Sesión de controversia: Cáncer Hereditario

Presentación del tema: "Sesión de controversia: Cáncer Hereditario"— Transcripción de la presentación:

1 Sesión de controversia: Cáncer Hereditario
Mutaciones en genes de moderada penetrancia y variantes de efecto desconocido ¿se deben informar? ¿cuáles deben ser las recomendaciones de seguimiento? T. Ramón y Cajal

2 Conflictos interés Inscripción y gastos de transporte/hotel congresos: Pfizer, Roche

3 Mutaciones en genes de moderada penetrancia y variantes de significado incierto ¿se deben informar?

4 Frecuencia del cáncer hereditario
Mama 10% (no seleccionada), 4.2 % (poblacional) Ovario 24% (no seleccionado) - Colon 10% (no seleccionada) Próstata 12% (metastásico no seleccionado) Páncreas 4% (no seleccionado) Tung et al, JCO 2016; Yurgelum et al, JCO2017, Pritchard et al, NEJM2016, Norquist et al, JAMA Oncol 2016; Couch et al, JAMA Oncol 2017; Walsh et al, Proc Natl Acad Sci USA 2011

5 Walsh et al, Proc Natl Acad Sci USA 2011; Buys et al Cancer 2017
Mutaciones en genes de moderada penetrancia 1-9% individuos In studies in the past 3–5 years, investigators have identified moderate-penetrance mutations in 1.1–9.4% of individuals tested; some of these mutations are potentially actionable RIESGO ALTO RR >5 RIESGO MODERADO RR 2-5 Easton et al, NEJM 2015; Hollestelle et al Curr Opin Genet Dev. 2010; Pritchard et al, NEJM 2016; Walsh et al, Proc Natl Acad Sci USA 2011; Buys et al Cancer 2017

6 Prevalencia GEN N mut % portadores 1643/94845 1.73 867/95853 0.90
CHEK2* (truncantes) 1643/94845 1.73 PALB2* 867/95853 0.90 ATM* 920/94787 0.97 BRIP1 293/97539 0.30 (1) MSH6 167/72333 0.23 RAD51C 149/95616 0.15 (0.55) RAD51D 73/88970 0.08 (0.58) BARD1 201/97426 0.21 NBN 167/98096 0.17 APC*I1307K 7% askenazis MYH monoalelica 2 * HF CM NO factores clínicos predictivos de mutación en los genes de moderado riesgo The examination of larger cohorts of women with mutations in each gene will like- ly be required to identify gene-specific predictors. It is important to establish stringent levels of statistical significance. Although it would be ideal to have specific evidence for every variant detected, most variants for which there is a suspicion of association with a high risk of disease are rare, and the sample sizes required to establish allele-specific associations with risk are so large as to make the task infeasible. Consequently, some form of burden testing is frequently used in which the association between carrying any variant in a specific class and the risk of disease is evaluated. A potential problem with this method is that it does not indicate whether any specific variant identified is associated with disease. It is often assumed that all protein-truncating variants are equally pathogenic; however, all such variants do not confer the same risks. For missense variants, the situation is even more problematic (Easton) Suszynska et al, Gynecol Oncol 2019

