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R Eeles

Publications and source records attributed to R Eeles.

At least 19 recordsLinked to original sources
PubMed2006

Diversity of TMPRSS2-ERG fusion transcripts in the human prostate.

TMPRSS2-ERG gene fusions have recently been reported to be present in a high proportion of human prostate cancers. In the current study, we show that great diversity exists in the precise structure of TMPRSS2-ERG hybrid transcripts found in human prostates. Fourteen distinct hybrid transcripts are characterized, each containing different combinations of sequences from the TMPRSS2 and ERG genes. The transcripts include two that are predicted to encode a normal full-length ERG protein, six that encode N-terminal truncated ERG proteins and one that encodes a TMPRSS2-ERG fusion protein. Interestingly, distinct patterns of hybrid transcripts were found in samples taken from separate regions of individual cancer-containing prostates, suggesting that TMPRSS2-ERG gene fusions may be arising independently in different regions of a single prostate.

Gene Expression Regulation, Neoplastic↗
PubMed2006

Cost-effectiveness of screening with contrast enhanced magnetic resonance imaging vs X-ray mammography of women at a high familial risk of breast cancer.

Contrast enhanced magnetic resonance imaging (CE MRI) is the most sensitive tool for screening women who are at high familial risk of breast cancer. Our aim in this study was to assess the cost-effectiveness of X-ray mammography (XRM), CE MRI or both strategies combined. In total, 649 women were enrolled in the MARIBS study and screened with both CE MRI and mammography resulting in 1881 screens and 1-7 individual annual screening events. Women aged 35-49 years at high risk of breast cancer, either because they have a strong family history of breast cancer or are tested carriers of a BRCA1, BRCA2 or TP53 mutation or are at a 50% risk of having inherited such a mutation, were recruited from 22 centres and offered annual MRI and XRM for between 2 and 7 years. Information on the number and type of further investigations was collected and specifically calculated unit costs were used to calculate the incremental cost per cancer detected. The numbers of cancer detected was 13 for mammography, 27 for CE MRI and 33 for mammography and CE MRI combined. In the subgroup of BRCA1 (BRCA2) mutation carriers or of women having a first degree relative with a mutation in BRCA1 (BRCA2) corresponding numbers were 3 (6), 12 (7) and 12 (11), respectively. For all women, the incremental cost per cancer detected with CE MRI and mammography combined was pound28 284 compared to mammography. When only BRCA1 or the BRCA2 groups were considered, this cost would be reduced to pound11 731 (CE MRI vs mammography) and pound15 302 (CE MRI and mammography vs mammography). Results were most sensitive to the unit cost estimate for a CE MRI screening test. Contrast-enhanced MRI might be a cost-effective screening modality for women at high risk, particularly for the BRCA1 and BRCA2 subgroups. Further work is needed to assess the impact of screening on mortality and health-related quality of life.

Adult↗
PubMed2006

Clinical outcome and service implications of screening women at increased breast cancer risk from a family history.

INTRODUCTION: The value of special screening for women at moderate breast cancer risk with a family history of breast cancer remains controversial. Little is known about recall rates, false negative outcomes and the impact on clinical service. Despite this, surveillance programmes within breast units have been established in the United Kingdom. PATIENTS AND METHODS: In our institution, screening of women at moderate (lifetime risk, 17-30%) and high risk (>30%) consisted of annual clinical examination and mammography from the age of 35 years. The active study period ran for four months and each patient was followed through a further screening cycle (whole study period), providing information on interval cancers and detection at the subsequent screen. RESULTS: One thousand one hundred and thirty-two women attended for their incident screen: 137 at high risk, 803 at moderate risk and 192 at standard risk. The median age at cancer diagnosis in the moderate risk group was 54 (range, 45-68) years and the high-risk group 51 (46-52) years, compared to 63 (45-69) years in the standard risk group. Seven cancers were diagnosed during the four-month active study period. Two patients were diagnosed with interval cancers and eight at the next screen, giving a cancer incidence in the whole study period of 17/1132 (1.5%). Thirteen patients had invasive cancer and four had ductal carcinoma in situ (DCIS) The median invasive tumour size was 15 had (range, 7-28)mm and the median DCIS size was 4 (2-30)mm. 10/13 (76.9%) invasive cancers were < or =20mm and 2/13 patients (15.4%) with invasive cancer were lymph node positive. The sensitivity and specificity of mammography were 85.7% and 98.8%, respectively. The mammogram recall rate was 27.6 per 1000. The benign to malignant surgery ratio was 8:17. CONCLUSION: Screening women at increased breast cancer risk is effective. Early detection and recall rates are comparable to that of older women attending the British National Breast Screening Programme.

