review dei test genomici
TRANSCRIPT
![Page 1: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/1.jpg)
![Page 2: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/2.jpg)
Review dei test genomici: risultati e indicazioni
Stefania Gori
Direttore Dipartimento Oncologico
IRCCS Ospedale Sacro Cuore Don Calabria, Negrar di Valpolicella
Presidente Fondazione AIOM
Presidente ROPI- Rete Oncologica Pazienti Italia
![Page 3: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/3.jpg)
HR+
HER2 +
TN10%
15%
75%
EBC: sottogruppi fenotipici
![Page 4: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/4.jpg)
Carcinoma mammario infiltrante in fase iniziale:
fattori prognostici e predittivi
FATTORI PROGNOSTICI
▪ DIAMETRO DEL TUMORE
▪ STATO E NUMERO DI LINFONODI METASTATICI
▪ ISTOLOGIA (NST; lobulare; mucinoso, tubulare, papillare; midollare, adenoido-
cistico, apocrino)
▪ GRADO ISTOLOGICO
▪ ATTIVITA’ PROLIFERATIVA (Ki67/MIB-1)
▪ STATO DEI RECETTORI ORMONALI E LIVELLO DI ESPRESSIONE DEI
RECETTORI ORMONALI
▪ STATO DI HER2
▪ Invasione vascolare
▪ ETA’ DELLA PAZIENTE
▪ Profili di espressione genica
▪ Test genomici prognostici (se disponibili)
▪ Linfociti infiltranti il tumore (TILs)
FATTORI PREDITTIVI
▪ STATO DEI RECETTORI ORMONALI E LIVELLO DI ESPRESSIONE DEI
RECETTORI ORMONALI
▪ STATO DI HER2
NST= Carcinoma invasivo non di istotipo speciale LG AIOM 2020
![Page 5: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/5.jpg)
HR+
HER2 +
TN10%
15%
75%
EBC: sottogruppi fenotipici
EBC
70% sonoHR+/HER2-
In Italia36.175/ nuovi casi
HR+/HER2- nel 2020
![Page 6: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/6.jpg)
Carcinoma mammario infiltrante NON METASTATICO OPERATO HR+/HER2-: Terapia sistemica adiuvante
LG AIOM 2020
![Page 7: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/7.jpg)
Cosa sono i test genomici?
![Page 8: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/8.jpg)
I test genomici profilano l’espressione di una serie di geni presenti nel
tessuto tumorale mammario
![Page 9: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/9.jpg)
Quali test genomici sono oggi disponibili?
![Page 10: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/10.jpg)
Test genomici e prognosi per HR+/HER2- BC
Paik NEJM
2006
Vijver NEJM
2002
Dowsett JCO 2013 Filipits CCR 2011
MammaPrintOncotypeDX PROSIGNA(PAM50 ROR)
EndoPredict
(include tumor size+nodal status)
Breast Cancer Index
Ma CCR 2008
![Page 11: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/11.jpg)
Quali le evidenze scientifiche e le indicazioni?
![Page 12: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/12.jpg)
ONCOTYPE DX
![Page 13: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/13.jpg)
Paik S, NEJM 2004; 24:351-2817-26
ONCOTYPE DX
![Page 14: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/14.jpg)
6.8%
14.3%
30.5%
P<0.001
![Page 15: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/15.jpg)
Low risk -RS <18 Intermediate risk –RS 18-30
High risk –RS >= 31
Paik S et al,JCO 2006
Test interazione tra Chemio e Recurrence Score
p=0.038
![Page 16: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/16.jpg)
Paik S et al,JCO 2006
Chemotherapy benefitas function of Recurrence Score(RS) risk category
Beneficio dall’aggiunta della CT: 27,6%
![Page 17: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/17.jpg)
Sparano JA et al. N Engl J Med 2015
HR+/HER2-, pN0,T1c-2 any grade or T1b and G2/3
Primary endpoint: non-inferiority (iDFS) of HT vs CT+HT in women in the RS 11-25 group
TAILORx: TRIAL ASSIGNING INDIVIDUALIZED OPTIONS FOR TREATMENT
(Rx)
Oncotype DX® assay
Primary study group
RS 11–25RS >25RS <11
ARM D: CT plus endocrine
therapy
ARM A: endocrine therapy
alone
ARM C: CT plus endocrine
therapy
ARM B: endocrine
therapy alone
N=1626 (15.9%)
N=6897 (67.3%)
N=1730 (16.9%)
Eligible 10253 pts
(2006-2010) 900 sites, 6 countries
R
![Page 18: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/18.jpg)
