Tollenaar, R.A.E.M.

CHEK2*1100delC homozygosity in the Netherlands-prevalence and risk of breast and lung cancer (Article)

2013-05-08T00:00:00Z

The 1100delC mutation in the CHEK2 gene has a carrier frequency of up to 1.5% in individuals from North-West Europe. Women heterozygous for 1100delC have an increased breast cancer risk (odds ratio 2.7). To explore the prevalence and clinical consequences of 1100delC homozygosity in the Netherlands, we genotyped a sporadic breast cancer hospital-based cohort, a group of non-BRCA1/2 breast cancer families, and breast tumors from a tumor tissue bank. Three 1100delC homozygous patients were found in the cohort of 1434 sporadic breast cancer patients, suggesting an increased breast cancer risk for 1100delC homozygotes (odds ratio 3.4, 95% confidence interval 0.4-32.6, P=0.3). Another 1100delC homozygote was found in 592 individuals from 108 non-BRCA1/2 breast cancer families, and two more were found after testing 1706 breast tumors and confirming homozygosity on their wild-type DNA. Follow-up data was available for five homozygous patients, and remarkably, three of them had developed contralateral breast cancer. A possible relationship between 1100delC and lung cancer risk was investigated in 457 unrelated lung cancer patients but could not be confirmed. Due to the small number of 1100delC homozygotes identified, the breast cancer risk estimate associated with this genotype had limited accuracy but is probably higher than the risk in heterozygous females. Screening for CHEK2 1100delC could be beneficial in countries with a relatively high allele frequency.European Journal of Human Genetics advance online publication, 8 May 2013; doi:10.1038/ejhg.2013.85.

Increasing prevalence of comorbidity in patients with colorectal cancer in the South of the Netherlands 1995-2010 (Article)

2013-05-01T00:00:00Z

Comorbidity has large impact on colorectal cancer (CRC) treatment and outcomes and may increase as the population ages. We aimed to evaluate the prevalence and time trends of comorbid diseases in patients with CRC from 1995 to 2010. The Eindhoven Cancer Registry registers comorbidity in all patients with primary CRC in the South of the Netherlands. We analyzed the prevalence of serious comorbid diseases in four time frames from 1995 to 2010. Thereby, we addressed its association with age, gender and socio-economic status (SES). The prevalence of comorbidity was registered in 27,339 patients with primary CRC. During the study period, the prevalence of comorbidity increased from 47% to 62%, multimorbidity increased from 20% to 37%. Hypertension and cardiovascular diseases were most prevalent and increased largely over time (respectively 16-29% and 12-24%). Pulmonary diseases increased in women, but remained stable in men. Average age at diagnosis increased from 68.3 to 69.5 years (p = 0.004). A low SES and male gender were associated with a higher risk of comorbidity (not changing over time). This study indicates that comorbidity among patients with CRC is common, especially in males and patients with a low SES. The prevalence of comorbidity increased from 1995 to 2010, in particular in presumably nutritional diseases. Ageing, increased life expectancy and life style changes may contribute to more comorbid diseases. Also, improved awareness among health care providers on the importance of comorbidity may have resulted in better registration. The increasing burden of comorbidity in patients with CRC emphasizes the need for more focus on individualized medicine. What's new Treating cancer in a patient who also has other diseases or conditions can be challenging, but is not unusual. In this study, the authors looked at comorbidity in patients with colorectal cancer over a period of 16 years, and found it increased over the time frame of the study, particularly hypertension and cardiovascular diseases. Patients with multiple conditions are less likely to respond well to treatment. These data underscore the importance of individualized treatment and awareness of other conditions that are increasingly present alongside the cancer. Copyright

The CARTS study: Chemoradiation therapy for rectal cancer in the distal rectum followed by organ-sparing transanal endoscopic microsurgery (Article)

2011-12-16T00:00:00Z

Background: The CARTS study is a multicenter feasibility study, investigating the role of rectum saving surgery for distal rectal cancer. Methods/Design. Patients with a clinical T1-3 N0 M0 rectal adenocarcinoma below 10 cm from the anal verge will receive neoadjuvant chemoradiation therapy (25 fractions of 2 Gy with concurrent capecitabine). Transanal Endoscopic Microsurgery (TEM) will be performed 8 - 10 weeks after the end of the preoperative treatment depending on the clinical response. Primary objective is to determine the number of patients with a (near) complete pathological response after chemoradiation therapy and TEM. Secondary objectives are the local recurrence rate and quality of life after this combined therapeutic modality. A three-step analysis will be performed after 20, 33 and 55 patients to ensure the feasibility of this treatment protocol. Discussion. The CARTS-study is one of the first prospective multicentre trials to investigate the role of a rectum saving treatment modality using chemoradiation therapy and local excision. The CARTS study is registered at clinicaltrials.gov (NCT01273051).

