CP0105

Cáncer de Mama Hereditario: genes de

moderado/bajo riesgo

Joan Brunet
Programa de Cáncer Hereditario-ICO y
Servicio de Oncología Médica-ICO-H. Josep Trueta de Girona
Objetivos Docentes
1. Conocer los genes más allá de BRCA1/2 y PALB2 que
confieren riesgo moderado de cáncer de mama
2. Comprender el concepto de riesgo moderado y bajo
3. Qué entendemos por utilidad clínica
4. Qué genes debemos estudiar asistencialmente
5. Reconocer la importancia de la historia familiar en el
contexto de los genes de riesgo moderado
6. Qué debemos recomendar y a partir de qué edad
Guión
1. Base genética
2. Conceptos de validez y utilidad clínica
3. Tipos y niveles de riesgo
4. Riesgos estimados para los diferentes genes
5. Historia familiar y PRS como modificadores riesgo
6. Recomendaciones de prevención en guías clínicas
Base genética del Cáncer de Mama
Hereditario
Conceptos de validez y utilidad clínica
 Concepto de Validación y Utilidad Clínica:
criterios ACCE
1. Validación Analítica
2. Validación Clínica
3. Utilidad Clínica
4. Aspectos Éticos, Legales y Sociales

ACCE Model process for evaluating Genetic Test, CDC-OPHG 2003

 Riesgo a 5 años,
Validación acumulado, riesgo
¿Identifica el síndrome? ¿Cual es el riesgo?
Clínica relativo

¿Qué se puede hacer para reducir el riesgo?

Accionabilidad ¿A partir de cuándo?
Prevención

Utilidad ¿Las decisones clínicas van a mejorar los Incidencia/

Clínica resultados en salud? Supervivencia
Posicionamiento ASCO

1. ASCO affirms that is sufficient for cancer risk assessment to evaluate

genes of established clinical utility that are suggested by the patient’s
personal and/or family history”
2. “Clinical utility remains the fundamental issue with respect to testing
for mutations in moderate-penetrance genes. It is not yet clear
whether the management of an indivdual patient or his or her family
should change based on the presence or absence of a mutation”

VOLUME 33 ! NUMBER 31 ! NOVEMBER 1 2015

JOURNAL OF CLINICAL ONCOLOGY A S C O S P E C I A L A R T I C L E

American Society of Clinical Oncology Policy

Mark E. Robson, Memorial Sloan
Kettering Cancer Center; Mark E.
Robson and Stephen M. Lipkin, Weill
Cornell Medical College, New York, NY;
Angela R. Bradbury and Susan M.
Domchek, Hospital of the University of
Pennsylvania, Philadelphia, PA; Banu
Arun, MD Anderson Cancer Center,
Houston, TX; James M. Ford, Stanford
University Medical Center, Stanford,
CA; Heather L. Hampel, Ohio State
University Comprehensive Cancer
Center, Columbus, OH; Sapna Syngal,
Dana-Farber Cancer Institute, Boston,
MA; Dana S. Wollins, American Society
of Clinical Oncology, Alexandria, VA;
Statement Update: Genetic and Genomic
Testing for Cancer Susceptibility
Mark E. Robson, Angela R. Bradbury, Banu Arun, Susan M. Domchek, James M. Ford, Heather L. Hampel,
Stephen M. Lipkin, Sapna Syngal, Dana S. Wollins, and Noralane M. Lindor
See accompanying editorial on page 3533
A B S T R A C T
The American Society of Clinical Oncology (ASCO) has long affirmed that the recognition and
management of individuals with an inherited susceptibility to cancer are core elements of
oncology care. ASCO released its first statement on genetic testing in 1996 and updated that
statement in 2003 and 2010 in response to developments in the field. In 2014, the Cancer
Prevention and Ethics Committees of ASCO commissioned another update to reflect the impact
of advances in this area on oncology practice. In particular, there was an interest in addressing the
opportunities and challenges arising from the application of massively parallel sequencing—also
known as next-generation sequencing—to cancer susceptibility testing. This technology intro-
duces a new level of complexity into the practice of cancer risk assessment and management,
requiring renewed effort on the part of ASCO to ensure that those providing care to patients with
cancer receive the necessary education to use this new technology in the most effective,
 Utilidad Clínica en Genes Riesgo
Moderado
1. Aumento del riesgo con significación clínica RR ≥ 2
o Cambio en las medidas de prevención
o Conocimiento sobre la edad inicio
o Efecto de la historia familiar: importante en los no portadores