TAILORx: PATIENT CHARACTERISTICS
All RS 0-10 RS 11-25 RS>26
All 9719 1619 (16.7%) 6711 (69.0%) 1389 (14.2%)
Age <50y 2694 (31.4%) 429 (26%) 2216 (33%) 409 (29%)
Postmenopausal
Premenopausal
6419 (66%)
3300 (34%)
1141 (70%)
478 (30%)
4296 (64%)
2415 (36%)
982 (71%)
407 (29%)
T, median (range) NA 1.5 (1.2-2.0) 1.5 (1.2-2.0) 1.7 (1.3-2.3)
G1
G2
G3
2512 (27%)
5242 (55%)
1676 (18%)
530 (34%)
931 (59%)
111 (7%)
1893 (29%)
3721(57%)
884 (14%)
89 (7%)
590 (43%)
681 (50%)
PgR neg
PgR pos
951 (10%)
8571 (90%)
28 (2%)
1555 (98%)
518 (8%)
6061 (92%)
405 (30%)
948 (70%)
Clin low risk
Clin high risk
6615 (70%)
2812 (30%)
1227 (78%)
345 (22%)
4799 (74%)
1697 (26%)
589 (43%)
770 (57%)
Sparano JA, et al. N Engl J Med 2015;373(21):2005–14.
![Page 19: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/19.jpg)
Sparano JA et al. N Engl J Med 2015
HR+/HER2-, pN0,T1c-2 any grade or T1b and G2/3
Primary endpoint: non-inferiority (iDFS) of HT vs CT+HT in women in the RS 11-25 group
TAILORx: TRIAL ASSIGNING INDIVIDUALIZED OPTIONS FOR TREATMENT
(Rx)
Oncotype DX® assay
Primary study group
RS 11–25RS >25RS <11
ARM D: CT plus endocrine
therapy
ARM A: endocrine therapy
alone
ARM C: CT plus endocrine
therapy
ARM B: endocrine
therapy alone
N=1626 (15.9%)
N=6897 (67.3%)
N=1730 (16.9%)
Eligible 10253 pts
(2006-2010) 900 sites, 6 countries
R
![Page 20: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/20.jpg)
5yrs rate 93.8% 5yrs rate 99.3%
5yrs rate 98.7% 5yrs rate 98%
TAILORx: prognosis of RS low patients
Invasive disease-free survival Freedom from recurrence at distant site
Freedom from recurrence at any site Overall survival
Sparano J, et al. NEJM 2015
![Page 21: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/21.jpg)
Sparano JA, JAMA Oncol 2019
![Page 22: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/22.jpg)
Sparano JA et al. N Engl J Med 2019
HR+/HER2-, pN0,T1c-2 any grade or T1b and G2/3
Primary endpoint: non-inferiority (iDFS) of HT vs CT+HT in women in the RS 11-25 group
TAILORx: TRIAL ASSIGNING INDIVIDUALIZED OPTIONS FOR TREATMENT (Rx)
Oncotype DX® assay
Primary study group
RS 11–25RS >25RS <11
ARM D: CT plus endocrine
therapy
ARM A: endocrine therapy
alone
ARM C: CT plus endocrine
therapy
ARM B: endocrine
therapy alone
N=1626 (15.9%)
N=6897 (67.3%)
N=1730 (16.9%)
Eligible 10253 pts
(2006-2010) 900 sites, 6 countries
R
![Page 23: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/23.jpg)
42% delle pts avevano un RS 26-3058% delle pts avevano un RS>30 fino a 100
Sovrapponibile all’89,6% a 5 anni stimato nel braccio CT del trial B-20 emigliore del 78,8% stimato a 5 anni senza CT(solo TAM)
Sparano JA, JAMA Oncol 2019
![Page 24: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/24.jpg)
Sparano JA et al. N Engl J Med 2018
HR+/HER2-, pN0,T1c-2 any grade or T1b and G2/3
Primary endpoint: non-inferiority (iDFS) of HT vs CT+HT in womenin the RS 11-25 group
TAILORx: TRIAL ASSIGNING INDIVIDUALIZED OPTIONS FOR TREATMENT (Rx)
Oncotype DX® assay
Primary study group
RS 11–25RS >25RS <11
ARM D: CT plus endocrine
therapy
ARM A: endocrine therapy
alone
ARM C: CT plus endocrine
therapy
ARM B: endocrine
therapy alone
N=1626 (15.9%)
N=6897 (67.3%)
N=1730 (16.9%)
Eligible 10253 pts
(2006-2010) 900 sites, 6 countries
R
![Page 25: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/25.jpg)
TAILORx (pN0): RS 11–25PRIMARY ENDPOINT
RS 11–25, randomised to CT+ET or ET alone n=6711
CT+ET
ET iDFS 5 y % 9 y
%
ET 92.8 83.3
CT+
ET
93.1 84.3
Sparano J, et al. NEJM 2018
Lo studio ha evidenziato la NON inferiorità della ET vs CT+ET in iDFS, ma anche in
distant free-survival e OS
![Page 26: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/26.jpg)
CT + ET:
93.0%
ET:
99.3%
ET: 98.0%
CT: 98.2%
ET:
99.7%
ET: 98.1%
CT+ET: 98.9%
ET: 93.2%
CT+ET: 96.4%
CT+ET:
91.1%
ET: 98.8%
CT+ET: 98.5%
TAILORx: Freedom From Recurrence of BC at a Distant Site
5-year rates
