A.J. Rijnsburger

BRCA1-Associated Breast Cancers Present Differently From BRCA2-Associated and Familial Cases: Long-Term Follow-Up of the Dutch MRISC Screening Study

PURPOSE The Dutch MRI Screening Study on early detection of hereditary breast cancer started in 1999. We evaluated the long-term results including separate analyses of BRCA1 and BRCA2 mutation carriers and first results on survival. PATIENTS AND METHODS Women with higher than 15% cumulative lifetime risk (CLTR) of breast cancer were screened with biannual clinical breast examination and annual mammography and magnetic resonance imaging (MRI). Participants were divided into subgroups: carriers of a gene mutation (50% to 85% CLTR) and two familial groups with high (30% to 50% CLTR) or moderate risk (15% to 30% CLTR). RESULTS Our update contains 2,157 eligible women including 599 mutation carriers (median follow-up of 4.9 years from entry) with 97 primary breast cancers detected (median follow-up of 5.0 years from diagnosis). MRI sensitivity was superior to that of mammography for invasive cancer (77.4% v 35.5%; P<.00005), but not for ductal carcinoma in situ. Results in the BRCA1 group were worse compared to the BRCA2, the high-, and the moderate-risk groups, respectively, for mammography sensitivity (25.0% v 61.5%, 45.5%, 46.7%), tumor size at diagnosis≤1 cm (21.4% v 61.5%, 40.9%, 63.6%), proportion of DCIS (6.5% v 18.8%, 14.8%, 31.3%) and interval cancers (32.3% v 6.3%, 3.7%, 6.3%), and age at diagnosis younger than 30 years (9.7% v 0%). Cumulative distant metastasis-free and overall survival at 6 years in all 42 BRCA1/2 mutation carriers with invasive breast cancer were 83.9% (95% CI, 64.1% to 93.3%) and 92.7% (95% CI, 79.0% to 97.6%), respectively, and 100% in the familial groups (n=43). CONCLUSION Screening results were somewhat worse in BRCA1 mutation carriers, but 6-year survival was high in all risk groups.

Mammography benefit in the Canadian National Breast Screening Study-2: A model evaluation†

The CNBSS‐2 among women aged 50–59 did not show any significant difference in breast cancer mortality between a control arm screened annually by CBE and a study arm screened by CBE and mammography. Because of this design, the benefit of screening compared to no screening could not be evaluated. We therefore conducted a modeling effort to estimate the benefit of mammography or CBE compared to no screening. We incorporated demographic, epidemiologic and screening characteristics of the CNBSS‐2 in MISCAN. Stage‐specific sensitivities of CBE, with and without mammography, and breast cancer incidence rate in the trial were estimated by comparing observed trial data with model predictions. We predicted the number of breast cancer deaths for both study arms of the CNBSS‐2 and in the absence of screening, assuming improvement in prognosis by early detection. We estimated a 24–29% higher breast cancer incidence rate in the CNBSS‐2 than the average Canadian rate. Estimated sensitivity of CBE (control arm) varied from 0.29 to 0.48 for stage T1c and from 0.6 to 0.65 for stage T2+. Estimated sensitivity of CBE supplemented with mammography (study arm) varied from 0.5 to 0.79 for stage T1c and was 0.95 for stage T2+. Expected breast cancer mortality reduction by annual CBE screening is 20.5% compared to no screening. Estimated breast cancer mortality reduction by mammography screening compared to no screening for the CNBSS‐2 fell within the range 13.6–34.1%. Enrolled women had above average risk. Screening sensitivity in both arms was high. A benefit of mammography screening is supported by our modeling of the CNBSS‐2 results.

Impact of screening for breast cancer in high-risk women on health-related quality of life.

