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In Lynch Syndrome, the risk of developing endometrial cancer ( is very high and equals or even exceeds the risk of colorectal cancer (CRC) in female gene carriers.49 The overall prognosis of patients diagnosed with EC is relatively good, with a 10-year survival of approximately 80%. However, 20% of the patients will ultimately die from the disease. Moreover, a substantial proportion of patients need treatment with radiation and/or chemotherapy.
The main goal of surveillance for EC is detection and treatment of premalignant lesions (ie, endometrial hyperplasia) or EC at an early stage and thereby improving the prognosis for the patients. The World Health Organization classifies endometrial hyperplasia as simple or complex determined by the degree of architectural abnormality, and as having or not having atypia. Nieminen et al50 studied serial specimens of normal endometrium, simple hyperplasia and complex hyperplasia with and without atypia during 10 years of surveillance. MMR deficiency was observed in 7% of normal endometrium, 40% of simple hyperplasia, 100% of complex hyperplasia without atypia and 92% of complex hyperplasia with atypia, suggesting that in LS, contrary to the traditional view, complex hyperplasia with and without atypia was equally important as precursor lesions of EC.
In 2011, Auranen and Joutsiniemi51 performed a systematic review of all studies that addressed gynaecological cancer surveillance in women who belonged to LS families. The authors identified five studies in the literature that included a total of 647 women.52–56 The screening methods applied in the studies varied from only transvaginal (or transabdominal) ultrasound (two studies) to a combination of transvaginal ultrasound and endometrial biopsy (two studies) and hysteroscopic endometrial biopsy (one study). The intervals between examinations varied between 1 year in three studies, 1–2 years in one study and 2–3 years in another study. In the studies that used only ultrasound as the screening tool, no EC were detected and only interval cancers occurred. However, in the studies with a protocol that also included endometrial biopsies, the detection of premalignant lesions and EC was improved.
Renkonen-Sinisalo et al54 compared the Federation of Gynecology and Obstetrics (FIGO) stages of the screen-detected cancers with those of EC diagnosed after presentation of signs or symptoms. Although less advanced cancers were observed in the screen-detected group, the difference was not statistically significant. The main advantage of the surveillance programme seems to be the identification of precursor lesions. No benefit was shown for ovarian cancer surveillance. Auranen and Joutsiniemi51 concluded that the available studies do not adequately allow for evidence-based clinical decisions.
Since that review, another retrospective study was published on the impact of gynaecological screening in MSH2 carriers (n=54).57 Nine women were diagnosed with EC, five of which were within 1 year of the previous negative screening test (transvaginal ultrasound and/or endometrial biopsy) and two were at initial screening. Of the nine EC, seven were localised cancers (stage I), and one was at an advanced stage (stage III). There were no deaths due to EC. Six women had ovarian cancer, three of which were within 1 year of a previous normal screening. Two died from ovarian cancer. The authors concluded that gynaecological screening did not result in earlier detection of gynaecological cancer.
In view of the uncertain effect of the surveillance programme, it is important to consider possible disadvantages of the programme. Elmasry et al58 assessed the patient acceptability of the available screening modalities. Transvaginal ultrasound was associated with less discomfort than hysteroscopy or Pipelle biopsy. There was no significant difference between the pain scores for hysteroscopy and Pipelle biopsy. Huang et al59 compared a new patient-centered approach by combining endometrial biopsies and colonoscopy under sedation. This approach was much more acceptable than an endometrial biopsy as a single procedure without sedation.
Wood et al60 evaluated the effect of gynaecological screening in LS families on psychological morbidity. The authors did not demonstrate any adverse psychological effect in the screened population, even in those with false positive screening results.
The value of surveillance for EC is still unknown. Surveillance of the endometrium by gynaecogical examination, transvaginal ultrasound and aspiration biopsy starting from the age of 35–40 years may lead to the detection of premalignant disease and early cancers (category of evidence III) and should be offered to mutation carriers (grade of recommendation C). The pros and cons should be discussed (table 5). Given the lack of evidence of any benefit, gynaecological surveillance should preferably be performed as part of a clinical trial.