7 Panel germinal en CMH Cohorte retrospectiva de base poblacional de casos CM 25% CM estudiados Estudio panel >>> BRCA1/2 Panel x2 detección mutación 4% sólo BRCA- 12% panel VUS x10 The examination of larger cohorts of women with mutations in each gene will like- ly be required to identify gene-specific predictors. It is important to establish stringent levels of statistical significance. Although it would be ideal to have specific evidence for every variant detected, most variants for which there is a suspicion of association with a high risk of disease are rare, and the sample sizes required to establish allele-specific associations with risk are so large as to make the task infeasible. Consequently, some form of burden testing is frequently used in which the association between carrying any variant in a specific class and the risk of disease is evaluated. A potential problem with this method is that it does not indicate whether any specific variant identified is associated with disease. It is often assumed that all protein-truncating variants are equally pathogenic; however, all such variants do not confer the same risks. For missense variants, the situation is even more problematic (Easton) RESULTS Among 5026 patients (mean [SD] age, 59.9 [10.7]), 1316 (26.2%)were linked to genetic results from any laboratory. Multiple-gene sequencing increasingly replaced BRCA1/2-only testing over time: in 2013, the rate of multiple-gene sequencingwas 25.6%and BRCA1/2-only testing, 74.4%;in 2015 the rate of multiple-gene sequencingwas 66.5%and BRCA1/2-only testing, 33.5%. Multiple-gene sequencingwas more often ordered by genetic counselors (multiple-gene sequencing, 25.5%and BRCA1/2-only testing, 15.3%) and delayed until after surgery (multiple-gene sequencing, 32.5%and BRCA1/2-only testing, 19.9%). Multiple-gene sequencing substantially increased rate of detection of any pathogenic variant (multiple-gene sequencing: higher-risk patients, 12%; average-risk patients, 4.2%and BRCA1/2-only testing: higher-risk patients, 7.8%; average-risk patients, 2.2%) and variants of uncertain significance, especially in minorities (multiple-gene sequencing: white patients, 23.7%; black patients, 44.5%; and Asian patients, 50.9%and BRCA1/2-only testing: white patients, 2.2%; black patients, 5.6%; and Asian patients, 0%). Multiple-gene sequencingwas not associated with an increase in the rate of prophylactic mastectomy use, whichwas highest with pathogenic variants in BRCA1/2 (BRCA1/2, 79.0%; other pathogenic variant, 37.6%; variant of uncertain significance, 30.2%; negative, 35.3%). CONCLUSIONS AND RELEVANCE Multiple-gene sequencing rapidly replaced BRCA1/2-only testing for patients with breast cancer in the community and enabled 2-fold higher detection of clinically relevant pathogenic variants without an associated increase in prophylactic mastectomy.However, important targets for improvement in the clinical utility of multiple-gene sequencing include postsurgical delay and racial/ethnic disparity in variants of uncertain significance. Kurian et al JAMA Oncol 2018

8 Genes de moderada penetrancia
SÓLO se justifica en los casos en los que hay mayor evidencia sobre el grado de asociación al desarrollo de tumores (VALIDEZ CLÍNICA) y en espera de demostrar la mejora del curso evolutivo de los individuos testados (UTILIDAD CLÍNICA)

9 MAMA GEN Couch et al, JAMA Oncol 2017 Suszynska et al,
Gynecol Oncol 2019 PALB2 7.5 ( ) 4.79 ( ) ATM 2.78 ( ) 2.4 ( ) CHEK 2 - Truncantes - Missense 2.3 ( ) 1.5 ( ) 1.7 ( )* NBN (c.657del5) NBN 1 1 ( ) BARD1 2.2 ( ) 2.3 (1.8-3) BRIP1 1.6 ( ) 1.3 ( ) RAD51C 0.8 ( ) 1.1 ( ) RAD51D 3.1 ( ) 1.2 ( ) RR inconstantes Intervalos de confianza Homocigosidad Diferencias poblacionales Factores modificadores riesgo genéticos y no genéticos CHEK2 (0.3% CM homocigotos y 5% heterocigotos pob.holandesa) In the Netherlands, CHEK2 mutations are much more common because 1.2% of the population is heterozygous for the 1100delC mutation. A single germline 1100delC mutation in CHEK2 is seen in 5% of Dutch women with breast cancer and homozygous mutations are found in 0.3%.5 La HF modificador de riesgo para CHEK2 y PALB2 *after exclusion of two common variants: c.470T>C, and c.1283C>T * Exclusión c.470T>C & c.1283C>T

10 Fenotipo CM 5589 p BRCA1/2 negativas vs 2189 controles
ATM OR 3.6 ( ) CHEK2 OR 2.9 ( ) PALB2 OR 9.5 ( ) In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors. 5589 p BRCA1/2 negativas vs 2189 controles Panel: ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, y TP53

11 Fenotipo CM IMultigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium (TNBCC)n this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors. 8753 CMTN seleccionados por HF (21 genes) & 2148 CMTN no seleccionados (17 genes) Shimelis et al, JNCI 2018

12 OVARIO GEN Liliquist et al Gyn Onc 2017 Suszynska et al,
Gynecol Oncol 2019 PALB2 3.08 ( ) 1.16 ( ) 2.1 ( ) ATM 2.25 ( ) 1.9 ( ) BRIP1 4.99 ( ) 4.8 ( ) RAD51C 5.12 ( ) 4.2 (2.5-7) RAD51D 6.34 ( ) 7.2 (4-13.1) MSH2 3.9 ( ) MLH1 1.4 ( ) MSH6 4 ( ) PALB2 mutations were linked to ovarian-cancer risk in two studies, but the associations were not uniformly statistically significant; for BARD1 the results of only one of these studies indicated an increased ovarian cancer risk29, but coinheritance of BRCA1 mutations confounded the potential association.

