Ereditarietà e
counseling genetico
Dr.ssa Laura Cortesi Dr.ssa Angela Toss DH Oncologico di Modena
Università di Modena e Reggio Emilia
BRCA1 and BRCA2
The primary genetic risk factors for BC and OC
BRCA1 or BRCA2 mutation are dominant with subsequent epigenetic silencing or loss of the normal allele in the somatic cell
Identification of predisposed individuals
Kuchenbaecker KB et al. JAMA 2017
Kuchenbaecker KB et al. JAMA 2017
Antoniou A. et al. Am J Hum Genet 2003 Brose MS, et al. J Natl Cancer Inst 2002 Breast Cancer Linkage Consortium. J Natl Cancer Inst 1999
Ford D, et al. Am J Hum Genet 1998 Petrucelli N, et al. GeneReviews® [Internet]. Pagon RA, Adam MP, Ardinger HH, et al., editors. 1993-2016.
BMC Cancer. 2017 Jun 21;17(1):438
Pre-test Oncogenetic Counseling
Discuss risks, benefits and limiting for testing Test procedure
Alternative to testing Management options Informed consent Blood sample
DNA testing
Informative
TRUE POSITIVE:
intensive surveillance
program
Prophylactic surgery Chemoprevention
TRUE NEGATIVE:
National program of breast screening
No Informative
UNCLASSIFIED VARIANT:
Surveillance according to Family
History
No mutation detected Surveillance according to Family
History
Post -Test Oncogenetic Counselling
BRCA1 p.His1673del is a pathogenic mutation
associated with a predominant ovarian cancer phenotype
Zuntini et al., Oncotarget 2017
Easton DF, et al. N Engl J Med. 2015
Easton DF, et al. N Engl J Med. 2015
A = annual; B = biennial; S = six-monthly; EOBC = Early Onset Breast Cancer
RISK PROFILE START US MX MRI
Profile 1 45 yrs If suspected
mammogram image
45 -50 yrs A 51 -74 yrs B (Population
Screening)
Profile 2
25 yrs (if familiar with EOBC)
36 yrs
> 41yrs if high breast density or
suspected
mammogram image
40 -50 yrs A 51 -74 yrs B (Population
Screening)
According to FONCAM
guidelines
Profile 3 (without detected
mutations)
25 yrs 25 – 60 yrs S 35-69 yrs A
70-74 yrs B
According to FONCAM
guidelines
Profile 3 (with detected
mutations)
From the mutation detection
From the mutation detection-69 yrs S
35-69 yrs A
70-74 yrs B > 25 yrs A
Rischio N° TM
Detection rate per 1000
(95%CI)
TM
attesi SIR
®p
BRCA1/2 136 46* 37.9 (3.7–53.5) 0.39 117.9 (3.1–150) <0.001 Alto 1749 115 8.5 (1.9–10.6) 15.6 7.3 (1.5–8.3) <0.001 Intermedio 428 50 16.1 (1.3–25.5) 2.23 22.4 (2.0–27.1) <0.001 Totale 2313 211 11.2 (2.2–21.1) 17.03 12.4 (1.6–17.6) <0.001
Dati dal Registro Tumori di Modena appaiati nel periodo 2012-2017
® SIR = Standardized Incidence Ratio
* Due pazienti con tumori bilaterali
Breast ultrasonography (BU) in the screening protocol for women at hereditary-familial risk of breast cancer: has the time come to
rethink the role of BU according to different risk categories?
BRCA1/2 (%) High Risk (%) Intermediate Risk (%)
Total Population
(%) P value
Median age of diagnosis (range)
48 (29-79) 53 (34-87) 50 (34-67) 51 (29-87) 0.04
US Sensitivity
N° of BC by Age (%) < 50 y
> 50 y
10/44 (22.7) 5/22 (22.7) 5/22 (22.7)
39/116 (33.6)
17/51 (33.3) 22/65 (33.8)
13/51 (24.5)
7/19 (36.9)°
6/32 (18.2)°
62/211 (29.4)
29/92 (31.5) 33/119 (27.7)
0.07
<0.001°°
MMG Sensitivity N° of BC by Age (%) < 50 y
> 50 y
11/44 (25) 3/22 (13.6)§
8/22 (36.4)§
77/116 (66.4)
34/51 (66.7) 43/65 (66.1)
28/51 (56.6)
12/19 (63.1) 16/32 (50)
116/211 (55)
49/92 (53.3) 67/119 (56.3)
<0.001
<0.001§
MRI* Sensitivity N° of BC by Age (%) < 50 y
> 50 y
15/16** (93.7) 6/6 (100)
9/10 (90)
0 0 15/16° (93.7)
6/6 (100) 9/10 (90)
NA***
Total Sensitivity N° of BC by age ≤ 50 y
> 50 y
36/44 (81.9) 14/22 (63.6)
22/22 (100)
116/116 (100)
51/51 (100) 65/65 (100)
41/51 (80.4)
19/19 (100) 22/32 (68.7)
193/211 (91.5)
84/92 (91.3) 109/119 (91.6)
<0.01
Cortesi L., Int J Cancer 2018
Sensitivity of BC screening by modality and risk groups’
Survival Analisys of Cancer Risk Reduction Strategies for BRCA 1/2
Mutation Carriers
Survival probability after different risk-reducing strategies performed at various ages in 25-year- old women with mutations
in (A) BRCA1 and (B) BRCA2, compared with women without BRCA1/2
mutations.
De Felice F et al. Ann Surg Oncol. 2015
Oophorectomy was associated with a statistically significant 82% reduction in breast cancer diagnosed prior to age 50 years among women with a BRCA2 mutation.
