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Su1947 Risk of Thyroid Cancer Among Caribbean Hispanic Patients With Familial Adenomatous Polyposis: A Population-Based Study
Su1948
AGA Abstracts
Cost-Effectiveness of Routine Screening for Lynch Syndrome in Colorectal Cancer Patients up to 70 Years of Age Anne Goverde, Celine H. Leenen, Esther W. Bekker-de Grob, Anja Wagner, Margot G. van Lier, Manon C. Spaander, Marco J. Bruno, Carli Tops, Ans Van den Ouweland, Erik Jan Dubbink, Ernst J. Kuipers, W. Dinjens, Monique E. van Leerdam, Ewout W. Steyerberg Introduction: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC). Identifying LS carriers among CRC patients is of great importance, since surveillance programs for their affected relatives can reduce CRC morbidity and mortality by 56-70%. However, many LS carriers are still not identified. Routine molecular screening for LS among CRC patients was recently recommended by the AGA. The aim of this study was to assess the cost-effectiveness of routine molecular screening for LS in CRC patients up to 70 years of age. Methods: A population-based series of CRC patients aged ≤70 years was routinely screened for LS by analysis of microsatellite instability, immunohistochemistry and MLH1 hypermethylation, followed by germline mutation analysis in indicated cases. Effectiveness of screening was expressed in life years gained (LYG), based on the number of LS carriers detected among CRC patients and their relatives. Total costs consisted of LS diagnostics and surveillance, including gynaecological surveillance and prophylactic surgery for female LS carriers. Future costs and benefits were discounted at 3% annually. We calculated incremental cost-effectiveness ratios (ICERs) comparing different age cut-offs and comparing age-targeted screening with the revised Bethesda guidelines. One-way sensitivity analyses were performed to test the robustness of ICERs. Results: Screening among 1117 CRC patients identified 23 LS carriers, of whom 7 were ≤50, 7 were 51-60 and 9 were 6170 years of age. Additionally, 70 LS carriers were identified among relatives (14, 42 and 14 per age category respectively). Overall, screening amounted to 76.0 LYG or 15.9, 43.9 and 16.1 LYG per age category. Total costs for LS screening and surveillance increased from ¤232,573 (¤11,075 per LS carrier detected) for LS screening among CRC patients ≤50 years of age to ¤1,056,916 (¤11,365 per LS carrier detected) for screening CRC patients ≤70 years of age (Figure 1). ICERs were ¤11,541/LYG for LS screening in CRC patients ≤60 years compared with ≤50 years and ¤19,699/LYG for screening CRC patients ≤70 years compared with ≤60 years. The revised Bethesda guidelines identified 17/23 (74%) LS carriers among CRC patients and 53/70 (76%) LS carriers among relatives. The ICER for LS screening in CRC patients ≤70 years of age was ¤20,174/LYG compared with LS screening according to the revised Bethesda guidelines. The ICERs were most sensitive to the assumed LYG by relatives. All ICERs remained <¤27,000/LYG (<$32,000/LYG) in sensitivity analyses. Conclusion: Routine LS screening by analysis of microsatellite instability, immunohistochemistry, and MLH1 hypermethylation in CRC patients up to 70 years of age is a cost-effective strategy according to currently accepted standards, with important clinical benefits for LS carriers among CRC patients and their relatives.
