Kirsi Pylvänäinen

Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial

Summary Background Observational studies report reduced colorectal cancer in regular aspirin consumers. Randomised controlled trials have shown reduced risk of adenomas but none have employed prevention of colorectal cancer as a primary endpoint. The CAPP2 trial aimed to investigate the antineoplastic effects of aspirin and a resistant starch in carriers of Lynch syndrome, the major form of hereditary colorectal cancer; we now report long-term follow-up of participants randomly assigned to aspirin or placebo. Methods In the CAPP2 randomised trial, carriers of Lynch syndrome were randomly assigned in a two-by-two factorial design to 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was in blocks of 16 with provision for optional single-agent randomisation and extended postintervention double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint was development of colorectal cancer. Analysis was by intention to treat and per protocol. This trial is registered, ISRCTN59521990. Results 861 participants were randomly assigned to aspirin or aspirin placebo. At a mean follow-up of 55·7 months, 48 participants had developed 53 primary colorectal cancers (18 of 427 randomly assigned to aspirin, 30 of 434 to aspirin placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 0·63 (95% CI 0·35–1·13, p=0·12). Poisson regression taking account of multiple primary events gave an incidence rate ratio (IRR) of 0·56 (95% CI 0·32–0·99, p=0·05). For participants completing 2 years of intervention (258 aspirin, 250 aspirin placebo), per-protocol analysis yielded an HR of 0·41 (0·19–0·86, p=0·02) and an IRR of 0·37 (0·18–0·78, p=0·008). No data for adverse events were available postintervention; during the intervention, adverse events did not differ between aspirin and placebo groups. Interpretation 600 mg aspirin per day for a mean of 25 months substantially reduced cancer incidence after 55·7 months in carriers of hereditary colorectal cancer. Further studies are needed to establish the optimum dose and duration of aspirin treatment. Funding European Union; Cancer Research UK; Bayer Corporation; National Starch and Chemical Co; UK Medical Research Council; Newcastle Hospitals trustees; Cancer Council of Victoria Australia; THRIPP South Africa; The Finnish Cancer Foundation; SIAK Switzerland; Bayer Pharma.

Cancer incidence and survival in Lynch syndrome patients receiving colonoscopic and gynaecological surveillance: first report from the prospective Lynch syndrome database.

Objective Estimates of cancer risk and the effects of surveillance in Lynch syndrome have been subject to bias, partly through reliance on retrospective studies. We sought to establish more robust estimates in patients undergoing prospective cancer surveillance. Design We undertook a multicentre study of patients carrying Lynch syndrome-associated mutations affecting MLH1, MSH2, MSH6 or PMS2. Standardised information on surveillance, cancers and outcomes were collated in an Oracle relational database and analysed by age, sex and mutated gene. Results 1942 mutation carriers without previous cancer had follow-up including colonoscopic surveillance for 13 782 observation years. 314 patients developed cancer, mostly colorectal (n=151), endometrial (n=72) and ovarian (n=19). Cancers were detected from 25 years onwards in MLH1 and MSH2 mutation carriers, and from about 40 years in MSH6 and PMS2 carriers. Among first cancer detected in each patient the colorectal cancer cumulative incidences at 70 years by gene were 46%, 35%, 20% and 10% for MLH1, MSH2, MSH6 and PMS2 mutation carriers, respectively. The equivalent cumulative incidences for endometrial cancer were 34%, 51%, 49% and 24%; and for ovarian cancer 11%, 15%, 0% and 0%. Ten-year crude survival was 87% after any cancer, 91% if the first cancer was colorectal, 98% if endometrial and 89% if ovarian. Conclusions The four Lynch syndrome-associated genes had different penetrance and expression. Colorectal cancer occurred frequently despite colonoscopic surveillance but resulted in few deaths. Using our data, a website has been established at http://LScarisk.org enabling calculation of cumulative cancer risks as an aid to genetic counselling in Lynch syndrome.

Long-term effect of resistant starch on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial.

