Profili Genici e
Personalizzazione del trattamento adiuvante nel
carcinoma mammario
G. RICCIARDI
UOC Oncologia Medica, A.O. Papardo, Messina
Dir. Prof. V. Adamo
“Adjuvant”
Medical Therapies Lung Liver
Bone Brain
Localized Disease Curable
Generalized Disease Very difficult to cure
But risk of:
•Overtreatment
•Undertreatment
•Wrog treatment
•Suboptimal treatment
Adapted by M. Piccart AACR 2016
BREAST CANCER
100 BC patients 20% HER2+ BC 15% TN BC
65 HR+/HER2- BC patients 5% >4 Node positive
2-3% too frail for CT
50 HR+/HER2- BC PATIENTS POTENTIALLY CANDIDATE TO ADJUVANT CHEMOTHERAPY BENEFIT/NO TOXICITY
BENEFIT/TOXICITY
NO BENEFIT/NO TOXICITY NO BENEFIT/TOXICITY
Treatment Individualization
G1, T≤2, N -; ER & PgR + HER2 –; LVI Absent
Age <35, G2-3; T>2, Node – or Node + (1-3), ER & PgR+,
HER2 -
Node + (1-3), HER2+, Node + (>4)
R I S k
R I S k Low
Intermedie
High
Only 20% of patienst!
Most difficult group for CT
decision!
St Gallen Definition Risk
Benefit
Increase Survival (2 to12%)
Long-Term Risks
Secondary Cancer
Cardiac toxicity
Early Menopause
Reduction cognitive function
… and Socio-Economic Burden
Adpted by M. Piccart AACR 2016
Adjuvant Chemotherapy in Early Breast
Cancer: Benefit/Risk Balance
WHO CAN BE SPARED TREATMENT? WHO SHOULD RECEIVE TREATMENT?
QUESTION
TOOL CLINICAL
PROBLEM AVOID UNNECESSARY Tx MAXIMIZE BENEFIT
PROGNOSTIC MARKERS PREDICTIVE MARKERS
INDIVIDUALIZED TREATMENT CHOICE
The Road To Treatment Individualization
Clinical validity
Clinical utility
Correlation of score with outcome
Evaluation of Gene-Expression Profiles
Kwa M, Nat Rev Clin Oncol 2017
Analytic Validity Refers to the ability to accurately and reliably measure the genotype of interest.
is the ability of a test result to divide a population into two or more groups that differ either biologically or clinically
Refers to whether using the test leads to an
improvement in clinical decision-making,
with measurable improvements in clinical
outcomes compared with those observed
when the test is not used
Most Common Commercially Available
Prognostic Gene Signatures for Breast Cancer
Kwa M, Nat Rev Clin Oncol 2017
*FDA Approval: Mammaprint & PAM50 ROR
¿ We can identify a subset of patients who do not require
adjuvant chemotherapy?
YES!
Early Breast Cancer HR+/HER2-
Paik NEJM 2006
Vijver NEJM 2002 Dowsett JCO 2013 Filipits CCR 2011
MammaPrint OncotypeDX PAM50 ROR EndoPredict
(include tumor size+nodal status) Analytical Validation of Decentralized
Gene Expression-based tests (only EndoPredict and PROSIGNA)
Predicting Baseline Prognosis
All tests have at least level IB evidence for HR+/HER2-, T1-2 and N0-1 early BC
DATA FROM PROSPECTIVE
RANDOMIZED TRIALS
ONCOTYPE DX
It was developed on the basis of the NSABP B-20 and B-14 trials.The RS is a continuous variable, ranging from 0 to100,and classified the pts
into three categories, ilow risk (RS,18),intermediate risk(RS18-31),and high risk(RS.31), The optimal management of the intermediate-risk group is uncertain and is being studied in the TailorX trial, in which patients with ER+ N0 were assigned to low-risk (RS , 11), intermediate-
risk (RS 11-25), and high-risk groups(RS.25).The main results of the intermediate-risk score group are eagerly awaited.
