Originally published as JCO Early Release 10.1200/JCO.2007.11.1179 on July 16 2007

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Oral Contraceptives and Breast Cancer Risk in the International BRCA1/2 Carrier Cohort Study: A Report From EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group

Richard M. Brohet, David E. Goldgar, Douglas F. Easton, Antonis C. Antoniou, Nadine Andrieu, Jenny Chang-Claude, Susan Peock, Rosalind A. Eeles, Margaret Cook, Carol Chu, Catherine Noguès, Christine Lasset, Pascaline Berthet, Hanne Meijers-Heijboer, Anne-Marie Gerdes, Håkan Olsson, Trinidad Caldes, Flora E. van Leeuwen, Matti A. Rookus

From the Netherlands Cancer Institute, Department of Epidemiology; Free University, Amsterdam; Erasmus University Hospital, Rotterdam, the Netherlands; International Agency for Research on Cancer, Department of Genetic Epidemiology; Centre Léon Bérard, Lyon; Institut National de la Santé et de la Recherche Médicale (INSERM) U794 et Service de Biostatistiques, Institut Curie, Paris; Centre René Huguenin, Saint Cloud; Centre François Baclesse, Caen, France; Department of Dermatology, University of Utah, School of Medicine, Salt Lake City, Utah; Department of Public Health and Primary Care, Genetic Epidemiology Unit, Cancer Research UK, University of Cambridge, Cambridge; Royal Marsden Hospital, London; Yorkshire Regional Genetics Service, Leeds, United Kingdom; Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany; Odense University Hospital, Odense, Denmark; Lund University Hospital, Lund, Sweden; and the Hospital Clinico San Carlos, Madrid, Spain

Address reprint requests to Matti A. Rookus, PhD, Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, the Netherlands, e-mail: m.rookus{at}nki.nl

	ABSTRACT

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Purpose: Earlier studies have shown that endogenous gonadal hormones play an important role in the etiology of breast cancer among BRCA1/2 mutation carriers. So far, little is known about the safety of exogenous hormonal use in mutation carriers. In this study, we examined the association between oral contraceptive use and risk of breast cancer among BRCA1/2 carriers.

Patients and Methods: In the International BRCA1/2 Carrier Cohort study (IBCCS), a retrospective cohort of 1,593 BRCA1/2 mutation carriers was analyzed with a weighted Cox regression analysis.

Results: We found an increased risk of breast cancer for BRCA1/2 mutation carriers who ever used oral contraceptives (adjusted hazard ratio [HR] = 1.47; 95% CI, 1.16 to 1.87). HRs did not vary according to time since stopping use, age at start, or calendar year at start. However, a longer duration of use, especially before first full-term pregnancy, was associated with an increased risk of breast cancer for both BRCA1 and BRCA2 mutation carriers (4 or more years of use before first full-term pregnancy: HR = 1.49 [95% CI, 1.05 to 2.11] for BRCA1 carriers and HR = 2.58 [95% CI, 1.21 to 5.49] for BRCA2 carriers).

Conclusion: No evidence was found among BRCA1/2 mutation carriers that current use of oral contraceptives is associated with risk of breast cancer more strongly than is past use, as is found in the general population. However, duration of use, especially before first full-term pregnancy, may be associated with an increasing risk of breast cancer among both BRCA1 and BRCA2 mutation carriers.

	INTRODUCTION

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Germline mutations in BRCA1 and BRCA2 carriers confer substantial risks of breast and ovarian cancer.^1,2 An important ongoing area of research is to determine whether factors that alter breast cancer risk in the general population also affect risk in carriers. Recent studies have indicated a marked reduction of breast cancer risk in carriers after a prophylactic oophorectomy, comparable to that in the general population, which suggests that endogenous hormone exposure plays an important role in the etiology of breast cancer among BRCA1/2 mutation carriers.^3,4 Therefore, a particularly important question is whether oral contraceptive use confers a risk of breast cancer in carriers. A large meta-analysis of studies conducted in the general population showed that current use of oral contraceptives was associated with a slightly increased risk of breast cancer (relative risk [RR] = 1.24; 95% CI, 1.15 to 1.33), whereas the risk steadily decreased during 10 years after stopping.⁵ The elevated risk did not increase with longer duration of use. Knowing the magnitude of the breast cancer risk associated with use of oral contraceptives in carriers is of particular importance to carriers because of their high breast cancer risk at a young age. Simultaneously, oral contraceptives may reduce the risk of ovarian cancer in carriers,^6-9 although this is not found in all studies.¹⁰