2. Contribuya a decisiones terapéuticas

Niveles de riesgo y de intervención
Tipos de riesgo

1. LTR (CLTR) à riesgo acumulado de los 20 a los 80-85 años

2. RMR à riesgo residual desde la edad actual hasta los 80 años
3. A 5 años à Riesgo de desarrollar cáncer en los próximos 5 años
4. A 10 añosà Riesgo de desarrollar cáncer en los próximos 10 años
(NICE: entre los 40 y los 50 años)
5. Razón de riesgos à el riesgo estimado comparado con el riesgo de
la población general
Niveles de riesgo Special Report

great majority do not.63,64 For these genes, algo-

A Mutation in PALB2
rithms based on conservation, pedigree data, 0.70
and analysis of tumor subtype can be used to
predict the pathogenicity of some variants.63,65,66 0.60
Similar considerations may apply to ATM and
CHEK2 — missense variants falling in key func- 0.50
tional domains and at positions that show a

Cumulative Risk
high degree of species conservation are more 0.40

likely to be associated with increased risk.67

0.30
However, even for BRCA1 and BRCA2, the breast-
cancer risk associated with the large majority of
0.20
missense variants remains unknown; such vari-
ants are referred to as variants of unknown 0.10
significance. Moreover, clearly pathogenic mis-
sense variants need not be associated with the 0.00
same risk as truncating variants. For example, 0 20 40 60 80

the CHEK2 missense variant p.Ile157Thr confers Age (yr)

a lower risk High Riskcancer
of breast RR 4than the CHEK2
B Mutation in CHEK2
Moderate
c.1100delC truncating Risk33 RR
variant, 2-4 ATM
whereas
0.70
p.Val2424Gly appears to be associated with a
higher risk of breast cancer than truncating vari- 0.60
ants (8.0; 90% CI, 2.8 to 22.5; P = 0.0005).68 A
more systematic approach to this problem would 0.50
involve defining risks on the basis of variant
Cumulative Risk

classes that are defined through prediction algo- 0.40

rithms based on in silico data. However, even
though existing data provide good evidence that 0.30

missense variants falling at highly conserved

0.20
positions in several genes confer disease risk,
and that such variants may make an important 0.10
contribution to the heritability of breast cancer,69
no system has been established for use in the 0.00
classification of variants that would allow such 0 20 40 60 80
estimates of risk to be used clinically. Age (yr)

Figure 1. Predicted Cumulative Risk of Breast Cancer for a Carrier of a

Risk Modifier s and A b solu te Risk s Deleterious Mutation in PALB2 and for a Deleterious Mutation in CHEK2.
Niveles de riesgo

• Bajo riesgo asimilable al de la población general

o RR <2
o LTR <18%
• Riesgo Moderado
o RR 2-3 (4)
o LTR 18-20 (30)
• Alto Riesgo
o RR > 3 (4)
o LTR > 20 (30)
Intervención en base a nivel de riesgo

3-8% / 17-30%
Grupo de A 5 A 10 años Lifetime risk Intervención preventiva
Riesgo años

Bajo- <3% <17% (NICE) Mx / 2 años de 50-69a

poblacional <15% (SEOM)
Moderado 3%-8% 17%-30% (NICE) Mx. Anual
15%-20% (SEOM) Quimioprevención?

Alto >1.7 ≥8% ≥30% (NICE) RMN y Mx anual

>20% (NCCN) Mastectomía RR
>20% (SEOM) Quimiprevención?
Riesgo estimado para los diferentes
genes
Base genética del Cáncer de Mama
Hereditario
Frecuencia poblacional y riesgo relativo

Easton D et al, NEJM, 2015

 Características de las variantes de bajo
riesgo
1. El conocimiento proviene de grandes estudios GWAS (Genome Wide
Association)
2. El riesgo relativo es muy bajo pero preciso, varía con la edad, estado RE
3. Las variantes son marcadores de asociación, no se les conoce una
causalidad
4. La combinación de múltiples (centenares..) variantes se denomina
Polygenic Risc Score (PRS) y proporciona una mejora en la estratificación
del riesgo
Estudio BCAC. New Engl2021J Med, 2021
BCAC, NEJM
 Estudio CARRIERS. New Engl J Med, 2021
Tipos histológicos asociados: estudio CARRIERS

Couch F, SABCS 2018

Estudio BCAC. New Engl J Med, 2021

BCAC, NEJM 2021

The ten genes for….Foulkes W Nat Rev, 2021
Grupo Consenso Catalán Paneles CMOH
Mayo 2022. Pendiente aprobación CatSalut

Incluye cribado oportunista genes de utilidad clínica

en Ca Ovario, Ca Colorectal y Ca Endometrio
Historia familiar y PRS como
modificadores de riesgo
 A
Efecto Ha Familiar y PRS. J Clin Oncol, 2021
Figure: A) The effect of PRS on breast cancer odds ratio of non-carriers versus carriers of BRCA1/BRCA2/CHE
women who are 60-70 years old (right). The red dot indicates the reference point (median PRS, no family histor
B) The predicted 5-year absolute risk of breast cancer using our final model of different variant carriers across 1