The effectiveness of intensive surveillance in women at high risk for breast cancer due to a familial or genetic predisposition is uncertain and is currently being evaluated in a Dutch magnetic resonance imaging (MRI) screening (MRISC) study, in which annual imaging consists of mammography and MRI. Unfavourable side effects on health-related quality of life may arise from this screening process. We examined the short-term effects of screening for breast cancer in high-risk women on generic health-related quality of life and distress. A total of 519 participants in the MRISC study were asked to complete generic health-status questionnaires (SF-36, EQ-5D) as well as additional questionnaires for distress and items relating to breast cancer screening, at three different time points around screening. The study population showed significantly better generic health-related quality of life scores compared to age-/sex-adjusted reference scores from the general population. Neither generic health-related quality of life scores nor distress scores among the study sample (n=334) showed significant changes over time. The impact of the screening process on generic health status did not differ between risk categories. Relatively more women reported mammography as quite to very painful (30.1%) compared to MRI. Anxiety was experienced by 37% of the women undergoing MRI. We conclude that screening for breast cancer in high-risk women does not have an unfavourable impact on short-term generic health-related quality of life and general distress. In this study, high-risk women who opted for regular breast cancer screening had a better health status than women from the general population.

The impact of having relatives affected with breast cancer on psychological distress in women at increased risk for hereditary breast cancer

AbstractPurpose.Being at hereditary risk of breast cancer (BC) may lead to elevated levels of distress because of the impact of the BC-process in relatives. Objective.Determine the association between psychological distress and BC in relatives. We studied: kind of kinship with the affected relative(s), degree of involvement with the relative’s BC, time elapsed since the BC diagnosis of the relative, and loss of a relative as a consequence of BC. Methods.The study cohort consisted of women at increased risk of developing BC, adhering to regular surveillance and participating in the Dutch MRISC-study. Two months prior to the surveillance appointment, demographics, general and BC specific distress and experience with BC in the family were assessed. Results.347 out of 351 participants (mean age 40 1/2) had at least one relative affected with BC. The following variables were significantly, positively related to BC specific distress: having at least one affected sister (n=105; p  < 0.04); close involvement in a sister’s BC process (n=94; p < 0.03); and a recent (less than three years ago) BC diagnosis in a sister (n=30; p < 0.03). General distress did not show any significant associations with the experience of BC in the family. Conclusion. These findings show the impact of a BC diagnosis in a sister, particularly a recent diagnosis, on psychological distress. Women who have experienced BC in their sister may be in need of additional counselling or of more attention during the surveillance process.

Psychological Distress and Breast Self-Examination Frequency in Women at Increased Risk for Hereditary or Familial Breast Cancer

Background: The Magnetic Resonance Imaging Screening study evaluates the efficacy and psychological impact of a surveillance program for women at increased risk for hereditary or familial breast cancer in the Netherlands. Surveillance consists of biannual physical examination, annual mammography, annual MRI and monthly breast self-examination (BSE). Objective: To examine the association between psychological distress and reported BSE frequency. Methods: Two months prior to surveillance demographics, BSE frequency, general distress (Hospital Anxiety and Depression Scale and the somatic scale of the Symptom Checklist-90) and breast cancer-specific distress (Impact of Event Scale) were assessed in 316 women (mean age 40.5 years, range 21–63 years). Results: The majority (57%) reported performing monthly BSE. Ten percent reported never performing BSE, 20% less frequently than once a month and 13% at least once a week. Women below the age of 40 who examined their breasts more frequently than recommended (i.e. at least once a week) were shown to be significantly more distressed than the other women in the sample (p = 0.03). These women represented 15% of all the women below the age of 40 years in our study sample. Conclusion: Higher breast cancer-specific distress scores were observed among younger women who examined their breasts at least once a week. It is important for physicians to be aware of this hypervigilant behaviour, especially since it is correlated with breast cancer-specific distress.