Adult↗
PubMed2006

The feasibility and results of a population-based approach to evaluating prostate-specific antigen screening for prostate cancer in men with a raised familial risk.

The feasibility of a population-based evaluation of screening for prostate cancer in men with a raised familial risk was investigated by studying reasons for non-participation and uptake rates according to postal recruitment and clinic contact. The levels of prostate-specific antigen (PSA) and the positive predictive values (PPV) for cancer in men referred with a raised PSA and in those biopsied were analysed. First-degree male relatives (FDRs) were identified through index cases (ICs): patients living in two regions of England and diagnosed with prostate cancer at age < or =65 years from 1998 to 2004. First-degree relatives were eligible if they were aged 45-69 years, living in the UK and had no prior diagnosis of prostate cancer. Postal recruitment was low (45 of 1687 ICs agreed to their FDR being contacted: 2.7%) but this was partly due to ICs not having eligible FDRs. A third of ICs in clinic had eligible FDRs and 49% (192 out of 389) agreed to their FDR(s) being contacted. Of 220 eligible FDRs who initially consented, 170 (77.3%) had a new PSA test taken and 32 (14.5%) provided a previous PSA result. Among the 170 PSA tests, 10% (17) were > or =4 ng ml(-1) and 13.5% (23) tests above the age-related cutoffs. In 21 men referred, five were diagnosed with prostate cancer (PPV 24%; 95% CI 8, 47). To study further the effects of screening, patients with a raised familial risk should be counselled in clinic about screening of relatives and data routinely recorded so that the effects of screening on high-risk groups can be studied.

Age of Onset↗
PubMed2006

Feasibility of familial PSA screening: psychosocial issues and screening adherence.

This study examined factors that predict psychological morbidity and screening adherence in first-degree relatives (FDRs) taking part in a familial PSA screening study. Prostate cancer patients (index cases - ICs) who gave consent for their FDRs to be contacted for a familial PSA screening study to contact their FDRs were also asked permission to invite these FDRs into a linked psychosocial study. Participants were assessed on measures of psychological morbidity (including the General Health Questionnaire; Cancer Worry Scale; Health Anxiety Questionnaire; Impact of Events Scale); and perceived benefits and barriers, knowledge; perceived risk/susceptibility; family history; and socio-demographics. Of 255 ICs, 155 (61%) consented to their FDRs being contacted. Of 207 FDRs approached, 128 (62%) consented and completed questionnaires. Multivariate logistic regression revealed that health anxiety, perceived risk and subjective stress predicted higher cancer worry (P = 0.05). Measures of psychological morbidity did not predict screening adherence. Only past screening behaviour reliably predicted adherence to familial screening (P = 0.05). First-degree relatives entering the linked familial PSA screening programme do not, in general, have high levels of psychological morbidity. However, a small number of men exhibited psychological distress.

Aged↗
PubMed2006

Increased level of chromosomal damage after irradiation of lymphocytes from BRCA1 mutation carriers.

