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The original version of this Article did not contain details of Dutch Cancer Society (DCS) funding (grant number UL 2017-8223) in the Acknowledgements section. This has now been corrected in both the PDF and HTML versions of the Article.

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., link_to_OA_fulltext

Lynch syndrome (LS) is characterised by the\ud development of colorectal cancer, endometrial cancer\ud and various other cancers, and is caused by a mutation\ud in one of the mismatch repair genes: MLH1, MSH2,\ud MSH6 or PMS2. In 2007, a group of European experts\ud (the Mallorca group) published guidelines for the clinical\ud management of LS. Since then substantial new\ud information has become available necessitating an\ud update of the guidelines. In 2011 and 2012 workshops\ud were organised in Palma de Mallorca. A total of 35\ud specialists from 13 countries participated in the\ud meetings. The first step was to formulate important\ud clinical questions. Then a systematic literature search\ud was performed using the Pubmed database and manual\ud searches of relevant articles. During the workshops the\ud outcome of the literature search was discussed in detail.\ud The guidelines described in this paper may be helpful for\ud the appropriate management of families with LS.\ud Prospective controlled studies should be undertaken to\ud improve further the care of these families.

Background Duodenal adenomas develop in patients with familial adenomatous polyposis, incurring a risk of carcinoma. When this risk is high, surgery is indicated. The choice of surgical treatment can be difficult as evidence-based data are lacking. Methods This is a systematic review of the literature on the non-medical management of duodenal lesions arising in the setting of familial adenomatous polyposis. Studies were identified through searching MEDLINE. Studies published between January 1965 and October 2009 were included. Data regarding number of subjects, complications, length of follow-up, recurrence rate and outcome were extracted. Results Transduodenal resection does not differ from an endoscopic approach in terms of recurrence. Ampullectomy has limited application as only papillary lesions are amenable to treatment in this manner. Duodenectomy with pancreas preservation is preferable to pancreaticoduodenectomy unless malignancy is present, or cannot be excluded. Conclusion Surgery should be reserved for advanced or malignant polyps.

Evidence supporting aspirin and resistant starch (RS) for colorectal cancer prevention comes from epidemiologic and laboratory studies (aspirin and RS) and randomized controlled clinical trials (aspirin). Familial adenomatous polyposis (FAP) strikes young people and, untreated, confers virtually a 100% risk of colorectal cancer and early death. We conducted an international, multicenter, randomized, placebo-controlled trial of aspirin (600 mg/d) and/or RS (30 g/d) for from 1 to 12 years to prevent disease progression in FAP patients from 10 to 21 years of age. In a 2 × 2 factorial design, patients were randomly assigned to the following four study arms: aspirin plus RS placebo; RS plus aspirin placebo; aspirin plus RS; RS placebo plus aspirin placebo; they were followed with standard annual clinical examinations including endoscopy. The primary endpoint was polyp number in the rectum and sigmoid colon (at the end of intervention), and the major secondary endpoint was size of the largest polyp. A total of 206 randomized FAP patients commenced intervention, of whom 133 had at least one follow-up endoscopy and were therefore included in the primary analysis. Neither intervention significantly reduced polyp count in the rectum and sigmoid colon: aspirin relative risk = 0.77 (95% CI, 0.54–1.10; versus nonaspirin arms); RS relative risk = 1.05 (95% CI, 0.73–1.49; versus non-RS arms). There was a trend toward a smaller size of largest polyp in patients treated with aspirin versus nonaspirin—mean 3.8 mm versus 5.5 mm for patients treated 1 or more years (adjusted P = 0.09) and mean 3.0 mm versus 6.0 mm for patients treated more than 1 year (P = 0.02); there were similar weaker trends with RS versus non-RS. Exploratory translational endpoints included crypt length (which was significantly shorter in normal-appearing mucosa in the RS group over time) and laboratory measures of proliferation (including Ki67). This clinical trial is the largest ever conducted in the setting of FAP and found a trend of reduced polyp load (number and size) with 600 mg of aspirin daily. RS had no clinical effect on adenomas. Cancer Prev Res; 4(5); 655–65. ©2011 AACR.