BACKGROUND Observational studies report that higher intake of dietary fibre (a heterogeneous mix including non-starch polysaccharides and resistant starches) is associated with reduced risk of colorectal cancer, but no randomised trials with prevention of colorectal cancer as a primary endpoint have been done. We assessed the effect of resistant starch on the incidence of colorectal cancer. METHODS In the CAPP2 study, individuals with Lynch syndrome were randomly assigned in a two-by-two factorial design to receive 600 mg aspirin or aspirin placebo or 30 g resistant starch or starch placebo, for up to 4 years. Randomisation was done with a block size of 16. Post-intervention, patients entered into double-blind follow-up; participants and investigators were masked to treatment allocation. The primary endpoint for this analysis was development of colorectal cancer in participants randomly assigned to resistant starch or resistant-starch placebo with both intention-to-treat and per-protocol analyses. This study is registered, ISRCTN 59521990. FINDINGS 463 patients were randomly assigned to receive resistant starch and 455 to receive resistant-starch placebo. At a median follow-up 52·7 months (IQR 28·9-78·4), 53 participants developed 61 primary colorectal cancers (27 of 463 participants randomly assigned to resistant starch, 26 of 455 participants assigned to resistant-starch placebo). Intention-to-treat analysis of time to first colorectal cancer showed a hazard ratio (HR) of 1·40 (95% CI 0·78-2·56; p=0·26) and Poisson regression accounting for multiple primary events gave an incidence rate ratio (IRR) of 1·15 (95% CI 0·66-2·00; p=0·61). For those completing 2 years of intervention, per-protocol analysis yielded a HR of 1·09 (0·55-2·19, p=0·80) and an IRR of 0·98 (0·51-1·88, p=0·95). No information on adverse events was gathered during post-intervention follow-up. INTERPRETATION Resistant starch had no detectable effect on cancer development in carriers of hereditary colorectal cancer. Dietary supplementation with resistant starch does not emulate the apparently protective effect of diets rich in dietary fibre against colorectal cancer. FUNDING European Union, Cancer Research UK, Bayer Corporation, National Starch and Chemical Co, UK Medical Research Council, Newcastle Hospitals Trustees, Cancer Council of Victoria Australia, THRIPP South Africa, The Finnish Cancer Foundation, SIAK Switzerland, and Bayer Pharma.

Direct contact in inviting high-risk members of hereditary colon cancer families to genetic counselling and DNA testing

Background: Identification of hereditary predisposition to cancer has limited significance if not followed by efficient cancer prevention in the family. Probands are traditionally left to inform their relatives about the increased risk, but distant relatives may remain uninformed. An approach to contacting directly at-risk persons assumed to be unaware of their increased cancer risk was taken. With cancer prevention as the ultimate goal, the study was aimed at investigating attitudes towards and psychosocial consequences of this novel strategy. Methods: In families with hereditary non-polyposis colorectal cancer (Lynch syndrome), 286 healthy adult relatives with a 50% risk of a predisposing mutation were contacted by letter. Of these, 112 participated in counselling and predictive testing. Baseline information and information obtained 1 month after the test for 73 respondents were compared with 299 corresponding subjects, approached via the proband (family-mediated approach in our previous study) in these families. Results: After the contact letter, 51% consented to the study. Of these, 92% approved of the direct contact and 33% had tried to seek information. In 34% of the mutation carriers, neoplasia was identified in the first post-test colonoscopy. Although post-test fear of cancer increased among the mutation carriers and decreased among noncarriers, almost all participants were satisfied with their decision to participate, independently of their test results, parallel to the family-mediated approach. Conclusion: In this large-scale study, relatives in cancer families were actively contacted to inform them of the condition and genetic counselling. Their attitudes were encouraging, and the psychosocial consequences were similar to the family-mediated approach. Our results suggest the appropriateness of direct contact as an alternative method of contact in cases of life-threatening treatable disease.

Compliance and Satisfaction with Long-Term Surveillance in Finnish HNPCC Families