Deleterious mutations in the BRCA1 gene predispose women to an increased risk of breast and ovarian cancer. Many functional studies have suggested that BRCA1 has a role in DNA damage repair and failure in the DNA damage response pathway often leads to the accumulation of chromosomal aberrations. Here, we have compared normal lymphocytes with those heterozygous for a BRCA1 mutation. Short-term cultures were irradiated (8Gy) using a high dose rate and subsequently metaphases were analysed by 24-colour chromosome painting (M-FISH). We scored the chromosomal rearrangements in the metaphases from five BRCA1 mutation carriers and from five noncarrier control samples 6 days after irradiation. A significantly higher level of chromosomal damage was detected in the lymphocytes heterozygous for BRCA1 mutations compared with normal controls; the average number of aberrations per mitosis was 3.48 compared with 1.62 in controls (P=0.0001). This provides new evidence that heterozygous mutation carriers have a different response to DNA damage compared with noncarriers and that BRCA1 has a role in DNA damage surveillance. Our finding has implications for treatment and screening of BRCA1 mutation carriers using modalities that involve irradiation.

Chromosome Aberrations↗
PubMed2006

Radiotherapy and genetic predisposition to breast cancer.

Cancer genetics is becoming increasingly integrated into oncological care; particularly in breast cancer management. The recognition of monogenic breast cancer predisposition syndromes, such as BRCA, is critical as there is also a risk of other cancers in addition to a markedly elevated risk of contralateral breast cancer. In individuals with breast cancer due to some predisposition genes, radiation should be avoided, e.g. the ATM and TP53 genes, but there is still controversy as to whether radiation should be used in BRCA1/2 mutation carriers and more follow-up is needed. There are some radiation-sensitive genetic conditions where, if breast cancer occurs (as it may occur in any individual, not necessarily due to an increased risk associated with the condition), radiation should be avoided. These conditions are often associated with dysmorphic features. If such features are noticed then the advice of a geneticist should be sought urgently prior to giving radiation.

Breast Neoplasms↗
PubMed2005

Construction of tissue microarrays from prostate needle biopsy specimens.

Needle biopsies are taken as standard diagnostic specimens for many cancers, but no technique exists for the high-throughput analysis of multiple individual immunohistochemical (IHC) markers using these samples. Here we present a simple and highly reliable technique for constructing tissue microarrays (TMAs) from prostatic needle biopsies. Serial sectioning of the TMAs, called 'Checkerboard TMAs', facilitated expression analysis of multiple proteins using IHC markers. In total, 100% of the analysed biopsies within the TMA both preserved their antigenicity and maintained their morphology. Checkerboard TMAs will allow the use of needle biopsies (i) alongside other tissue specimens (trans-urethral resection of prostates and prostatectomies in the case of prostate cancer) in clinical correlation studies when searching for new prognostic markers, and (ii) in a diagnostic context for assessing expression of multiple proteins in cancers from patients prior to treatment.

Biopsy, Needle↗
PubMed2005

Association between polymorphisms of the GPX1 gene and second primary tumours after index squamous cell cancer of the head and neck.

We investigated the association between genetic polymorphisms in GPX1 gene amongst patients who had index squamous cell carcinoma (SCCHN) and a second primary tumour (SPT) after a primary SCCHN in a case-control study. GPX1 genotypes were determined for 61 patients with SPT and for 259 control subjects by a PCR technique using a fluorescent-labelled primer. Analysis was by an ABI automated fluorescent sequencer. The associations between specific genotypes and the development of SPT were examined by logistic regression. A significant difference was found between the control group and the SPT cases in allele frequencies of GPX1 ALA( *)6 and ALA( *)7 (p(trend)=0.04). These results suggest that polymorphisms in the GPX1 gene may be a marker for SPT development and further studies are indicated.

Adult↗
PubMed2005

Phase III pilot study of dose escalation using conformal radiotherapy in prostate cancer: PSA control and side effects.