All patients
Young patients (≤50 yrs), n=2216
0–10 26-10011–25
0–10 11–15 16–20 21–25 26-100
Sparano JA et al. N Engl J Med 2018
ET non inferiorto CT+ET
Pts con > 50 anni e RS 0-25 possono evitare CT
Pts con<=50 anni e RS 0-15 possono evitare CT
Δ=
+0.8%Δ=
+3.2%
![Page 27: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/27.jpg)
CT + ET:
86.8%
ET:
96.8%
ET: 94.5%
CT: 95.0%
ET:
98.5%
ET: 93.6%
CT+ET: 95.2%
ET: 86.9%
CT+ET: 93.4%
CT+ET:
88.7%
ET: 97.2%
CT+ET: 98.0%
TAILORx: Freedom From Recurrence of BC at a Distant Site
9-year rates
All patients
Young patients (≤50 yrs), n=2216
0–10 26-10011–25
0–10 11–15 16–20 21–25 26-100
Sparano JA et al. N Engl J Med 2018
ET noninferiorto CT+OT
Pts con<=50 anni e RS 0-15 possono evitare CT
Δ=
+1.6%Δ=
+5.3%
Pts con > 50 anni e RS 0-25 possono evitare CT
![Page 28: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/28.jpg)
Kalinsky K, SABCS 2020
![Page 29: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/29.jpg)
RxPONDER: HR+/HER2-, pN+ (1-3) BC
Kalinsky K,SABCS 2020
![Page 30: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/30.jpg)
RxPONDER: HR+/HER2-, pN+ (1-3) BC
Primary HypothesisChemotherapy benefit will increase as the RS increases from 0 to 25 in ITT analysis
Kalinsky K, SABCS 2020
![Page 31: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/31.jpg)
![Page 32: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/32.jpg)
Kalinsky K, SABCS 2020
![Page 33: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/33.jpg)
Kalinsky K, SABCS 2020
![Page 34: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/34.jpg)
RxPONDER: Primary Analysis
Analysis without interaction term
Chemotherapy use and
Recurrence Scoreare independentlyprognostic for iDFS
Kalinsky K, SABCS 2020
![Page 35: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/35.jpg)
![Page 36: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/36.jpg)
RxPONDER: iDFS in overall population by
treatment arm
Kalinsky K, SABCS 2020
![Page 37: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/37.jpg)
Kalinsky K, SABCS 2020
RxPONDER results: iDFS stratified by menopausal status
![Page 38: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/38.jpg)
Kalinsky K, SABCS 2020
RxPONDER results: iDFS stratified by Recurrence Score and menopausal status
![Page 39: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/39.jpg)
Kalinsky K, SABCS 2020
RxPONDER results: iDFS stratified by number of nodesand menopausal status
![Page 40: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/40.jpg)
Kalinsky K, SABCS 2020
![Page 41: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/41.jpg)
Kalinsky K, SABCS 2020
HR+/HER2- , pN+ (1-3) EBC
![Page 42: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/42.jpg)
Kalinsky K, SABCS 2020
HR+/HER2- , pN+ (1-3) EBC
![Page 43: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/43.jpg)
Luglio 2020
![Page 44: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/44.jpg)
Development and validation of a tool integrating the 21-gene recurrence score and clinical-pathological features to individualizeprognosis and prediction of chemotherapy benefit in EBC- Sparano JA etal
![Page 45: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/45.jpg)
OncotypeDX
• Should always be integrated with traditional clinico-
pathological factors
(6%-11%) (13%-24%)
![Page 46: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/46.jpg)
MAMMAPRINT
![Page 47: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/47.jpg)
Mammaprint (70 genes) and prognosis in EBC (=295 )
and prognosis
Van der Vijver MG. A gene-expression signature as a predictor of survival in breast cancer. NEJM 2002; 347;1999-2009
All patients
LN -positive LN -negative
![Page 48: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/48.jpg)
MINDACT: study design
Cardoso F, et al. N Engl J Med 2016;375(8):717–29; Piccart M, et al. Presented at AACR 2016..