So far, among BRCA1/2 mutation carriers, only a few studies have examined the effect of oral contraceptive use on breast cancer risk.^11-16 Two studies were less informative due to the small sample size (98 BRCA1/2 carriers,¹⁴ 83 BRCA1/2 carriers¹⁵) and because BRCA1/2 carrier cases were compared with population-based controls, who are likely to be noncarriers even though they were not tested.¹⁵ In two small case-case studies, long-term oral contraceptive use before first full-term pregnancy or ever use before age 20 years were found to be associated with being a BRCA1/2 mutation carrier, suggesting effect modification.^11,12 However, the case-only design of these studies depends on the assumption that oral contraceptive use is independent of the mutation. This assumption may be violated by the finding of Haile et al¹⁶ that women with a family history of breast cancer use oral contraceptives for shorter durations. Among 981 case-control pairs of BRCA1 carriers, Narod et al¹³ found a modestly increased risk of breast cancer for ever use of oral contraceptives (odds ratio [OR] = 1.20; 95% CI, 1.02 to 1.40) and for use of at least 5 years (RR = 1.33; 95% CI, 1.11 to 1.60). In contrast, in another case-control study of women younger than 50 years (BRCA1: 195 cases v 302 controls; BRCA2: 128 cases v 179 controls), Haile et al¹⁶ found no association for ever use for BRCA1 and BRCA2 carriers, whereas an increased risk for long duration of use was observed among BRCA2 carriers (OR = 2.06 and 95% CI, 1.08 to 3.94 for 5 or more years of use). To further address this important problem, we have performed a large retrospective cohort study among women who tested positive for a BRCA1 or BRCA2 mutation as part of the International BRCA1/2 Carriers Cohort Study (IBCCS). In this analysis, we have specifically addressed the potential problems of survival and testing bias.

	PATIENTS AND METHODS

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Study Group
The cohort comprised 1,601 women with proven pathogenic BRCA1/2 mutations derived from the IBCCS.^17-19 Women were eligible for the study if they were 18 years or older and had been tested positive for BRCA1 or BRCA2 and informed of their mutation status. More than two thirds of the participants were enrolled onto the international study through one of the three large ongoing nationwide studies in the United Kingdom and Ireland (Epidemiological Study of Familial Breast Cancer [EMBRACE]), France (Gene Etude Prospective Sein Ovaire [GENEPSO]) and the Netherlands (Gen en Omgeving studie van de werkgroep Hereditair Borstkanker Onderzoek Nederland [GEO-HEBON]). The current analysis is restricted to women born after 1920 (n = 1,593), because they had their reproductive years in the time period during which oral contraceptives were available. A standardized questionnaire on lifestyle and reproductive factors was administered including ever use, starting age and years of duration, or starting and stopping age for each period of oral contraceptive use.