A C--A polymorphism within the CDH1 (E-cadherin) promoter seems to be associated with a reduced efficiency of gene transcription in vitro. Due to the crucial role of E-cadherin in epithelia, tissue-specific effect of C--A change on CDH1 transcription was tested and a case-control study was performed on patients affected with epithelial tumors.The -178/+93 CDH1 region containing either C or A nucleotide was inserted upstream of the Luciferase reporter gene in the pGL-2 vector, and the construct activity was assessed by transient transfection assay in HeLa and HCT116 cells.A significantly lower activity for pGL-2A was found compared to pGL-2C, both in HeLa (54% decrease) and in HCT116 (67% decrease) cells. Genotyping of 246 controls and 505 patients affected with breast, gastric, colorectal, cervical and endometrial cancers demonstrated an association between the A allele and an increased risk of colorectal, gastric and endometrial tumors (1.66-, 1.81- and 2.35-fold, respectively).Our data support the notion that the A allele may act as a low-penetrance cancer susceptibility gene.

OBJECTIVE: The authors analyzed the incidence of rectal cancer in patients with hereditary nonpolyposis colorectal cancer (HNPCC) after an abdominal colectomy. SUMMARY BACKGROUND DATA: The treatment of choice for a newly diagnosed patient with HNPCC with colon cancer is an abdominal colectomy. The incidence of rectal cancer after abdominal colectomy in HNPCC is not known. MATERIALS AND METHODS: A questionnaire was mailed to all International Collaborative Group on HNPCC members to identify patients in whom rectal cancer developed after total, subtotal or completion colectomy. Statistics were performed using the log-rank test, Kaplan-Meier method, and Cox's proportional hazards model. RESULTS: Rectal cancer developed in 8 (11%) of 71 patients a median of 158 months (range, 38-282 months) from their primary procedure. Of these eight patients, adenomas in the rectal mucosa developed in five at risk either before (4) or synchronous (1) with the diagnosis of rectal cancer. At the time of diagnosis of rectal cancer, six of eight patients were being observed. Age at first procedure and whether the patient was under surveillance were the only significant variables (p < 0.05) in the multivariate analysis in terms of rectal cancer risk. The risk of developing rectal cancer was estimated to be 3% every 3 years after abdominal colectomy for the first 12 years. CONCLUSIONS: The risk of rectal cancer in patients with HNPCC after an abdominal colectomy is approximately 12% at 12 years. Age at first surgical procedure and surveillance correlated with rectal cancer risk. Aggressive endoscopic surveillance of the rectum should be performed after abdominal colectomy.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a common autosomal dominant cancer susceptibility condition. Inherited mutations in at least four DNA mismatch repair genes, hMSH2, hMLH1, hPMS1, and hPMS2, are known to cause HNPCC. In this study we used denaturing gradient gel electrophoresis (DGGE) to screen for hMLH1 mutations in 34 unrelated HNPCC families (30 Dutch, 3 Italian, and 1 Danish). Ten novel pathogenic germ-line mutations (seven affecting splice sites, two frameshifts, and one in-frame deletion of a single amino acid) have been identified in 12 (35%) of these families. In a previous study, hMSH2 mutations were found in 21% of the same families. While the spectrum of mutations at the hMSH2 gene among HNPCC patients appears heterogeneous, a cluster of hMLH1 mutations has been found in the region encompassing exons 15 and 16, which accounts for 50% of all the independent hMLH1 mutations described to date and for > 20% of the unrelated HNPCC kindreds here analyzed. This unexpected finding has a great practical value in the clinical scenario of genetic services.

Hereditary nonpolyposis colorectal cancer (HNPCC) is a relatively common autosomal dominant cancer-susceptibility condition. The recent isolation of the DNA mismatch repair genes (hMSH2, hMLH1, hPMS1, and hPMS2) responsible for HNPCC has allowed the search for germ-line mutations in affected individuals. In this study we used denaturing gradient-gel electrophoresis to screen for mutations in the hMSH2 gene. Analysis of all the 16 exons of hMSH2, in 34 unrelated HNPCC kindreds, has revealed seven novel pathogenic germ-line mutations resulting in stop codons either directly or through frameshifts. Additionally, nucleotide substitutions giving rise to one missense, two silent, and one useful polymorphism have been identified. The proportion of families in which hMSH2 mutations were found is 21%. Although the spectrum of mutations spread at the hMSH2 gene among HNPCC patients appears extremely heterogeneous, we were not able to establish any correlation between the site of the individual mutations and the corresponding tumor spectrum. Our results indicate that, given the genomic size and organization of the hMSH2 gene and the heterogeneity of its mutation spectrum, a rapid and efficient mutation detection procedure is necessary for routine molecular diagnosis and presymptomatic detection of the disease in a clinical setup.