Kotsopoulos J, et al. JNCI 2017
Preventive oophorectomy was associated with an 80% reduction in the risk of ovarian, fallopian tube,
or peritoneal cancer in BRCA1 or BRCA2 carriers and a 77% reduction in all-cause mortality.
Finch APM, et al. JCO 2014
Kotsopoulos J, et al. JAMA Oncology 2018
Oncogenetic Counselling
BRCA1
BRCA2
Prognostic factor
Predictive
Factor
BRCA1-associated BC characteristics
J Natl Cancer Inst. 2004 Nov 17;96(22):1659-68 Br J Cancer. 2003 Apr 22;88(8):1285-91 Cancer J. 2011 Nov-Dec;17(6):492-9
∼10% of TNBC tumors have BRCA1 mutation
up to 50% of TNBC have non-germline BRCA1 or homologous recombination defects
90% of BRCA1-mutated tumors are TNBC 80–90% of BRCA1-associated BC display
a basal-like phenotype
Germline BRCA mutation and outcome in young-onset breast cancer (POSH): a prospective cohort study
Copson ER et al. Lancet Oncol 2018
Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in TNBC
Hehnen E. Jama Oncol 2017
Robson M. NEJM 2017
Primary End-Point:PFS by BICR
Litton JK NEJM 2018
Interim OS Analysis: Secondary Endpoint
Solo 1
Punti deboli del percorso tradizionale
Identificazione soggetti eleggibili al test
Consulenza Oncogenetica Consulenza pre-test (prelievo di
sangue) Analisi
Consulenza post-test (risultato test)
Scelte terapeutiche basate sul test
Se il test è positive proposta del test ai familiari
Tempi lunghi tra identificazione e consulenza
Il counseling oncogenetico si focalizza solo sul test a scopo preventivo e non fornisce spiegazioni sull’uso clinico
Tempi d’attesa del test genetico lunghi
BC diagnosis
Evaluation of
hereditary risk
Informative session
GENETIC TEST
Informative session about reconstructive
surgery procedures
BPM
07days 4weeks
5days 3 weeks
2days
Multidisciplinary Clinical Pathway for Rapid OGC
Psychologist Oncology
Surgeon Plastic Surgeon
2-3 days
2-3 days
3 weeks 2 days
1 week
Cortesi L., Ann Oncol 2014
Adapted from Couch, Nathanson, & Offit, Science 2014
Hereditary breast cancer
Multi-Gene (NGS) Panels
• Genetic tests to look at dozens of genes related to cancer
• Similar cost and turn around time as gene specific testing
• Higher risk of uncertain results
Summary of Clinical Validity
GENE BREAST OVARY OTHER
ATM Y N ?Pancreas
CHEK2 Y N ?Colon
P53 Y
PALB2 Y N
?Pancreas
PTEN Y
STK11 Y Colon
NBN Y (657del5) N
NF1 Y N
BRIP1 N Y
RAD51C/D N Y
MSR N Y Colon
Estimated average 5 year and lifetime breast-cancer risks for women with moderate-penetrance mutations in selected genes .
Tung N, et al. Nat Rev Clin Oncol. 2016
Estimated ovarian-cancer risks linked with moderate-penetrance mutations.
Tung N, et al. Nat Rev Clin Oncol. 2016
N° of UV in different genes for patients
Kurian AW et al., JCO 2014
N° of UV per gene across 198 patients
Kurian AW et al., JCO 2014
Tung N, et al. Nat Rev Clin Oncol. 2016
Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD
51D/BRIP1/PALB2 testing is more cost- effective than BRCA1/BRCA2 testing alone.
Population-based BRCA1/BRCA2/RAD51C/RAD
51D/BRIP1/PALB2 testing is more cost-effective than any
clinical criteria/FH-based strategy.
Manchanda R, et al. J Natl Cancer Inst 2018
Prof. Cascinu Stefano Dr. Cortesi Laura
Dr. Toss Angela Dr. Razzaboni Elisabetta
Dr. Marchi Isabella Dr. Medici Veronica Dr. Venturelli Marta Dr. Eleonora Molinaro
Inf. Bevini Paola
Prof. Pietro Torricelli Dr. Rachele Battista Dr. Barbara Canossi Dr. Annarita Pecchi Dr. Dal Molin Chiara
Dr. Antonella Drago Dr. Giovanni Grandi
LE NUOVE SFIDE…
Tung N, et al. Nat Rev Clin Oncol. 2016
Tung N, et al. Nat Rev Clin Oncol. 2016
Tung N, et al. J Clin Oncol 2016
Estimated average 5 year and lifetime breast-cancer risks for women with moderate-penetrance mutations in selected genes .
Tung N, et al. Nat Rev Clin Oncol. 2016
Estimated ovarian-cancer risks linked with moderate-penetrance mutations.
Tung N, et al. Nat Rev Clin Oncol. 2016
Tung N, et al. Nat Rev Clin Oncol. 2016
Clinical criteria/FH-based BRCA1/BRCA2/RAD51C/RAD
51D/BRIP1/PALB2 testing is more cost- effective than BRCA1/BRCA2 testing alone.
Population-based BRCA1/BRCA2/RAD51C/RAD
51D/BRIP1/PALB2 testing is more cost-effective than any
clinical criteria/FH-based strategy.
Manchanda R, et al. J Natl Cancer Inst 2018
Prof. Cascinu Stefano Dr. Cortesi Laura
Dr. Toss Angela Dr. Razzaboni Elisabetta
Dr. Marchi Isabella Dr. Medici Veronica Dr. Venturelli Marta Dr. Eleonora Molinaro
Inf. Bevini Paola
Prof. Pietro Torricelli Dr. Rachele Battista Dr. Barbara Canossi Dr. Annarita Pecchi Dr. Dal Molin Chiara
Dr. Antonella Drago Dr. Giovanni Grandi