Statistical Methods
Risks of breast cancer were estimated by calculating hazard ratios (HRs) using a Cox regression assuming a proportional hazards model. Standard Cox regression may lead to biased estimates of the HR because the women in this study were selected from high-risk families qualifying for genetic testing. The disease status may therefore have affected the likelihood of testing. As a result, affected women may be oversampled. To correct for this potential testing bias, the analyses were performed using the weighted regression approach described by Antoniou et al²⁰ in which women with breast cancer and unaffected women were differentially weighted such that the breast cancer incidence rates in the study cohort were consistent with age- and birth cohort–specific breast cancer risk estimates for BRCA1 and BRCA2 mutation carriers reported by Antoniou et al.² In fact, carriers who developed breast cancer were underweighted (weights < 1) and the unaffected carriers were overweighted (weights > 1). The weights applied to all person-years of each subject in the Cox model.²⁰

Follow-up started at birth and ended at age of diagnosis of first primary breast cancer (n = 846). The remaining 747 participants in the cohort were censored at age of ovarian cancer diagnosis (n = 122), age at diagnosis of another cancer (n = 16), age at prophylactic mastectomy (n = 31), or age at interview (n = 578), whichever came first. Oral contraceptive use changed over time and was therefore determined for each year of observation and analyzed as a time-dependent variable in the Cox model. The Cox analyses were stratified for birth cohort (1920 to 1939, 1940 to 1949, 1950 to 1959, > 1960), gene (BRCA1, BRCA2), and four country groupings (group 1: Austria, Belgium, Germany, Holland, Hungary; group 2: Iceland, Denmark, Sweden; group 3: France, Spain, Italy, Canada (Québec); group 4: United Kingdom and Ireland). Analyses were adjusted for oophorectomy (yes, no) and number of full-term pregnancies (0, 1, 2, 3, 4+) as time-dependent variables. Missing values were coded as an additional category. Since some participants were members of the same family, SEs of all parameter estimates were determined using robust variance estimators clustering on family membership to account for familial correlations in the risk factors. Analyses were conducted for the entire cohort and, separately, for each gene, and by attained age ( 40 v 40+ years), birth cohort, and country. Tests for trend were conducted on the medians of the reported categories of use among users of oral contraceptives.

In addition to testing bias, survival bias may be present resulting from the inclusion of prevalent cases. To examine this potential survival bias in a separate analysis, we restricted the person-years to those within the last 5 years preceding the date of interview. Within this so-called pseudoincident cohort consisting of 967 unaffected individuals at the start, 294 incident breast cancer cases were diagnosed during follow-up at a mean age of 42.7 years. The mean survival (interval between dates of diagnoses and interview) reduced from 9 years in the entire cohort to 2 years in the pseudoincident cohort. Weights were estimated separately for the entire cohort and the pseudoincident cohort, and the pseudoincident cohort analyses were additionally adjusted for age at start of follow-up. All statistical analyses were performed using STATA version 7 (StataCorp, College Station, TX).

	RESULTS

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The entire cohort, born after 1920, comprised 1,593 individuals including 1,181 BRCA1 and 412 BRCA2 mutation carriers and 65,180 person-years of observations. In total, 846 women (597 BRCA1 and 249 BRCA2) were diagnosed with breast cancer. The average age at breast cancer diagnosis in the cohort was 40.9 years, ranging from 19 to 74 years.

In total, 1,167 mutation carriers (73%) had ever used oral contraceptives. They were diagnosed with breast cancer at an earlier age than never users (39.6 v 44.6 years, respectively; P < .001) and reported a lower mean number of children (two v three children; P < .001). In contrast, ever and never users hardly differed according to age at first full-term pregnancy (25.7 v 25.2 years; P = .07) and number of women with an oophorectomy (3% v 5%; P = .183).