Su1946 Clinical Characterization and Mutation Spectrum in Caribbean Hispanic Families With Lynch Syndrome: Molecular and Social Disparities Marcia R. Cruz-Correa, Yaritza Diaz-Algorri, Sofia Margarita Lopez-Diaz, Julyann PerezMayoral, Maria del Mar Gonzalez-Pons, Francis M. Giardiello Background Lynch Syndrome is an inherited form of colorectal cancer caused by germline mutations in the Mismatch Repair (MMR) genes. It accounts for approximately 5% of all colorectal cancers. The prevalence of Lynch Syndrome among US Hispanics is unknown. The objective of this study was to describe the germline mutation spectrum and clinicopathological associations of Lynch Syndrome in Caribbean Hispanics from Puerto Rico and Dominican Republic. Methods Subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry between January 2010 to June 2014 and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. Results 89 CRC Caribbean Hispanic patients, with suspected LS were referred to the Hereditary Cancer Clinic. Nine-teen (21.3%) patients met Amsterdam Criteria (I/II) and 70 (78.7%) met Bethesda guidelines. From the 89 patients who received genetic counseling, 31 had direct MMR germline analysis and 21 (71.0%) had a germline mutation in one of the MMR genes. The mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7 %) mutations, followed by MLH1 (25.0 %). Only one mutation was identified in MSH6 (8.3 %). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutationpositive individuals were more likely to have a prominent family history of CRC and tumors located at the proximal colon compared to MMR mutation-negative CRC patients. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC, earlier age at diagnosis and LS-associated cancers. Insurance coverage for genetic testing was found to be limited in the study population with most patients (66%) of the individuals been denied coverage. Conclusions This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 mutations, followed by MLH1. Due to genetic ancestry background differences among Caribbean Hispanics, compared to other Hispanics groups, there is potential for identifying novel MMR mutations associated with LS and Variables of unknown significance (VUS). Future studies should be directed towards understanding the differences in the mutation spectrum of Hispanic LS patients and implementation of widespread clinical guidelines for LS screening according to the National Comprehensive Cancer Network. Su1947
Figure 1. Total costs and life years gained (LYG) for Lynch Syndrome screening in colorectal cancer patients ≤50 years, ≤60 years and ≤70 years of age. Incremental cost-effectiveness ratios (ICERs) are expressed as incremental cost per additional LYG, relative to the previous strategy.
Risk of Thyroid Cancer Among Caribbean Hispanic Patients With Familial Adenomatous Polyposis: A Population-Based Study Marcia R. Cruz-Correa, Nicolas Casellas, Yaritza Diaz-Algorri, Carlos E. BertranRodriguez, Marievelisse Soto-Salgado, Francis M. Giardiello
Su1949 Comparison of Pathogenic APC and Biallelic MUTYH Mutations Between Ashkenazi Jews and Non-Ashkenazi Jews With Colorectal Adenomas Zohar Levi, Jennifer Inra, Chinedu Ukaegbu, Anu Chittenden, Ewout W. Steyerberg, Shilpa Grover, Fay Kastrinos, Sapna Syngal
Background & Aims: Familial adenomatous polyposis (FAP) is an inherited form of colorectal cancer (CRC) characterized by the presence of hundreds of adenomatous polyps in the colon and rectum. FAP is also associated with thyroid cancer (TC), but the lifetime risk is still unknown. This study assessed the standardized incidence ratio of TC in Hispanic patients with FAP. Methods: The incidence rates of TC in patients with FAP were compared with the general population through direct database linkage from the Puerto Rico Central Cancer Registry (PRCCR) and the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR) between the periods of January 1, 2006 to December 31, 2013. Due to the limited number of TC cases in the general pediatric (19 or less) PRH population (n=47, 1.43%), we excluded all patients with FAP equal or younger than 19 years of age (n=11, 17%). The Standardized incidence ratio (SIR) was calculated using the Indirect Method, defined as observed TC incidence among patients with FAP in PURIFICAR's cohort divided by the expected TC incidence based on the PR population rates. This study received IRB approval (protocol # A2210207). Results: The study population consisted of 51 Hispanic patients with FAP and 3,239 individuals with thyroid cancer from the general Hispanic population. The age of diagnosis for TC ranged between the ages of 27 and 52 with a mean age (SD) of 39.75 (10.21) years. Thyroid cancers among FAP patients were the cribriform-morular variant of papillary thyroid cancer. In Hispanic patients with FAP the Standardized Incidence Risk (SIR) (95% CI) for TC was 251.73 (51.91 - 735.65), with higher risk for females 461.18 (55.85-1665.94) than males 131.91 (3.34-734.95). Conclusions: Hispanic patients with FAP are at a high risk for TC compared to the general population. Our incidence rates (SIR) are higher than previous studies, suggesting that this Hispanic FAP community may be at a higher risk for thyroid malignancy than previously assumed. Implementation of clinical surveillance guidelines and regular ultrasound neck screening in Hispanic patients with this syndrome is recommended.