Objective: Nation-wide preventative colonoscopic surveillance for mutation carriers in HNPCC families has been organized since the early 1980 by the Finnish HNPCC registry. After characterization of MMR genes, a predisposing mutation has been verified in 111 HNPCC families and over 1500 family members at risk have been tested. The aim of this study was to evaluate the compliance and satisfaction of mutation carriers during life-long colonoscopic surveillance. Materials and Methods: Hospital records of long-term surveillance were obtained for all mutation carriers (n=664). A questionnaire assessing overall experience, willingness to continue the surveillance, painfulness (a three-rank scale), possible interruption of endoscopy and the need for pain relief medication during colonoscopy, was sent to all living mutation carriers (n=587). The questionnaire was returned by 441 persons (75%) of whom 415 persons under colonoscopic surveillance were included in the study and 26 young mutation carriers excluded as they were still pending their first endoscopy. Results: Out of 664 mutation carriers, surveillance had been interrupted in 8 cases (1.2%). Colonoscopies were described as painful by 151 (36%), uncomfortable by 161 (39%) and easy by 103 (25%) patients. Endoscopy was more often rated as painful by females (1.36, SD 0.71) than by males (0.86, SD 0.75), P<0.001. Medication for pain during colonoscopies was administered more often to females (32%) than males (15%), P<0.001. Colonoscopy had to be discontinued because of pain at least once in 10% of the patients. Conclusion: Patient compliance under life-long surveillance was excellent, but painfulness, especially in females, must be seen as a risk for compliance and the quality of endoscopies.

Incidence of and survival after subsequent cancers in carriers of pathogenic MMR variants with previous cancer: a report from the prospective Lynch syndrome database

Objective Today most patients with Lynch syndrome (LS) survive their first cancer. There is limited information on the incidences and outcome of subsequent cancers. The present study addresses three questions: (i) what is the cumulative incidence of a subsequent cancer; (ii) in which organs do subsequent cancers occur; and (iii) what is the survival following these cancers? Design Information was collated on prospectively organised surveillance and prospectively observed outcomes in patients with LS who had cancer prior to inclusion and analysed by age, gender and genetic variants. Results 1273 patients with LS from 10 countries were followed up for 7753 observation years. 318 patients (25.7%) developed 341 first subsequent cancers, including colorectal (n=147, 43%), upper GI, pancreas or bile duct (n=37, 11%) and urinary tract (n=32, 10%). The cumulative incidences for any subsequent cancer from age 40 to age 70 years were 73% for pathogenic MLH1 (path_MLH1), 76% for path_MSH2 carriers and 52% for path_MSH6 carriers, and for colorectal cancer (CRC) the cumulative incidences were 46%, 48% and 23%, respectively. Crude survival after any subsequent cancer was 82% (95% CI 76% to 87%) and 10-year crude survival after CRC was 91% (95% CI 83% to 95%). Conclusions Relative incidence of subsequent cancer compared with incidence of first cancer was slightly but insignificantly higher than cancer incidence in patients with LS without previous cancer (range 0.94–1.49). The favourable survival after subsequent cancers validated continued follow-up to prevent death from cancer. The interactive website http://lscarisk.org was expanded to calculate the risks by gender, genetic variant and age for subsequent cancer for any patient with LS with previous cancer.

Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database

Background Most patients with path_MMR gene variants (Lynch syndrome (LS)) now survive both their first and subsequent cancers, resulting in a growing number of older patients with LS for whom limited information exists with respect to cancer risk and survival. Objective and design This observational, international, multicentre study aimed to determine prospectively observed incidences of cancers and survival in path_MMR carriers up to 75 years of age. Results 3119 patients were followed for a total of 24 475 years. Cumulative incidences at 75 years (risks) for colorectal cancer were 46%, 43% and 15% in path_MLH1, path_MSH2 and path_MSH6 carriers; for endometrial cancer 43%, 57% and 46%; for ovarian cancer 10%, 17% and 13%; for upper gastrointestinal (gastric, duodenal, bile duct or pancreatic) cancers 21%, 10% and 7%; for urinary tract cancers 8%, 25% and 11%; for prostate cancer 17%, 32% and 18%; and for brain tumours 1%, 5% and 1%, respectively. Ovarian cancer occurred mainly premenopausally. By contrast, upper gastrointestinal, urinary tract and prostate cancers occurred predominantly at older ages. Overall 5-year survival for prostate cancer was 100%, urinary bladder 93%, ureter 85%, duodenum 67%, stomach 61%, bile duct 29%, brain 22% and pancreas 0%. Path_PMS2 carriers had lower risk for cancer. Conclusion Carriers of different path_MMR variants exhibit distinct patterns of cancer risk and survival as they age. Risk estimates for counselling and planning of surveillance and treatment should be tailored to each patient’s age, gender and path_MMR variant. We have updated our open-access website www.lscarisk.org to facilitate this.

