Diagnostica molecolare e
impiego dei test genomici nelle scelte terapeutiche
Jennifer Foglietta
USL UMBRIA2- P.O. Narni-Amelia
►Which test to choose
►Genomic tests vs clinicopathological features
►For which patients
Optimizing the use of genomic prognostic tests
Rationale for treatment individualization for early HR+/HER2- BC patients
100 BC pts
20% HER2+ BC 15% TN BC
65 HR+/HER2- BC pts candidate to HT 5% >4 Node positive
2-3% too frail for CT
50 HR+/HER2- BC PATIENTS
POTENTIALLY CANDIDATE TO
ADJUVANT Ct + HT
• CT produces the same proportional risk reduction in all patients (EBCTCG).
• This translates into different degrees of absolute benefit, depending on the individual estimate of absolute risk of recurrence.
• What is the threshold of absolute risk of recurrence that defines patients that can be safely spared CT?
Absolute distant recurrence risk at baseline
Relative risk reduction with CT
Absolute risk reduction from CT
Risk of Fatal, life-threatening, permanent CT toxicity
50-60% 30% 15-20% 2-3%
10-15% 30% 2-3% 2-3%
Paik NEJM 2006
Vijver NEJM 2002 Dowsett JCO 2013 Filipits CCR 2011
MammaPrint
OncotypeDX PAM50 ROR EndoPredict
(include tumor size+nodal status)
Multigene prognostic tests for HR+/HER2-
All have at least LoE1B as prognostic tests: results from >2 prospective
trials analyzed retrospectively, not designed to test the marker
Paik NEJM 2006
Vijver NEJM 2002 Dowsett JCO 2013 Filipits CCR 2011
MammaPrint
OncotypeDX PAM50 ROR EndoPredict
(include tumor size+nodal status)
Multigene prognostic tests for HR+/HER2-
LoE1A: results from >1 prospective trial
specifically designed to test the marker
MINDACT: Study Design
32%
Cardoso F, NEJM 2016
MINDACT DISCORDANT GROUP: PRIMARY ENDPOINT
Cardoso F, NEJM 2016
Median FU 5yrs N=1550 C-High/G-low
90% ER+/HER2- 52% N0 42% T<2cm 71% G1-2
LoE 1A
N=644 no CT
Sparano JA et al. N Engl J Med 2015;
Sparano JA et al. NEJM 2018
HR+/HER2-, N-negative
T1c-2 any grade or T1b and G2/3
Primary analysis: non-inferiority (iDFS) of HT vs CT+HT in women in the RS 11-25 group.
Oncotype DX®assay
Primary study group
RS 11–25
RS >25
RS <11
Randomize 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%) Enrolled 10,071 pts
(2006-2010) 900 sites, 6 countries
Trial Assigning IndividuaLized Options for
Treatment (Rx) TAILORx
TailorX: prognosis of RS low patients
5yrs rate 94.0% ±0.6 5yrs rate 99.3% ±0.62
5yrs rate 98.8% ±0.3 5 yrs rate 98.0% ±0.4
LoE 1A for N-
Sparano JA et al. N Engl J Med 2015• Hormone-receptor-positive
• HER2-negative
• Axillary node-negative
Trial Assigning IndividuaLized Options for Treatment (Rx)
TAILORx
TailorX (N0): RS 11-25, primary endpoint
CT+ET ET
RS 11-25, randomized to CT+ET or ET alone n=6711
Sparano JA et al. N Engl J Med 2018
iDFS 5yrs % 9yrs % ET 92.8 ±0.5 83.3 ±0.9 CT+ET 93.1 ±0.5 84.3 ±0.8
A 5-year rate of invasive disease–free survival of 90% with chemoendocrine therapy and of 87% or less with endocrine therapy alone, which corresponds to a 32.2% higher risk of an invasive disease recurrence, second primary cancer, or death as a result of not administering chemotherapy (hazard ratio, 1.322).
TAILORx: different cut-offs for young patients
All patients
0-11 >26
Assigned to CT + ET
Young patients (<50 yrs), n=2216
0-11 11-15 16-20 21-25 >26
Good prognosis with ET:
95.1% iDFS 5 yrs
ET: 92.0% iDFS 5 yrs CT: 94.7% iDFS 5yrs 9% fewer iDFS events
with CT (2% distant)
ET: 93.2% iDFS 5 yrs CT: 96.4% iDFS 5yrs 6% fewer iDFS events with CT (mainly distant)
Assigned to CT+ET Good prognosis with ET:
94.0% iDFS 5 yrs
11-25
ET: 92.8% iDFS 5 yrs CT: 93.1% iDFS 5yrs
ET: 95.1% iDFS 5 yrs CT: 94.3% iDFS 5yrs
Sparano JA et al. N Engl J Med 2015;
Sparano JA et al. N Engl J Med 2018;
Sparano JA et al. N Engl J Med 2019
Validated gene expression profiles may be used to gain additional prognostic and/or predictive information to complement pathology assessment and help in adjuvant ChT
decision making [I, A].
In cases of uncertainty regarding indications for adjuvant ChT (after consideration of all clinical and pathological factors),expression of uPA-PAI1 [I, A] or gene expression assays, such as MammaPrint [I, A], Oncotype DX [I, A], Prosigna, Endopredict or Breast Cancer Index, can be used.
TMMP non rientrano nei Livelli Essenziali di Assistenza (LEA)
Dieci MV et al, Oncologist 2018
• 52% of these patients were candidate to ET alone
• 16% rate of change in treatment
recommendation, mostly from CT+HT to HT.
• According to nodal status, rate of change in treatment decision was 12% for the N0 cohort and
20% for the N1 cohort
• 8% net reduction in CT recommendation
BREAST-DX Italy Study
Characteristics:
- Grade 2 tumors 71%
- median age 55 years
- median tumor size 16 mm
- median Ki67 exp 20%.
ROXANE: PRospective multicenter study to assess the impact of the Oncotype DX® Breast Cancer Assay on Resources Optimization and Treatment Decisions for Women with Estrogen Receptor-
Positive, Node-Negative and Node-Positive Breast Carcinoma Prospective observational multicentric study
Sponsor: Istituto Oncologico Veneto IRCCS, Padova Support: Genomic Health (RS tests free of charge)
Rationale:
the impact of RS test on adjuvant treatment decisions in a scenario where, whenever physicians are unsure about treatment recommendation, the test is available
• Overall change in treatment recommendation: 30% (75/251)
• Main change from CT+HT to HT: 77% (58/75)
Dieci MV et al, Oncologist 2019
• Chemioterapia si o no?
• ALWAYS consider classical clinicopathological features
• It is challenging to provide a universally accepted definition of the patients for whom the test would be most useful:
•
Avoid offering the test to patients not suitable for chemotherapy
•