Table 1:Lifetime absolute risk of breast cancer (invasive and in-situ) for different variant carriers with
respect to different PRS percentile and family history status
No Family History Family History
OR 10th% PRS median PRS 90th% PRS 10th% PRS median PRS 90th% PRS
non-carrier 0.067 0.111 0.182 0.091 0.148 0.239
ATM carrier 0.128 0.204 0.321 0.170 0.268 0.409
CHEK2 carrier 0.152 0.241 0.373 0.202 0.312 0.467
PALB2 carrier 0.214 0.330 0.489 0.279 0.418 0.592
BRCA1 carrier 0.287 0.438 0.626 0.369 0.540 0.729
BRCA2 carrier 0.349 0.514 0.703 0.441 0.621 0.795

Gao, JCO 2021

Efecto Ha Familiar y PRS. J Clin Oncol, 2021

Gao, SABCS 2019

Efecto del tipo de mutación

Hall M, SABCS 2019

CanRisk: integración factores riesgo
canrisk.org/es

Hall M, SABCS 2019

Proyecto PRiSma

Hall M, SABCS 2019

Recomendaciones de prevención
(y a partir de qué edad!)
P¿Cuándo
E R S P E C T I V E Shay que empezar?
Table 2 | Estimated average 5-year and lifetime breast-cancer risks for women with moderate-penetrance mutations in selected genes
ATM/NBN CHEK2 (1100delC) CHEK2 (I157T)
Population (RR 2.7–2.8)* ‡
PALB241
Age 5-year Cumulative 5-year Cumulative 5-year Cumulative 5-year Cumulative 5 year Cumulative
(years) (%) (%) (%) (%) (%) (%) (%) (%) (%) (%)
25–29 0.04 0.1 0.12 0.1 0.13 0.2 0.07 0.1 0.35 0.4
30–34 0.14 0.2 0.38 0.5 0.41 0.6 0.21 0.3 1.05§ 2
35–39 0.30 0.5 0.84 1.4 0.90 1.5 0.48 0.8 2.5||
4
40–44 0.61 1.1 1.70§ 3.0 1.83§ 3.2 0.96§ 1.7 4.25|| 8
45–49 0.94§ 2.0 2.64|| 5.6 2.83|| 5.9 1.49§ 3.2 6.35|| 14
50–54 1.12 §
3.1 3.14 ||
8.5 3.36 ||
9.1 1.77 §
4.9 8.00 ||
20
55–59 1.33§ 4.4 3.71|| 11.8 3.98|| 12.6 2.09§ 6.8 7.25|| 26
60–64 1.72§ 6.0 4.81|| 16.0 5.15|| 17.0 2.71|| 9.3 7.35|| 31
65–69 2.11 §
8.0 5.92 ||
20.8 6.34 ||
22.1 3.34 ||
12.3 5.95 ||
35
70–75 2.20|| 10.0 6.17|| 25.5 6.61|| 27.1 3.48|| 15.3 6.70|| 40
CLTR (80) NA 12.0 NA 30.0 NA 31.8 NA 18.3 NA 44
These data represent the estimated cumulative 5-year incidence of breast cancer associated with moderate-penetrance mutations with established clinical validity
(based on the method of Song 28
) CLTR, cumulative lifetime risk; NA, not applicable; RR, relative risk. *ATM
31
). Data for NBN derived from study of a single truncating mutation.‡CHEK2
Riesgo a 5 años para inicio cribrado con mamografía: 1.12
truncating mutation CLTR (80) estimated to be 23.4% if RR declines with age (according to the CHEK2 Breast Cancer Case–Control Consortium40). §Indicates the
||
Indicates the age
ranges at which the 5-year risk of breast cancer exceeds 2.2% (the highest risk estimated for US women in the general population, specifically, those aged between

different recommendations for the same
woman, depending on the model used58.
The guidelines also do not discuss the
appropriateness of MRI screening for
and certain missense mutations in CHEK2) exceeded at the age of 30 years; reasoning by
should not undergo MRI screening based on Tung et al,
analogy, Natureone
therefore, Revwould
Clin recommend
Oncol, 2016
the presence of the mutation alone. For these beginning mammographic surveillance in
women, however, a family-history-based women harbouring these mutations at those
Guías clínicas: SEOM 2019

BARD1
Guías clínicas: NCCN v.2.2022
Guías clínicas: NCCN v.2.2022
Guías clínicas: NCCN v.2.2022
A recordar…
A recordar…

1. Incluir genes con utilidad clínica

2. Diferenciar investigación de diagnóstico
3. El tipo de mutación importa
4. Tener en cuenta la historia familiar
5. Individualizar los no portadores, especialmente
cuando hay historia familiar de cáncer de mama
6. El PRS se encuentra en fase de desarrollo, y podrá
ayudar en la individualización del riesgo en familias
con mutaciones en genes de riesgo moderado
7. Muy recomendable discutir las familias en comités
multidisciplinares