Which factors may determine the necessary and feasible type of effectiveness evidence? A mixed methods approach to develop an instrument to help coverage decision-makers

Objectives Reimbursement decisions require evidence of effectiveness and, in general, a blinded randomised controlled trial (RCT) is the preferred study design to provide it. However, there are situations where a cohort study, or even patient series, can be deemed acceptable. The aim of this study was to develop an instrument that first examines which study characteristics of a blinded RCT are necessary, and then, if particular characteristics are considered necessary, examines whether these characteristics are feasible. Design We retrospectively studied 22 interventions from 20 reimbursement reports concerning medical specialist care made by the Dutch National Health Care Institute (ZIN) to identify any factors that influenced the necessity and feasibility of blinded RCTs, and their constituent study characteristics, that is, blinding, randomisation and a control group. A literature review was performed to identify additional factors. Additional expertise was included by interviewing eight experts in epidemiology, medicine and ethics. The resulting instrument was called the FIT instrument (Feasible Information Trajectory), and was prospectively validated using three consecutive reimbursement reports. Results (Blinded) RCT evidence was lacking in 5 of 11 positive reimbursement decisions and 3 of 11 negative decisions. In the reimbursement reports, we found no empirical evidence supporting situations where a blinded RCT is unnecessary. The literature also revealed few arguments against the necessity of a blinded RCT. In contrast, many factors influencing the feasibility of randomisation, a control group and blinding, were found in the reimbursement reports and the literature; for example, when a patient population is too small or when an intervention is common practice, randomisation will be hindered. Conclusions Policy regarding the necessity and feasibility of different types of evidence of effectiveness would benefit from systematic guidance. The FIT instrument has the potential to support transparent, reproducible and well-founded decisions on appropriate evidence of effectiveness in medical specialist care.

The psychological impact of regular surveillance in women at increased risk for hereditary breast cancer

textabstractVrouwen met een verhoogd risico op het krijgen van borstkanker vanwege een erfelijke of familiaire aanleg komen in aanmerking voor regelmatige controles bestaand uit halfjaarlijks lichamelijk onderzoek en jaarlijks een mammografie. In een nationaal onderzoek wordt de meerwaarde bestudeerd van een jaarlijkse MRI scan van het borstklierweefsel in vergelijking met de mammografie (MRISC studie). In het Erasmus Medisch Centrum Rotterdam is bij 350 vrouwen die deelnemen aan de MRISC studie onderzocht welke psychologische gevolgen deze regelmatige controle heeft. De vrouwen vulden psychologische vragenlijsten over angst, depressie en borstkankergerelateerde zorgen in rondom twee halfjaarlijkse controles. De belangrijkste bevinding was dat participatie aan deze controles niet leidde tot klinisch relevante, aanhoudende angst, depressie en borstkankergerelateerde zorgen. Psychologische stress was wel groter in een aantal subgroepen, namelijk: vrouwen die meer dan ee! ns per week hun eigen borsten onderzoeken, vrouwen die hun eigen risico op het krijgen van borstkanker als (heel) erg hoog ervaren, en vrouwen die borstkanker bij een zus van dichtbij hebben meegemaakt. Tevens bleek dat vrouwen die op een passieve manier omgaan met problemen meer psychologische stress hebben, terwijl het uiten van emoties en het zoeken van sociale steun daarentegen gepaard bleek te gaan met minder psychologische stress. Ongeveer 10 tot 20% van de vrouwen ondervond minstens enig ongemak van de MRI scan (zoals: het liggen in een tunnel, lawaai van het apparaat, en niet mogen bewegen). Toch werd 64% van de vrouwen gerustgesteld door een gunstige uitslag van een MRI scan, tegenover 40% door een gunstige mammografie uitslag. Geconcludeerd kan worden dat meedoen aan regelmatige controles voor borstkanker geen bedreiging vormt voor het psychologische welbevinden van vrouwen met een familiebelasting. Wel zullen artsen, psychologen en psychosociaal werkers in hun voorlichting, behandeling en begeleiding rekening moeten houden met de in deze studie gevonden factoren die samenhangen met psychologische stress.