Pros and cons of surveillance for gynaecological cancer
|Identification of precursor lesions of endometrial cancer||Small risk of death|
|Identification of early stage endometrial cancer (not proved)||Physical burden of surveillance examination especially Pipelle biopsy|
|No evidence of efficacy for early stage ovarian cancer detection|
Schmeler et al61 have shown in a retrospective study that prophylactic hysterectomy and oophorectomy is very effective in LS: none of the patients who underwent prophylactic surgery (61 out of 315) developed endometrial or ovarian cancer, whereas 33% of patients who did not have surgery developed EC and 5.5% developed ovarian cancer.
A recent study documented two cases of LS patients who developed primary peritoneal cancers after prophylactic surgery.62 A cost-effectiveness analysis of prophylactic surgery versus gynaecological screening showed that risk-reducing surgery was associated with both the lowest costs and highest number of quality-adjusted life years.63 ,64
In view of the very high risk of EC, the substantial proportion of women who will die from the disease, the morbidity associated with treatment and the effectiveness of prophylactic surgery, there is agreement that the option of prophylactic hysterectomy should be discussed with mutation carriers who have completed their family. However, there are still some important questions that should be addressed.
First, should prophylactic surgery include salpingo-oophorectomy? The risk of developing ovarian cancer in mutation carriers is approximately 9% with the highest risks in MLH1 and MSH2 mutation carriers and the lowest risk in MSH6 mutation carriers. Although the prognosis of unselected patients with ovarian cancer (and also of patients with ovarian cancer associated with BRCA1 and BRCA2 mutations) is very poor, recent studies suggested that the biology of ovarian cancer associated with LS may be different. Three studies showed that the majority of symptomatic ovarian cancers (77–81%) in LS are diagnosed at an early stage (FIGO stages I and II).65–67 In a multicentre study, Grindedal et al66 collected a large number (n=144) of prospectively diagnosed cases of ovarian cancer and demonstrated a very good prognosis with a 10-year survival of 81%.
Prophylactic surgery in postmenopausal women should include salpingo-oophorectomy. However, salpingo-oophorectomy in premenopausal women is associated with various adverse effects such as an immediate onset of menopause as a result of oestrogen deprivation potentially resulting in vasomotor symptoms and possible sexual dysfunction. Oestrogen deprivation may also lead to a higher risk of osteoporosis. A large study by Madalinska et al68 in 846 carriers of a BRCA1 and BRCA2 mutations reported significantly more endocrine symptoms in the patients who underwent prophylactic oophorectomy compared to women who underwent surveillance of the ovaries. No significant differences were observed in the level of sexual activities between the two groups, but women in the prophylactic surgery group reported significantly more discomfort (vaginal dryness and dyspareunia), less pleasure and less satisfaction during sexual activities. Despite this, the study did not reveal any other differences in quality of life. Usually, hormone replacement therapy is prescribed in premenopausal women after salpingo-oophorectomy, which may partly reduce the vasomotor symptoms but has no effect on sexual discomfort.
In view of the recent study that suggests a relatively good prognosis of ovarian cancer in LS, it is questionable whether the possible small gain in life expectancy outweighs the adverse effects of prophylactic salpingo-oophorectomy at a young age.
The second question is how these issues should be discussed with the patient and how the patient can be supported in their decision-making? The best approach is to inform the patient fully about all pros and cons of prophylactic surgery. As a basis for this discussion, the pros and cons are summarised in table 6. Depending on the type of information, a gynaecologist, geneticist, clinical psychologist or other specialists should be involved. Ideally, this information should also be available in written form.
Pros and cons of prophylactic hysterectomy with and without salpingo-oophorectomy
|Prevention of endometrial and ovarian cancer||Small risk of death|
|Prevention of morbidity related to treatment||Mortality surgery (0.1%)|
|Morbidity surgery (5–9%)|
|Pelvic surgery makes colonoscopy more difficult and painful and may reduce chance of full colonoscopy|
|Psychosocial problems (10–20%)|
|Early menopause depending of age at surgery|
|Sexual problems related to hysterectomy and early menopause|
|Probably very small risk of developing primary peritoneal carcinoma after oophorectomy|
The third question is from which age surgery should be recommended. The risk of endometrial and ovarian cancer increases from the age of 40 years. The optimal timing of prophylactic surgery, therefore, would be around the age of 40 years.
Hysterectomy and bilateral oophorectomy largely prevents the development of endometrial and ovarian cancer (category of evidence III) and is an option to be discussed with mutation carriers who have completed their families especially after the age of 40 years (grade of recommendation C). Also, if CRC surgery is scheduled, the option of prophylactic surgery at the same time should be considered. All pros and cons of prophylactic surgery should be discussed.
