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T Dent,
J Jbilou,
I Rafi,
N Segnan,
S Törnberg,
S Chowdhury,
A Hall,
G Lyratzopoulos,
R Eeles,
D Eccles,
N Hallowell,
N Pashayan, P Pharoah,
H Burton
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ABSTRACT: Background: Improving understanding of the genetic basis of disease susceptibility enables us to estimate individuals' risk of developing cancer and offer them disease prevention, including screening, stratified to reflect that risk. Little attention has so far been given to the implementation of stratified screening. This article reviews the issues that would arise in delivering such tailored approaches to prevention in practice. Results: Issues analysed include the organisational context within which implementation of stratified prevention would occur, how the offer of screening would be made, making sure consent is adequately informed, how individuals' risk would be assessed, the age at which risk estimation should occur, and the potential use of genetic data for other purposes. The review also considers how management might differ depending on individuals' risk, how their results would be communicated and their follow-up arranged, and the different issues raised by modification of an existing screening programme, such as that for breast cancer, and the establishment of a new one, for example for prostate cancer. Conclusion: Stratified screening based on genetic testing is a radically new approach to prevention. Various organisational issues would need to be considered before it could be introduced, and a number of questions require further research.
Public Health Genomics 01/2013; · 2.33 Impact Factor
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ABSTRACT: We modelled the efficiency of a personalised approach to screening for prostate and breast cancer based on age and polygenic risk-profile compared with the standard approach based on age alone.
We compared the number of cases potentially detectable by screening in a population undergoing personalised screening with a population undergoing screening based on age alone. Polygenic disease risk was assumed to have a log-normal relative risk distribution predicted for the currently known prostate or breast cancer susceptibility variants (N=31 and N=18, respectively).
Compared with screening men based on age alone (aged 55-79: 10-year absolute risk ≥2%), personalised screening of men age 45-79 at the same risk threshold would result in 16% fewer men being eligible for screening at a cost of 3% fewer screen-detectable cases, but with added benefit of detecting additional cases in younger men at high risk. Similarly, compared with screening women based on age alone (aged 47-79: 10-year absolute risk ≥2.5%), personalised screening of women age 35-79 at the same risk threshold would result in 24% fewer women being eligible for screening at a cost of 14% fewer screen-detectable cases.
Personalised screening approach could improve the efficiency of screening programmes. This has potential implications on informing public health policy on cancer screening.
British Journal of Cancer 04/2011; 104(10):1656-63. · 5.04 Impact Factor
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ABSTRACT: Breast cancer relative survival (BCRS), which compares the observed survival of women with breast cancer with the expected survival of women for the whole population of the same age, time period, and geographical region, tends to be poorer in older women, but the reasons for this are not clear. We examined the influence of patient and tumour characteristics, and treatment on BCRS to see whether these could explain the age-specific effect.
Data for 14,048 female breast cancer patients diagnosed from 1999 to 2007, aged 50 years or over were obtained from the Eastern Cancer Registration and Information Centre. We estimated relative 5- and 10-year survival for patients in four age groups (50-69, 70-74, 75-79, and 80+ years). We also modelled relative excess mortality (REM) rate using Poisson regression adjusting for patient characteristics and treatment. The REMs derived from these models quantify the extent to which the hazard of death differs from the hazard in the reference category, after taking into account the background risk of death in the general population. We compared the results with those obtained for breast cancer-specific mortality, analysed using multivariate Cox regression.
Median follow-up time was 4.7 years. Relative 5-year survival was 89, 81, 76, and 70% for patients aged 50-69, 70-74, 75-79, and 80+ years, respectively. Corresponding relative 10-year survival was 84, 77, 67, and 66%. Unadjusted REM was 1.93, 2.74, and 3.88 for patients aged 70-74, 75-79, and 80+ years, respectively, (50-69 years as reference). The equivalent hazard ratios from the Cox model were 1.88, 2.45, and 3.81. These were attenuated after adjusting for confounders (REM - 1.49, 1.36, and 1.23; Cox - 1.47, 1.50, and 1.76).
We confirmed poorer BCRS in older women in our region. This was partially explained by known prognostic factors. Further research is needed to determine whether biological differences or suboptimal management can explain the residual excess mortality.