Common variants of the BRCA1 wild-type allele modify the risk of breast cancer in BRCA1 mutation carriers (Article)

2011-12-01T00:00:00Z

Mutations in the BRCA1 gene substantially increase a woman's lifetime risk of breast cancer. However, there is great variation in this increase in risk with several genetic and non-genetic modifiers identified. The BRCA1 protein plays a central role in DNA repair, a mechanism that is particularly instrumental in safeguarding cells against tumorigenesis. We hypothesized that polymorphisms that alter the expression and/or function of BRCA1 carried on the wild-type (non-mutated) copy of the BRCA1 gene would modify the risk of breast cancer in carriers of BRCA1 mutations. A total of 9874 BRCA1 mutation carriers were available in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) for haplotype analyses of BRCA1. Women carrying the rare allele of single nucleotide polymorphism rs16942 on the wild-type copy of BRCA1 were at decreased risk of breast cancer (hazard ratio 0.86, 95% confidence interval 0.77-0.95, P 5 0.003). Promoter in vitro assays of the major BRCA1 haplotypes showed that common polymorphisms in the regulatory region alter its activity and that this effect may be attributed to the differential binding affinity of nuclear proteins. In conclusion, variants on the wild-type copy of BRCA1 modify risk of breast cancer among carriers of BRCA1 mutations, possibly by altering the efficiency of BRCA1 transcription.

Common alleles at 6q25.1 and 1p11.2 are associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers (Article)

2011-08-01T00:00:00Z

Two single nucleotide polymorphisms (SNPs) at 6q25.1, near the ESR1 gene, have been implicated in the susceptibility to breast cancer for Asian (rs2046210) and European women (rs9397435). A genome-wide association study in Europeans identified two further breast cancer susceptibility variants: rs11249433 at 1p11.2 and rs999737 in RAD51L1 at 14q24.1. Although previously identified breast cancer susceptibility variants have been shown to be associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers, the involvement of these SNPs to breast cancer susceptibility in mutation carriers is currently unknown. To address this, we genotyped these SNPs in BRCA1 and BRCA2 mutation carriers from 42 studies from the Consortium of Investigators of Modifiers of BRCA1/2. In the analysis of 14 123 BRCA1 and 8053 BRCA2 mutation carriers of European ancestry, the 6q25.1 SNPs (r2= 0.14) were independently associated with the risk of breast cancer for BRCA1 mutation carriers [hazard ratio (HR) = 1.17, 95% confidence interval (CI): 1.11-1.23, P-trend = 4.5 × 10-9for rs2046210; HR = 1.28, 95% CI: 1.18-1.40, P-trend = 1.3 × 10-8for rs9397435], but only rs9397435 was associated with the risk for BRCA2 carriers (HR = 1.14, 95% CI: 1.01-1.28, P-trend = 0.031). SNP rs11249433 (1p11.2) was associated with the risk of breast cancer for BRCA2 mutation carriers (HR = 1.09, 95% CI: 1.02-1.17, P-trend = 0.015), but was not associated with breast cancer risk for BRCA1 mutation carriers (HR = 0.97, 95% CI: 0.92-1.02, P-trend = 0.20). SNP rs999737 (RAD51L1) was not associated with breast cancer risk for either BRCA1 or BRCA2 mutation carriers (P-trend = 0.27 and 0.30, respectively). The identification of SNPs at 6q25.1 associated with breast cancer risk for BRCA1 mutation carriers will lead to a better understanding of the biology of tumour development in these women.

The MDM2 Promoter SNP285C/309G Haplotype Diminishes Sp1 Transcription Factor Binding and Reduces Risk for Breast and Ovarian Cancer in Caucasians (Article)

2011-02-15T00:00:00Z

MDM2 plays a key role in modulating p53 function. The MDM2 SNP309T > G promoter polymorphism enhances Sp1 binding and has been linked to cancer risk and young age at diagnosis although with conflicting evidence. We report a second MDM2 promoter polymorphism, SNP285G > C, residing on the SNP309G allele. SNP285C occurs in Caucasians only, where 7.7% (95% CI 7.6%-7.8%) of healthy individuals carry the SNP285C/309G haplotype. In vitro analyses reveals that SNP309G enhances but SNP285C strongly reduces Sp1 promoter binding. Comparing MDM2 promoter status among different cohorts of ovarian (n = 1993) and breast (n = 1973) cancer patients versus healthy controls (n = 3646), SNP285C reduced the risk of both ovarian (OR 0.74; CI 0.58-0.94) and breast cancer (OR 0.79; CI 0.62-1.00) among SNP309G carriers.

