Wouter H. de Vos tot Nederveen Cappel

Surveillance for hereditary nonpolyposis colorectal cancer - A long-term study on 114 families

PURPOSE Hereditary nonpolyposis colorectal cancer is caused by germline mutations in DNA mismatch repair genes. Mutation carriers have a 60 to 85 percent risk of developing colorectal cancer. In the Netherlands hereditary nonpolyposis colorectal cancer families are monitored in an intensive surveillance program. The aim of this study was to examine the stage of the screening-detected tumors in relation to the surveillance interval and to assess the risk of developing colorectal cancer while on the program. METHODS The Dutch hereditary nonpolyposis colorectal cancer family registry was used. A total of 114 families had a mismatch repair gene defect and/or met the clinical criteria for hereditary nonpolyposis colorectal cancer. The interval between surveillance and colorectal cancer was investigated in initially healthy family members who underwent at least one surveillance examination without showing evidence for colorectal cancer (surveillance group) and in family members who previously underwent partial or subtotal colectomy for colorectal cancer. The risk of colorectal cancer was calculated for proven mutation carriers (surveillance group) and for putative carriers after partial or subtotal colectomy. RESULTS A total of 35 cancers were detected while on the program. With intervals between colorectal cancer and the preceding surveillance examination of two years or less, tumors were at Dukes Stage A (n = 4), B (n = 11), and C (1). With intervals of more than two years, tumors were at Dukes Stage A (n = 3), B (n = 10), and C (n = 6). The 10-year cumulative risk of developing colorectal cancer was 10.5 (95 percent confidence interval, 3.8–17.2) percent in proven mutation carriers, 15.7 (95 percent confidence interval, 4.1–27.3) percent after partial colectomy, and 3.4 percent after subtotal colectomy. CONCLUSION There is a substantial risk of developing colorectal cancer while on the program. However, all tumors but one of subjects who underwent a surveillance examination two years or less before detection were at a local stage. We recommend surveillance for hereditary nonpolyposis colorectal cancer with an interval of two years or less.

One to 2-year surveillance intervals reduce risk of colorectal cancer in families with Lynch syndrome

BACKGROUND & AIMS Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program. METHODS The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy. RESULTS After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without. CONCLUSIONS With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended.

Magnetic Resonance Imaging Surveillance Detects Early-Stage Pancreatic Cancer in Carriers of a p16-Leiden Mutation

BACKGROUND & AIMS Surveillance of high-risk groups for pancreatic cancer might increase early detection and treatment outcomes. Individuals with germline mutations in p16-Leiden have a lifetime risk of 15% to 20% of developing pancreatic cancer. We assessed the feasibility of detecting pancreatic cancer at an early stage and investigated the outcomes of patients with neoplastic lesions. METHODS Individuals with germline mutations in p16-Leiden (N = 79; 31 male; mean age, 56 years; range, 39-72 years) were offered annual surveillance by magnetic resonance imaging (MRI) and magnetic resonance cholangiopancreatography (MRCP). Those found to have neoplastic lesions were offered options for surgery or intensive follow-up. Individuals found to have possible neoplastic lesions were examined again by MRI/MRCP within 2 to 4 months. RESULTS After a median follow-up period of 4 years (range, 0-10 years), pancreatic cancer was diagnosed in 7 patients (9%). The mean age at diagnosis was 59 years (range, 49-72 years). Three of the tumors were present at the first examination, and 4 were detected after a negative result in the initial examination. All 7 patients had a resectable lesion; 5 underwent surgery, 3 had an R0 resection, and 2 had lymph node metastases. Possible precursor lesions (ie, duct ectasias, based on MRCP) were found in 9 individuals (11%). CONCLUSIONS MRI/MRCP detects small, solid pancreatic tumors and small duct ectasias. Although surveillance increases the rate of resectability, carriers of a p16-Leiden mutation develop aggressive tumors.

Survival after adjuvant 5-FU treatment for stage III colon cancer in hereditary nonpolyposis colorectal cancer.