British Journal of Cancer 02/2011; 104(4):564-70. · 5.04 Impact Factor
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K. Bolton,
C. Goh,
S. Ramus,
D. Goldgar,
J. Benitez,
A. Osorio,
D. Easton,
S. Peock,
A. Godwin,
A. Kwong, [......],
L. Sucheston,
M. Montagna,
E. Despierre,
D. Lambrechts,
J. Gross,
C. Walsh,
B. Karlan,
G. Chenvix-Trench,
A. Antoniou, P. Pharoah
102nd annual meeting of the AACR, Orlando, Fl, USA; 01/2011
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S J Dawson,
N Makretsov,
F M Blows,
K E Driver,
E Provenzano,
J Le Quesne,
L Baglietto,
G Severi,
G G Giles,
C A McLean,
G Callagy,
A R Green,
I Ellis,
K Gelmon,
G Turashvili,
S Leung,
S Aparicio,
D Huntsman,
C Caldas, P Pharoah
British Journal of Cancer 09/2010; 103(7):1137. · 5.04 Impact Factor
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S-J Dawson,
N Makretsov,
F M Blows,
K E Driver,
E Provenzano,
J Le Quesne,
L Baglietto,
G Severi,
G G Giles,
C A McLean,
G Callagy,
A R Green,
I Ellis,
K Gelmon,
G Turashvili,
S Leung,
S Aparicio,
D Huntsman,
C Caldas, P Pharoah
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ABSTRACT: Background: Breast cancer is heterogeneous and the existing prognostic classifiers are limited in accuracy, leading to unnecessary treatment of numerous women. B-cell lymphoma 2 (BCL2), an antiapoptotic protein, has been proposed as a prognostic marker, but this effect is considered to relate to oestrogen receptor (ER) status. This study aimed to test the clinical validity of BCL2 as an independent prognostic marker.
British Journal of Cancer 07/2010; 103(5):668-675. · 5.04 Impact Factor
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ABSTRACT: A synonymous single nucleotide polymorphism (SNP) rs172378 (A>G, Gly->Gly) in the complement component C1QA has been proposed to be associated with distant breast cancer metastasis. We previously reported overexpression of this gene to be significantly associated with better prognosis in oestrogen-receptor-negative tumours. The purpose of this study was to investigate the association of rs172378 with expression of C1QA and breast cancer survival.
We analysed the gene expression pattern of rs172378 in normal and tumour tissue samples, and further explored its involvement in relation to mortality in 2270 women with breast cancer participating in Studies of Epidemiology and Risk factors in Cancer Heredity, a population-based case-control study.
We found that although rs172378 showed differential allelic expression significantly different between normal (preferentially expressing the G allele) and tumour tissue samples (preferentially expressing the A allele), there was no significant difference in survival by rs172378 genotype (per allele hazard ratio (HR) 1.02, 95% CI: 0.88-1.19, P=0.78 for all-cause mortality; HR 1.03, 95% CI: 0.87-1.22, P=0.72 for breast-cancer-specific mortality).
Our study results show that rs172378 is linked to a cis-regulatory element affecting gene expression and that allelic preferential expression is altered in tumour samples, but do not support an association between genetic variation in C1QA and breast cancer survival.
British Journal of Cancer 03/2010; 102(8):1294-9. · 5.04 Impact Factor
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ABSTRACT: Several recent studies have shown that screen detection remains an independent prognostic factor after adjusting for disease stage at presentation. This study compares the molecular characteristics of screen-detected with symptomatic breast cancers to identify if differences in tumour biology may explain some of the survival benefit conferred by screen detection.
A total of 1379 women (aged 50-70 years) with invasive breast cancer from a large population-based case-control study were included in the analysis. Individual patient data included tumour size, grade, lymph node status, adjuvant therapy, mammographic screening status and mortality. Immunohistochemistry was performed on tumour samples using 11 primary antibodies to define five molecular subtypes. The effect of screen detection compared with symptomatic diagnosis on survival was estimated after adjustment for grade, nodal status, Nottingham Prognostic Index (NPI) and the molecular markers.
Fifty-six per cent of the survival benefit associated with screen-detected breast cancer was accounted for by a shift in the NPI, a further 3-10% was explained by the biological variables and more than 30% of the effect remained unexplained.