13 COLON GEN OR (IC 95%) REFERENCIA
CHEK2 (1100delC)* 1.88 (1.29–2.73) Ma et al, Gut 2014 CHEK2 ( I157T) 1.56 ( 1.32–1.84) APC** (I1307K) 1.96 (1.37–2.79) Locker et al, Fam Cancer 2004 MYH (monoalélica) 1.61 (1.40–1.87) colorectal cancer (CRC); however, the common CHEK2 mutation 1100delC, the Ashkenazi founder APC mutation I1307K, and monoallelic mutations in MUTYH are all associated with CRC risk, although the level of risk conferred by these mutations is less than that associated with having a first-degree relative affected with the disease (RR 2.25)32, 33 *Historia familiar de CCR es un modificador de riesgo ** Mutación fundadora askenazi Katona et al, Gen Med 2018 Riesgos inferiores a HF 1 FPG con CCR (RR 2.25, 2.53)

14 PÁNCREAS PRÓSTATA GEN OR (IC 95%) REFERENCIA GEN OR (IC 95%)
ATM (LOF) 3.81 ( ) Helgason et al Nat Genet 2015 PRÓSTATA GEN OR (IC 95%) REFERENCIA CHEK2 (1100delC) 3.29 ( ) Wang et al Int J Clin Exp Med 2015 CHEK2 ( I157T) 1.8 ( ) ATM (LOF) 2.18 ( ) Helgason et al Nat Genet 2015 colorectal cancer (CRC); however, the common CHEK2 mutation 1100delC, the Ashkenazi founder APC mutation I1307K, and monoallelic mutations in MUTYH are all associated with CRC risk, although the level of risk conferred by these mutations is less than that associated with having a first-degree relative affected with the disease (RR 2.25)32, 33 NO hay datos de OR de PALB2 o CHEK2 en Cpa. APC es un gen asociado con increased PC risk by 4.5-fold y RR 1.7% at 80 years of age (Giardiello, F.M.; Offerhaus, G.J.; Lee, D.H.; Krush, A.J.; Tersmette, A.C.; Booker, S.V.; Kelley, N.C.; Hamilton, S.R. Increased risk of thyroid and pancreatic carcinoma in familial adenomatous polyposis. Gut 1993, 34, 1394–1396.)

15 ¿Se deben informar las variantes en los genes de moderado riesgo?
Sí, las VP o VPP cuando su presencia modifica el manejo preventivo (accionable) American college of medical genetics and genomics and the association for molecular pathology variant classification guidelines. The value of multigene-panel testing remains controversial, however, because of the uncertainty regarding the strength of association between mutations in some genes and the development of cancer (clinical validity)3, and a lack of evidence demonstrating improved outcomes for the individuals tested (clinical utility)16.the appropriate management of individuals harbouring such moderate-penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-penetrance genes are lower and different than those reported for high penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch síndrome Paradoxically in recent years, the introduction of cost- effective multigene panel sequencing in diagnostics laborato- ries has led to an explosion of genetic data in cancer-prone families. Very often, 20–25 genes or more are being screened in parallel to BRCA1 and BRCA2 in HBOC families,4 but data attributing a causative role for potentially deleterious variants identified in many of these genes are usually lacking, and pre- cise risk estimates per variant category ACMG Guidelines 2015

16 Multigene testing of moderate-risk genes: be mindful of the missense
ATM, CHEK2 Variantes truncantes o splicing/missense 1:2 o 1:3 BRCA1/2 Variantes truncantes o splicing/missense: 10:1 Young et al, Cancer Genet 2016; Suszynska et al, Gynecol Oncol 2019