Yarnall, Crouch & Lewis (Division of Genetics and Molecular Medicine, King’s College London, United Kingdom.). Cancer Epidemiology 2013 Jan 29
Background: Epidemiological studies have identified potentially modifiable risks for colorectal cancer, including alcohol intake, diet and a sedentary lifestyle. Modelling these environmental factors alongside genetic risk is critical in obtaining accurate estimates of disease risk and improving our understanding of behavioural modifications. Methods: 14 independent single nucleotide polymorphisms identified though GWAS studies and reported on by the international consortium COGENT were used to model genetic disease risk at a population level. Six well validated environmental risks were selected for modelling together with the genetic risk factors (alcohol intake; smoking; exercise levels; BMI; fibre intake and consumption of red and processed meat). Through a simulation study using risk modelling software, we assessed the potential impact of behavioural modifications on disease risk. Results: Modelling the genetic data alone leads to 24% of the population being classified as reduced risk; 60% average risk; 10% elevated risk and 6% high risk for colorectal cancer. Adding alcohol consumption to the model reduced the elevated and high risk categories to 9% and 5% respectively. The simulation study suggests that a substantial proportion of individuals could reduce their disease risk profile by altering their behaviour, including reclassification of over 62% of heavy drinkers. Conclusion: Modelling lifestyle factors alongside genetic risk can provide useful strategies to select individuals for screening for colorectal cancer risk. Impact: Quantifying the impact of moderating behaviour, particularly related to alcohol intake and obesity levels, is beneficial for informing health campaigns and tailoring prevention strategies.
Over the last 30 years the lifetime risk of colorectal cancer (CRC) for men has almost doubled, from 3.5% to 6.9% in the UK in 2008. For women the increase is more than a quarter, rising from 3.9% to 5.4%. Since both genetic and environmental factors contribute to the susceptibility to colorectal cancer, this trend may be due to a change in the dietary and lifestyle factors of the general population leading to higher levels of obesity and more sedentary pastimes.
The major risk factor for colorectal cancer is age and over 85% of colorectal cancer occurs in people over the age of 60. Other risk factors include the presence of polyps and people having an Ashkenazi Jewish genetic heritage. The use of non-steroidal anti-inflammatory drugs (NSAIDs), hormone replacement therapy and aspirin use have also been associated with disease risk. However, it is estimated that between 52 and 57% of colorectal cancers are associated with lifestyle and environmental factors. Many risk factors for colorectal cancer may be modified by intervention, ranging from known risks, such as increased risk from a sedentary lifestyle and dietary changes. The evidence for dietary factors indicates possible increased risk from diets low in fibre, garlic, calcium, fruit, vegetables and fish and high in red and processed meat. In addition to alcohol, BMI, smoking and exercise, we chose to model the most consistent and well validated dietary findings, which suggest that low levels of fibre and high levels of red and processed meat are both significant risk factors.
The international consortium COGENT (COlorectal cancer GENeTics) have identified many of the known genetic variants that predispose to CRC with the 14 single nucleotide polymorphisms (SNPs) found to be convincingly associated with CRC risk from GWA studies summarized in Houlston et al.’s recent update. Of these 14 SNPs, the mean odds ratio per allele is 1.14, with the highest odds ratio reported for SNP rs16892766 near the EIF3H gene (OR 1.28).
The identification of SNPs that contribute to susceptibility for CRC has raised the prospect of genetic screening. Companies such as DeCODEme and 24andme include panels of SNPs for CRC in their genetic testing panels, yet research suggests that the genetic risk prediction alone is of questionable utility. In this research study, we combined the known genetic risk with data on the environmental risks for CRC, enabling more complete risk prediction. We applied a statistical risk model and to determine the impact of modelling environmental factors alongside the 14 genetic susceptibility loci identified by the COGENT consortium.