Currently known biomarkers remain limited in their ability to explain the heterogeneity of breast cancer fully. A more complete understanding of the biological profile of breast tumours will be necessary to assess the true impact of tumour biology on the improvement in survival seen with screen detection.
British Journal of Cancer 09/2009; 101(8):1338-44. · 5.04 Impact Factor
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ABSTRACT: This study aimed to assess the mean sojourn time (MST) of prostate cancer, to estimate the probability of overdiagnosis, and to predict the potential reduction in advanced stage disease due to screening with PSA. The MST of prostate cancer was derived from detection rates at PSA prevalence testing in 43,842 men, aged 50-69 years, as part of the ProtecT study, from the incidence of non-screen-detected cases obtained from the English population-based cancer registry database, and from PSA sensitivity obtained from the medical literature. The relative reduction in advanced stage disease was derived from the expected and observed incidences of advanced stage prostate cancer. The age-specific MST for men aged 50-59 and 60-69 years were 11.3 and 12.6 years, respectively. Overdiagnosis estimates increased with age; 10-31% of the PSA-detected cases were estimated to be overdiagnosed. An interscreening interval of 2 years was predicted to result in 37 and 63% reduction in advanced stage disease in men 65-69 and 50-54 years, respectively. If the overdiagnosed cases were excluded, the estimated reductions were 9 and 54%, respectively. Thus, the benefit of screening in reducing advanced stage disease is limited by overdiagnosis, which is greater in older men.
British Journal of Cancer 05/2009; 100(7):1198-204. · 5.04 Impact Factor
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ABSTRACT: We have performed a systematic review and meta-analysis of proliferation markers (Ki-67, mitotic index (MI), proliferating cell nuclear antigen (PCNA) and thymidine or bromodeoxyuridine labelling index (LI)) with respect to survival in early breast cancer. Eighty-five studies involving 32,825 patients were analysed. Ki-67 (43 studies, 15,790 patients), MI (20 studies, 7021 patients), and LI (11 studies, 7337 patients) were associated with significantly shorter overall and disease free survival, using results from univariate and multivariate analyses from the individual studies. PCNA (11 studies, 2677 patients) was associated with shorter overall survival by multivariate analysis only, because of lack of data. There was some evidence for publication bias, but all markers remained significant after allowing for this. Ki-67, MI, PCNA and LI are associated with worse survival outcomes in early breast cancer. However, whether these proliferation markers provide additional prognostic information to commonly used prognostic indices remains unclear.
The Breast 05/2008; 17(4):323-34. · 2.49 Impact Factor
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ABSTRACT: Women (N=21) who had had breast cancer and had been enrolled in a large genetic breast cancer epidemiological study were interviewed about their experience of participation in the study, their attitudes to the confidentiality of data, and the feedback of personal and general research results. Collection of family history information seemed more salient in indicating the genetic nature of the study than the enrolment information sheet. There were no concerns about confidentiality. While participants would have welcomed general feedback about the results of the study and were critical that this had not been provided, the feedback of personal information proved complicated and, sometimes, difficult. It is suggested that individual feedback of genetic test information in epidemiological studies should be undertaken only when there are specific reasons.
Journal of Medical Ethics 05/2003; 29(2):93-6. · 1.36 Impact Factor
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J C Machado, P Pharoah,
S Sousa,
R Carvalho,
C Oliveira,
C Figueiredo,
A Amorim,
R Seruca,
C Caldas,
F Carneiro,
M Sobrinho-Simões
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ABSTRACT: Interleukin (IL)-1 gene cluster proinflammatory polymorphisms have been associated with development of gastric atrophy and with increased risk of gastric carcinoma. We aimed to determine the association between IL-1 loci polymorphisms and increased risk of gastric carcinoma in samples from a Portuguese population, and to find whether there was any relationship with the histologic types of gastric carcinoma.
In a case-control study including 220 controls and 152 patients with gastric carcinoma (intestinal, 76; diffuse, 37; and atypical, 39), both the IL-1B-511 biallelic polymorphism and the IL-1RN penta-allelic variable number of tandem repeats were genotyped.
