Updates on Extracolonic Cancer Risks in Lynch syndrome
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1 Updates on Extracolonic Cancer Risks in Lynch syndrome Fay Kastrinos, MD, MPH Columbia University Medical Center New York Presbyterian Hospital New York, NY
2 Extracolonic Malignancies in Lynch syndrome Extracolonic cancers Breast Cancer Endometrial Cancer Ovarian Cancer Gastric Small bowel Upper Urinary Tract Sebaceous neoplasms Brain/CNS Hepatobiliary tract Pancreatic Cancer Bladder Cancer Prostate Cancer 60% of Lynch syndrome cancer deaths are non-crc, non-ec Pylvanainen K Fam Cancer 2012; 11: 467
3 Extracolonic cancers in Lynch Syndrome 100 % with cancer Colorectal 78% 40 Endometrial 43% Stomach 19% Biliary tract 18% Urinary tract 10% Ovarian 9% * Age (years) Aarnio M, et al. Int J Cancer 1997;74:551-5
4 Estimating Cancer Risk in Lynch Syndrome Historically, most cancer risks are estimated from families with a strong family history of early-onset cancers Issues: - Overestimation of age-specific cumulative risk - Incomplete testing of full pedigree - Analyses based on observed genotype lack power
5 Redefining Cancer Risk in Lynch syndrome Recent reports employ new analytical tools Modified Segregation Analysis Corrects for ascertainment and overestimation of penetrance Accounts for genotyped and ungenotyped relatives Likelihood for each pedigree conditioned on the phenotype of the pedigree, the probands age of diagnosis and gene mutation carrier status
6 Gastroenterology 2009; 137: Calculation of Risk of Colorectal and Endometrial Cancer Among Patients With Lynch Syndrome Elena Stoffel, Bhramar Mukherjee, Victoria M. Raymond, Nabihah Tayob, Fay Kastrinos, Jennifer Sparr, Fei Wang, Prathap Bandipalliam, Sapna Syngal, Stephen B. Gruber 147 families with deleterious MMR mutations: Dana-Farber Cancer Institute & University of Michigan Cancer Center Modified segregation analysis used to estimate Overall Hazard ratio (HR) estimates Age-specific cumulative risks Results conditioned on genotype and phenotype of probands and CRC phenotype of first-degree relatives
7 HR=148 HR= % Cumulative risk of CRC: Men: 66.1% (95% CI, 59.5%-76.2%) Women: 42.7% (95% CI, 36.6%-52.8%) HR=39 HR=66 Cumulative risk of EC=39.5% (95% CI, 30.8%-46.9%) HR 39.0 (95% CI, ) Cumulative risk for women of CRC or EC 73.4% (63.7%-80.5%)
8 JAMA 2011; 305: Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome Valérie Bonadona, MD, PhD; Bernard Bonaïti, MSc; Sylviane Olschwang, MD, PhD; Sophie Grandjouan, MD; Laetitia Huiart, MD; Michel Longy, MD, PhD; Rosine Guimbaud, MD; Bruno Buecher, MD, PhD; Yves-Jean Bignon, MD, PhD; Olivier Caron, MD; Chrystelle Colas, MD; Catherine Noguès, MD; Sophie Lejeune-Dumoulin, MD; Laurence Olivier-Faivre, MD, PhD; Florence Polycarpe-Osaer, MD; Tan Dat Nguyen, MD; Françoise Desseigne, MD; Jean-Christophe Saurin, MD, PhD; Pascaline Berthet, MD; Dominique Leroux, MD, PhD; Jacqueline Duffour, MD; Sylvie Manouvrier, MD, PhD; Thierry Frébourg, MD, PhD; Hagay Sobol, MD, PhD; Christine Lasset, MD, PhD; Catherine Bonaïti-Pellié, MD, PhD; for the French Cancer Genetics Network. 537 families: 248 with MLH1; 256 with MSH2; 33 with MSH6
9 Gynecological Cancers in Lynch syndrome
