Richard M Brohet

Bias Correction Methods Explain Much of the Variation Seen in Breast Cancer Risks of BRCA1/2 Mutation Carriers.

Authors:

Janet R Vos Li Hsu Richard M Brohet Marian J E Mourits Jakob de Vries Kathleen E Malone Jan C Oosterwijk Geertruida H de Bock

J Clin Oncol 2015 Aug 6;33(23):2553-62. Epub 2015 Jul 6.

Janet R. Vos, Marian J.E. Mourits, Jakob de Vries, Jan C. Oosterwijk, and Geertruida H. de Bock, University of Groningen, University Medical Center Groningen, Groningen; Richard M. Brohet, Spaarne Hospital, Hoofddorp, the Netherlands; and Li Hsu and Kathleen E. Malone, Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: Recommendations for treating patients who carry a BRCA1/2 gene are mainly based on cumulative lifetime risks (CLTRs) of breast cancer determined from retrospective cohorts. These risks vary widely (27% to 88%), and it is important to understand why. We analyzed the effects of methods of risk estimation and bias correction and of population factors on CLTRs in this retrospective clinical cohort of BRCA1/2 carriers.

Patients And Methods: The following methods to estimate the breast cancer risk of BRCA1/2 carriers were identified from the literature: Kaplan-Meier, frailty, and modified segregation analyses with bias correction consisting of including or excluding index patients combined with including or excluding first-degree relatives (FDRs) or different conditional likelihoods. These were applied to clinical data of BRCA1/2 families derived from our family cancer clinic for whom a simulation was also performed to evaluate the methods. CLTRs and 95% CIs were estimated and compared with the reference CLTRs.

Results: CLTRs ranged from 35% to 83% for BRCA1 and 41% to 86% for BRCA2 carriers at age 70 years width of 95% CIs: 10% to 35% and 13% to 46%, respectively). Relative bias varied from -38% to +16%. Bias correction with inclusion of index patients and untested FDRs gave the smallest bias: +2% (SD, 2%) in BRCA1 and +0.9% (SD, 3.6%) in BRCA2.

Conclusion: Much of the variation in breast cancer CLTRs in retrospective clinical BRCA1/2 cohorts is due to the bias-correction method, whereas a smaller part is due to population differences. Kaplan-Meier analyses with bias correction that includes index patients and a proportion of untested FDRs provide suitable CLTRs for carriers counseled in the clinic.

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http://dx.doi.org/10.1200/JCO.2014.59.0463	DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4979233	PMC

August 2015

High correlation of the Oxford Knee Score with postoperative pain, but not with performance-based functioning.

Authors:

Ruud P van Hove Richard M Brohet Barend J van Royen Peter A Nolte

Knee Surg Sports Traumatol Arthrosc 2016 Oct 29;24(10):3369-3375. Epub 2015 Mar 29.

Department of Orthopaedics, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, Netherlands.

Purpose: The Oxford Knee Score (OKS) is a widely known patient-related outcome measure (PROM) to determine pain and knee functioning before and after total knee arthroplasty (TKA). Self-reported function is mainly influenced by change in pain; therefore, it was hypothesized that the OKS correlates more with pain than with performance-based functioning.

Methods: In a prospective cohort of 88 patients, who had a cementless mobile-bearing TKA, included in a randomized clinical trial, the correlation between the overall OKS, and its subscales for pain (PCS) and function (FCS), with performance-based functioning using the DynaPort Knee Score (DKS), visual analogue scale score for pain (VAS) and the Knee Society Score (KSS) was evaluated. All scores were measured preoperatively, 6 months and 1 year after surgery. Overall change in outcome over time was analysed until 5 years after surgery.

Results: All scores improved over time. The DKS was influenced by sex, preoperative BMI and age. The internal consistency of the OKS PCS increased over time, whereas the OKS FCS remained the same. The mean postoperative OKS FCS showed moderate correlation with the DKS (r = 0.65, p < 0.001), and the mean postoperative OKS and OKS PCS showed high correlation with the VAS (r = -0.79 and r = -0.82, respectively, p < 0.001). The mean postoperative KSS showed high correlations with the OKS (r = 0.80, p < 0.001), the OKS PCS (r = 0.72 p < 0.001) and OKS FCS (r = 0.74, p < 0.001).

Conclusion: The postoperative OKS and the OKS PCS showed high correlation with pain, but only the postoperative OKS FCS was well correlated with performance-based functioning. This suggests that the OKS is more related to pain and tells us less on postoperative functioning. This is important when the OKS as PROM is used to evaluate the quality of orthopaedic care of patients with TKA.