Variation in lymph node evaluation in rectal cancer: A Dutch nationwide population-based study (Article)

2011-01-01T00:00:00Z

Background: For adequate staging and subsequent accurate estimation of prognosis, a sufficient number of lymph nodes (LNs) has to be evaluated. This study aimed to identify factors associated with adequate nodal evaluation and to determine its relationship with survival. Methods: Data from all patients with stage I to III rectal carcinoma who underwent surgical treatment and who were diagnosed in the period 2000 to 2006 were retrieved from the Netherlands Cancer Registry. Multilevel logistic analysis was performed to examine the influence of relevant factors on the number of evaluated LNs. Kaplan-Meier and Cox regression analyses were used to analyze the association with overall survival. Results: The number of evaluated LNs was determined for 10,788 (91%) of 11,818 tumors. Median number of evaluated LNs was 7, ranging from 4 to 11 between pathology laboratories. The proportion of patients with positive LNs increased with increasing number of evaluated LNs. Men, younger patients, tumors with deeper invasion and nodal involvement, patients without preoperative radiotherapy who underwent a low anterior resection, and patients whose LNs were evaluated in an academic pathology laboratory were more likely to have ≥12 LNs evaluated. After adding these factors to the model, unexplained variation between pathology laboratories and between hospitals remained. The overall survival increased with increasing number of evaluated LNs. Conclusions: A large variation in LN evaluation among patients with rectal cancer was revealed. Improvement in LN evaluation by both hospitals and pathology laboratories could improve staging, leading to more reliable estimation of prognosis.

Large variation between hospitals and pathology laboratories in lymph node evaluation in colon cancer and its impact on survival, a nationwide population based study in The Netherlands (Article)

2011-01-01T00:00:00Z

Background: Adequate lymph node (LN) evaluation is important for planning treatment in patients with colon cancer. Aims of this study were to identify factors associated with adequate nodal examination and to determine its relationship with stage distribution and survival. Patients and methods: Data from patients with colon carcinoma stages I-III who underwent surgical treatment and diagnosed in the period 2000-2006 were retrieved from the Netherlands Cancer Registry. Multilevel logistic analysis was carried out to examine the influence of relevant factors on the number of evaluated LNs. The relationship with survival was analysed using Cox regression analysis. Results: The number of examined LN was determined for 30 682 of 33 206 tumours. Median number of evaluated LN was 8, ranging from 4 to 15 between pathology laboratories. Females, younger patients, right-sided pN+ tumours with higher pT stage and patients diagnosed in an academic centre were less likely to have nine or less LN evaluated. Unexplained variation between hospitals and pathology laboratories remained, leading to differences in stage distribution. With increasing number of evaluated LN, the risk of death decreased. Conclusion: There was large diversity in nodal examination among patients with colon cancer, leading to differences in stage distribution and being associated with survival.

The ladies trial: Laparoscopic peritoneal lavage or resection for purulent peritonitisA and Hartmann's procedure or resection with primary anastomosis for purulent or faecal peritonitisB in perforated diverticulitis (NTR2037) (Article)

2010-10-20T00:00:00Z

Background: Recently, excellent results are reported on laparoscopic lavage in patients with purulent perforated diverticulitis as an alternative for sigmoidectomy and ostomy. The objective of this study is to determine whether LaparOscopic LAvage and drainage is a safe and effective treatment for patients with purulent peritonitis (LOLA-arm) and to determine the optimal resectional strategy in patients with a purulent or faecal peritonitis (DIVA-arm: perforated DIVerticulitis: sigmoidresection with or without Anastomosis). Methods/Design: In this multicentre randomised trial all patients with perforated diverticulitis are included. Upon laparoscopy, patients with purulent peritonitis are treated with laparoscopic lavage and drainage, Hartmann's procedure or sigmoidectomy with primary anastomosis in a ratio of 2:1:1 (LOLA-arm). Patients with faecal peritonitis will be randomised 1:1 between Hartmann's procedure and resection with primary anastomosis (DIVA-arm). The primary combined endpoint of the LOLA-arm is major morbidity and mortality. A sample size of 132:66:66 patients will be able to detect a difference in the primary endpoint from 25% in resectional groups compared to 10% in the laparoscopic lavage group (two sided alpha = 5%, power = 90%). Endpoint of the DIVA-arm is stoma free survival one year after initial surgery. In this arm 212 patients are needed to significantly demonstrate a difference of 30% (log rank test two sided alpha = 5% and power = 90%) in favour of the patients with resection with primary anastomosis. Secondary endpoints for both arms are the number of days alive and outside the hospital, health related quality of life, health care utilisation and associated costs. Discussion: The Ladies trial is a nationwide multicentre randomised trial on perforated diverticulitis that will provide evidence on the merits of laparoscopic lavage and drainage for purulent generalised peritonitis and on the optimal resectional strategy for both purulent and faecal generalised peritonitis. Trial registration. Nederlands Trial Register NTR2037.