Acknowledgement to the Reviewers

Stephen J.J. Clarke, St. Leonards, Australia Robert L. Coleman, Houston, USA Pier Franco Conte, Modena, Italy Jay Cooper, Brooklyn, USA Daniela Cornelio, Porto Alegre, Brazil Renzo Corvo, Genoa, Italy Long H. Dang, Gainesville, USA Aimery de Gramont, Paris, France Marc Denis, Nantes, France Francesco Di Costanzo, Florence, Italy Phillip J. DiSaia, Orange, USA Tomislav Dragovich, Gilbert, USA Elisabeth L. Dupont, Lakeland, USA Grace K. Dy, Buffalo, USA Florian Eckel, Munich, Germany Patricia Eifel, Houston, USA Bassel F. El-Rayes, Atlanta, USA Matti Eskelinen, Kuopio, Finland Marwan G. Fakih, Ann Arbor, USA Nicola Fazio, Milan, Italy Kate Fife, Cambridge, UK Eric Francois, Nice, France Martin Fruh, St. Gallen, Switzerland Masashi Fujii, Tokyo, Japan Sirish M. Gadgeel, Detroit, USA Vassilis Georgoulias, Heraklion, Greece Domenico Germano, Benevento, Italy Julia Glade Bender, New York, USA Martin Glas, Bonn, Germany Boon-Cher Goh, Singapore, Singapore Erdem Goker, Bornova, Turkey Maria Gonzalez Cao, Barcelona, Spain Christian Gratzke, Munich, Germany Juan-Jose Grau, Barcelona, Spain Tim F. Greten, Bethesda, USA Francesco Grossi, Genova, Italy Victor Gruenwald, Hannover, Germany Pascal Hammel, Clichy, France Toshiyuki Harada, Sapporo, Japan Motohiro Hirao, Osaka, Japan Wolfgang Hohenforst-Schmidt, Coburg, Germany Michael Holick, Boston, USA Masaru Horio, Osaka, Japan Dieter Horsch, Bad Berka, Germany Ghassan K. Abou-Alfa, New York, USA Ana Lucia Abujamra, Porto Alegre, Brazil Banke Agarwal, Saint Louis, USA Jaffer A. Ajani, Houston, USA Masashi Akiyama, Nagoya, Japan Frederic Amant, Leuven, Belgium Peter M. Anderson, Houston, USA Rose Anorlu, Lagos, Nigeria Makoto Arai, Chiba City, Japan Yasuaki Arai, Tokyo, Japan S.A. Arnold, Nashville, USA Ofer Arnon, Beer-Sheva, Israel David August, New Brunswick, USA Hideo Baba, Kumamoto, Japan Alexander Bachmann, Basel, Switzerland Joseph M. Backer, Brookfield, USA Aristotle Bamias, Vrilissia, Athens, Greece Thomas I. Barron, Dublin, Ireland Jean-Pierre Bellocq, Strasbourg, France Jaafar Bennouna, Nantes, France Al B. Benson, Chicago, USA Thierry Berghmans, Brussels, Belgium Jordan D. Berlin, Nashville, USA Stefan Bielack, Stuttgart, Germany Julie Bienertova-Vasku, Brno, Czech Republic Stefan Biesterfeld, Dusseldorf, Germany Narikazu Boku, Sunto-gun, Japan Olivier Braissant, Basel, Switzerland Nguyen Binh Bui, Bordeaux, France Ronald M. Bukowski, Pepper Pike, USA Abdullah Buyukcelik, Kayseri, Turkey Alfredo Carrato, Madrid, Spain Marc Carrier, Ottawa, Canada James Cassidy, Nutley, USA Darko Cerne, Ljubljana, Slovenia Stephen Lam Chan, Hong Kong, China Judy-Anne W. Chapman, Kitchener, Canada Kazuaki Chayama, Hiroshima, Japan Ming-Huang Chen, Taipei, Taiwan Ann-Lii Cheng, Taipei, Taiwan Ya-Wen Cheng, Taichung, Taiwan Marco Chinol, Milan, Italy Julia C. Chisholm, Sutton, UK