Level Of Evidence: III.

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http://dx.doi.org/10.1007/s00167-015-3585-9	DOI Listing

October 2016

Lynch syndrome caused by germline PMS2 mutations: delineating the cancer risk.

J Clin Oncol 2015 Feb 15;33(4):319-25. Epub 2014 Dec 15.

Sanne W. ten Broeke, Carli M. Tops, Heleen M. van der Klift, Manon Suerink, Frederik J. Hes, Hans F. Vasen, Maartje Nielsen, and Juul T. Wijnen, Leiden University Medical Center; Hans F. Vasen, The Netherlands Foundation for the Detection of Hereditary Tumors, Leiden; Richard M. Brohet, Research Center Linnaeus Institute, Spaarne Hospital, Hoofddorp; Mary E. Velthuizen and Tom G.W. Letteboer, University Medical Center Utrecht, Utrecht; Encarna Gomez Garcia, Maastricht University Medical Center, Maastricht; Nicoline Hoogerbrugge, Arjen R. Mensenkamp, and Liesbeth Spruijt, Radboud University Medical Center, Nijmegen; Fred H. Menko, Vrije Universiteit, University Medical Center; Theo A. van Os and Bert J.W. Redeker, Academic Medical Center, Amsterdam; Rolf H. Sijmons and Yvonne J. Vos, University of Groningen, University Medical Center Groningen, Groningen; Anja Wagner, Erasmus University Medical Center, Rotterdam, the Netherlands; Inge Bernstein, Aalborg University Hospital, Aalborg; Inge Bernstein, Danish Hereditary Nonpolyposis Colorectal Cancer Registry, Hvidovre University Hospital Copenhagen, Denmark; Gabriel Capellá Munar, Hereditary Cancer Program, Catalan Institute of Oncology-Institut D'Investigació Biomèdica de Bellvitge, l'Hospitalet de Llobregat, Spain; Annika Lindblom, Karolinska Institutet, Karolinska University Hospital, Solna; Pal Moller, Research Group Inherited Cancer, Oslo University Hospital, Oslo, Norway; and Nils Rahner, Institute of Human Genetics, University of Dusseldorf, Dusseldorf, Germany.

Purpose: The clinical consequences of PMS2 germline mutations are poorly understood compared with other Lynch-associated mismatch repair gene (MMR) mutations. The aim of this European cohort study was to define the cancer risk faced by PMS2 mutation carriers.

Methods: Data were collected from 98 PMS2 families ascertained from family cancer clinics that included a total of 2,548 family members and 377 proven mutation carriers. To adjust for potential ascertainment bias, a modified segregation analysis model was used to calculate colorectal cancer (CRC) and endometrial cancer (EC) risks. Standardized incidence ratios (SIRs) were calculated to estimate risks for other Lynch syndrome-associated cancers.

Results: The cumulative risk (CR) of CRC for male mutation carriers by age 70 years was 19%. The CR among female carriers was 11% for CRC and 12% for EC. The mean age of CRC development was 52 years, and there was a significant difference in mean age of CRC between the probands (mean, 47 years; range, 26 to 68 years) and other family members with a PMS2 mutation (mean, 58 years; range, 31 to 86 years; P < .001). Significant SIRs were observed for cancers of the small bowel, ovaries, breast, and renal pelvis.

Conclusion: CRC and EC risks were found to be markedly lower than those previously reported for the other MMR. However, these risks embody the isolated risk of carrying a PMS2 mutation, and it should be noted that we observed a substantial variation in cancer phenotype within and between families, suggesting the influence of genetic modifiers and lifestyle factors on cancer risks.

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http://dx.doi.org/10.1200/JCO.2014.57.8088	DOI Listing

February 2015

No clinical benefit of titanium nitride coating in cementless mobile-bearing total knee arthroplasty.

Authors:

Ruud P van Hove Richard M Brohet Barend J van Royen Peter A Nolte

Knee Surg Sports Traumatol Arthrosc 2015 Jun 5;23(6):1833-40. Epub 2014 Oct 5.

Department of Orthopaedics, Spaarne Hospital, Spaarnepoort 1, 2134 TM, Hoofddorp, The Netherlands,

Purpose: Titanium nitride (TiN) coating of cobalt-chromium-molybdenum (CoCrMo) implants has shown to improve the biomechanical properties of the implant surface and to reduce adhesive wear in vitro. It is yet unknown whether TiN coating of total knee prosthesis (TKP) affects the postoperative clinical outcome of total knee arthroplasty (TKA).