1. Paik S, NEJM 2004, 2.Sparano JA, NEJM2015; 3.Paik S, JCo2006; 4. Albain KS, Lancet 2010; 5.Dowsett M, JCO 2010; 6. Kraw, Nat Rev Clin Oncol 2017
Trial Assigning Individualized Options
for Treatment or TAILORx
Sparano JA et al. N Engl J Med 2015
TailorX: prognosis of RS low patients
5yrs rate 93.8%
(95% CI, 92.4 to 94.9)
5yrs rate 99.3%
(95% CI, 98.7 to 99.6)
5yrs rate 98.7%
(95% CI, 97.9 to 99.2)
5 yrs rate 98.0%
(95% CI, 97.1 to 98.6)
PlanB: Translational subprotocol <br />5-year DFS in per-protocol population<br />(no chemotherapy in pN0-1 and Recurrence Score 0-11)
MAMMAPRINT
“…The MammaPrint, was the first microarray-based prognostic signature to be approved by the U.S. FDA.
The 70-gene profile may be used for determining the prognosis of patients with stage I and/or II, N0 as well as
for nodes 1 to 3 positive disease.This gene profile was first established using RNA from fresh, frozen tumor tissues;however from 2012 onward, It is also evaluable in formalin-fixed, paraffin-embedded tumor tissue. A list
of 70 genes that could accurately predict poor versus good prognosis for these patients was identified by a supervised analysis of 25,000 genes included in the microarrays. The true clinical utility of MammaPrint is being tested in a randomized prospective phase III trial:
MINDACT…”
1. Sapino A, J Mol Diagn 2014; 2.Mook S, Breast Cancer Res Treat 2009; 3.Knauer M, Breast Cancer Res Treat 2009; 4 Van de Vijver NEJM 2012., 5.
Knaw Nat Rev Clin Oncol 2017
MINDACT
Cardoso F, NEJM 2016
The primary end point was survival without distant metastasis (event-free
rate at 5 years)
“…Among women with early-stage breast cancer who were at high clinical risk and low genomic risk for recurrence, the receipt of no chemotherapy on the basis of the 70-gene signature led to a 5-year rate of survival without distant metastasis that was 1.5 percentage points lower than the rate with chemotherapy.
Given these findings, approximately 46% of women with breast cancer who are at high clinical risk might not require chemotherapy…”
Survival without distant metastasis of 94.7% among pts who did not received chemotherapy 95% CI: 92.5
-96.2); thus, the primary objective of the study (i.e., to show whether the lower boundary of the 95% CI for the rate of survival without distant metastasis
would be at least 92%) was achieved.
Cardoso F, NEJM 2016
Tryfonidis K, ESMO 2017
DMFS at 5-years DFS at 5-years OS at 5-years
Tryfonidis K, ESMO 2017
PAM50 (PROSIGNA)
“…PAM 50 was originally developed for intrinsic subtyping of breast cancer, but later it started to be used to predict recurrence. Its score, PAM 50 ROR is calculated by using the expression profile of 50 selected genes from four intrinsic subtypes, a proliferation score (18-gene subset), and pathologic tumor size and nodal status. It can be used with formalin-
fixed, paraffin-embedded tissue samples and was approved by the U.S. FDA in 2013.. The results of ATAC and ABCSG-8 meet this high level of evidence (Level I) for clinical validity using archived specimens . It is, therefore, a more useful
signature to predict late distant relapses compared with Oncotype DX or MammaPrint.…”
1. Parker JS, JCO 2009; 2.Gnant M, Ann of Oncol 2014; Filipits M, Clin Cancer Res 2014; Coates, Ann of Oncol 2015.
ENDOPREDICT
“The Endopredict analyzed 12 genes with the qRT-PCR for the classification of patients into two recurrence risk groups. The assay was validated in the
ABCSG-6 and ABCSG-8 trials. Additionally, EndoPredictClin, which combines the EndoPredict score with tumor size and nodal status in a linear
model, identified a subgroup of pts with an excellent long-term prognosis after a standard 5 years of endocrine therapy, thus making it useful for evaluating risk of late elapse.Relative gene expression levels are used to calculate the EndoPredict score (EP score) ranging from 0 to 15. Patients
with a score below or equal to 5 are classified as low risk for distant recurrence under endocrine therapy, those with a score above 5 as high risk”
.
1. Filiptis M, Clin Cancer Res 2011; 2. Dubsky P, Br J Cancer. 2013
*could be considered in low burden nodal status.