Disparities in quality of care for colon cancer between hospitals in the Netherlands (Article)

2010-09-01T00:00:00Z

Background: Aim of this study was to describe treatment patterns and outcome according to region, and according to hospital types and volumes among patients with colon cancer in the Netherlands. Methods: All patients with invasive colon carcinoma diagnosed in the period 2001-2006 were selected from the Netherlands Cancer Registry. Logistic regression analyses were performed to examine the influence of relevant factors on the odds of having adequate lymph node evaluation, receiving adjuvant chemotherapy and postoperative mortality. Relative survival analysis was used to estimate relative excess risk of dying according to hospital type and volume. Results: In total, 39 907 patients were selected. Patients diagnosed in a university hospital had a higher odds (OR 2.47; 95% CI 2.19-2.78) and patients diagnosed in a hospital with >100 colon carcinoma diagnoses annually had a lower odds (OR 0.70; 95% CI 0.64-0.77) of having ≥10 lymph nodes evaluated. The odds of receiving adjuvant chemotherapy was lower in patients diagnosed in teaching hospitals (OR 0.85; 95% CI 0.73-0.98) and university hospitals (OR 0.56; 95% CI 0.45-0.70) compared to patients diagnosed in non-teaching hospitals. Funnel plots showed large variation in these two outcome measures between individual hospitals. No differences in postoperative mortality were found between hospital types or volumes. Patients diagnosed in university hospitals and patients diagnosed in hospitals with >50 diagnoses of colon carcinoma per year had a better survival. Conclusions: Variation in treatment and outcome of patients with colon cancer in the Netherlands was revealed, with differences between hospital types and volumes. However, variation seemed mainly based on the level of the individual hospital.

Variation in treatment and outcome of patients with rectal cancer by region, hospital type and volume in the Netherlands (Article)

2010-09-01T00:00:00Z

Background: Aim of this study was to describe treatment patterns and outcome according to region and hospital type and volume among patients with rectal cancer in the Netherlands. Methods: All patients with rectal carcinoma diagnosed in the period 2001-2006 were selected from the Netherlands Cancer Registry. Logistic regression analyses were performed to examine the influence of relevant factors on the odds of receiving preoperative radiotherapy and on the odds of postoperative mortality. Relative survival analysis was used to estimate relative excess risk of dying according to hospital type and volume. Results: In total, 16 039 patients were selected. Patients diagnosed in a teaching or university hospital had a lower odds (OR 0.85; 95% CI 0.73-0.99 and OR 0.70; 95% CI 0.52-0.92) and patients diagnosed in a hospital performing >50 resections per year had a higher odds (OR 1.95; 95% CI 1.09-1.76) of receiving preoperative radiotherapy. A large variation between individual hospitals in rates of preoperative radiotherapy and between Comprehensive Cancer Centre-regions in the administration of preoperative chemoradiation was revealed. Postoperative mortality was not correlated to hospital type or volume. Patients with T1-M0 tumours diagnosed in a hospital with >50 resections per year had a better survival compared to patients diagnosed in a hospital with <25 resections per year (RER 0.11; 95% CI 0.02-0.78). Conclusion: This study demonstrated variation in treatment and outcome of patients with rectal cancer in the Netherlands, with differences related to hospital volume and hospitals teaching or academic status. However, variation in treatment patterns between individual hospitals proved to be much larger than could be explained by the investigated characteristics. Future studies should focus on the reasons behind these differences, which could lead to a higher proportion of patients receiving optimal treatment for their stage of the disease.

Missense variants in ATM in 26,101 breast cancer cases and 29,842 controls (Article)

2010-09-01T00:00:00Z

Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend= 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23; Ptrend= 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility.