The APC gene is a putative human tumor-suppressor gene responsible for adenomatous polyposis coli (APC), an inherited, autosomal dominant predisposition to colon cancer. It is also implicated in the development of sporadic colorectal tumors. The characterization of APC gene mutations in APC patients is clinically important because DNA-based tests can be applied for presymptomatic diagnosis once a specific mutation has been identified in a family. Moreover, the identification of the spectrum of APC gene mutations in patients is of great interest in the study of the biological properties of the APC gene product. We analyzed the entire coding region of the APC gene by the PCR–single-strand conformation polymorphism method in 42 unrelated Italian APC patients. Mutations were found in 12 cases. These consist of small (5–14 bp) base-pair deletions leading to frameshifts; all are localized within exon 15. Two of these deletions, a 5-bp deletion at position 3183–3187 and a 5-bp deletion at position 3926–3930, are present in 3/42 and 7/42 cases of our series, respectively, indicating the presence of mutational hot spots at these two sites.

The chronology of first recurrences, their topographic distribution and survival from mastectomy were retrospectively studied in a series of 800 mastectomized women with special reference to the relationship between these data and treatment delay, T N categories and free interval. Visceral metastases were more frequent in patients under 50 years, whereas local recurrences were more common in patients over 50. The average free interval was 26 months (over 5 years in 18% of cases) and seemed to be influenced little by the treament delay or by tumor size; it was shorter in patients under 50 years and shorter still in patients with lymph node involvement at operation. A similar correlation exists between these parameters and survival. The 5 year survival rate of the 800 cases with recurrence was 52%, which is quite different from the rate generally indicated for surgical cases, and much higher than the rate for the natural history of untreated breast cancer. The survival rate in cases with first metastases confined to the soft tissues is much higher than in those with bone and/or with visceral metastases. The survival after recurrence proves to be significantly influenced by the length of the free interval, but much more by the presence or absence of regional lymph node involvement, so that the lymph nodes status (N–- or N+) turns out to be a prognostic item of primary importance, even after the onset of recurrence.

One hundred and fifty-five cases of scintigraphically "cold" thyroid nodules were examined telethermographically to determine their thermal gradient. All nodules hyperthermic greater than or equal to 1.5 degrees C were successively removed, as were those (regardless of the thermal gradient) present in men, those in women younger than 21 years and older than 45 years of age, and those clinically suspect, the latter regardless of age or sex of the patient. Of 95 operated cases, 79 proved to be benign or nontumoral nodules, and 16 were carcinomas at histology. Hyperthermia greater than or equal to 1.5 degrees C had been present in 43% of the benign cases and in only 25% of the carcinomas. Out of ten cases were hyperthermia greater than or equal to 2 degrees C, none was a carcinoma. A malignancy was found in 26% of 23 normothermic cases, 17.6% of 34 slightly hyperthermic cases, and only 10.5% of 38 markedly hyperthermic (greater than or equal to 1.5 degrees C) cases. There was no evident correlation between the thermal gradient and the clinical diameter of the thyroid nodule. Our study affirms that thermography is not reliable when used to select cold thyroid nodules for surgical removal.

In the present study we report the long-term results for 120 female patients who underwent mastectomy for breast cancer, from 1955 to 1965, and in whom the first relapse was represented by a skin recurrence or a supraclavicular lymph node metastastis. Eighty-nine patients had been submitted only to local therapy, 11 had also undergone bilateral oophorectomy, and in the remaining 20 hormonal compounds had been administered in addition to local therapy. The disease-free interval between the first and the second relapse, and survival after the treatment of the first relapse were strictly related to the presence and the number of axillary lymph node metastases at the time of the mastectomy (N category). In fact, the median survival was 19.5 months for 63 cases with more than 3 metastatic lymph nodes, 29 months for 24 cases with 1–3 involved lymph nodes, and 59 months for 38 cases without axillary involvement. No significant difference in survival was observed in relation to chronological age and menopausal status of the patients or to the lenght of the disease-free interval. The association of endocrine therapies to local treatment of the recurrences also did not increase the survival rate in these cases. The present data indicate that the prognosis for patients with recurrent breast cancer is mainly related to the N category.