Clinical risk (c)
Adjuvant online
Enrolled N=6,693
Primary endpoints: Distant metastasis-free survival (DMFS) at 5 years Lower boundary of 95%CI for 5-year DMFS 92% or higher
Alpha: 2.5% (1-sided);Power: 80% when true 5-year DMFS rate=95%
Genomic risk (g)
70-gene signature or
MammaPrint®
N=644
c-Low/g-Low
Discordant
c-High/g-Highc-Low/g-High c-High/g-Low
No CT CT
N=2745N=592 N=1550 N=1806
32%
Women aged 18-70 years T1 - T2 or operable T3N0 (up to 08/2009);N0-N1 afterwards
Frozen Sample
R CTOT R
CTNo CT
![Page 49: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/49.jpg)
MINDACT: study design
Cardoso F, et al. N Engl J Med 2016;375(8):717–29; Piccart M, et al. AACR 2016..
Clinical risk (c)
Adjuvant online
Enrolled N=6,693
Genomic risk (g)
70-gene signature or
MammaPrint®
N=644
c-Low/g-Low
Discordant
c-High/g-Highc-Low/g-High c-High/g-Low
No CT CT
N=2745N=592 N=1550 N=1806
32%
Women aged 18-70 years T1 - T2 or operable T3N0 (up to 08/2009);N0-N1 afterwards
Frozen Sample
R CTOT R
CTNo CT
Primary endpoints: Distant metastasis-free survival (DMFS) at 5 years
Lower boundary of 95%CI for 5-year DMFS 92% or higher
Alpha: 2.5% (1-sided);Power: 80% when true 5-year DMFS rate=95%
![Page 50: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/50.jpg)
Patients Events 5-year DMFS
(95% CI)
644 38 94.7 (92.5-96.2)
Patients Events 5-year DMFS
(95% CI)
644 78 95.1 (93.1-96.6)
Median FU 5 years Median FU 8.7 years
MINDACT: primary endpointDistant metastasis-free survival in clinical high/genomic low (no CT)
Cardoso F, et al. N Engl J Med 2016;375(8):717–29; Piccart M, et al. Presented at AACR 2016; Cardoso F, et al. ASCO 2020
95% CI excludes 92%: primary endpoint met
Primary endpoint still met with moremature data → lower bound of 95%CIexceed 92% 5-y DMFS (null hypotesis)
Primary statistical analysis
≈95% DMFS -> ≈90% DFS
![Page 51: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/51.jpg)
MINDACTfollow up 8.7 anni
Cardoso F, et al. ASCO 2020
Analisi secondarie prespecificate (under-poweder) per valutare sopravvivenza libera da ripresa a distanza nelle pts clinical high/genomic low risk trattate con chemio
![Page 52: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/52.jpg)
MINDACT: study design
Cardoso F, et al. N Engl J Med 2016;375(8):717–29; Piccart M, et al. AACR 2016..