AGA Abstracts
Background: Evaluating the outcomes of genetic testing in ethnic populations has enabled the development of high-yield test panels. Among Ashkenazi Jews, there are three founder mutations that occur frequently in the BRCA1 and BRCA2 genes. This mutation panel is often the initial genetic test in persons of Ashkenazi descent being evaluated for Hereditary Breast and Ovarian Cancer syndrome. To explore this in polyposis, we compared the frequency of APC and MUTYH alterations between Ashkenazi Jews (AJ) and non-Ashkenazi Jews (NAJ) with colorectal adenomas. Methods: A cross-sectional study conducted in 5236 subjects with colorectal adenomas who underwent full gene sequencing and large rearrangement analysis of the APC gene and DNA sequence analysis for the two common Caucasian MUTYH mutations (p.Y165C, p.G382D). Individuals with either mutation had subsequent MUTYH full sequencing. We compared the prevalence of pathogenic APC and MUTYH mutations by adenoma count in AJ and NAJ and evaluated the phenotype of APC*I1307K carriers using multivariable logistic regression analysis controlling for age, gender, adenoma count and family history of colorectal cancer (CRC). Results: Pathogenic APC mutations were found in 22/208 AJ (10.6%) and 983/5028 NAJ (19.6%; p=0.0008) and biallelic MUTYH mutations in 1 (0.5%) AJ and 286 (5.7%) NAJ (p=0.0001). The prevalence of pathogenic APC or MUTYH mutations was 10/23 (43.5%) and 745/1139 (65.4%) in subjects with ≥ 100 adenomas (p=0.04), 10/98 (10.2%) and 414/2379 (17.4%) with 20-99 adenomas (p=0.07), 3/40 (7.5%) and 58/686 (8.5%) with 10 -19 adenomas (p=1) and 0/47 (0%) and 52/824 (6.3%) with 1-9 adenomas (p=0.11), in AJ and NAJ respectively. In AJ, the R332X alteration in the APC gene was the most common pathogenic mutation and was present in
S-558
AGA Abstracts
Cost-Effectiveness of Routine Screening for Lynch Syndrome in Colorectal Cancer Patients up to 70 Years of Age Anne Goverde, Celine H. Leenen, Esther W. Bekker-de Grob, Anja Wagner, Margot G. van Lier, Manon C. Spaander, Marco J. Bruno, Carli Tops, Ans Van den Ouweland, Erik Jan Dubbink, Ernst J. Kuipers, W. Dinjens, Monique E. van Leerdam, Ewout W. Steyerberg Introduction: Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC). Identifying LS carriers among CRC patients is of great importance, since surveillance programs for their affected relatives can reduce CRC morbidity and mortality by 56-70%. However, many LS carriers are still not identified. Routine molecular screening for LS among CRC patients was recently recommended by the AGA. The aim of this study was to assess the cost-effectiveness of routine molecular screening for LS in CRC patients up to 70 years of age. Methods: A population-based series of CRC patients aged ≤70 years was routinely screened for LS by analysis of microsatellite instability, immunohistochemistry and MLH1 hypermethylation, followed by germline mutation analysis in indicated cases. Effectiveness of screening was expressed in life years gained (LYG), based on the number of LS carriers detected among CRC patients and their relatives. Total costs consisted of LS diagnostics and surveillance, including gynaecological surveillance and prophylactic surgery for female LS carriers. Future costs and benefits were discounted at 3% annually. We calculated incremental cost-effectiveness ratios (ICERs) comparing different age cut-offs and comparing age-targeted screening with the revised Bethesda guidelines. One-way sensitivity analyses were performed to test the robustness of ICERs. Results: Screening among 1117 CRC patients identified 23 LS carriers, of whom 7 were ≤50, 7 were 51-60 and 9 were 6170 years of age. Additionally, 70 LS carriers were identified among relatives (14, 42 and 14 per age category respectively). Overall, screening amounted to 76.0 LYG or 15.9, 43.9 and 16.1 LYG per age category. Total costs for LS screening and surveillance increased from ¤232,573 (¤11,075 per LS carrier detected) for LS screening among CRC patients ≤50 years of age to ¤1,056,916 (¤11,365 per LS carrier detected) for screening CRC patients ≤70 years of age (Figure 1). ICERs were ¤11,541/LYG for LS screening in CRC patients ≤60 years compared with ≤50 years and ¤19,699/LYG for screening CRC patients ≤70 years compared with ≤60 years. The revised Bethesda guidelines identified 17/23 (74%) LS carriers among CRC patients and 53/70 (76%) LS carriers among relatives. The ICER for LS screening in CRC patients ≤70 years of age was ¤20,174/LYG compared with LS screening according to the revised Bethesda guidelines. The ICERs were most sensitive to the assumed LYG by relatives. All ICERs remained <¤27,000/LYG (<$32,000/LYG) in sensitivity analyses. Conclusion: Routine LS screening by analysis of microsatellite instability, immunohistochemistry, and MLH1 hypermethylation in CRC patients up to 70 years of age is a cost-effective strategy according to currently accepted standards, with important clinical benefits for LS carriers among CRC patients and their relatives.