Association between a germline OCA2 polymorphism at chromosome 15q13.1 and estrogen receptor-negative breast cancer survival (Article)

2010-05-01T00:00:00Z

Background Traditional prognostic factors for survival and treatment response of patients with breast cancer do not fully account for observed survival variation. We used available genotype data from a previously conducted two-stage, breast cancer susceptibility genome-wide association study (ie, Studies of Epidemiology and Risk factors in Cancer Heredity [SEARCH]) to investigate associations between variation in germline DNA and overall survival. MethodsWe evaluated possible associations between overall survival after a breast cancer diagnosis and 10621 germline single-nucleotide polymorphisms (SNPs) from up to 3761 patients with invasive breast cancer (including 647 deaths and 26978 person-years at risk) that were genotyped previously in the SEARCH study with high-density oligonucleotide microarrays (ie, hypothesis-generating set). Associations with all-cause mortality were assessed for each SNP by use of Cox regression analysis, generating a per rare allele hazard ratio (HR). To validate putative associations, we used patient genotype information that had been obtained with 5′ nuclease assay or mass spectrometry and overall survival information for up to 14096 patients with invasive breast cancer (including 2303 deaths and 70019 person-years at risk) from 15 international case-control studies (ie, validation set). Fixed-effects meta-analysis was used to generate an overall effect estimate in the validation dataset and in combined SEARCH and validation datasets. All statistical tests were two-sided. ResultsIn the hypothesis-generating dataset, SNP rs4778137 (C>G) of the OCA2 gene at 15q13.1 was statistically significantly associated with overall survival among patients with estrogen receptor-negative tumors, with the rare G allele being associated with increased overall survival (HR of death per rare allele carried = 0.56, 95% confidence interval [CI] = 0.41 to 0.75, P = 9.2 × 10-5). This association was also observed in the validation dataset (HR of death per rare allele carried = 0.88, 95% CI = 0.78 to 0.99, P =. 03) and in the combined dataset (HR of death per rare allele carried = 0.82, 95% CI = 0.73 to 0.92, P = 5 × 10-4). Conclusion The rare G allele of the OCA2 polymorphism, rs4778137, may be associated with improved overall survival among patients with estrogen receptor-negative breast cancer.

Variation in Lymph Node Evaluation in Rectal Cancer: A Dutch Nationwide Population-Based Study (Article)

2010-01-01T00:00:00Z

Centralization of Esophageal Cancer Surgery: Does It Improve Clinical Outcome? (Article)

2009-07-01T00:00:00Z

Background: The volume-outcome relationship for complex surgical procedures has been extensively studied. Most studies are based on administrative data and use in-hospital mortality as the sole outcome measure. It is still unknown if concentration of these procedures leads to improvement of clinical outcome. The aim of our study was to audit the process and effect of centralizing oesophageal resections for cancer by using detailed clinical data. Methods: From January 1990 until December 2004, 555 esophagectomies for cancer were performed in 11 hospitals in the region of the Comprehensive Cancer Center West (CCCW); 342 patients were operated on before and 213 patients after the introduction of a centralization project. In this project patients were referred to the hospitals which showed superior outcomes in a regional audit. In this audit patient, tumor, and operative details as well as clinical outcome were compared between hospitals. The outcome of both cohorts, patients operated on before and after the start of the project, were evaluated. Results: Despite the more severe comorbidity of the patient group, outcome improved after centralizing esophageal resections. Along with a reduction in postoperative morbidity and length of stay, mortality fell from 12% to 4% and survival improved significantly (P = 0.001). The hospitals with the highest procedural volume showed the biggest improvement in outcome. Conclusion: Volume is an important determinant of quality of care in esophageal cancer surgery. Referral of patients with esophageal cancer to surgical units with adequate experience and superior outcomes (outcome-based referral) improves quality of care.

Risk of estrogen receptor-positive and -negative breast cancer and single-nucleotide polymorphism 2q35-rs13387042 (Article)

