a set of dose volume parameters deemed to be surrogate outcome parameters, both for tumour control and toxicity. Two pilot studies were carried out in six RT institutes. In the first pilot study, data were manually entered into a secured web-based system. In the second pilot study, an automatic Digital Imaging and Communications in Medicine (DICOM) RT upload module was created and tested. Results The NBCA-R dataset was created by selecting RT parameters describing given dose, target volumes, coverage and homogeneity, and dose to organs at risk (OAR). Entering the data was made mandatory for all Dutch RT departments. In the first pilot study (N = 1093), quite some variation was already detected. Application of partial breast irradiation varied from 0 to 17% between the 6 institutes and boost to the tumour bed from 26.5 to 70.2%. For patients treated to the left breast or chest wall only, the average mean heart dose (MHD) varied from 0.80 to 1.82 Gy; for patients treated to the breast/chest wall only, the average mean lung dose (MLD) varied from 2.06 to 3.3 Gy. In the second pilot study 6 departments implemented the DICOM-RT upload module in daily practice. Anonymised data will be available for researchers via a FAIR (Findable, Accessible, Interoperable, Reusable) framework. Conclusions We have developed a set of RT parameters and implemented registration for all Dutch BC patients. With the use of an automated upload module registration burden will be minimized. Based on the data in the NBCA-R analyses of the practice variation will be done, with the ultimate aim to improve quality of BC RT. Trial registration Retrospectively registered. Show less
Background: Previous studies have shown that survival outcomes for older patients with breast cancer vary substantially across Europe, with worse survival reported in the United Kingdom. It has... Show moreBackground: Previous studies have shown that survival outcomes for older patients with breast cancer vary substantially across Europe, with worse survival reported in the United Kingdom. It has been hypothesised that these differences in survival outcomes could be related to treatment variation. Objectives: We aimed to compare patient and tumour characteristics, treatment selection and survival outcomes between two large prospective cohorts of older patients with operable breast cancer from the United Kingdom (UK) and The Netherlands.Methods: Women diagnosed with operable breast cancer aged >70 years were included. A baseline comprehensive geriatric assessment was performed in both cohorts, with data collected on age, comorbidities, cognition, nutritional and functional status. Baseline tumour characteristics and treatment type were collected. Univariable and multivariable Cox regression models were used to compare overall survival between the cohorts. Results: 3262 patients from the UK Age Gap cohort and 618 patients from the Dutch Climb cohort were included, with median ages of 77.0 (IQR: 72.0-81.0) and 75.0 (IQR: 72.0-81.0) years, respectively. The cohorts were generally comparable, with slight differences in rates of comorbidity and frailty. Median follow-up for overall survival was 4.1 years (IQR 2.9-5.4) in Age Gap and 4.3 years (IQR 2.9-5.5) in Climb. In Age Gap, both the rates of primary endocrine therapy and adjuvant hormonal therapy after surgery were approximately twice those in Climb (16.6% versus 7.3%, p < 0.001 for primary endocrine therapy, and 62.2% versus 38.8%, p < 0.001 for adjuvant hormonal therapy). There was no evidence of a difference in overall survival between the cohorts (adjusted HR 0.94, 95% CI 0.74-1.17, p Z 0.568). Conclusions: In contrast to previous studies, this comparison of two large national prospective longitudinal multi-centre cohort studies demonstrated comparable survival outcomes between older patients with breast cancer treated in the UK and The Netherlands, despite differences in treatment allocation.(C) 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 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
BackgroundPrevious studies have shown that survival outcomes for older patients with breast cancer vary substantially across Europe, with worse survival reported in the United Kingdom. It has been... Show moreBackgroundPrevious studies have shown that survival outcomes for older patients with breast cancer vary substantially across Europe, with worse survival reported in the United Kingdom. It has been hypothesised that these differences in survival outcomes could be related to treatment variation.ObjectivesWe aimed to compare patient and tumour characteristics, treatment selection and survival outcomes between two large prospective cohorts of older patients with operable breast cancer from the United Kingdom (UK) and The Netherlands.MethodsWomen diagnosed with operable breast cancer aged ≥70 years were included. A baseline comprehensive geriatric assessment was performed in both cohorts, with data collected on age, comorbidities, cognition, nutritional and functional status. Baseline tumour characteristics and treatment type were collected. Univariable and multivariable Cox regression