Su1946 Clinical Characterization and Mutation Spectrum in Caribbean Hispanic Families With Lynch Syndrome: Molecular and Social Disparities Marcia R. Cruz-Correa, Yaritza Diaz-Algorri, Sofia Margarita Lopez-Diaz, Julyann PerezMayoral, Maria del Mar Gonzalez-Pons, Francis M. Giardiello Background Lynch Syndrome is an inherited form of colorectal cancer caused by germline mutations in the Mismatch Repair (MMR) genes. It accounts for approximately 5% of all colorectal cancers. The prevalence of Lynch Syndrome among US Hispanics is unknown. The objective of this study was to describe the germline mutation spectrum and clinicopathological associations of Lynch Syndrome in Caribbean Hispanics from Puerto Rico and Dominican Republic. Methods Subjects were recruited through the Puerto Rico Familial Colorectal Cancer Registry between January 2010 to June 2014 and were classified according to Amsterdam and Bethesda clinical guidelines. For those tumors with lack of expression of MMR protein, gene sequencing was ordered. Results 89 CRC Caribbean Hispanic patients, with suspected LS were referred to the Hereditary Cancer Clinic. Nine-teen (21.3%) patients met Amsterdam Criteria (I/II) and 70 (78.7%) met Bethesda guidelines. From the 89 patients who received genetic counseling, 31 had direct MMR germline analysis and 21 (71.0%) had a germline mutation in one of the MMR genes. The mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 (66.7 %) mutations, followed by MLH1 (25.0 %). Only one mutation was identified in MSH6 (8.3 %). A previously unidentified mutation in MLH1 gene c.2044_2045del was found in one Caribbean Hispanic family. MMR mutationpositive individuals were more likely to have a prominent family history of CRC and tumors located at the proximal colon compared to MMR mutation-negative CRC patients. Compared to MSH2 mutation carriers, MLH1 mutation-positive individuals were more likely to have a strong family history of CRC, earlier age at diagnosis and LS-associated cancers. Insurance coverage for genetic testing was found to be limited in the study population with most patients (66%) of the individuals been denied coverage. Conclusions This report presents the first description of the mutation spectrum and clinicopathologic characteristics of LS Caribbean Hispanics patients. Our results show that the mutation spectrum of Caribbean Hispanic LS patients was composed mostly of MSH2 mutations, followed by MLH1. Due to genetic ancestry background differences among Caribbean Hispanics, compared to other Hispanics groups, there is potential for identifying novel MMR mutations associated with LS and Variables of unknown significance (VUS). Future studies should be directed towards understanding the differences in the mutation spectrum of Hispanic LS patients and implementation of widespread clinical guidelines for LS screening according to the National Comprehensive Cancer Network. Su1947
Figure 1. Total costs and life years gained (LYG) for Lynch Syndrome screening in colorectal cancer patients ≤50 years, ≤60 years and ≤70 years of age. Incremental cost-effectiveness ratios (ICERs) are expressed as incremental cost per additional LYG, relative to the previous strategy.