10 J Clin Oncol 2012; 30: Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study Aung Ko Win, Joanne P. Young, Noralane M. Lindor, Katherine M. Tucker, Dennis J. Ahnen, Graeme P. Young, Daniel D. Buchanan, Mark Clendenning, Graham G. Giles, Ingrid Winship, Finlay A. Macrae, Jack Goldblatt, Melissa C. Southey, Julie Arnold, Stephen N. Thibodeau, Shanaka R. Gunawardena, Bharati Bapat, John A. Baron, Graham Casey, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Robert W. Haile, John L. Hopper and Mark A. Jenkins 446 unaffected MMR gene mutation carriers + 1,029 unaffected relatives without gene mutations in CCFR Subjects followed every 5 years prospective design minimizes ascertainment bias: observation time for carriers and noncarriers commenced before cancer diagnosis
11 Other Cancer Risks for Carriers and Noncarriers * * * * * From Families With Lynch Syndrome Cancer Carriers Observed No. Expected No. SIR* 95% CI P Colorectal cancer to <.001 Endometrial cancer to <.001 Ovary cancer to <.001 Renal cancer to <.001 Pancreas cancer to Gastric cancer to Urinary bladder cancer to Breast cancer to Prostate cancer to Noncarriers Colorectal cancer to Lung cancer to Breast cancer to Prostate cancer to *Age-, Sex-, and Country-Specific SIRs for Carriers & Noncarriers Compared With the General Population
12 Cumulative Risk (%) Original Contribution. JAMA. 2009;302(16): Risk of Pancreatic Cancer in Families With Lynch Syndrome Fay Kastrinos, MD, MPH; Bhramar Mukherjee, PhD; Nabihah Tayob, MS; Fei Wang, MS; Jennifer Sparr, MD; Victoria M. Raymond, MS; Prathap Bandipalliam, MD; Elena M. Stoffel, MD, MPH; Stephen B. Gruber, MD, MPH, PhD; Sapna Syngal, MD, MPH Age* Cumulative Risk Population % Cumulative Risk MMR Carriers % (95% CI) Population MMR Carriers Age* Hazard Ratio (95% CI) (13.8, 83.6) (0.56, 3.22) (1.52, 6.63) (2.0, 14.2) Overall HR 8.91 (4.35, 18.24) Age (years) Surveillance Epidemiology and End Results
13 Screening for Pancreatic Cancer? Benefit of screening is unknown Screening for pancreatic cancer in Lynch syndrome is not recommended NCCN Consensus Statement US Multi-Society Task Force on CRC Guidelines per European expert consensus Mallorca Research programs related to pancreatic cancer screening in high-risk groups are ongoing Vasen H, et al. Gut 2013; 62: National Comprehensive Cancer Network 2014 Giardiello F, et al. Gastroenterol 2014;147:
14 Breast Cancer: Is it part of the Lynch Syndrome spectrum? Controversial as to whether it is associated Most studies have been limited small numbers, retrospective design, ascertainment bias Evaluation of MMR deficiency in tumors has been included to the epidemiologic approach MSI/IHC are very rare in sporadic breast cancer (0-3%) but observed in >50% of cases diagnosed in MMR carriers
15 Research Article. Breast Cancer Research 2013; 15:R27 Risk of breast cancer in LS: a systematic review Risk of Breast Cancer in Lynch syndrome: a systematic review Aung Ko Win, Noralane M. Lindor, Mark A. Jenkins Molecular studies reporting on MSI/IHC (n=15) Risk studies including confirmed MMR gene mutation carriers or clinically/pathologically defined families (n=21) Results: 13/21 of risk studies did not observe association 8/21 found increased risk of breast cancer ranging from 2- to 18-fold compared with the general population (or non-carriers); only one prospective study: SIR: 3.95, 95% CI:1.59, /122 (51%; 95% CI 42-60%) tumors in carriers were MMR-deficient
16 Risk Estimates of breast cancer in Lynch syndrome Increased risk in MLH1 (18%) Overall risk: 14% MLH1: 17%; MSH2: 14.4%; MSH6: 11% Risk increased after 40 years.