Clinical risk (c)
Adjuvant online
Enrolled N=6,693
Genomic risk (g)
70-gene signature or
MammaPrint®
N=644
c-Low/g-Low
Discordant
c-High/g-Highc-Low/g-High c-High/g-Low
No CT CT
N=2745N=592 N=1550 N=1806
32%
Women aged 18-70 years T1 - T2 or operable T3N0 (up to 08/2009);N0-N1 afterwards
Frozen Sample
R CTOT R
CTNo CT
Primary endpoints: Distant metastasis-free survival (DMFS) at 5 years
Lower boundary of 95%CI for 5-year DMFS 92% or higher
Alpha: 2.5% (1-sided);Power: 80% when true 5-year DMFS rate=95%
![Page 53: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/53.jpg)
MINDACT: secondary analysis at median f up 8.7 y
Cardoso F, et al. ASCO 2020
Absolute difference in DMFS between CT and no CT groups:
◆ At 5 years: 0.9 ± 1.1% points◆ At 8 years: 2.6 ± 1.6% points
Type of first event (n=150)◆ Distant recurrences: 74.7%
◆ Death of any cause: 25.3%
![Page 54: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/54.jpg)
MINDACT: ANALISI ESPLORATORIE PRE-SPECIFICATECT vs no CT in cH/gL, HR+/HER2– patients
stratified by age
Age ≤50 years Age >50 years
5% difference No difference
Cardoso F, et al. ASCO 2020
![Page 55: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/55.jpg)
Luglio 2020
![Page 56: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/56.jpg)
PROSIGNA
![Page 57: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/57.jpg)
PROSIGNA
Test genomico sviluppato a partire dalla firma genomica PAM-50, che permette quindi di classificare i tumori nei sottotipi Luminal A, Luminal B, HER2-enriched, Basal-like.
Prosigna inserisce nell’algoritmo di calcolo del rischio, accanto ai dati del profilo di espressione genica PAM-50,anche variabili clinico-patologiche (diametro T e stato LN).
L’algoritmo produce un punteggio numerico da 1 a 100 detto ROR ( Risk Of Recurrence) che predice il rischio di ripresa a distanza a 10 anni.
![Page 58: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/58.jpg)
Valore di ROR
0-40
41-60
61-100
PROSIGNA
Gnant M, et al. Ann Oncol 2014
![Page 59: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/59.jpg)
Valore di ROR
0-40
41-100
PROSIGNA 1-3+
Gnant M, et al. Ann Oncol 2014
![Page 60: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/60.jpg)
Risk of recurrence by 10 yearsROR low-risk group: 2.4% ROR intermediate-risk group: 8.3%High risk-group: 16.6%
95% CI1.6-3.5%6.1-11.2%
13.1-20.9% Sestak I, JCO 2015
![Page 61: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/61.jpg)
Luglio 2020
![Page 62: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/62.jpg)
ENDOPREDICT
![Page 63: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/63.jpg)
ENDOPREDICT
Il test, che valuta l’espresione di 12 geni ( 8 target+4 controllo) può essere effettuato sia su tumori pN0 che pN+ (1-3) ER+/HER2-
Nel calcolo del punteggio di rischio di sviluppo di metastasi a distanza include anche diametro del T e stato LN (EPclin risk score).
![Page 64: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/64.jpg)
Filipits M, Clin Cancer Res 2011
4%
22%
28%
4%
EPclin risk score
Distant Recurrencesurvival according toEpclin risk score in ptsfrom the 2 validationcohorts (ABCSG-6 and ABCSG-8).
![Page 65: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/65.jpg)
ENDOPREDICT
Poiché il valore prognostico è particolarmente evidente nelle recidive tardive, potrebbe risultare utile nella scelta della terapia ormonale OLTRE i 5 anni
ASCO Guidelines 2019: I test genomici non sono raccomandati nelle pts pN0 per guidare la decisione relativa all’extended endocrine therapy
![Page 66: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/66.jpg)
Luglio 2020
![Page 67: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/67.jpg)
BREAST CANCER INDEX
![Page 68: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/68.jpg)
Luglio 2020
ASCO Guidelines 2019: Non raccomandato in pts pN+
![Page 69: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/69.jpg)
Test genomici e neo-adiuvante:quali evidenze?