Risk of Thyroid Cancer Among Caribbean Hispanic Patients With Familial Adenomatous Polyposis: A Population-Based Study Marcia R. Cruz-Correa, Nicolas Casellas, Yaritza Diaz-Algorri, Carlos E. BertranRodriguez, Marievelisse Soto-Salgado, Francis M. Giardiello
Su1949 Comparison of Pathogenic APC and Biallelic MUTYH Mutations Between Ashkenazi Jews and Non-Ashkenazi Jews With Colorectal Adenomas Zohar Levi, Jennifer Inra, Chinedu Ukaegbu, Anu Chittenden, Ewout W. Steyerberg, Shilpa Grover, Fay Kastrinos, Sapna Syngal
Background & Aims: Familial adenomatous polyposis (FAP) is an inherited form of colorectal cancer (CRC) characterized by the presence of hundreds of adenomatous polyps in the colon and rectum. FAP is also associated with thyroid cancer (TC), but the lifetime risk is still unknown. This study assessed the standardized incidence ratio of TC in Hispanic patients with FAP. Methods: The incidence rates of TC in patients with FAP were compared with the general population through direct database linkage from the Puerto Rico Central Cancer Registry (PRCCR) and the Puerto Rico Familial Colorectal Cancer Registry (PURIFICAR) between the periods of January 1, 2006 to December 31, 2013. Due to the limited number of TC cases in the general pediatric (19 or less) PRH population (n=47, 1.43%), we excluded all patients with FAP equal or younger than 19 years of age (n=11, 17%). The Standardized incidence ratio (SIR) was calculated using the Indirect Method, defined as observed TC incidence among patients with FAP in PURIFICAR's cohort divided by the expected TC incidence based on the PR population rates. This study received IRB approval (protocol # A2210207). Results: The study population consisted of 51 Hispanic patients with FAP and 3,239 individuals with thyroid cancer from the general Hispanic population. The age of diagnosis for TC ranged between the ages of 27 and 52 with a mean age (SD) of 39.75 (10.21) years. Thyroid cancers among FAP patients were the cribriform-morular variant of papillary thyroid cancer. In Hispanic patients with FAP the Standardized Incidence Risk (SIR) (95% CI) for TC was 251.73 (51.91 - 735.65), with higher risk for females 461.18 (55.85-1665.94) than males 131.91 (3.34-734.95). Conclusions: Hispanic patients with FAP are at a high risk for TC compared to the general population. Our incidence rates (SIR) are higher than previous studies, suggesting that this Hispanic FAP community may be at a higher risk for thyroid malignancy than previously assumed. Implementation of clinical surveillance guidelines and regular ultrasound neck screening in Hispanic patients with this syndrome is recommended.
AGA Abstracts
Background: Evaluating the outcomes of genetic testing in ethnic populations has enabled the development of high-yield test panels. Among Ashkenazi Jews, there are three founder mutations that occur frequently in the BRCA1 and BRCA2 genes. This mutation panel is often the initial genetic test in persons of Ashkenazi descent being evaluated for Hereditary Breast and Ovarian Cancer syndrome. To explore this in polyposis, we compared the frequency of APC and MUTYH alterations between Ashkenazi Jews (AJ) and non-Ashkenazi Jews (NAJ) with colorectal adenomas. Methods: A cross-sectional study conducted in 5236 subjects with colorectal adenomas who underwent full gene sequencing and large rearrangement analysis of the APC gene and DNA sequence analysis for the two common Caucasian MUTYH mutations (p.Y165C, p.G382D). Individuals with either mutation had subsequent MUTYH full sequencing. We compared the prevalence of pathogenic APC and MUTYH mutations by adenoma count in AJ and NAJ and evaluated the phenotype of APC*I1307K carriers using multivariable logistic regression analysis controlling for age, gender, adenoma count and family history of colorectal cancer (CRC). Results: Pathogenic APC mutations were found in 22/208 AJ (10.6%) and 983/5028 NAJ (19.6%; p=0.0008) and biallelic MUTYH mutations in 1 (0.5%) AJ and 286 (5.7%) NAJ (p=0.0001). The prevalence of pathogenic APC or MUTYH mutations was 10/23 (43.5%) and 745/1139 (65.4%) in subjects with ≥ 100 adenomas (p=0.04), 10/98 (10.2%) and 414/2379 (17.4%) with 20-99 adenomas (p=0.07), 3/40 (7.5%) and 58/686 (8.5%) with 10 -19 adenomas (p=1) and 0/47 (0%) and 52/824 (6.3%) with 1-9 adenomas (p=0.11), in AJ and NAJ respectively. In AJ, the R332X alteration in the APC gene was the most common pathogenic mutation and was present in
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