17 MMR deficiency in breast cancer CASE SERIES Author Year Country Method #MMR-deficient breast cancers/ # MMR gene mutation carriers Age, years, mean ± SD Risinger et al USA MSI, IHC 3/5 (60%) NR Muller et al USA MSI, IHC 0/3 (0%) NR de Leeuw et al The Netherlands MSI 7/11 (64%) 43.6 ± 9.2 Blokhuis et al South Africa MSI, IHC 5/6 (83%) 51.8 ± 16.9 Shanley et al Australia MSI, IHC 3/4 (75%) 65.0 ± 12.3 Jensen et al Denmark IHC 7/16 (44%) 50.4 ± 13.1 Walsh et al Australia, USA, Canada MSI, IHC 18/35 (51%) 57.5 ± 8.1 Buerki et al Switzerland MSI, IHC 6/7 (86%) 53.7 ± 15.2 Lotsari et al Finland MSI, IHC 13/20 (65%) 52.7 ± 7.0 Grandval et al France MSI 0/15 (0%) 53.1 ± 10.0
18 Breast Cancer Res. 2012;15:R90 Breast carcinoma and Lynch syndrome: molecular analysis of tumors arising in mutation carriers, non-carriers, and sporadic cases Lotsari JE, Gylling A, Abdel-Rahman WM, Nieminen TT, Aittomaki K, Friman M, Pitkanen R, Aarnio M, Jarvinen HJ, Mecklin JP, Kuopio T, Peltomaki P. Molecular testing of all LS-associated breast cancers in the Hereditary CRC Registry of Finland MMR mutation carriers (n=23) Non-carriers from MMR+ positive families (n=18) Sporadic breast cancers (n=49)
19 Breast cancer and Lynch syndrome MMR deficiency only detected in the MMR+ carriers 13/20 (66%) with loss of IHC; 18/23 (35%) exhibited MSI Heterogeneity in MMR activity by gene Abnormal IHC: 100% MLH1, 73% MSH2, 33% MSH6 MSI-H: 60% MLH1, 45% MSH2, 0% MSH6 Age at diagnosis Most carriers developed breast cancer >50 years No difference between groups (56 years vs 54 years)
20 Breast cancer and Lynch syndrome Screening recommendations should not deviate from those in the general population Are population-based breast cancer screening programs adequate for mutation carriers Large, prospective studies with long-term follow-up are needed
21 Prostate Cancer and Lynch syndrome Increased risk of prostate cancer in carriers been controversial
22 17/1011 carriers Cumulative risks: MSH2: 18% vs MLH1: 0% and MSH6: 4% Ryan S, et al. Cancer Epidemiol Biomarkers Prev 2014; 23:437-49
23 Prostate Cancer Screening Screening for prostate cancer in Lynch Syndrome is not recommended outside of appropriate research studies Ongoing study: screening male MMR gene mutation carriers using DRE+PSA
24 Cancers of the Urinary Tract Risk of urothelial cancers of upper urinary tract: 5-20% Highest risk in male carriers MSH2 gene mutation carriers Prognosis depends on stage and grade of tumors: 5-year survival of non-invasive, low grade cancers: >90% 5-year survival of high grade cancers: 60 70% Recent studies also demonstrate an increased risk of bladder cancer
25 J Med Genet 2010;47: Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers R S van der Post, LA Kiemeney, MJL Ligtenberg, JA Witjes, CA Hulsbergen-van de Kaa, D Bodmer, L Schaap, CM Kets, JHJM van Krieken, N Hoogerbrugge Carriers and FDR of 95 families: MLH1 (n=26), MSH2 (n=43), or MSH6 (n=26) Bladder cancer in 21 patients (90% men) 2 MLH1, 15 MSH2, and 4 MSH6 Average age 60 ± 12 years (range: 41-84) MSI-H: 6/7 tumors; loss of IHC staining: 14/17 tumors
26 Cancers of the Urinary Tract in Lynch syndrome Cumulative Risks by 70 years Gender Bladder Ureter and Pelvis Urinary Tract Overall M= (13) 3.7 (7) 11.2 (20) F= (1) 2.7 (5) 3.7 (7) MLH1 M= (2) 4.8 (1) 15.6 (3) F=148 0 (0) 2.4 (1) 2.4 (1) MSH2 M= (10) 5.9 (5) 18.2 (15) F= (2) 5.8 (4) 8.4 (6) MSH6 M= (1) 1.3 (1) 2.6 (2) F=