![Page 70: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/70.jpg)
![Page 71: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/71.jpg)
Recurrence score as a predictor of clinical response to NAHTfor ER+, HER2-negative breast cancer: the TransNEOS study
Primary endpoint: clinical (complete or partial) response to 6-months neoadjuvant letrozole for RS < 18 versus RS ≥ 31
Iwata H et al. Breast Cancer Res Treat 2019
295 ER+, HER2- post-menopausal women, T1c-T2, N0 breast cancerreceiving 24 weeks neoadjuvant letrozole
Oncotype DX performed on core biopsies taken before neoadjuvant Tx
![Page 72: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/72.jpg)
Pooled analysis of risk ratio for pCR to NACT in pts withhigh vslow RS before treatment
Boland MR et al. Br J Surg 2021
Recurrence score as a predictor of pathological response to NACT in BC
![Page 73: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/73.jpg)
Recurrence Score pCR
All pts (=1.744) 5.4%
Low-intermediate risk(<11- <25)
1.1%
High risk(>25- >30)
10.9%
Boland MR et al. Br J Surg 2021
Recurrence score as a predictor of pathological response to NACT in BC
![Page 74: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/74.jpg)
Sono necessari studi prospettici con ampie casistiche per valutareil ruolo del Recurrence Score
nel setting neoadiuvante
Test genomici eterapia neo-adiuvantenei tumori ER+/HER2-
![Page 75: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/75.jpg)
Test genomici
![Page 76: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/76.jpg)
Test genomico N. Genivalutati
Effettuabile su tessuto tumorale mammario fissato e incluso in paraffina
ApprovazioneFDA
MarchioCE-IVD
Tipo analisimRNA
Oncotype 21 (16+5) SI SI NO RT-PCR
Mammaprint 70 SI SI SI NGS-Illumina
PROSIGNA 55 (50+5) SI SI SI N-Counter, Nanostring
Endopredict 12 (8+4) SI NO SI RT-PCR
Breast CancerIndex
7 SI NO NO RT-PCR
Position Paper 2020- AIOM, SIAPEC/IAP, SIBioC, SIF
![Page 77: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/77.jpg)
Test genomici e prognosi per HR+/HER2- BC
APPLICABILITÀ TECNICA
Di pronto utilizzo direttamente in Laboratorio
Paik NEJM
2006
Vijver NEJM
2002
Dowsett JCO 2013 Filipits CCR 2011
MammaPrintOncotypeDX PROSIGNA(PAM50 ROR)
EndoPredict
(include tumor size+nodal status)
Breast Cancer Index
Ma CCR 2008
![Page 78: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/78.jpg)
Test genomici e prognosi per HR+/HER2- BC
Disponibili i risultati di studi prospettici randomizzati
disegnati per testare questi test(LEVEL 1A)
Paik NEJM
2006
Vijver NEJM
2002
Dowsett JCO 2013 Filipits CCR 2011
MammaPrintOncotypeDX PROSIGNA(PAM50 ROR)
EndoPredict
(include tumor size+nodal status)
Breast Cancer Index
Ma CCR 2008
![Page 79: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/79.jpg)
Test genomico N. genivalutati
Effettuabile su tessuto tumorale mammario fissato e incluso in paraffina
Definizione del rischio di ripresa a distanza a 10 anni dalla chirurgia
Studi prospettici
Oncotype 21 (16+5) SI SI SI
Mammaprint 70 SI SI SI
PROSIGNA 55 (50+5) SI SI NO
Endopredict 12 (8+4) SI SI NO
Breast CancerIndex
7 SI SI NO
![Page 80: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/80.jpg)
CT + ET:
93.0%
ET:
99.3%
ET: 98.0%
CT: 98.2%
ET:
99.7%
ET: 98.1%
CT+ET: 98.9%
ET: 93.2%
CT+ET: 96.4%
CT+ET:
91.1%
ET: 98.8%
CT+ET: 98.5%
ONCOTYPE DXTAILORx: Freedom From Recurrence of BC at a Distant Site
5-year rates
All patients
Young patients (≤50 yrs), n=2216
0–10 26-10011–25
0–10 11–15 16–20 21–25 26-100
Sparano JA et al. N Engl J Med 2018
ET non inferiorto CT+ET
Pts con > 50 anni e RS 0-25 possono evitare CT
Pts con<=50 anni e RS 0-15 possono evitare CT
Δ=
+0.8%Δ=
+3.2%
![Page 81: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/81.jpg)
I test genomici si differenziano per tipo di informazioni fornite, popolazioni di pts e studi clinici condotti per
validarli.