2009-07-01T00:00:00Z

BackgroundA recent genome-wide association study identified single-nucleotide polymorphism (SNP) 2q35-rs13387042 as a marker of susceptibility to estrogen receptor (ER)-positive breast cancer. We attempted to confirm this association using the Breast Cancer Association Consortium.Methods2q35-rs13387042 SNP was genotyped for 31 510 women with invasive breast cancer, 1101 women with ductal carcinoma in situ, and 35 969 female control subjects from 25 studies. Odds ratios (ORs) were estimated by logistic regression, adjusted for study. Heterogeneity in odds ratios by each of age, ethnicity, and study was assessed by fitting interaction terms. Heterogeneity by each of invasiveness, family history, bilaterality, and hormone receptor status was assessed by subclassifying case patients and applying polytomous logistic regression. All statistical tests were two-sided.ResultsWe found strong evidence of association between rs13387042 and breast cancer in white women of European origin (per-allele OR = 1.12, 95% confidence interval [CI] = 1.09 to 1.15; Ptrend = 1.0 × 10-19). The odds ratio was lower than that previously reported (P =. 02) and did not vary by age or ethnicity (all P ≥. 2). However, it was higher when the analysis was restricted to case patients who were selected for a strong family history (P = .02). An association was observed for both ER-positive (OR = 1.14, 95% CI = 1.10 to 1.17; P = 10-15) and ER-negative disease (OR = 1.10, 95% CI = 1.04 to 1.15; P =. 0003) and both progesterone receptor (PR)-positive (OR = 1.15, 95% CI = 1.11 to 1.19; P = 5 × 10-14) and PR-negative disease (OR = 1.10, 95% CI = 1.06 to 1.15; P =. 00002).ConclusionThe rs13387042 is associated with both ER-positive and ER-negative breast cancer in European women.

Newly discovered breast cancer susceptibility loci on 3p24 and 17q23.2 (Article)

2009-05-01T00:00:00Z

Genome-wide association studies (GWAS) have identified seven breast cancer susceptibility loci, but these explain only a small fraction of the familial risk of the disease. Five of these loci were identified through a two-stage GWAS involving 390 familial cases and 364 controls in the first stage, and 3,990 cases and 3,916 controls in the second stage. To identify additional loci, we tested over 800 promising associations from this GWAS in a further two stages involving 37,012 cases and 40,069 controls from 33 studies in the CGEMS collaboration and Breast Cancer Association Consortium. We found strong evidence for additional susceptibility loci on 3p (rs4973768: per-allele OR = 1.11, 95% CI = 1.08-1.13, P = 4.1 Ã 10-23) and 17q (rs6504950: per-allele OR = 0.95, 95% CI = 0.92-0.97, P = 1.4 Ã 10-8). Potential causative genes include SLC4A7 and NEK10 on 3p and COX11 on 17q.

Five polymorphisms and breast cancer risk: Results from the breast cancer association consortium (Article)

2009-05-01T00:00:00Z

Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small sample size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5%; TNF 1.00 (0.95-1.06), 5.0%; CASP10 1.02 (0.98-1.07), 6.5%; PGR 1.02 (0.99-1.06), 15.3%; and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. Copyright

A family history of breast cancer will not predict female early onset breast cancer in a population-based setting (Article)

2008-07-23T00:00:00Z

Background: An increased risk of breast cancer for relatives of breast cancer patients has been demonstrated in many studies, and having a relative diagnosed with breast cancer at an early age is an indication for breast cancer screening. This indication has been derived from estimates based on data from cancer-prone families or from BRCA1/2 mutation families, and might be biased because BRCA1/2 mutations explain only a small proportion of the familial clustering of breast cancer. The aim of the current study was to determine the predictive value of a family history of cancer with regard to early onset of female breast cancer in a population based setting. Methods: An unselected sample of 1,987 women with and without breast cancer was studied with regard to the age of diagnosis of breast cancer. Results: The risk of early-onset breast cancer was increased when there were: (1) at least 2 cases of female breast cancer in first-degree relatives (yes/no; HR at age 30: 3.09; 95% CI: 128-7.44), (2) at least 2 cases of female breast cancer in first or second-degree relatives under the age of 50 (yes/no; HR at age 30: 3.36; 95% CI: 1.12-10.08), (3) at least 1 case of female breast cancer under the age of 40 in a first- or second-degree relative (yes/no; HR at age 30: 2.06; 95% CI: 0.83-5.12) and (4) any case of bilateral breast cancer (yes/no; HR at age 30: 3.47; 95%: 1.33-9.05). The positive predictive value of having 2 or more of these characteristics was 13% for breast cancer before the age of 70, 11% for breast cancer before the age of 50, and 1% for breast cancer before the age of 30. Conclusion: Applying family history related criteria in an unselected population could result in the screening of many women who will not develop breast cancer at an early age.

Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics (Article)

2008-04-01T00:00:00Z

A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10-13). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10-5, 10-8, 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10-4, respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.