17 LoF en CHEK2 se asocia a diagnostico más temprano
Distintos tipos de VP o VPP en un gen se asocian a diferentes niveles de riesgo LoF en CHEK2 se asocia a diagnostico más temprano LoF ATM (OR 17) >>> missense (OR 1.6) Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study and implications for multigene panel testing The purpose of our study was to assess the contribution of rare, deleterious-predicted variants in DNA repair genes in familial breast cancer (BC) in a well-characterized and homogeneous population. We analyzed 113 DNA repair genes selected from either an exome sequencing or a candidate gene approach in the GENESIS study, which includes familial BC cases with no BRCA1 or BRCA2 mutation and having a sister with BC (N = 1,207), and general population controls (N = 1,199). Sequencing data were filtered for rare loss-of-function variants (LoF) and likely deleterious missense variants (MV). We confirmed associations between LoF and MV in PALB2, ATM and CHEK2 and BC occurrence. We also identified for the first time associations between FANCI, MAST1, POLH and RTEL1 and BC susceptibility. Unlike other associated genes, carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; pHet = 0.002). Hence, our approach allowed us to specify BC relative risks associated with deleterious-predicted variants in PALB2, ATM and CHEK2 and to add MAST1, POLH, RTEL1 and FANCI to the list of DNA repair genes possibly involved in BC susceptibility. We also highlight that different types of variants within the same gene can lead to different risk estimates. What’s new? Pathogenic variants in BRCA1 and BRCA2 only explain the genetic cause of about 10% of hereditary breast and ovarian cancer families, and the clinical usefulness of testing other genes following the recent introduction of cost-effective multigene panel sequencing in diagnostics laboratories remains questionable. This large case-control study describes genetic variation in 113 DNA repair genes and specifies breast cancer relative risks associated with rare deleterious- predicted variants in PALB2,ATM,and CHEK2. Importantly, different types of variants within the same gene can lead to different risk estimates. The results may help improve risk prediction models and define gene-specificconsensus management guidelines. Most of the known pathogenic variants associated with BC are LoF (i.e. frameshift, stop-gain and canonical splice variants predicted to result in a truncated protein)19 but a significant fraction of BC risk may be attribut- able to rare MV in some genes such as ATM, CHEK2 and TP53,9,11,20 and this fraction may be even bigger than that attrib- utable to LoF  An average of 18.2 (11–29) LoF, 6.8 (1–14) inframe indels and (105–170) MV were identified per individual. Targeted sequencing of the 113 genes identified 3,930 distinct variants with MAF lower than 0.5% in GENESIS controls. These included 264 LoF variants (155 in cases and 132 in controls) and 1,994 MV bioinformatically predicted to alter protein function or stability (1,213 in cases and 1,103 in controls). Both LoF and MV in PALB2, ATM and CHEK2 were associ- ated with an increased BC risk, but carriers of an ATMLoF had a significantly higher risk ofdeveloping BC than carriers ofan ATM MV (ORLoF = 17.4 vs. ORMV =1.6; pHet = 0.002) (Table 2). In con- trast for CHEK2 and PALB2 there was no significant heterogeneity in risk according to variant type (CHEK2:ORLoF + MV = 3.0; 95% CI 1.9–5.0; PALB2:ORLoF + MV = 3.5; 95%CI 1.7–7.5). Furthermore, we found that carriers of a LoF in CHEK2 were diagnosed with BC at a younger age than noncarriers of a CHEK2 variant (46.7 years vs years, pT test = 0.007). Such a difference was not observed for carriers of a MV (50.1 years vs years, pT test = 0.16). For all other genes, no difference in age at diagnosis was observed (data not shown). Decker Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in BC cases and 5488 controls from East Anglia, UK. Methods Gene coding regions were enriched via PCR, sequenced, variant called and filtered for quality. ORs for BC risk were estimated separately for carriers of truncating variants and of rare missense variants, which were further subdivided by functional domain and pathogenicity as predicted by four in silico algorithms. Results Truncating variants in PALB2 (OR=4.69, 95% CI 2.27 to 9.68), ATM (OR=3.26; 95% CI 1.82 to 6.46) and CHEK2 (OR=3.11; 95% CI 2.15 to 4.69), but not XRCC2 (OR=0.94; 95% CI 0.26 to 4.19) were associated with increased BC risk. Truncating variants in ATM and CHEK2 were more strongly associated with risk of oestrogen receptor (ER)-positive than ER-negative disease, while those in PALB2 were associated with similar risks for both subtypes. There was also some evidence that missense variants in ATM, CHEK2 and PALB2 may contribute to BC risk, but larger studies are necessary to quantify the magnitude of this effect. Conclusions Truncating variants in PALB2 are associated with a higher risk of BC than those in ATM or CHEK2. A substantial risk of BC due to truncating XRCC2 variants can be excluded Considered together, rare missense variants in ATM, CHEK2 and PALB2 were associated with an estimated OR=1.24; 95% CI 1.08 to 1.43, p= (table 3). Vari- ants localised within protein domains (as defined by UniProt or Pfam) of these three genes had a somewhat higher risk estimate (OR=1.45; 95% CI 1.17 to 1.80; figure 3 and table 3) than those outside of the annotated domains (OR=1.09; 95% CI 0.92 to 1.31; Pdiff =0.060) Missense raras en ATM, CHEK2 y PALB2 OR=1.24 ( ) Girad et al, Int. J. Cancer: 2018; Decker B, et al. J Med Genet 2017;54:732–741