We found a significant association between the IL-1 polymorphisms and increased risk for tumor development in patients with intestinal-type gastric carcinoma. A trend towards an increased risk of tumor development was also observed in patients with diffuse-type gastric carcinoma. No significant relationship was observed in patients with atypical carcinoma. Carriers of IL-1B-511T and IL-1RN*2 homozygotes had increased risk for developing intestinal-type gastric carcinoma with odds ratios of 2.7 (95% confidence interval [CI], 1.5-4.9) and 3.1 (95% CI, 1.5-6.5), respectively. Statistical analysis showed an interaction between the 2 loci with the risk conferred by the IL-1B-511T allele substantially increased (odds ratio, 9.0; 95% CI, 3.5-23.0) in individuals homozygous for the IL-1RN*2 allele.
Our results provide further support to the association between IL-1 gene cluster proinflammatory polymorphisms and increased risk of gastric carcinoma. Furthermore, we found evidence pointing to the existence of a synergistic interaction between the IL-1B and IL-1RN polymorphisms.
Gastroenterology 10/2001; 121(4):823-9. · 11.68 Impact Factor
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ABSTRACT: Residual disease following primary debulking surgery is a recognized prognostic factor in ovarian cancer. Few studies have looked at the effect of initial ovarian tumor diameter on survival. As larger tumors are more likely to be detected by ultrasound, this information may be important in determining a survival benefit in screen-detected cancers. We reviewed the case notes and pathology of 168 consecutive cases of primary debulking surgery in epithelial ovarian cancer. We examined the influence of ovarian tumor diameter on survival and its relationship to CA125 levels and stage. For the purposes of analyses, we divided subjects into two groups: those with tumors < 6 cm and those with tumors > 6 cm. There were significant differences between the groups, with smaller tumors having more advanced stage disease compared to larger tumors (chi23 = 15.7, P = 0.0013) The median survival for tumors less than or equal to 6 cm was 17months (95% confidence interval [95% CI], 12 to 22), while for tumors greater than 6cm, the median survival was 36 months (95% CI, 13 to 59; logrank test = 8.61, P = 0.003). However, stage is also an important predictor of survival, and in a multivariate analysis, tumor size was not found to be an independent prognostic factor. There was no significant difference between the groups for CA125 levels. As larger diameter ovaries are more likely to be detected by ultrasound, it may be that screen-detected ovarian cancers will show a survival benefit simply because they detect a subset of ovarian cancers that are associated with a better prognosis.
International Journal of Gynecological Cancer 12/2000; 10(6):449-451. · 1.65 Impact Factor
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S A Gayther,
K A de Foy,
P Harrington, P Pharoah,
W D Dunsmuir,
S M Edwards,
C Gillett,
A Ardern-Jones,
D P Dearnaley,
D F Easton,
D Ford,
R J Shearer,
R S Kirby,
A L Dowe,
J Kelly,
M R Stratton,
B A Ponder,
D Barnes,
R A Eeles
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ABSTRACT: Predisposition to prostate cancer has a genetic component, and there are reports of familial clustering of breast and prostate cancer. Two highly penetrant genes that predispose individuals to breast cancer (BRCA1 and BRCA2) are known to confer an increased risk of prostate cancer of about 3-fold and 7-fold, respectively, in breast cancer families. Blood DNA from affected individuals in 38 prostate cancer clusters was analyzed for germ-line mutations in BRCA1 and BRCA2 to assess the contribution of each of these genes to familial prostate cancer. Seventeen DNA samples were each from an affected individual in families with three or more cases of prostate cancer at any age; 20 samples were from one of affected sibling pairs where one was < or = 67 years at diagnosis. No germ-line mutations were found in BRCA1. Two germ-line mutations in BRCA2 were found, and both were seen in individuals whose age at diagnosis was very young (< or = 56 years) and who were members of an affected sibling pair. One is a 4-bp deletion at base 6710 (exon 11) in a man who had prostate cancer at 54 years, and the other is a 2-bp deletion at base 5531 (exon 11) in a man who had prostate cancer at 56 years. In both cases, the wild-type allele was lost in the patient's prostate tumor at the BRCA2 locus. However, intriguingly, in neither case did the affected brother also carry the mutation. Germ-line mutations in BRCA2 may therefore account for about 5% of prostate cancer in familial clusters.
Cancer Research 08/2000; 60(16):4513-8. · 7.86 Impact Factor
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ABSTRACT: To estimate the relative risk and lifetime risk of ovarian cancer in women with various categories of family history.