Methods: In a double-blind randomized controlled clinical trial, 101 patients received an uncemented mobile-bearing CoCrMo TKP, either TiN coated or uncoated. Primary outcome measure visual analogue scale (VAS) score for pain, and secondary outcome measures Knee Society Score (KSS), revision rate and adverse events, range of motion of the knee as well as knee circumference and knee skin temperature were assessed 6 weeks, 6 months, 1 year and 5 years postoperative. Repeated measures analysis was used to evaluate the postoperative outcome measures over time.

Results: There was no difference between the two groups in VAS score, KSS, revision rate, range of motion of the knee, knee circumference and knee skin temperature. There were no adverse events that could be related to the TiN coating.

Conclusions: TiN-coated TKP does not influence the postoperative outcome of uncemented mobile-bearing TKA regarding postoperative pain, revision rate, range of motion, swelling and temperature of the knee. Therefore, TiN coating of CoCrMo TKP has no clinical benefit on the outcome of cementless mobile-bearing TKA.

Level Of Evidence: Therapeutic study, Level I.

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http://dx.doi.org/10.1007/s00167-014-3359-9	DOI Listing

June 2015

Variation in mutation spectrum partly explains regional differences in the breast cancer risk of female BRCA mutation carriers in the Netherlands.

Cancer Epidemiol Biomarkers Prev 2014 Nov 7;23(11):2482-91. Epub 2014 Aug 7.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Background: We aimed to quantify previously observed relatively high cancer risks in BRCA2 mutation carriers (BRCA2 carriers) older than 60 in the Northern Netherlands, and to analyze whether these could be explained by mutation spectrum or population background risk.

Methods: This consecutive cohort study included all known pathogenic BRCA1/2 carriers in the Northern Netherlands (N = 1,050). Carrier and general reference populations were: BRCA1/2 carriers in the rest of the Netherlands (N = 2,013) and the general population in both regions. Regional differences were assessed with HRs and ORs. HRs were adjusted for birth year and mutation spectrum.

Results: All BRCA1 carriers and BRCA2 carriers younger than 60 had a significantly lower breast cancer risk in the Northern Netherlands; HRs were 0.66 and 0.64, respectively. Above age 60, the breast cancer risk in BRCA2 carriers in the Northern Netherlands was higher than in the rest of the Netherlands [HR, 3.99; 95% confidence interval (CI), 1.11-14.35]. Adjustment for mutational spectrum changed the HRs for BRCA1, BRCA2 <60, and BRCA2 ≥60 years by -3%, +32%, and +11% to 0.75, 0.50, and 2.61, respectively. There was no difference in background breast cancer incidence between the two regions (OR, 1.03; 95% CI, 0.97-1.09).

Conclusions: Differences in mutation spectrum only partly explain the regional differences in breast cancer risk in BRCA2 carriers, and for an even smaller part in BRCA1 carriers.

Impact: The increased risk in BRCA2 carriers older than 60 may warrant extension of intensive breast screening beyond age 60.

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http://dx.doi.org/10.1158/1055-9965.EPI-13-1279	DOI Listing

November 2014

Prevalence of symptomatic rotator cuff ruptures after shoulder trauma: a prospective cohort study.

Authors:

Kars P Valkering Remco D Stokman Taco S Bijlsma Richard M Brohet Arthur van Noort

Eur J Emerg Med 2014 Oct;21(5):349-53

aDepartment of Orthopaedic Surgery, Academic Medical Center, University of Amsterdam bDepartment of Orthopaedic Surgery, Onze Lieve Vrouwe Gasthuis, Amsterdam cDepartment of Trauma Surgery, Medical Center Alkmaar, Alkmaar dGenetic Epidemiologist, Research Center Linnaeus Institute, Spaarne Hospital eDepartment of Orthopedic Surgery, Spaarne Hospital, Hoofddorp, The Netherlands.

Objective: After shoulder trauma, most fractures and dislocations are easily recognized on radiographic examination; however, the opposite is true for rotator cuff injuries. As a consequence, shoulder complaints may persist or arise due to unrecognized cuff injury. The objective of this study was to investigate the prevalence of shoulder pain and symptomatic rotator cuff ruptures 1 year after shoulder trauma without fracture or dislocation.