18 Variantes específicas
GEN MUTACIÓN OR (CI95%) ATM c.7271T>G (p.Val2424Gly) 9 (4-19) CHEK2 c.470T>C (p.Ile157Thr) c.1283C>T (p.Ser428Phe) 1.58 ( ) PALB2 c.1592delT 6 (2.2-17) c.3113G>A (p.W1038X) >10 The group led further investigations on PALB2 c.1592delT(fundadora truncante finlandesa) and reported a 40% increased risk of BC (hazard ratio 6.1; 95% CI, 2.2–17.2; P = 0.01) by age 70 years (95% CI, 17–77) approaching that for BRCA2 mutation carriers in the same country. The hazard ratio for BC was estimated to decrease with age by4.2% peryear (95%CI, 0.2–8.1; P = 0.06) from 7.5-fold at30years old to 2.0-fold at 60 years old [46]. Missense ATM c.7271T > G (p.Val2424Gly), appears to confer a high risk of breast cancer and to act as a dominant negative, risk for this mutation was estimated to be increased by ninefold (95% CI, 4 to 19) However, even for BRCA1 and BRCA2, the breast-cancer risk associated with the large majority of missense variants remains unknown; such variants are referred to as variants of unknown significance. Moreover, clearly pathogenic missense variants need not be associated with the same risk as truncating variants. For example, the CHEK2 missense variant p.Ile157Thr confers a lower risk of breast cancer than the CHEK2 c.1100delC truncating variant,33 whereas ATM p.Val2424Gly appears to be associated with a higher risk of breast cancer than truncating variants (8.0; 90% CI, 2.8 to 22.5; P = ).

19 ¿Se deben informar las VUS en los genes de moderado riesgo?
PALB2, CHEK2, ATM: fenotipo familia SI>NO (similar genes alto riesgo) Incidentales o con validez clínica incierta: NO>SI INFORMAR  American college of medical genetics and genomics and the association for molecular pathology variant classification guidelines. The value of multigene-panel testing remains controversial, however, because of the uncertainty regarding the strength of association between mutations in some genes and the development of cancer (clinical validity)3, and a lack of evidence demonstrating improved outcomes for the individuals tested (clinical utility)16.the appropriate management of individuals harbouring such moderate-penetrance genetic variants is unclear. The cancer risks associated with mutations in moderate-penetrance genes are lower and different than those reported for high penetrance gene mutations (such as mutations in BRCA1 and BRCA2, and those associated with Lynch síndrome Paradoxically in recent years, the introduction of cost- effective multigene panel sequencing in diagnostics laborato- ries has led to an explosion of genetic data in cancer-prone families. Very often, 20–25 genes or more are being screened in parallel to BRCA1 and BRCA2 in HBOC families,4 but data attributing a causative role for potentially deleterious variants identified in many of these genes are usually lacking, and pre- cise risk estimates per variant category

20 Recomendaciones de manejo preventivo

21 Cribado CMH: consenso de expertos
LTR acumulado >20-30%, según las guías Edad comienzo: - MAMOGRAFÍA: edad riesgo 5 años (0.6-1%) - RESONANCIA: edad riesgo 5 años >2.5% edad riesgo 5 años >6% (WISDOM) Ajuste por historia familiar, especialmente si CM premenopáusicas LIMITACIONES Riesgo acumulado o riesgo remanente Modelo óptimo predictor riesgo Aplicabilidad a pacientes con dx previo cáncer MX:The 5-year breast-cancer incidence in 40-year-old women in the USA is 0.6%. RM: in the USA, the highest population 5-year incidence of this disease is 2.2% in women aged 70–80 years Tung et al Nat Rev Clin Oncol