Early screening for colorectal cancer can be extremely helpful in identifying individuals with polyps and nonpolypoid lesions and preventing the development of cancer. Regular faecal occult blood tests (FOBT) in the over 50 s for example have been found to reduce the number of deaths due to CRC by 15–33%. In the UK, screening is offered to all men and women aged between 60 and 69 at a cost of £77.3 million and this will be extended to 74 year olds. However, it has been suggested that if individuals are provided with a personalized disease risk assessment from their combined genetic and environmental profile, they are likely to be more motivated to alter their lifestyle as a preventative measure, which would increase the effectiveness of health campaigns. In this study we develop predictions of CRC risk in different sub populations and assess the impact of modifying lifestyle factors on risk levels. By providing predictions of disease risk both before and after a lifestyle change for a given genetic profile, the study illustrates the potential benefits for both selection of candidates for screening programmes and the tailored promotion of healthier lifestyle choices, in high risk groups.
There are several modifiable risk factors for colorectal cancer and building predictive models encompassing both genetic and environmental factors enables us to move in the direction of a complete assessment of disease risk. This paper describes a predictive model which takes account of the known genetic contribution as well as the modifiable risks. There is considerable evidence to suggest that detecting polyps in the early stages can reduce mortality rates for colorectal cancer and whilst the interactions between the genetic and environmental elements are undeniably complex, separating out the inherited risk from the lifestyle factors using this model helps to illustrate the potential gains from modifying lifestyle behaviour and could usefully inform healthy lifestyle campaigns.
Our findings indicate that that cessation of alcohol consumption and reducing obesity levels lead to the most significant changes to the proportion of the population reducing their disease risk category. Whilst this could have been predicted to some extent by the higher odds ratios for these factors, it is the combination of relative risk, together with the prevalence of the factor within the population that determines the overall impact. In addition, being able to create personalized risk predictions in this way, has the potential to motivate greater behavioural change, showing for example, that it is possible to significantly reduce disease risk by moving from a high risk category to an average risk category though increasing fibre levels; cessation of alcohol consumption or weight management, given a particular genetic profile. Further research is required to increase understanding of how individuals respond to risk assessment based on genetic information. This may increases their motivation since the results are personal, or decrease their motivation because they consider that their genetic risk cannot be modified.
Our focus has been on risk categorization, and not on the absolute level of risk estimated from the combination of genetic and environmental risk factors, which is modest for most categories. There are two advantages to this strategy. Firstly it moves away from the strategy used, for example, by direct-to-consumer genetic testing companies such as 23andme and deCODEme (who provide a single figure of risk with no confidence intervals) towards the strategy deployed in genetic counselling of using a qualitative risk level, which can be more easily interpreted for the purpose of risk prediction. Secondly, it puts a stronger statistical framework on the risk model: an assignment to elevated risk implies that the risk is statistically distinct from the risk of the average, baseline, individual, given the uncertainty of the parameters used in the model.
There are several limitations of the model. Firstly, the model is built from estimates in the literature extracted from different studies. This enables researchers to select the best study to capture information on each risk factor, but assumes that information is directly comparable between studies. This limits the precision with which risk estimates can be calculated. A further limitation is that the model assumes all risk factors entered are independent. For known gene and environment interactions, this can be overcome by either modelling the interaction explicitly as an environmental risk factor, or by omitting known genetic loci to prevent over-representation of a risk factor (such as SNPs on the FTO gene which are associated with BMI). Within the genetic component, linkage disequilibrium between SNPs can be tested to confirm no correlation at a population level; few interactions of risk between genetic loci have been identified, so the assumption of independence should not be a major problem. For the environmental component, assumptions of independence are more difficult to assess. Lack of independence may lead to inaccuracies in the population frequencies estimated, but the contribution of environmental factors to the model is based on relative risks that are estimated in the presence of relevant covariates, so levels of risk should not be inflated. Increasing our understanding of the association between lifestyle factors, as well as between genes and the environment, will be important in obtaining more accurate assessments of risk. In addition, the accuracy could be further improved by more specific modelling of the population being targeted. Applying data with relative risks by sex, by population group, or for individuals with a first degree relative with CRC for example, would provide more accurate estimations of disease risk specific to those populations.
Colorectal cancer screening programmes are widespread, but are age-targeted and look for signs of cancer in early development. In contrast, the methods described here can be used to target lifestyle factors, and are relevant for younger age-groups. The approach could encourage behavioural changes and help to reduce CRC rates. Although the model indicates that certain individuals can reduce their CRC risk by changing their behaviour, the time taken for changes in environmental risk factors to have an effect on risk is unknown, and will differ by factor. Additional research is needed to further elucidate the genetic and environmental contributions to disease risk and to measure the longer term impact of behavioural change on disease outcomes.