Patients And Methods: This prospective descriptive study included all the patients presented at our emergency department between January 2007 and January 2008 after a trauma to the shoulder without fracture or dislocation. One year after trauma, this cohort was interviewed by telephone and re-examined at the outpatient clinic on indication.

Results: Of the 217 patients included, all had been pain-free before the trauma. One year after trauma, 69 patients (32%) were still suffering from shoulder pain. Of these patients, 31 were re-examined and 27 had already been re-examined in the meantime. In total, 20 of these 58 patients (34%) were diagnosed with a symptomatic rotator cuff rupture, representing a prevalence of 9% among the included patients.

Conclusion: Emergency physicians should be aware that normal radiography does not exclude the presence of a rotator cuff tear in patients with a history of shoulder trauma. Regular follow-up is essential for discovering rotator cuff injuries. In this study, 32% still suffered from shoulder pain 1 year after shoulder trauma, and re-examination revealed a prevalence of 9% symptomatic rotator cuff ruptures.

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http://dx.doi.org/10.1097/MEJ.0000000000000097	DOI Listing

October 2014

Local infiltration analgesia following total knee arthroplasty: effect on post-operative pain and opioid consumption--a meta-analysis.

Authors:

Renée Keijsers Rogier van Delft Michel P J van den Bekerom Dirk C A A de Vries Richard M Brohet Peter A Nolte

Knee Surg Sports Traumatol Arthrosc 2015 Jul 30;23(7):1956-63. Epub 2013 Nov 30.

Department of Orthopaedic Surgery, Spaarne Hospital, P.O. Box 770, 2130 AT, Hoofddorp, The Netherlands,

Introduction: Local infiltration analgesia (LIA) is a popular method for decreasing post-operative pain after total knee arthroplasty (TKA). The goal of this meta-analysis is to compare the effect of LIA with placebo on the intensity of post-operative pain and the consumption of opioids.

Methods: A search was performed in the PubMed/MEDLINE, Cochrane, EMBASE and TRIP databases. All (quasi)-randomized controlled trials (RCTs) were included. LIA consists of intra-operative infiltration with at least one analgesic component. Data were pooled using Cochrane software.

Results: Seven placebo-controlled RCTs were included, involving 405 TKAs. On the first post-operative day, LIA provides an average decrease in VAS scores at rest of 12.3 % compared to placebo. Six RCTs studied opioid consumption in patients following TKA. There was a decrease in opioid consumption of 14.8 % compared to placebo 24 h after surgery. This suggests a reduced pain perception due to LIA. On the second post-operative day, the effect on both outcome measures was diminished and no longer significant. Heterogeneity between the studies was 71 % for pain and 39 % for opioid consumption (p = 0.002 and p = 0.0005). No major complications were reported with the use of LIA.

Conclusion: LIA might be able to decrease pain and the use of opioids on the first post-operative day following TKA. However, due to the high level of heterogeneity between the studies, no firm conclusions can be drawn.

Level Of Evidence: Meta-analysis, Level II.

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http://dx.doi.org/10.1007/s00167-013-2788-1	DOI Listing

July 2015

Breast and ovarian cancer risks in a large series of clinically ascertained families with a high proportion of BRCA1 and BRCA2 Dutch founder mutations.

J Med Genet 2014 Feb 27;51(2):98-107. Epub 2013 Nov 27.

Department of Epidemiology & Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: BRCA1 or BRCA2 mutations confer increased risks of breast and ovarian cancer, but risks have been found to vary across studies and populations.

Methods: We ascertained pedigree data of 582 BRCA1 and 176 BRCA2 families and studied the variation in breast and ovarian cancer risks using a modified segregation analysis model.

Results: The average cumulative breast cancer risk by age 70 years was estimated to be 45% (95% CI 36 to 52%) for BRCA1 and 27% (95% CI 14 to 38%) for BRCA2 mutation carriers. The corresponding cumulative risks for ovarian cancer were 31% (95% CI 17 to 43%) for BRCA1 and 6% (95% CI 2 to 11%) for BRCA2 mutation carriers. In BRCA1 families, breast cancer relative risk (RR) increased with more recent birth cohort (p heterogeneity = 0.0006) and stronger family histories of breast cancer (p heterogeneity < 0.001). For BRCA1, our data suggest a significant association between the location of the mutation and the ratio of breast to ovarian cancer (p<0.001). By contrast, in BRCA2 families, no evidence was found for risk heterogeneity by birth cohort, family history or mutation location.