The estimated risks associated with different patterns of oral contraceptive use from the unweighted, weighted, and pseudoincident cohort weighted Cox regression analyses are summarized in Table 1. In the weighted analysis of the entire cohort, ever use of oral contraceptives was associated with an increased risk of breast cancer (HR = 1.47; 95% CI, 1.16 to 1.87). As expected, the unweighted HR estimates were biased towards the null with smaller confidence (eg, unweighted HR for ever use was 1.27; 95% CI, 1.08 to 1.49). Overall, no trend was seen with time since last use, however, the weighted risk of breast cancer in the entire cohort seemed to increase with longer duration of oral contraceptive use ( 9 years of use: HR = 1.61; 95% CI, 1.18 to 2.20; P for trend = .257). This association for lifetime duration of use appeared to be attributable to use before first full-term pregnancy ( 9 years of use before first full-term pregnancy: HR = 1.85; 95% CI, 1.17 to 2.93; P for trend =.062). The associations for use of oral contraceptives before first full-term pregnancy were present for parous as well as nulliparous women (for parous women HR = 1.38 [95% CI, 1.01 to 1.88] and for nulliparous women HR = 1.72 [95% CI, 1.00 to 2.96]; data not shown). For age at starting use of oral contraceptives or calendar year of starting use, no differences were found. In general, the HR estimates of the pseudoincident cohort analysis were not markedly different from estimates based on the entire cohort. Although the trend in risks for lifetime duration and duration of use before first full-term pregnancy were less clear. This suggested that survival bias was limited.

	DISCUSSION

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In the general population, current use of oral contraceptives was associated with an increased relative risk of breast cancer of 1.24 (95% CI, 1.15 to 1.33), and this risk gradually disappeared during the 10 years after stopping.⁵ However, an effect of recency of use was not found in our study, nor in the other studies of BRCA1/2 carriers. Among BRCA1 carriers, risk of breast cancer even seemed to increase rather than to decrease with longer time since last use in the study of Narod et al.¹³ For other aspects of use, Narod et al found a modestly increased risk for ever use and an increased risk for duration of use only in BRCA1 carriers, whereas Haile et al found no association for ever use but stronger duration effects for BRCA2.¹⁶ We found an increasing risk with duration of use before first full-term pregnancy among both BRCA1 and BRCA2 carriers. This effect seemed to be stronger among BRCA2 carriers, which was in accordance with the findings of Haile et al.¹⁶

The present results are based on retrospective information from women who opted for genetic testing. To adjust for the over-representation of cases among women who opt for a test, we applied the weighted regression approach described by Antoniou et al.^2,20 The weighting resulted in a slight shift of the HRs away from zero and some loss of power (wider CIs), but the weighting had no material effect on the interpretation of the HRs. In a nested case-control study on 1,311 matched pairs of BRCA1/2 mutation carriers, Narod et al chose to exclude every case as a possible control.¹³ This approach might have resulted in bias away from zero because carriers have a high risk of breast cancer and, thus, cases should be eligible as controls at ages preceding their age at diagnosis. In the case-control study of Haile et al,¹⁶ potential selection bias was reduced because carriers identified in a research setting were included in addition to clinically tested carriers.

One assumption underlying the method of weighting is that the decision to opt for genetic testing is similarly associated with use of oral contraceptives for cases and unaffected women.²⁰ To verify that assumption, we compared use of oral contraceptives between tested and untested members of BRCA1/2 families for women with or without breast cancer, separately (50 affected pairs and 123 unaffected pairs, matched on age at date of testing) in the Dutch national study where this information was available. Although oral contraceptive users proved to be more likely to opt for a test than were never users, this testing behavior was comparable between women with or without breast cancer (HR = 2.4 [95% CI, 0.9 to 6.8] and HR = 2.1 [95% CI, 1.1 to 4.0], respectively). This indicates that this type of testing bias may not have a great impact on the association between oral contraceptive use and breast cancer risk, although the association between oral contraceptive use and testing remains unexplained.

In addition to testing bias, survival bias may occur in a study that includes prevalent cases. Survival bias might operate to increase or reduce the apparent risk, depending on whether survival is better or worse in users of oral contraceptives. In any event, the impact of survival bias is likely to be smaller in the pseudoincident cohort than in the entire cohort. Haile et al¹⁶ used a similar approach, restricting the cases to those diagnosed within 5 years from date of interview, as did Narod et al.¹³ In our study, most risks estimated in the entire or pseudoincident cohort were virtually unchanged, although the trends of risk with lifetime duration and with duration of use before first full-term pregnancy were less clear. Thus, the impact of survival bias seems to be limited, although some influence cannot be ruled out.