22 CLTR ≥30% CLTR 6-13% GEN MAMA OVARIO COLON PALB2 MX/ consid tomosint.
RM > 30 ---- ATM MX/consid tomosint. RM > 40 CHEK2 truncantes VCC >40-45 c/ 5 años NBN (c.657del5) BARD1 BRIP1 SOBP >45-50 RAD51C RAD51D MSH2 MLH1 MSH6 APC (I1307K) MYH monoalélica FPG CCR No historia familiar VCC >40 c/ 5 años VCC >50 c/ 10 años CLTR ≥30% Variantes missense comunes (p.I157T or p.S428F) CLTR <20% CLTR 6-13% El manejo más adecuado de los portadores de mutación en los genes de moderado riesgo debe ser definido y hasta estar disponible se basa en la opinión consenso de expertos. Debemos traducir el RR en riesgo de la portadora a 5 años La recomendación de mamografía y RM se basa en guias de practica clínica con punto de corte de riesgo en 20%. Existing guidelines do not specify whether cumulative risk or remaining LTR is the relevant parameter in decisions on who to screen, or which model should be used when calculating remaining LTR. Thus, the guidelines can be interpreted variably, leading to different recommendations for the same woman, depending on the model used NCCN CMOH guidelines v. 2019; NCCN Colon guidelines v. 2018 Katona et al, Gen Med 2018

23 Mastectomia reductora riesgo
PORTADORAS SANAS Riesgo CM muy inferior al que asocia BRCA1/2 Incerteza sobre el beneficio de la cirugía Muy probable ausencia de impacto en supervivencia Incerteza sobre el beneficio de la cirugía por nivel riesgo y eficacia del cribado radiológico o tratamiento Lee et al, Gen Med 2016

24 Mastectomia reductora riesgo
PORTADORAS CON ANTECEDENTE DE CM Riesgo CM contralateral anual ≦ 1% (pat.riesgo o CM esporádico %) NO beneficio en supervivencia global o específica a largo plazo en CM esporádico CHEK2 (1100delC): RR 2.77, riesgo absoluto 10-15% PALB2: riesgo CMC de 10% a 5 años ATM: impacto deletéreo de la RT de algunas variantes (missense) Evidencia limitada Among the 5589 BC index patients, 629 were affected by bilateral BC. In this subgroup, 8.3% of patients (52 of 629) carried a deleterious variant in at least one of the eight selected genes. This was significantly higher than the prevalence of deleterious variants in the 4960 BC index patients affected by unilateral BC (5.8%, 289 in 4960; P = .021). On a gene- specific level, the CHEK2 c.1000del founder variant (2.5% vs. 1.3%; P = .018), deleterious variants in the PALB2 gene (2.2% vs. 1.1%; P = .020), and deleterious variants in the TP53 gene (0.79% vs. 0.24%; P = .035) were significantly associated with bilateral BC (Table 3). Of the 5589 BC index patients, 934 reported a family history of OC. The prevalence of deleterious variants was not significantly different in BC index patients with a family history of OC versus the 4655 BC index patients who had no family history of OC Concanon et al, Cancer Res 2008; Bernstein et al JNCI 2010; Weischer et al, JCO 2012; Cybulski et al, Lancet Oncol 2015; Hauke et al, Cancer Medicine 2018; Wong et al, Ann Surg 2016; The Breast 39 (2018) 70-79

25 Salpingooforectomia bilateral
Ausencia de cribado Edad recomendada (45-50 años, peri o postmenopausia): LTR es >2.64% Genes con validez clínica incierta: PALB2, CHEK2, ATM, BARD1, MRE11A, NBN, RAD51B Considerar según HF The timing of this surgery is of great importance, given the substantial effects on quality-of-life related to premature menopause. RRSO is not recommended routinely for women whose only risk factor for ovarian cancer is an affected first-degree relative. A woman’s cumulative risk of ovarian cancer should, therefore, approach or exceed the LTR of a woman with an affected BRCA-negative first-degree relative (approximately 2.64%) before Carriers of mutations in BRIP1 or RAD51B/RAD51C/RAD51D cross this threshold at around the ages of 50–55 years, and can likely defer RRSO until they are perimenopausal or postmenopausal (TABLE 5). Women with mutations in these genes who also have a family history of ovarian cancer in a first-degree relative might cross the risk threshold earlier, assuming a multiplicative effec