Radical radiotherapy is a standard form of management of localised prostate cancer. Conformal treatment planning spares adjacent normal tissues reducing treatment-related side effects and may permit safe dose escalation. We have tested the effects on tumour control and side effects of escalating radiotherapy dose and investigated the appropriate target volume margin. After an initial 3-6 month period of androgen suppression, 126 men were randomised and treated with radiotherapy using a 2 by 2 factorial trial design. The initial radiotherapy tumour target volume included the prostate and base of seminal vesicles (SV) or complete SV depending on SV involvement risk. Treatments were randomised to deliver a dose of 64 Gy with either a 1.0 or 1.5 cm margin around the tumour volume (1.0 and 1.5 cm margin groups) and also to treat either with or without a 10 Gy boost to the prostate alone with no additional margin (64 and 74 Gy groups). Tumour control was monitored by prostate-specific antigen (PSA) testing and clinical examination with additional tests as appropriate. Acute and late side effects of treatment were measured using the Radiation Treatment and Oncology Groups (RTOG) and LENT SOM systems. The results showed that freedom from PSA failure was higher in the 74 Gy group compared to the 64 Gy group, but this did not reach conventional levels of statistical significance with 5-year actuarial control rates of 71% (95% CI 58-81%) in the 74 Gy group vs 59% (95% CI 45-70%) in the 64 Gy group. There were 23 failures in the 74 Gy group and 33 in the 64 Gy group (Hazard ratio 0.64, 95% CI 0.38-1.10, P=0.10). No difference in disease control was seen between the 1.0 and 1.5 cm margin groups (5-year actuarial control rates 67%, 95% CI 53-77% vs 63%, 95% CI 50-74%) with 28 events in each group (Hazard ratio 0.97, 95% CI 0.50-1.86, P=0.94). Acute side effects were generally mild and 18 weeks after treatment, only four and five of the 126 men had persistent > or =Grade 1 bowel or bladder side effects, respectively. Statistically significant increases in acute bladder side effects were seen after treatment in the men receiving 74 Gy (P=0.006), and increases in both acute bowel side effects during treatment (P=0.05) and acute bladder sequelae (P=0.002) were recorded for men in the 1.5 cm margin group. While statistically significant, these differences were of short duration and of doubtful clinical importance. Late bowel side effects (RTOG> or =2) were seen more commonly in the 74 Gy and 1.5 cm margin groups (P=0.02 and P=0.05, respectively) in the first 2 years after randomisation. Similar results were found using the LENT SOM assessments. No significant differences in late bladder side effects were seen between the randomised groups using the RTOG scoring system. Using the LENT SOM instrument, a higher proportion of men treated in the 74 Gy group had Grade > or =3 urinary frequency at 6 and 12 months. Compared to baseline scores, bladder symptoms improved after 6 months or more follow-up in all groups. Sexual function deteriorated after treatment with the number of men reporting some sexual dysfunction (Grade> or =1) increasing from 38% at baseline to 66% at 6 months and 1 year and 81% by year 5. However, no consistent differences were seen between the randomised groups. In conclusion, dose escalation from 64 to 74 Gy using conformal radiotherapy may improve long-term PSA control, but a treatment margin of 1.5 cm is unnecessary and is associated with increased acute bowel and bladder reactions and more late rectal side effects. Data from this randomised pilot study informed the Data Monitoring Committee of the Medical Research Council RT 01 Trial and the two studies will be combined in subsequent meta-analysis.

Adenocarcinoma↗
PubMed2005

Men's decision-making about predictive BRCA1/2 testing: the role of family.