Kittaneh M et al for Breast Cancer Therapy Expert Group. Clin Breast Cancer 2020
![Page 82: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/82.jpg)
Oncotype DX, Mammaprint, Prosigna, MammaTyper , IHC4-AQUA, IHCA
![Page 83: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/83.jpg)
Oncotype DX, Mammaprint, Prosigna, MammaTyper , IHC4-AQUA, IHCA
OPTIMAL preliminary Trial: HIGH rates of discordance across alltests
Bartlett JM e t al. JNCI J Natl Cancer Inst 2016;108:djw050
![Page 84: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/84.jpg)
Oncotype DX, Mammaprint, Prosigna, MammaTyper , IHC4-AQUA, IHCA
•Only moderate agreement existed between tests ( K values for risk assignmentrange 0.33-0.60)
•Risk assignment by all 5 tests agreed for only 119 (39%) tumors with 31% agreement for 4/5 tests and subtype assignment by all 3 tests for 179 (59%) tumours.
OPTIMAL preliminary Trial: HIGH rates of discordance acrossall assays
Concordance by risk (n=131)
Kappa statistic(95% CI)
Mammaprint Prosigna IHC4(low/int)
IHC4-AQUA(low/low-mid)
RecurrenceScore 0-25
0.40(0.30-0.49)
0.44(0.33-0.54)
0.53(0.41-0.65)
0.40(0.30-0.51)
Bartlett JM e t al. JNCI J Natl Cancer Inst 2016;108:djw050
![Page 85: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/85.jpg)
![Page 86: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/86.jpg)
Modificata da Arpino G, 3 febbraio 2021
![Page 87: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/87.jpg)
Rimborsabilità in Italia
![Page 88: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/88.jpg)
Stato Tipo rimborso
Data 1°rimborso
Popolazione rimborsata
Test rimborsabilità
Oncotype DX Mammaprint Endopredict Prosigna
Grecia Nazionale 2013 HR+ HER2- N0 X X
Spagna Regionale 2012 HR+ HER2- N0 X X X X
Rep Ceca Nazionale 2014 HR+ HER2- N0 Nmic, G2 ( con almeno 1 fattore di
rischio: PR-,Ki67 alto, mic)
X
Ungheria Nazionale 2017 HR+ HER2- N0 N1 X
UK Nazionale 2015 HR+ HER2- N0 Nmic
rischio intermedio
X X X
Irlanda Nazionale 2011 HR+ HER2- N0 N1 X
Svizzera Nazionale 2015 HR+ HER2- N0 N1 X X X X
Germania Nazionale 2019 HR+ HER2- N0 N1 X
Francia Fondo Innovazione
2016 HR+ HER2- N0 Nmicrischio intermedio
X X X X
Belgio Fondo Innovazione
2019 HR+ HER2- N0 N1 X X
Canada Provinciale 2010 HR+ HER2- N0 in tutte
N1 solo in 2 province
X X X
USA Nazionale 2006 HR+ HER2- N0 N1 X X X X
Israele Nazionale 2006 HR+ HER2- N0 N1 X X
TEST GENOMICI: autorizzazione a livello internazionale
![Page 89: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/89.jpg)
Stato di avanzamento dell’autorizzazione ai test genomici a livello regionale in Italia
• Rimborso in Lombardia e Provincia Autonoma di Bolzano• Toscana: DGR 23-11-2020• Emilia Romagna, Lazio, Sardegna: dibattito attivo per ottenere la
rimborsabilità regionale
Centri che erogano i test gratuitamente per le proprie pazienti (in regioni dove il test non è rimborsabile):
• IOV (Padova)• IRCCS Ospedale Policlinico San Martino (Genova)• Università degli studi di Napoli Federico II (Napoli)• Istituto Nazionale Tumori IRCCS Fondazione G. Pascale (Napoli)• ASST Lanciano Vasto Chieti
![Page 90: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/90.jpg)
Exact Sciences
Criteri di accesso al test.
Le pazienti individuate per questa specifica prestazione sono pazienti concarcinoma invasivo della mammella endocrino responsivo in stadioprecoce considerate a rischio intermedio per le quali il clinico potrebbeporre una indicazione a chemioterapia adiuvante.
Vengono, pertanto, escluse dalla possibilità di effettuare il testgratuitamente tutte le pazienti a basso rischio, per le quali è indicata lasola ormonoterapia, e ad alto rischio per le quali è indicata l’associazioneormonoterapia-chemioterapia.