Conclusions: BRCA1 mutation carriers conferred lower overall breast and ovarian cancer risks than reported so far, while the estimates of BRCA2 mutations were among the lowest. The low estimates for BRCA1 might be due to older birth cohorts, a moderate family history, or founder mutations located within specific regions of the gene. These results are important for a more accurate counselling of BRCA1/2 mutation carriers.

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http://dx.doi.org/10.1136/jmedgenet-2013-101974	DOI Listing

February 2014

Implantation of resorbable gentamicin sponges in addition to irrigation and debridement in 34 patients with infection complicating total hip arthroplasty.

Authors:

Jesse W P Kuiper Richard M Brohet Sander Wassink Michel P J van den Bekerom Petrus A Nolte Diederik A Vergroesen

Hip Int 2013 Mar-Apr;23(2):173-80. Epub 2013 Jan 22.

Department of Orthopaedics, Spaarne Hospital, Spaarnepoort 1, Hoofddorp, The Netherlands.

We evaluated a prosthesis-retaining treatment protocol for prosthetic joint infection in patients presenting at a mean of 116 days (range 10-1216 days) after primary arthroplasty. Our regime involved irrigation and debridement followed by implantation of biodegradable gentamicin loaded sponges which do not require removal after implantation. Of 34 patients with a deep infection after total hip arthroplasty, Twenty-five were treated successfully, with a mean follow-up of 35 months. There were no permanent complications. This success rate is comparable to earlier studies. Early initiation of treatment demonstrated a tendency for better results, and late chronic infections had a worse outcome. Because the sponges are degradable, a number of further surgical procedures were avoided.

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http://dx.doi.org/10.5301/HIP.2013.10612	DOI Listing

December 2013

Body weight and risk of breast cancer in BRCA1/2 mutation carriers.

Authors:

Peggy Manders Anouk Pijpe Maartje J Hooning Irma Kluijt Hans F A Vasen Nicoline Hoogerbrugge Christi J van Asperen Hanne Meijers-Heijboer Margreet G E M Ausems Theo A van Os Encarna B Gomez-Garcia Richard M Brohet Flora E van Leeuwen Matti A Rookus

Breast Cancer Res Treat 2011 Feb 21;126(1):193-202. Epub 2010 Aug 21.

Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Obesity is an established risk factor for postmenopausal breast cancer in the general population. However, it is still unclear whether this association also exists in BRCA1/2 mutation carriers. We investigated the association between self-reported anthropometric measures and breast cancer risk in a nationwide retrospective cohort study, including 719 BRCA1/2 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. All time-varying Cox proportional hazards analyses were stratified by menopausal status. For premenopausal breast cancer, no statistically significant associations were observed for any of the anthropometric measures. The association between body mass index (BMI) at age 18 and premenopausal breast cancer risk suggested a trend of decreasing risk with increasing BMI (HR(22.50-24.99 vs. 18.50-22.49) = 0.83, 95% CI = 0.47-1.44 and HR(≥ 25.00 vs. 18.50-22.49) = 0.41, 95% CI = 0.13-1.27). For postmenopausal breast cancer, being 1.67 m and taller increased the risk 1.7-fold (HR = 1.67, 95% CI = 1.01-2.74) when compared to a height <1.67 m. Compared with a current body weight < 72 kg, a current body weight of ≥ 72 kg increased the risk of postmenopausal breast cancer 2.1-fold (95% CI = 1.23-3.59). A current BMI of ≥ 25.0 kg/m², an adult weight gain of 5 kg or more, and a relative adult weight gain of 20% or more were all non-significantly associated with a 50-60% increased risk of postmenopausal breast cancer [HR = 1.46 (0.86-2.51), HR = 1.56 (95% CI = 0.85-2.87), and HR = 1.60 (95% CI = 0.97-2.63), respectively], when compared with having a healthy or stable weight. No associations for body weight or BMI at age 18 were observed. In conclusion, menopausal status seemed to modify the association between body weight and breast cancer risk among BRCA1/2 carriers. We observed no clear association between body weight and premenopausal breast cancer, while overweight and weight gain increased postmenopausal breast cancer risk. Carriers may reduce their risk of postmenopausal breast cancer by maintaining a healthy body weight throughout life.

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http://dx.doi.org/10.1007/s10549-010-1120-8	DOI Listing

February 2011

Physical activity and the risk of breast cancer in BRCA1/2 mutation carriers.