Endometrial cancer risk factors among Lynch syndrome women: a retrospective cohort study

Background:Lynch syndrome (LS) is associated with a significant lifetime risk of endometrial cancer (EC). There are limited data on factors modifying the EC risk in LS patients.Methods:The study cohort included 136 LS mutation-positive women. Exposure data were collected by postal questionnaires. Cox regression model was used to estimate the associations between lifestyle, hormonal, reproductive and medical factors and the risk of EC.Results:Increased EC risk was associated with type II diabetes and hypercholesterolaemia in univariable (HR 3.21, (95% CI 1.34–7.78), P=0.009 and HR 2.08, (95% CI 1.11–3.90), P=0.02; respectively) and with diabetes and duration of hormone replacement therapy (HRT) in multivariable analysis (HR 4.18 (95% CI 1.52–11.52), P=0.006 and HR 1.07 (95% CI 1.02–1.13), P=0.010; respectively).Conclusions:Prevention of diabetes and avoiding long-duration HRT are potential targets for reduction of EC risk in women with LS.

Uptake of genetic testing by the children of Lynch syndrome variant carriers across three generations

Many Lynch syndrome (LS) carriers remain unidentified, thus missing early cancer detection and prevention opportunities. Tested probands should inform their relatives about cancer risk and options for genetic counselling and predictive gene testing, but many fail to undergo testing. To assess predictive testing uptake and demographic factors influencing this decision in LS families, a cross-sectional registry-based cohort study utilizing the Finnish Lynch syndrome registry was undertaken. Tested LS variant probands (1184) had 2068 children divided among three generations: 660 parents and 1324 children (first), 445 and 667 (second), and 79 and 77 (third). Of children aged >18 years, 801 (67.4%), 146 (43.2%), and 5 (23.8%), respectively, were genetically tested. Together, 539 first-generation LS variant carriers had 2068 children and grandchildren (3.84 per carrier). Of the 1548 (2.87 per carrier) eligible children, 952 (61.5%) were tested (1.77 per carrier). In multivariate models, age (OR 1.08 per year; 95% CI 1.06–1.10), family gene (OR 2.83; 1.75–4.57 for MLH1 and 2.59; 1.47–4.56 for MSH2 compared with MSH6), one or more tested siblings (OR 6.60; 4.82–9.03), no siblings (OR 4.63; 2.64–8.10), and parent under endoscopic surveillance (OR 5.22; 2.41–11.31) were independent predictors of having genetic testing. Examples of parental adherence to regular surveillance and genetically tested siblings strongly influenced children at 50% risk of LS to undergo predictive gene testing. High numbers of untested, adult at-risk individuals exist even among well-established cohorts of known LS families with good adherence to endoscopic surveillance.

Comparison of lifestyle, hormonal and medical factors in women with sporadic and lynch syndrome-associated endometrial cancer: A retrospective case-case study

Data available on lifestyle-associated hormonal and medical factors among endometrial cancer (EC)-affected women who carry the Lynch Syndrome (LS) mutation is limited. The aim of the present retrospective case study was to compare the reproductive and medical history, as well as lifestyle-associated factors, among patients with LS and sporadic EC. The study population consisted of 50 verified germline mismatch repair (MMR) gene mutation carriers diagnosed with EC, and 110 sporadic EC patients. Data were collected using postal questionnaires. Apart from the mean age at the time of the EC diagnosis (LS, 48.7 years compared with sporadic patients, 55.2 years; P<0.0001), the characteristics of sporadic and LS EC patients were similar with regard to body mass index (BMI) at age 18, 40 or at the time of the survey, and smoking and alcohol consumption. LS women reported a significantly lower rate of spontaneous abortion (P=0.043) and also more frequent use of contraceptives (P=0.004). The prevalence of co-morbidities, including diabetes, atherosclerosis, hypercholesterolemia and hypertension, was similar between the LS and the sporadic groups. A trend for a higher prevalence of endometriosis among mutation carriers was detected (16.0 vs. 8.1%, P=0.137). As anticipated, the prevalence of gastrointestinal tract, urinary tract and ovarian cancer was higher among the LS women (P<0.0001, P=0.006 and P=0.056, respectively). Co-morbidity and lifestyle-associated factors appeared to be comparable among patients with LS and sporadic EC. The reported difference in the use of contraceptives warrants further investigation. Future studies are also required to address the possible association between LS and endometriosis.