In vitro studies suggest that a deficient mismatch repair (MMR) system reduces 5‐Fluorouracil cytotoxicity. Colon cancer (CC) in hereditary nonpolyposis colorectal cancer (HNPCC) is due to a dysfunctioning MMR gene that leads to microsatellite instability (MSI). Clinical studies on the efficacy of 5‐Fluorouracil (5‐FU) in MSI high tumours are contradictory. In a retrospective study, we compared the survival of subjects with stage III CC from HNPCC families that were treated with and without adjuvant 5‐FU. The Dutch HNPCC family registry was used. Information on adjuvant chemotherapy for stage III CC was obtained from subjects of families with a mutation and/or who fulfilled the AMS criteria or who were strongly suspicious for HNPCC. CC specific survival was calculated. Observation time was measured either until the date of death, date of a second primary CC or until the closing date of the study, i.e., June 1, 2001. Statistical analysis was done by Kaplan‐Meier survival analysis. A total of 92 subjects with stage III CC were included. Twenty‐eight of them (17 males) had adjuvant treatment with 5‐FU. The median follow‐up was 4 (range: 1–17) years; 8 subjects died of CC. The 5‐year survival was 70% (95% Cl: 49–90). Sixty‐four subjects (36 males) did not have adjuvant therapy. Their median follow‐up was 6 (range: 0–23) years. Twenty of them died of CC. The 5‐year survival in this group was also 70% (95% Cl: 59–83). To date, the selection of patients with CC for 5‐FU treatment is based on the stage rather than the biology of the tumour. In our study, the 5‐year survival of subjects treated with and without adjuvant 5‐FU did not differ. Further studies are necessary to elucidate the role of MSI in 5‐FU treatment of MSI‐H tumours in HNPCC.

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.

Desmoid Tumors in a Dutch Cohort of Patients With Familial Adenomatous Polyposis

BACKGROUND & AIMS Desmoid tumors are a severe extracolonic manifestation in familial adenomatous polyposis (FAP). Identification of risk factors might be helpful in the management of FAP patients with such tumors. The aim of this study was to assess potential risk factors for the development of desmoids in a cohort of Dutch FAP patients. METHODS The medical records of 735 FAP patients were analyzed for the occurrence of desmoids. Relative risks and survival times were calculated to assess the influence of potential risk factors (female sex, family history, mutation site, abdominal surgery, and pregnancy) on desmoid development. RESULTS Desmoid tumors were identified in 66 of the 735 patients (9%). The cumulative risk of developing desmoids was 14%. No correlation was found between specific adenomatous polyposis coli mutation sites and desmoid development. Patients with a positive family history for desmoids had a significant increased risk to develop this tumor (30% vs 6.7%, P < .001). No association was found between female sex or pregnancy and desmoid development. Most desmoid patients (95%) had undergone previous abdominal surgery. In a substantial proportion of patients with an ileorectal anastomosis, it was impossible to convert the ileorectal anastomosis to an ileal pouch-anal anastomosis as a result of desmoid development. CONCLUSIONS A positive family history of desmoids is an evident risk factor for developing desmoids. Most desmoids develop after colectomy. No correlation was found between desmoids and the adenomatous polyposis coli gene mutation site, female sex, and pregnancy. Ileal pouch-anal anastomosis is the appropriate type of surgery in FAP patients with a positive family history for desmoids.

Benefit of Surveillance for Pancreatic Cancer in High-Risk Individuals: Outcome of Long-Term Prospective Follow-Up Studies From Three European Expert Centers