Information bias may be present in this retrospective study as a result of differential recall of history of oral contraceptives between cases and unaffected women. In the meta-analysis of observational studies, there was no difference in the association of oral contraceptives with breast cancer between prospective cohort studies and case-control studies.⁵ Theoretically, recall bias may be present among carriers while it is absent in the general population. However, no data are available to support or reject this possibility.

In conclusion, the design of studies among carriers, such as ours, suffers from more complications that cannot be easily solved, such as ascertainment bias, testing bias, survival bias and decreased power due to prophylactic surgeries, compared with observational studies conducted in the general population. Therefore, the current results should still be considered with caution, and it is still too early to give univocal advice to BRCA1/2 mutation carriers. Although oral contraceptives have repeatedly been proposed as a potential chemoprevention strategy for ovarian cancer,^6-8 the present findings may help to set potential cancer risks after use of oral contraceptives in perspective. We suggest that advice on use of oral contraceptives to BRCA1/2 mutation carriers needs to consider not only the positive effect on ovarian cancer risk, but also the potential increased risk of breast cancer, although this associated cannot yet be considered proven.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The author(s) indicated no potential conflicts of interest.

	AUTHOR CONTRIBUTIONS

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Conception and design: Richard M. Brohet, David E. Goldgar, Douglas F. Easton, Antonis C. Antoniou, Nadine Andrieu, Jenny Chang-Claude, Flora A. van Leeuwen, Matti A. Rookus

Administrative support: David E. Goldgar

Provision of study materials or patients: Richard M. Brohet, David E. Goldgar, Douglas F. Easton, Antonis C. Antoniou, Nadine Andrieu, Jenny Chang-Claude, Susan Peock, Rosalind A. Eeles, Carol Chu, Christine Lasset, Pascaline Berthet, Hanne Meijers-Heijboer, Anne-Marie Gerdes, Håkan Olsson, Trinidad Caldes, Flora A. van Leeuwen, Matti A. Rookus

Collection and assembly of data: Richard M. Brohet, David E. Goldgar, Douglas F. Easton, Antonis C. Antoniou, Nadine Andrieu, Jenny Chang-Claude, Susan Peock, Rosalind A. Eeles, Margaret Cook, Carol Chu, Catherine Noguès, Christine Lasset, Pascaline Berthet, Hanne Meijers-Heijboer, Anne-Marie Gerdes, Håkan Olsson, Trinidad Caldes, Flora A. van Leeuwen, Matti A. Rookus

Data analysis and interpretation: Richard M. Brohet, David E. Goldgar, Douglas F. Easton, Antonis C. Antoniou, Nadine Andrieu, Jenny Chang-Claude, Flora A. van Leeuwen, Matti A. Rookus

Manuscript writing: Richard M. Brohet, David E. Goldgar, Douglas F. Easton, Antonis C. Antoniou, Nadine Andrieu, Jenny Chang-Claude, Susan Peock, Flora A. van Leeuwen, Matti A. Rookus

Final approval of manuscript: Richard M. Brohet, David E. Goldgar, Douglas F. Easton, Antonis C. Antoniou, Nadine Andrieu, Jenny Chang-Claude, Susan Peock, Rosalind A. Eeles, Margaret Cook, Carol Chu, Catherine Noguès, Christine Lasset Pascaline Berthet, Hanne Meijers-Heijboer, Anne-Marie Gerdes, Håkan Olsson, Trinidad Caldes, Flora A. van Leeuwen, Matti A. Rookus

	Appendix

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IBCCS Collaborating Group
Study coordinator: David Goldgar at the International Agency for Research on Cancer, Department of Genetic Epidemiology, Lyon, France and at the University of Utah, School of Medicine, Department of Dermatology, Salt Lake City, USA.