Authors:

Anouk Pijpe Peggy Manders Richard M Brohet J Margriet Collée Senno Verhoef Hans F A Vasen Nicoline Hoogerbrugge Christi J van Asperen Charlotte Dommering Margreet G E M Ausems Cora M Aalfs Encarna B Gomez-Garcia Laura J Van't Veer Flora E van Leeuwen Matti A Rookus

Breast Cancer Res Treat 2010 Feb 13;120(1):235-44. Epub 2009 Aug 13.

Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

BRCA1/2 mutation carriers have a high lifetime risk of developing breast cancer. Differences in penetrance indicate that this risk may be influenced by lifestyle factors. Because physical activity is one of the few modifiable risk factors, it may provide a target to add to breast cancer prevention in this high-risk population. We examined the association between self-reported lifetime sports activity and breast cancer risk in a nationwide retrospective cohort study, including 725 carriers, of whom 218 had been diagnosed with breast cancer within 10 years prior to questionnaire completion. We found a nonsignificantly decreased risk for ever engaging in sports activity (HR = 0.84, 95%CI = 0.57-1.24). Among women who had participated in sports, a medium versus low level of intensity and duration (i.e., between 11.0 and 22.7 mean MET hours/week averaged over a lifetime) reduced the risk of breast cancer (HR = 0.59, 95%CI = 0.36-0.95); no dose-response trend was observed. For mean hours/week of sports activity, a nonsignificant trend was observed (HR(low versus never) = 0.93, 95%CI = 0.60-1.43; HR(medium versus never) = 0.81, 95%CI = 0.51-1.29; HR(high versus never) = 0.78, 95%CI = 0.48-1.29; p (trend overall) = 0.272; p (trend active women) = 0.487). For number of years of sports activity no significant associations were found. Among women active in sports before age 30, mean MET hours/week showed the strongest inverse association of all activity measures (HR(medium versus low) = 0.60, 95%CI = 0.38-0.96; HR(high versus low) = 0.58, 95%CI = 0.35-0.94; p (trend) = 0.053). Engaging in sports activity after age 30 was also inversely associated with breast cancer risk (HR = 0.63, 95%CI = 0.44-0.91). Our results indicate that sports activity may reduce the risk of breast cancer in BRCA1/2 mutation carriers.

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http://dx.doi.org/10.1007/s10549-009-0476-0	DOI Listing

February 2010

Chromosome 8q23.3 and 11q23.1 variants modify colorectal cancer risk in Lynch syndrome.

Gastroenterology 2009 Jan 25;136(1):131-7. Epub 2008 Sep 25.

Department of Human Genetics, Leiden University Medical Centre, The Netherlands.

Background & Aims: Recent genome-wide association studies have identified common low-risk variants for colorectal cancer (CRC). To assess whether these influence CRC risk in the Lynch syndrome, we genotyped these variants in a large series of proven mutation carriers.

Methods: We studied 675 individuals from 127 different families from the Dutch Lynch syndrome Registry whose mutation carrier status was known. We genotyped 8q24.21, 8q23.3, 10p14, 11q23.1, 15q13.3, and 18q21.1 variants in carriers of a mismatch repair gene mutation. Univariate and multivariate analysis was used to analyse the association between the presence of a risk variant and CRC risk.

Results: A significant association was found between CRC risk and rs16892766 (8q23.3) and rs3802842 (11q23.1). For rs16892766, possession of the C-allele was associated with an elevated risk of CRC in a dose-dependent fashion, with homozygosity for CC being associated with a 2.16-fold increased risk. For rs3802842, the increased risk of CRC associated with the C-allele was only found among female carriers, while CRC risk was substantially higher among homozygous (hazard ratio [HR] 3.08) than among heterozygous carriers of the C-allele (HR 1.49). In an additive model of both variants, the risk was significantly associated with the number of risk alleles (HR 1.60 for carriers of 2 or more risk alleles). The effects were stronger in female carriers than in male carriers.

Conclusion: We have identified 2 loci that are significantly associated with CRC risk in Lynch syndrome families. These modifiers may be helpful in identifying high-risk individuals who require more intensive surveillance.

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http://dx.doi.org/10.1053/j.gastro.2008.09.033	DOI Listing

January 2009

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.

Authors:

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

J Clin Oncol 2007 Sep 16;25(25):3831-6. Epub 2007 Jul 16.

Netherlands Cancer Institute, Department of Epidemiology, Amsterdam, The Netherlands.

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.

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http://dx.doi.org/10.1200/JCO.2007.11.1179	DOI Listing

September 2007

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