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Hereditary factors play a role in the development of PDAC in 3% to 5% of all patients. Surveillance of high-risk groups, may facilitate detection of PDAC at an early stage. The aim of this study was to assess whether surveillance aids detection of early-stage PDAC or precursor lesions (PRLs) and improves the prognosis. PATIENTS AND METHODS Screening outcomes were collected from three European centers that conduct prospective screening in high-risk groups including families with clustering of PDAC (familial pancreatic cancer [FPC]) or families with a gene defect that predisposes to PDAC. The surveillance program consisted of annual magnetic resonance imaging, magnetic resonance cholangiopancreatography, and/or endoscopic ultrasound. RESULTS Four hundred eleven asymptomatic individuals participated in the surveillance programs, including 178 CDKN2A mutation carriers, 214 individuals with FPC, and 19 BRCA1/2 or PALB2 mutation carriers. PDAC was detected in 13 (7.3%) of 178 CDKN2A mutation carriers. The resection rate was 75%, and the 5-year survival rate was 24%. Two CDKN2A mutation carriers (1%) underwent surgical resection for low-risk PRL. Two individuals (0.9%) in the FPC cohort had a pancreatic tumor, including one advanced PDAC and one early grade 2 neuroendocrine tumor. Thirteen individuals with FPC (6.1%) underwent surgical resection for a suspected PRL, but only four (1.9%) had high-risk lesions (ie, high-grade intraductal papillary mucinous neoplasms or grade 3 pancreatic intraepithelial neoplasms). One BRCA2 mutation carrier was found to have PDAC, and another BRCA2 mutation carrier and a PALB2 mutation carrier underwent surgery and were found to have low-risk PRL. No serious complications occurred as consequence of the program. CONCLUSION Surveillance of CDNK2A mutation carriers is relatively successful, detecting most PDACs at a resectable stage. The benefit of surveillance in families with FPC is less evident.

Quality of life after surgery for colon cancer in patients with Lynch syndrome: partial versus subtotal colectomy.

BACKGROUND: Lynch syndrome is a disorder caused by mismatch repair gene mutations. Mutation carriers have a high risk of developing colorectal cancer. In patients with Lynch syndrome in whom colon cancer has been diagnosed, in general, subtotal colectomy instead of partial colectomy is recommended because of the substantial risk of metachronous colorectal cancer. However, the effect of more extensive surgery on quality of life and functional outcome is unknown. OBJECTIVE: The aim of this study was to investigate quality of life and functional outcome in patients with Lynch syndrome after partial colectomy and subtotal colectomy. DESIGN: This is a nationwide cross-sectional study in the Netherlands. SETTINGS: Two quality-of-life questionnaires (Short Form-36 and The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module) and a functional outcome questionnaire (Colorectal Functional Outcome) were used. PATIENTS: Patients with Lynch syndrome who underwent surgery for colon cancer were included. MAIN OUTCOME MEASURES: The primary outcomes measured were quality of life and functional outcome. RESULTS: Questionnaires were sent to 192 patients with Lynch syndrome who underwent surgery for colorectal cancer. A total of 136 patients returned the questionnaire (response rate, 71%). Eighteen patients with rectal cancer, 9 patients with a permanent ileostomy, and 5 patients with an IPAA were excluded. Fifty-one patients underwent partial colectomy, and 53 underwent subtotal colectomy. None of the scales of the Short Form-36 survey showed a significant difference. Analysis of the Colorectal Functional Outcome questionnaire revealed that, after subtotal colectomy, patients have a significantly higher stool frequency (p ⩽ 0.01) and a significantly higher score on stool-related aspects (p = 0.06) and social impact (p = 0.03). The European Organization for Research and Treatment of Cancer Colorectal Cancer-specific Quality of Life Questionnaire Module presented more problems with defecation after subtotal colectomy (p ⩽ 0.01). LIMITATIONS: Certain selection bias cannot be ruled out. CONCLUSIONS: Although functional outcome is worse after subtotal colectomy than after partial colectomy, generic quality of life does not differ after the 2 types of surgery in Lynch syndrome. When discussing the options for surgery with the patient, all advantages and disadvantages of both surgical procedures, including quality of life and functional outcome, should be discussed.

Variation in Precursor Lesions of Pancreatic Cancer among High-Risk Groups

Purpose: Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups. Experimental Design: Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0–127 months) or 36 months (0–110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery. Results: Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable. Conclusion: In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group. Clin Cancer Res; 19(2); 442–9. ©2012 AACR.

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.