Aims and Background Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. Methods A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Results Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Conclusions Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.

Cancer prevention in the era of precision medicine has to consider integrated therapeutic approaches. Therapeutic cancer prevention should be offered to selected cohorts with increased cancer risk. Undoubtedly, carriers of hereditary cancer syndromes have a well-defined high cancer risk. Lynch Syndrome is one of the most frequent hereditary syndromes; it is mainly associated with colorectal cancer (CRC). Nonsteroidal anti-inflammatory drugs and, in particular, aspirin use, has been associated with reduced CRC risk in several studies, initially with contradictory results; however, longer follow-up confirmed a reduced CRC incidence and mortality. The CAPP2 study recruited 861 Lynch syndrome participants randomly assigned to 600 mg of aspirin versus placebo. Like sporadic CRCs, a significant CRC risk reduction was seen after an extended follow-up, with a median treatment time that was relatively short (2 years). The ongoing CAPP3 will address whether lower doses are equally effective. Based on pharmacology and clinical data on sporadic CRCs, the preventive effect should also be obtained with low-dose aspirin. The leading international guidelines suggest discussing with Lynch syndrome carriers the possibility of using low-dose aspirin for CRC prevention. We aim systematically promote this intervention with all Lynch syndrome carriers.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Purpose: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants.Methods: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years.Results: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery.Conclusion: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene-and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syn-drome to improve outcomes. (C) 2021 The Author(s). Published by Elsevier Ltd.

Purpose To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR ( path_MMR ) variants. Methods The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. Results Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1 , path_MSH2 , path_MSH6 , and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. Conclusion Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

An expert consensus panel convened by the Italian Association for Inherited and Familial Gastrointestinal Tumors (Associazione Italiana per lo Studio della Familiarita ed Ereditarieta dei Tumori Gastrointestinali, AIFEG) reviewed the literature and agreed on a number of position statements regarding the definition and management of polyposis coli without an identified pathogenic mutation on the APC or MUTYH genes, defined in the document as NAMP (non-APC/MUTYH polyposis).

Lynch syndrome (LS) results from pathogenic variants in the mismatch repair (MMR) genes and is the most common hereditary cancer syndrome, affecting an estimated 1 in 300 individuals. Pathogenic variants in each of the MMR genes path_MLH1, path_MSH2, path_MSH6, and path_PMS2 result in different risks for cancers in organs including the colorectum, endometrium, ovaries, stomach, small bowel, bile duct, pancreas, and upper urinary tract. Accurate estimates of these risks are essential for planning appropriate approaches to the prevention or early diagnosis of cancers but the robustness of previous studies has been limited by factors including retrospective design,1,2 lack of validation in independent cohorts,3-5 and inconsistent classification of genetic variants. Unexpected findings from previous studies have included path_MLH1 and path_MSH2 carriers appearing to have a lifetime risk of colorectal cancer (CRC) of approximately 50%, despite surveillance colonoscopy,6-8 and that shorter intervals between colonoscopies do not seem to reduce the incidence of CRC in LS.9,10 These findings challenge the assumptions that CRC in LS usually develops from a noninfiltrative adenoma precursor and that CRC can be prevented by colonoscopic detection and removal of adenomas in the colon and rectum. Additionally, previous studies in the Prospective Lynch Syndrome Database (PLSD) have shown no increase in cancer risk in path_PMS2 carriers before 40 years of age and, although observation years were limited in older path_PMS2 carriers, LS-associated cancers other than endometrial and prostate were not observed.6-8 In this study we collected prospective data from a new large cohort of path_MMR carriers to validate previous findings from PLSD. We also updated information on the original cohort to ensure consistent classification of pathogenicity of MMR gene variants. We then combined both data sets, providing larger numbers that allowed us to derive more precise risk estimates for cancers in LS categorized by gene and gender.

Background: It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear. Patients and methods: We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing. Results: Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs. Conclusion: These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin. © The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.