CONFIDENTIAL 93
Rimborsabilità dei Test Genomici in Italia
Lombardia – DGR XI 1986 del 23 Luglio 2019
![Page 91: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/91.jpg)
Exact Sciences
✓Le pazienti a basso e ad alto rischio sono definite in base alle caratteristiche descritte nella tabella seguente:
✓La stima delle pazienti lombarde che usufruiranno della prestazione è pari a circa 1500 pazienti/anno con possibile riduzione in circa il 50%-75% dei casi del ricorso a chemioterapia.
CONFIDENTIAL 94
Rimborsabilità dei Test Genomici in Italia
Lombardia – DGR XI 1986 del 23 Luglio 2019
La stima delle pazienti lombarde che usufruiranno della prestazione è pari a circa 1500 pazienti/anno con possibile riduzione in circa il 50%-75% dei casi del ricorso a chemioterapia.
![Page 92: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/92.jpg)
Exact Sciences
La Giunta Regionale a voti unanimi delibera di prevedere l’effettuazione a titolo gratuitodei test di analisi dei profili di espressione genica nel carcinoma mammario (cd. testgenomici) per le pazienti riconosciute idonee.
Per l’indicazione all’effettuazione del test, le pazienti saranno individuate dal GruppoOncologico Multidisciplinare, operate all’interno della rete senologica della RegioneToscana.
Saranno identificate per l’esecuzione gratuita del test solamente le pazienti con tumoredella mammella in stadio precoce, con positività dei recettori per estrogeni eprogesterone e HER2-negativi, le cui caratteristiche indicano tumori in cui il beneficiodell’aggiunta della chemioterapia alla terapia endocrina adiuvante è incerto.
Criteri di accesso al test. I referenti dei centri di senologia della Regione Toscana, hanno giàconcordato* con la seguente definizione di biologia incerta: HER2 negativo, e presenza ditutti i seguenti parametri: - ER > 20% e PgR > 20% e Ki67: tra 14% e 30% e G2. Seguendo icriteri del position paper del gruppo di lavoro AIOM – SIAPEC-IAP – SIBIOC – SIF, il testpotra’ essere proposto a donne con tumore di dimensioni <5 cm (pT1-2) e coninteressamento di <4 linfonodi (pN0-pN1a).
Scelta del Test: sarà data preferenza a test validati in studi prospettici.
CONFIDENTIAL 95
Rimborsabilità dei Test Genomici in Italia
Toscana – DGR 1432 del 23 Novembre 2020
![Page 93: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/93.jpg)
Exact Sciences
479. Al fine di garantire alle donne con carcinoma mammario ormonoresponsivo instadio precoce un trattamento personalizzato sulla base di informazioni genomiche,evitando il ricorso a trattamenti chemioterapici e l’aggravamento del rischio dicontagio da COVID-19 per la riduzione delle difese immunitarie, a decorrere dall’anno2021, nello stato di previsione del Ministero della Salute, è istituito un fondo, con unadotazione di 20milioni di euro annui, destinato, nei limiti del medesimostanziamento, al rimborso diretto, anche parziale, delle spese sostenute per l’acquistoda parte degli ospedali, sia pubblici sia privati convenzionati, di test genomici per ilcarcinoma mammario ormonoresponsivo in stadio precoce
480. Con decreto del Ministro della Salute sono stabilite le modalità di accesso e irequisiti per l’erogazione delle risorse del fondo di cui al comma 479, anche al finedel rispetto del limite di spesa previsto dal medesimo comma.
CONFIDENTIAL 96
Rimborsabilità dei Test Genomici in Italia
Italia – Legge di Bilancio 2021 art. 479-480
![Page 94: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/94.jpg)
Exact Sciences
CONFIDENTIAL 97
Rimborsabilità dei Test Genomici in Italia
Italia – Legge di Bilancio 2021, Decreto di Nomina della Commissione Tecnica
![Page 95: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/95.jpg)
Exact Sciences
CONFIDENTIAL 98
Rimborsabilità dei Test Genomici in Italia
Italia – Legge di Bilancio, accesso ai Test Genomici per tutte le pazienti eleggibili
![Page 96: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/96.jpg)
Exact Sciences
CONFIDENTIAL 99
Rimborsabilità dei Test Genomici in Italia
Italia – Legge di Bilancio, accesso ai Test Genomici per tutte le pazienti eleggibili
![Page 97: Review dei test genomici](https://reader035.vdocuments.mx/reader035/viewer/2022072021/62d8111d49894221002e4d45/html5/thumbnails/97.jpg)