models were used to compare overall survival between the cohorts.Results3262 patients from the UK Age Gap cohort and 618 patients from the Dutch Climb cohort were included, with median ages of 77.0 (IQR: 72.0–81.0) and 75.0 (IQR: 72.0–81.0) years, respectively. The cohorts were generally comparable, with slight differences in rates of comorbidity and frailty. Median follow-up for overall survival was 4.1 years (IQR 2.9–5.4) in Age Gap and 4.3 years (IQR 2.9–5.5) in Climb. In Age Gap, both the rates of primary endocrine therapy and adjuvant hormonal therapy after surgery were approximately twice those in Climb (16.6% versus 7.3%, p < 0.001 for primary endocrine therapy, and 62.2% versus 38.8%, p < 0.001 for adjuvant hormonal therapy). There was no evidence of a difference in overall survival between the cohorts (adjusted HR 0.94, 95% CI 0.74–1.17, p = 0.568).ConclusionsIn contrast to previous studies, this comparison of two large national prospective longitudinal multi-centre cohort studies demonstrated comparable survival outcomes between older patients with breast cancer treated in the UK and The Netherlands, despite differences in treatment allocation. Show less
Background Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor ... Show moreBackground Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear. Methods Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes. Results Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions. Conclusion This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction. Show less
The clinical potential of applying synthetic lethality to cancer treatment is famously demonstrated by the BRCA1/PARP1 paradigm: a tumor specific defect in BRCA1 – a component of the DNA double... Show moreThe clinical potential of applying synthetic lethality to cancer treatment is famously demonstrated by the BRCA1/PARP1 paradigm: a tumor specific defect in BRCA1 – a component of the DNA double-strand break (DSB) repair pathway homologous recombination (HR) – results in a remarkable sensitivity to PARP1 inhibition (PARPi). Despite spectacular initial responses in patients, resistance to PARPi treatment may develop and must be overcome to maximally exploit this interaction in the clinic. Genetically engineered (mouse) model systems have shown that PARPi resistance may arise through inactivation of the 53BP1 pathway. The 53BP1 pathway normally protects DSB ends from resection and the removal of this “brake” restores HR in the absence of BRCA1. However, how the 53BP1 pathway protects DSB ends from resection has remained elusive. In this thesis, advances in 3D tumor organoid culture protocols and CRISPR/Cas9 (screening) technology were applied to identify and validate new components of the 53BP1 pathway that render BRCA1 deficient cells resistant to PARPi upon their loss. Furthermore, a new acquired vulnerability that can be therapeutically exploited to deplete such PARPi resistant cells is described. Together, this thesis provides mechanistic insight in DSB repair and illustrates how such fundamental knowledge may stand at the basis to combat resistance. Show less
Partridge, A.H.; Niman, S.M.; Ruggeri, M.; Peccatori, F.A.; Azim, H.A.; Colleoni, M.; ... ; Pagani, O. 2021
Background: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and... Show moreBackground: Premenopausal women with early hormone-receptor positive (HR+) breast cancer receive 5-10 years of adjuvant endocrine therapy (ET) during which pregnancy is contraindicated and fertility may wane. The POSITIVE study investigates the impact of temporary ET interruption to allow pregnancy. Methods: POSITIVE enrolled women with stage I-III HR + early breast cancer, <42 years, who had received 18-30 months of adjuvant ET and wished to interrupt ET for pregnancy. Treatment interruption for up to 2 years was permitted to allow pregnancy, delivery and breastfeeding, followed by ET resumption to complete the planned duration. Findings: From 12/2014 to 12/2019, 518 women were enrolled at 116 institutions/20 countries/4 continents. At enrolment, the median age was 37 years and 74.9 % were nulliparous. Fertility preservation was used by 51.5 % of women. 93.2 % of patients had stage I/II disease, 66.0 % were node-negative, 54.7 % had breast conserving surgery, 61.9 % had received neo/adjuvant chemotherapy. Tamoxifen alone was the most prescribed ET (41.8 %), followed by tamoxifen + ovarian function suppression (OFS) (35.4 %). A greater proportion of North American women were <35 years at enrolment (42.7 %), had mastectomy (59.0 %) and received tamoxifen alone (59.8 %). More Asian women were nulliparous (81.0 %), had node negative disease (76.2%) and received tamoxifen + OFS (56.0 %). More European women had received chemotherapy (69.3 %). Interpretation: The characteristics of participants in the POSITIVE study provide insights to which patients and doctors considered it acceptable to interrupt ET to pursue pregnancy. Similarities and variations from a regional, sociodemographic, disease and treatment standpoint suggest specific sociocultural attitudes across the world. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