26 Quimioprevención Los genes asociados a un fenotipo tumoral con expresión RH positivos (CHEK2) son tributarios a considerar SERM o inhibidores de aromatasa No evidencia

27 Cribado otras neoplasias
PANCREAS: Considerar colangioRM y/o ecoendoscopia en ATM y PALB2 con FPG (CAPS 2013) COLON: Riesgos inferiores a 1 FPG afectado (RR 2.25, IC95% ) Periodicidad de VCC basada en HF CHEK2 1100delC y I157T, cribado >45 y 50, respectivamente, o según HF (extrapolable a todas las truncantes) c/5 años APC I1307K, cribado >45 c/ 5 años MYH monoalélica, sólo si HF o poliposis >40 c/5-10 años PRÓSTATA: CHEK2 1100delC, ATM no incluidos en Consenso de Philadelphia 2017 Valorar según HF Intervalos de confianza de CHEk2 1100delC y APC askenazi que se solapa con el de FPG y por tanto justifica el iniciar VCC a >40 años For the average-risk individual, where current guidelines recom- mend initiating screening colonoscopy at age 50, a CLTR of CRC of 0.6% is reached by age 50–54.3 However, for CHEK2 1100delC, CHEK2 I157T, and APC*I1307K carriers, this same level of CLTR of CRC is reached by age 45–49. Therefore, if initiation of CRC screening is based on the average-risk individual’s CLTR of CRC, earlier initiation of screening colonoscopy in this timeframe in pathogenic CHEK2 and APC*I1307K carriers without a family history of CRC would seem reasonable (Table 2) ATM (Consensus: 56%) mutation status should be factored into mCRPC treatment discussions. Katona et al, Genet Medi 2018; Giri et al JCO 2017

28 Estudios predictivos en familiares:
variantes patogénicas o probablemente patogénicas Individualizar, según el gen y la HF: CHEK2, ATM, PALB2, RAD51C, RAD51D, BRIP1, APC I1307K - Justificados FPG y FSG (ambos sexos), si modifican el manejo preventivo - No justificado MYH * atención genes HAR (PALB2, ATM, BRIP1 y RAD51C) Relevante reconocer la proporción de riesgo asociado (según HF) Asesoramiento y recomendaciones cribado de verdaderos negativos (según HF) Cascade testing As a result, a woman in a family with the ATM mutation and a very high rate of breast cancer will likely require increased breast cancer surveillance regardless of whether she carries the mutation. In contrast, a woman in a family with BRCA mutations who tests negative for the mutation likely has a risk similar to that of a woman in the general population. Thus, although genetic testing may help to refine risk assessment, it is important to understand the difference between high-risk and moderate-risk genes and not pro- vide false reassurance. Disclosure Katona et al, Genet Medi 2018; Tung, N Clin Adv in Hematology & Oncology 2018

29 Manejo de las variantes significado incierto
Genes con validez clínica : INDIVIDUALIZAR MANEJO SEGÚN MODELO PREDICTOR RIESGO Genes con validez clínica incierta para CM:

30 Estudios predictivos en familiares: variantes significado incierto
No realizar fuera del contexto de investigación Cascade testing As a result, a woman in a family with the ATM mutation and a very high rate of breast cancer will likely require increased breast cancer surveillance regardless of whether she carries the mutation. In contrast, a woman in a family with BRCA mutations who tests negative for the mutation likely has a risk similar to that of a woman in the general population. Thus, although genetic testing may help to refine risk assessment, it is important to understand the difference between high-risk and moderate-risk genes and not pro- vide false reassurance. Disclosure

31 Oncotarget, 2019, Vol. 10, (No. 4), pp: 417-423
Our findings showed that for non-benign variants in cancer-related genes, the rate of reclassification varied by ancestry and in ways that differed between BRCA1/2 and other genes [2]. Rates of reclassification overall were highest in minorities. Similar to recent publications on variant reclassifications [4-6], we determined that the vast majority of unique variant reclassifications were downgrades (90.3%) with a much smaller fraction (9.7%) being upgraded. In particular, only 7.5% of variants reclassified from the VUS category were upgraded. Oncotarget, 2019, Vol. 10, (No. 4), pp:

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