A meta-analysis of all published case-control and cohort studies.
Pooled relative risk estimates were calculated for the case control studies, using the Mantel-Haenzel method. These estimates were combined with the relative risks from the cohort studies. The pooled estimates of relative risk were used to estimate lifetime risks of ovarian cancer from age 15 up to age 75, for various categories of family history.
Relative risks and lifetime risks of developing ovarian cancer were calculated for the categories of women with 1. an affected first degree relative; 2. an affected mother; 3. an affected sister; and 4. women with more than one affected relative.
The relative risk to first degree relatives is 3.1 (95% CI 2.6-3.7). There is some evidence that this relative risk declines with age. The relative risk to mothers of cases 1.1 (95% CI 0.8-1.6) was lower than the relative risks to sisters: 3.8 (95% CI 2.9-5.1), and daughters: 6.0 (95% CI 3.0-11.9); the explanation of this difference is unclear.
Women with a family history of ovarian cancer have a substantially higher risk of developing ovarian cancer compared with women without such a history. However the risk is small for most categories of family history, except for the small number of individuals who have more than one affected relative.
British Journal of Obstetrics and Gynaecology 06/1998; 105(5):493-9.
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SR Lakhani,
S Manek,
F Penault-Llorca,
A Flanagan,
L Arnout,
S Merrett,
L McGuffog,
D. Steele,
P Devilee,
JGM Klijn, [......],
F Monti,
F. Schmitt,
G Lenoir,
S Seitz,
U Hamman, P Pharoah,
G Lane,
B Ponder,
DT Bishop,
DF Easton
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ABSTRACT: Purpose: Germline mutations in the BRCA1 and BRCA2 genes confer increased susceptibility to ovarian cancer. There is evidence that tumors in carriers may exhibit a distinct distribution of pathological features, but previous studies on the pathology of such tumors have been small. Our aim was to evaluate the morphologies and immunophenotypes in a large cohort of patients with familial ovarian cancer. Experimental Design: We performed a systematic review of ovarian tumors from 178 BRCA1 mutation carriers, 29 BRCA2 mutation carriers, and 235 controls with a similar age distribution. Tumors were evaluated by four pathologists blinded to mutation status. Both morphological features and immunochemical staining for p53 and HER2 were evaluated. Results: Tumors in BRCA1 mutation carriers were more likely than tumors in age-matched controls to be invasive serous adenocarcinomas (odds ratio, 1.84; 95% confidence interval, 1.21-2.79) and unlikely to be borderline or mucinous tumors. Tumors in BRCA1 carriers were of higher grade (P < 0.0001), had a higher percentage solid component (P 0.001), and were more likely to stain strongly for p53 (P = 0.018). The distribution of pathological features in BRCA2 carriers was similar to that in BRCA1 carriers. Conclusions: Use of pathological features can substantially improve the targeting of predictive genetic testing. Results also suggest that BRCA1 and BRCA2 tumors are relatively. aggressive and may be expected to have poor prognosis, although this may be treatment dependent.
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ABSTRACT: Micro-RNAs (miRNAs) are frequently dysregulated in a range of human malignancies, many have been shown to act either as tumour supressors or oncogenes and several have been implicated in breast cancer. However, breast cancer is a diverse disease and little is known about the relationships between miRNA expression, clinical outcome and tumour subtype. We used locked nucleic acid probe in situ hybridization (LNA-ISH) to visualize, in tissue micro-arrays (TMAs) of 2919 formalin-fixed paraffin-embedded (FFPE) archival breast tumours, the expression of two key miRNAs that are frequently lost in a range of solid malignancies, let-7b and miR-205. These miRNAs were also quantified by quantitative reverse transcription PCR in cores of FFPE tissue from 40 of these cases, demonstrating that LNA-ISH is semi-quantitative. The tumours in the TMAs were assigned to subtypes based on their immunohistochemical (IHC) staining with ER, PR, HER2, CK5/6 and EGFR. let-7b expression was shown to be associated with luminal tumours and to have an independent significant positive prognostic value in this group. miR-205 is associated with tumours of ductal morphology and is of significant positive prognostic value within these tumours. We propose that the expression of miR-205 may contribute to ductal tumour morphology.