27 Screening for Urinary Tract Cancers No consensus on how best to screen Options for urinary tract cancer screening: Urinalysis Urine cytology Abdominal ultrasound Cystoscopy is the gold standard for bladder cancer detection high sensitivity and positive predictive value not considered appropriate for screening in the general population or high risk groups due to its cost, procedural nature, and risks
28 Familial Cancer 2008; 4: Screening for Urinary Tract Cancers Screening for urinary tract cancer with urine cytology in Lynch syndrome and familial colorectal cancer T. Myrhoj, M. B. Andersen, I. Bernstein 977 patients had 1868 screening procedures 3213 person years (median 2.8 years, range ) 14/977 (1.4%) patients developed a urinary cancer: 11 bladder cancers, 3 renal pelvis tumors with invasion 5/14 tumors were interval cancers 11/14 tumors were diagnosed in MSH2 families Urine cytology: Sensitivity of 29%, Specificity of 96% 2 procedures (0.1%) diagnosed asymptomatic tumor 22 subjects had false positive screening diagnosis
29 Screening for Urinary Tract Cancers Urine cytology is not an effective screening method for urinary tract cancer Unknown if there is benefit of surveillance in subgroups of families (eg, those with the MSH2 mutation). Screening for urinary tract cancer in Lynch syndrome varies NCCN: Consider annual UA at years Mallorca group: Consider in research setting USMSTF: Consider annual UA at years
30 Gastric cancer in Lynch syndrome Cumulative risk by age 70 years up to 10% Study of 2013 MMR carriers: Lifetime risk in Men: 8%, Female: 5.3% MLH1: 4.8% (n=737); MSH2: 9% (n=897); MSH6: none diagnosed (n=398) Incidence of gastric cancer depends on geography and time Family G: Gastric cancer>>crc; familial clustering Correlates with HPylori prevalence Recent studies show no evidence for clustering in specific families Screening: USMSTF: Start at years and q3-5 years Mallorca: Screen >25 years for HPylori; EGD recommended in LS families from countries with high incidence of gastric cancer NCCN: Select individuals or families or those of Asian descent (30-35 years) Capelle LG, et al. Gastroenterol 2010; 138:
31 Cancer of the Small Bowel in Lynch Syndrome Risk of small bowel cancer in carriers ~5% For MLH1 or MSH2 gene mutation carriers, rare in MSH6 Tumors locations mainly: proximal small bowel (43%), jejunum (33%), ileum (7%) Screening for small bowel cancer is not recommended in Lynch syndrome As locations are frequently in duodenum and ileum, close inspection of the distal duodenum during EGD and ileum during colonoscopy is appropriate
32 J Natl Cancer Inst 2012;104: Risks Cancer of Primary Risks Extracolonic following Cancers Colorectal Following Colorectal Cancer Cancer in Lynch Syndrome Aung Ko Win, Noralane M. Lindor, Joanne P. Young, Finlay A. Macrae, Graeme P. Young, Elizabeth Williamson, Susan Parry, Jack Goldblatt, Lara Lipton, Ingrid Winship, Barbara Leggett, Katherine M. Tucker, Graham G. Giles, Daniel D. Buchanan, Mark Clendenning, Christophe Rosty, Julie Arnold, A. Joan Levine, Robert W. Haile, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, John L. Hopper, Mark A. Jenkins
33 Extracolonic Cancers following Colorectal Cancer
34 Future Considerations Evaluation of the MMR mutation spectrum Impact of genetic modifiers/environmental factors Collaborative prospective, long-term studies are necessary Studies on the effectiveness of screening programs related to extracolonic cancers associated with Lynch syndrome
Elevated Risk of Prostate Cancer Among Men With Lynch Syndrome
Published Ahead of Print on March 25, 2013 as 10.1200/JCO.2012.44.1238 The latest version is at http://jco.ascopubs.org/cgi/doi/10.1200/jco.2012.44.1238 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E
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