Men who have a family history of breast and/or ovarian cancer may be offered a predictive genetic test to determine whether or not they carry the family specific BRCA1/2 mutation. Male carriers may be at increased risk of breast and prostate cancers. Relatively little is known about at-risk men's decision-making about BRCA1/2 testing. This qualitative study explores the influences on male patients' genetic test decisions. Twenty-nine in-depth interviews were undertaken with both carrier and noncarrier men and immediate family members (17 male patients, 8 female partners, and 4 adult children). These explored family members' experiences of cancer and genetic testing, decision-making about testing, family support, communication of test results within the family, risk perception and risk management. Implicit influences on men's testing decisions such as familial obligations are examined. The extent to which other family members--partners and adult children--were involved in testing decisions is also described. It is demonstrated that mothers of potential mutation carriers not only perceive themselves as having a right to be involved in making this decision, but also were perceived by their male partners as having a legitimate role to play in decision-making. There was evidence that (adult) children were excluded from the decision-making, and some expressed resentment about this. The implications of these findings for the practice of genetic counseling are discussed.

Attitude↗
PubMed2005

The utility of digital rectal examination after radical radiotherapy for prostate cancer.

AIMS: The aim of the current study was to determine the utility of routine digital rectal examination (DRE) after radical radiotherapy for prostate cancer. MATERIALS AND METHODS: Between 1990 and 1999, 899 patients with clinically localised prostatic adenocarcinoma (T1-4, N0/Nx, M0/Mx) underwent neoadjuvant androgen deprivation and radical radiotherapy at the Royal Marsden Hospital. Patients were followed with serum prostate-specific antigen (PSA) test and DRE carried out at 6-monthly intervals for the first 2 years, and then annually. RESULTS: At a median follow-up of 5 years, 39 out of 899 cases (4.3%) had local recurrence detected on DRE. DRE failed to detect any local recurrences in the absence of a rising PSA. The lowest serum PSA concentration at the time of clinically detectable local recurrence was 1.7 ng/ml. CONCLUSIONS: These findings question the standard model of follow-up after radiotherapy for prostate cancer, and suggest that alternatives, such as telephone clinics, should be considered.

Adenocarcinoma↗
PubMed2005

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.

Adult↗
PubMed2005

Too much, too soon? Patients and health professionals' views concerning the impact of genetic testing at the time of breast cancer diagnosis in women under the age of 40.

Recent research suggests that women who develop breast cancer between the ages of 30-34 may have specific tumour characteristics: Those with high grade, oestrogen receptor negative, human epidermal growth factor receptor 2 (HER-2) negative tumours have between a 10% and 27% chance of being a BRCA1 gene carrier. Carriers of BRCA1 and BRCA2 mutations have an increased risk of contralateral breast cancer and cancer of the ovary. Furthermore, recent research indicates that prophylactic mastectomy and/or oophorectomy offer a significant risk reduction in the development of breast/ovarian cancer. In the near future, women in the UK may be offered the choice of a genetic test close to the time of diagnosis. This timing not only provides additional dimensions to treatment decisions, but has psycho-social and familial implications as well. This exploratory study investigates, first, whether or not women diagnosed with breast cancer under the age of 40 would want to be offered information about genetic testing close to the time of their diagnosis. Then secondly, it explores whether the health care professionals treating them support this idea. Third, it highlights the reasons for the women and the health professionals perspectives and concerns. We held focus groups of 13 women who had their only, or first, breast cancer under the age of 40 and who were subsequently identified as BRCA1 or BRCA2 mutation carriers, asking them how they felt about this timing. We also interviewed 17 health care professionals involved in various aspect of breast cancer care and cancer genetics. The majority of former breast cancer women and professionals believed that there was already emotional overload in coping with the cancer diagnosis and decisions regarding existing cancer treatment options and that offering genetic testing would add too much additional stress. Some members of both groups, however, thought that offering genetic testing around the time of breast cancer diagnosis would be more important if the results could alter treatment decisions.

Adult↗
PubMed2005

Communication about genetic testing in families of male BRCA1/2 carriers and non-carriers: patterns, priorities and problems.