EMBRACE Collaborating Centers, United Kingdom: Coordinating Center, Cambridge: Douglas Easton, Antonis Antoniou, Susan Peock, Margaret Cook, Cassandra Engel; North of Scotland Regional Genetics Service, Aberdeen: Neva Haites, Helen Gregory; Northern Ireland Regional Genetics Service, Belfast: Patrick Morrison; West Midlands Regional Clinical Genetics Service, Birmingham: Trevor Cole, Carole McKeown; South West Regional Genetics Service, Bristol: Alan Donaldson; East Anglian Regional Genetics Service, Cambridge: Joan Paterson; Medical Genetics Services for Wales, Cardiff: Jonathan Gray, Mark Rogers; St James's Hospital, Dublin & National Centre for Medical Genetics, Dublin: Peter Daly, David Barton; South East of Scotland Regional Genetics Service, Edinburgh: Mary Porteous, Michael Steel; Peninsula Clinical Genetics Service, Exeter: Carole Brewer, Julia Rankin; West of Scotland Regional Genetics Service, Glasgow: Rosemarie Davidson, Victoria Murday; South East Thames Regional Genetics Service, Guys Hospital London: Louise Izatt, Gabriella Pichert; North West Thames Regional Genetics Service, Harrow: Huw Dorkins; Leicestershire Clinical Genetics Service, Leicester: Richard Trembath; Yorkshire Regional Genetics Service, Leeds: Tim Bishop, Carol Chu; Merseyside & Cheshire Clinical Genetics Service, Liverpool: Ian Ellis; Manchester Regional Genetics Service, Manchester: Gareth Evans, Fiona Lalloo, Andrew Shenton; North East Thames Regional Genetics Service, NE Thames: James Mackay, Anne Robinson; Nottingham Centre for Medical Genetics, Nottingham: Susan Ritchie; Northern Clinical Genetics Service, Newcastle: Fiona Douglas, John Burn; Oxford Regional Genetics Service, Oxford: Sarah Durell, Lucy Side; Institute of Cancer Research and Royal Marsden NHS Foundation Trust: Rosalind Eeles, Susan Shanley, Nazneen Rahman, Richard Houlston, Elizabeth Bancroft, Fiona Lennard, Julian Barwell, Imogen Locke, Asher Salmon, Rebecca Doherty, Ella Lynch, Sarah Thomas, Audrey Ardern-Jones; North Trent Clinical Genetics Service, Sheffield: Jackie Cook, Oliver Quarrell; South West Thames Regional Genetics Service, London: Shirley Hodgson; Wessex Clinical Genetics Service, Southampton: Diana Eccles, Anneke Lucassen; GENEPSO Collaborating Centers, France: Coordinating Center, Centre René Huguenin, Saint Cloud: Catherine Noguès, Emmanuelle Fourme, Rosette Lidereau, Denise Stevens; Institut Curie, Paris: Dominique Stoppa-Lyonnet, Marion Gauthier-Villars; Institut Gustave Roussy, Villejuif: Agnès Chompret; Centre René Huguenin, Saint Cloud: Catherine Noguès; Centre Paul Strauss, Strasbourg: Jean-Pierre Fricker; Centre Léon Bérard, Lyon: Christine Lasset, Valérie Bonadona; Centre François Baclesse, Caen: Pascaline Berthet; Centre Alexis Vautrin, Vandoeuvre-les-Nancy: Elisabeth Luporsi; Institut Paoli-Calmettes, Marseille: Hagay Sobol, François Eisinger, Laetitia Huiart; Institut Claudius Regaud, Toulouse: Laurence Gladieff, Rosine Guimbaud; Centres Paul Papin, René Gauducheau and Catherine de Sienne, Angers, Nantes: Alain Lortholary; Centre Antoine Lacassagne, Nice: Marc Frénay; Hôpital D'Enfants CHU, Dijon: Laurence Faivre; Institut Bergonié, Bordeaux: Michel Longy; Institut Jean Godinot, Reims: Tan Dat Nguyen; CH Georges Renon, Niort: Paul Gesta; Centre Oscar Lambret, Lille: Philippe Vennin, Claude Adenis; Hôpital Charles Nicolle, Centre Henri Becquerel, Rouen: Annie Chevrier, Annick Rossi; Centre Jean Perrin, Clermont-Ferrand: Yves-Jean Bignon; Hôpital Civil, Strasbourg: Jean-Marc Limacher; Centre Eugène Marquis, Rennes: Catherine Dugast; Polyclinique Courlancy, Reims: Liliane Demange, Hôpital de la Timone, Marseille: Hélène Zattara-Cannoni; Clinique Sainte Catherine, Avignon: Hélène Dreyfus; CHU Arnaud Villeneuve, Montpellier: Mehrdad Noruzinia; CHRU Dupuytren, Limoges: Laurence Venat-Bouvet; Center U794, Service de Biostatistique, Institut Curie, Paris: Nadine Andrieu; Center U535, Villejuif : Catherine Bonaïti; Center U379, Marseille: Claire Julian-Reynier; Center U605 Villejuif: Florent de Vathaire; IPC, Center E-9939, Marseille: Hagay Sobol; GEO-HEBON Collaborating Centers, Netherlands: Coordinating center: Netherlands Cancer Institute, Amsterdam: Richard Brohet, Matti Rookus, Flora van Leeuwen, Laura van 't Veer, Senno Verhoef; Leiden University Medical Center, Leiden: Christi van Asperen; Erasmus Medical Center, Rotterdam: Hanne Meijers-Heijboer, Jan Klijn; Nijmegen Medical Center, Nijmegen: Nicoline Hoogerbrugge; the Netherlands Foundation for the detection of hereditary tumors, Leiden, Hans Vasen; University Medical Center Utrecht, Utrecht: Margreet Ausems; VU University Medical Center, Amsterdam: Fred Menko; Maastricht University Medical Center, Maastricht: Encarna Gomez-Garcia; other IBCCS Collaborating Centers: German Cancer Research Center, Heidelberg, Germany: Jenny Chang-Claude; Vienna, Austria: Teresa Wagner, Verena Korn; Christine Fürhauser; Odense, Denmark: Anne-Marie Gerdes; Budapest, Hungary: Edith Olah; Reykjavik, Iceland: Jorunn Eyford; Milan, Italy: Paolo Radice, Siranonoush Manoukian, Marco Pierotti; Madrid, Spain: Javier Benitez, Ana Osorio; Madrid Spain: Trinidad Caldes, Miguel de la Hoya; Szczecin, Poland: Jan Lubinski; Stockholm, Sweden: Brita Arver; Lund, Sweden: Hågan Olsson, Niklas Loman, Swedish Cancer Society; Quebec, Canada: Jacques Simard; Brussels, Belgium: Catherine Sibille.