Progression and tumor heterogeneity analysis in early rectal cancer (Article)

2008-02-01T00:00:00Z

Purpose: Adequate preoperative staging of large sessile rectal tumors requires identifying adenomas that already contain an invasive focus, specifically those that are growing in or beyond the submucosa. We systematically compared chromosomal instability patterns in adenoma and carcinoma fractions of the same lesion to assess specific steps in rectal tumor progression. Experimental Design: We analyzed 36 formalin-fixed, paraffin-embedded tumors. Both the adenoma and carcinoma fractions were typed with single nucleotide polymorphism arrays and compared with 21 previously described pure adenomas. Eighteen cases were included in an intratumor heterogeneity analysis. Results: Five specific "malignant" events (gain of 8q, 13q, and 20q and loss of 17p and 18q) and aberrant staining for p53 and SMAD4 were all increased in the adenoma fractions of carcinoma cases compared with pure adenomas. Paired analysis revealed that 31% of the samples had an equal amount of malignant aberrations in their adenoma and carcinoma fractions, whereas 25% had one and 33% had two or more extra malignant events in the carcinoma fraction. Analysis of three core biopsies per patient showed a large degree of intratumor heterogeneity. However, the number of malignant aberrations in the biopsy with the most aberrations per tumor correlated with the corresponding adenoma or carcinoma fraction (r = 0.807; P < 0.001). Conclusion: Five specific chromosomal aberrations, combined with immunohistochemistry for p53 and SMAD4, can predict possible progression of sessile rectal adenomas to early rectal cancer and can, after validation studies, be added to preoperative staging. Preferably, three biopsies should be taken from each tumor to address intratumor heterogeneity.

High-volume versus low-volume for esophageal resections for cancer: The essential role of case-mix adjustments based on clinical data (Article)

2008-01-01T00:00:00Z

Background: Most studies addressing the volume-outcome relationship in complex surgical procedures use hospital mortality as the sole outcome measure and are rarely based on detailed clinical data. The lack of reliable information about comorbidities and tumor stages makes the conclusions of these studies debatable. The purpose of this study was to compare outcomes for esophageal resections for cancer in low- versus high-volume hospitals, using an extensive set of variables concerning case-mix and outcome measures, including long-term survival. Methods: Clinical data, from 903 esophageal resections performed between January 1990 and December 1999, were retrieved from the original patients' files. Three hundred and forty-two patients were operated on in 11 low-volume hospitals (<7 resections/year) and 561 in a single high-volume center. Results: Mortality and morbidity rates were significantly lower in the high-volume center, which had an in-hospital mortality of 5 vs 13% (P < .001). On multivariate analysis, hospital volume, but also the presence of comorbidity proved to be strong prognostic factors predicting in-hospital mortality (ORs 3.05 and 2.34). For stage I and II disease, there was a significantly better 5-year survival in the high-volume center. (P = .04). Conclusions: Hospital volume and comorbidity patterns are important determinants of outcome in esophageal cancer surgery. Strong clinical endpoints such as in-hospital mortality and survival can be used as performance indicators, only if they are joined by reliable case-mix information.

Quality of life after transanal endoscopic microsurgery and total mesorectal excision in early rectal cancer (Article)

2007-07-01T00:00:00Z

Objective: Total mesorectal excision (TME) is the gold standard in rectal cancer, if curation is intended. Transanal endoscopic microsurgery (TEM) is a much safer technique and seems to have comparable survival in early rectal cancer. The impact of both procedures on quality of life has never been compared. In this study we compared quality of life after TEM and TME. Method: Fifty-four patients underwent TEM for a T1 carcinoma. Only patients without known locoregional or distant recurrences were included, resulting in 36 eligible patients in whom quality of life after TEM was studied. The questionnaires used included the EuroQol EQ-5D, EQ-VAS, EORTC QLQ-C30 and EORTC QLQ-CR38. The results were compared with a sex-and age-matched sample of T+N0 rectal cancer patients who had undergone sphincter saving surgery by TME and a sex- and age matched community-based sample of healthy persons. Result: Thirty-one patients after TEM returned completed questionnaires (overall response rate 86%). Quality of life was compared with 31 TME patients and 31 healthy controls. From the patients' and social perspective quality of life did not differ between the three groups. Compared with TEM, significant defecation problems were seen after TME (P < 0.05). A trend towards better sexual functioning after TEM, compared with TME, was seen, especially in male patients, although it did not reach statistical significance. Conclusion: Transanal endoscopic microsurgery and TME do not seem to differ in quality of life postoperatively, but defecation disorders are more frequently encountered after TME. This difference could play a role in the choice of surgical therapy in (early) rectal cancer. Further prospective studies are needed to confirm our conclusions.