This qualitative interview study explored the way in which information about predictive BRCA1/2 testing and its implications for children is disseminated within the families of at-risk men who undergo genetic testing. Twenty-nine in-depth interviews were carried out with family members [male patients (n = 17), their partners (n = 8) and adult children (n = 4)]. These explored the following themes: experiences of cancer and genetic testing, decision-making about testing and the communication of test results and genetic information within the immediate family. The interviews revealed that both male patients and their partners perceive themselves, rather than health professionals, as responsible for disclosing information about genetic testing and genetic risks to their children. Parents described three different communication strategies for the disclosure of genetic information to their children: complete openness, limited disclosure and total secrecy. The adoption of a particular communication strategy was justified in terms of children's rights to information vs their parental duties to protect their children from anxiety-provoking information. Some of the problems arising from the adoption of different disclosure patterns are identified and the implications for clinical practice are discussed.

Adult↗
PubMed2004

Psychosocial impact of breast/ovarian (BRCA1/2) cancer-predictive genetic testing in a UK multi-centre clinical cohort.

This multi-centre UK study assesses the impact of predictive testing for breast and ovarian cancer predisposition genes (BRCA1/2) in the clinical context. In the year following predictive testing, 261 adults (59 male) from nine UK genetics centres participated; 91 gene mutation carriers and 170 noncarriers. Self-report questionnaires were completed at baseline (pre-genetic testing) and 1, 4 and 12 months following the genetic test result. Men were assessed for general mental health (by general health questionnaire (GHQ)) and women for general mental health, cancer-related worry, intrusive and avoidant thoughts, perception of risk and risk management behaviour. Main comparisons were between female carriers and noncarriers on all measures and men and women for general mental health. Female noncarriers benefited psychologically, with significant reductions in cancer-related worry following testing (P<0.001). However, younger female carriers (<50 years) showed a rise in cancer-related worry 1 month post-testing (P<0.05). This returned to pre-testing baseline levels 12 months later, but worry remained significantly higher than noncarriers throughout (P<0.01). There were no significant differences in GHQ scores between males and females (both carriers and noncarriers) at any time point. Female carriers engaged in significantly more risk management strategies than noncarriers in the year following testing (e.g. mammograms; 92% carriers vs 30% noncarriers). In the 12 months post-testing, 28% carriers had bilateral risk-reducing mastectomy and 31% oophorectomy. Oophorectomy was confined to older (mean 41 yrs) women who already had children. However, worry about cancer was not assuaged by surgery following genetic testing, and this requires further investigation. In all, 20% of female carriers reported insurance problems. The data show persistent worry in younger female gene carriers and confirm changes in risk management consistent with carrier status. Men were not adversely affected by genetic testing in terms of their general mental health.

Adult↗
PubMed2004

Accommodating risk: responses to BRCA1/2 genetic testing of women who have had cancer.

The relationship between risk awareness and anxiety has been the subject of extensive theoretical debate and empirical research. Previous studies of women with a family history of hereditary breast and ovarian cancer suggest that both healthy at-risk women and former cancer patients report increased anxiety upon learning about their increased risks of developing these diseases. Indeed, anxiety about genetic risks has been reported as influencing decisions about DNA-testing and risk-reducing surgery on healthy breasts and ovaries. This qualitative study of women who had been treated for breast/ovarian cancer investigated their perceptions of, and reactions to, their genetic risks of developing further cancers following genetic testing (BRCA1/2 mutation searching). In-depth interviews were undertaken with 30 women (10 mutation carriers, 8 awaiting a result and 12 who received an inconclusive test result). Whilst the majority of women in all three groups adopted a fatalistic approach with regard to their future health and did not regard their genetic risks as a threat to self, a few reported heightened anxiety on learning they were at increased risk of developing a second primary cancer. The data suggest that affected women understand their genetic risks of cancer within the context of their previous disease experiences. It is observed that women's responses to their genetic risk are influenced by the degree to which they have accommodated their risk status in their biography following their diagnosis and treatment of cancer.

Adaptation, Psychological↗