	ACKNOWLEDGMENTS

 
We thank Helene Renard, Colette Bonnardel, and Othman Yaqoubi, IARC, France, and Mary Velthuizen, the Netherlands Foundation for the Detection of Hereditary Tumors, Leiden, the Netherlands, for technical assistance. The GENEPSO study appreciates the technical assistance of Marie-Lise Manche Thévenot and Claude Picard, Centre René Huguenin, Saint-Cloud, France.

	NOTES

 
published online ahead of print at www.jco.org on July 16, 2007.

Supported by National Institutes of Health Award CA81203 (D.G.); the Cancer Research United Kingdom (A.A.); and the Canadian Institutes of Health Research through the INHERIT BRCAs research program (D.F.E., D.G.). The EMBRACE study is supported by Cancer Research United Kingdom and The British Council and Health Research Board Research Visits Scheme; the IBCCS study has been supported by Grants No. SI2.328176 and SPC 2002482 from the Europe Against Cancer Programme of the European Commission; the GENEPSO study is supported by the Fondation de France and the Ligue Nationale Contre le Cancer; and the GEO-HEBON study is supported by the Dutch Cancer Society Grant No. NKI98-1854. D.F.E. is a Principal Research Fellow of Cancer Research United Kingdom.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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Submitted February 12, 2007; accepted May 22, 2007.

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