Genome-wide association study identifies novel breast cancer susceptibility loci (Article)

2007-06-28T00:00:00Z

Breast cancer exhibits familial aggregation, consistent with variation in genetic susceptibility to the disease. Known susceptibility genes account for less than 25% of the familial risk of breast cancer, and the residual genetic variance is likely to be due to variants conferring more moderate risks. To identify further susceptibility alleles, we conducted a two-stage genome-wide association study in 4,398 breast cancer cases and 4,316 controls, followed by a third stage in which 30 single nucleotide polymorphisms (SNPs) were tested for confirmation in 21,860 cases and 22,578 controls from 22 studies. We used 227,876 SNPs that were estimated to correlate with 77% of known common SNPs in Europeans at r2> 0.5. SNPs in five novel independent loci exhibited strong and consistent evidence of association with breast cancer (P < 10-7). Four of these contain plausible causative genes (FGFR2, TNRC9, MAP3K1 and LSP1). At the second stage, 1,792 SNPs were significant at the P < 0.05 level compared with an estimated 1,343 that would be expected by chance, indicating that many additional common susceptibility alleles may be identifiable by this approach.

Tumor characteristics and detection method in the MRISC screening program for the early detection of hereditary breast cancer (Article)

2007-05-01T00:00:00Z

In the MRISC study, women with an inherited risk for breast cancer were screened by a 6-month clinical breast examination (CBE) and yearly MRI and mammography. We found that the MRISC screening scheme could facilitate early breast cancer diagnosis and that MRI was a more sensitive screening method than mammography, but less specific. In the current study we investigated the contribution of MRI in the early detection of breast cancer in relation to tumor characteristics. From November 1999 to October 2003, 1909 women were included and 50 breast cancers were detected, of which 45 were evaluable and included in the current study. We compared the characteristics of tumors detected by MRI-only with those of all other (non-palpable) screen-detected tumors. Further, we compared the sensitivity of mammography and MRI within subgroups according to different tumor characteristics. Twenty-two (49%) of the 45 breast cancers were detected by MRI and not visible at mammography, of which 20 (44%) were also not palpable (MRI-only detected tumors). MRI-only detected tumors were more often node-negative than other screen-detected cancers (94 vs. 59%; P = 0.02) and tended to be more often ≤1 cm (58 vs. 31%; P = 0.11). MRI was more sensitive than mammography for a wide spectrum of invasive tumor characteristics i.e., size, nodal status, histology, grade and ER status. Half of the breast cancers detected in this study were visible by MRI only and these tumors were smaller and significantly more often node-negative than other screen-detected tumors, suggesting that MRI makes an important contribution to the early detection of hereditary breast cancer.

Efficacy of MRI and mammography for breast-cancer screening in women with a familial or genetic predisposition (Article)

2004-01-01T00:00:00Z

BACKGROUND: The value of regular surveillance for breast cancer in women with a genetic or familial predisposition to breast cancer is currently unproven. We compared the efficacy of magnetic resonance imaging (MRI) with that of mammography for screening in this group of high-risk women. METHODS: Women who had a cumulative lifetime risk of breast cancer of 15 percent or more were screened every six months with a clinical breast examination and once a year by mammography and MRI, with independent readings. The characteristics of the cancers that were detected were compared with the characteristics of those in two different age-matched control groups. RESULTS: We screened 1909 eligible women, including 358 carriers of germ-line mutations. Within a median follow-up period of 2.9 years, 51 tumors (44 invasive cancers, 6 ductal carcinomas in situ, and 1 lymphoma) and 1 lobular carcinoma in situ were detected. The sensitivity of clinical breast examination, mammography, and MRI for detecting invasive breast cancer was 17.9 percent, 33.3 percent, and 79.5 percent, respectively, and the specificity was 98.1 percent, 95.0 percent, and 89.8 percent, respectively. The overall discriminating capacity of MRI was significantly better than that of mammography (P<0.05). The proportion of invasive tumors that were 10 mm or less in diameter was significantly greater in our surveillance group (43.2 percent) than in either control group (14.0 percent [P<0.001] and 12.5 percent [P=0.04], respectively). The combined incidence of positive axillary nodes and micrometastases in invasive cancers in our study was 21.4 percent, as compared with 52.4 percent (P<0.001) and 56.4 percent (P=0.001) in the two control groups. CONCLUSIONS: MRI appears to be more sensitive than mammography in detecting tumors in women with an inherited susceptibility to breast cancer.