1.Harris L. J Clin Oncol 2016;
2. Krop I., J Clin Onco 2017
MINDACT : MammaPrint assay may be
used in those with high clinical risk HR+/HER2-neg and NODE-negative
INDICATION Evidence Quality Recommendation Strenght
OncotypeDX YES HIGH STRONG
PAM50 ROR YES HIGH STRONG
EndoPredict YES INTERMEDIATE MODERATE
MammaPrint NO INTERMEDIATE MODERATE
HR+/HER2-neg and NODE-positive
INDICATION Evidence Quality Recommendation Strenght
OncotypeDX NO INTERMEDIATE MODERATE
PAM50 ROR NO INTERMEDIATE MODERATE
EndoPredict NO INSUFFICIENT MODERATE
MammaPrint NO INTERMEDIATE MODERATE
YES HIGH STRONG
¿ we can identify with the Ki-67 a low-risk group that does not
need chemotherapy ?
NO
Early Breast Cancer HR+/HER2-
Ki67 was not taken into account
Goldhirsch A, Ann of Oncol 2009
St Gallen 2009
St Gallen 2011
Goldhirsch A, Ann of Oncol 2011
A majority of the Panel voted that a threshold of
≥14% was indicative of ‘high’ Ki-67 status
St Gallen 2013
Goldhirsch A, Ann of Oncol 2013
A majority of the Panel voted that a threshold of
≥20% was indicative of ‘high’ Ki-67 status
Ki-67 scores should be interpreted in the light of local laboratory values: as an example, if a laboratory has a
median Ki-67 score in HR+ disease of 20%, values of 30% or above could be considered clearly high; those
of 10% or less clearly low
St Gallen 2015
Coates A, Ann of Oncol 2015
Confusion Regarding Ki67 Scoring in the Clinical Setting
St Gallen 2017
The Panel raised an issue of caution about reproducibility of IHC for Ki67 and its use to make clinical decisions, due to the variability of this assayCurigliano G, Ann of Oncol 2017
J Clin Oncol 2016
Guide choice on adjuvant chemotherapy
INDICATION Evidence Quality Recommendation Strenght
Ki67 IHC NO INTERMEDIATE MODERATE
IHC4 NO INTERMEDIATE MODERATE
“…IHC for Ki-67 analysis lacks reproducibility across
laboratories and, therefore, cannot be consistently interpreted
when performed in a broad range of laboratories…”
¿ Changes the choice of adjuvant treatment ?
What if the Prognostic Gene Signatures
are inserted into clinical practice?
“…After receiving the GEP results, treatment recommendations were changed for 40 patients
(20%)…”
“…After receipt of the Prosigna results, physician confidence increased in 41.6% of cases.
The Prosigna results reinforced the confidence of clinicians in the accuracy of adjuvant therapy selected for the pts…”.
Martin M & Prat A, CMRO 2015
¿ Can we safely identify patients who do not need endocrine
therapy beyond 5 years ?
Early Breast Cancer HR+/HER2-
To identify a group of patients (T1-2/N0-N+ with HR+/HER2- disease
• That may be spared extended endocrine therapy (5-10 years) due to their low risk of recurrence
Sestak JCO 2015 Sestak JNCI 2013
Dubsky BJC 2013
PAM50 ROR EndoPredic
t
(include tumor size+nodal status)
Predicting Late Recurrence
“…ROR was the strongest molecular prognostic factor in predicting late recurrence and discriminating patients into low and high risk for late distant recurrence.
However, the St Gallen 2017 did not recommend the use of gene expression signatures for choosing whether to recommend extended adjuvant endocrine treatment, as no
prospective data exist and the retrospective data were not considered sufficient to justify the routine use of genomic assays in this setting. …”
1. Prat A Ann Oncol 2012; 2. Sestak I J Natl Cancer Inst 2013 ; 3. Curigliano G. Ann of Oncol 2017
Predicting Late Recurrence
• All provide prognostic information independent of traditional factors
• 4 tests based on gene expression (Oncotype DX®, PAM50 / Prosigna ™, Endopredict® and MammaPrint®) are available in the clinic.
• They have proven to be highly reproducible :
• 2 have been accredited FDA/510(k) (PAM50 y MammaPrint).
• 2 may be performed in local laboratories(PAM50 y EndoPredict).
• Majority validated in ER+/HER2-, N- BC patients, some also found to be prognostic in N1 pts
• Only OncotypeDx and Mammaprint have been tested in prospective randomized trials (some studies ongoing for other tests).
• The Ki67 IHC NO has shown the same evidence to identify low-risk patients who do not require adjuvant chemotherapy and another problem related to Ki67 is that of reproducibility
• IMPORTANT: They should be used with integration of clinical and pathological data (tumor size and lymph node involvement).
PAM50 and EndoPredict integrate these data in the report.
Oncotype DX does not consider this data in the report.
• It is unclear whether routine use is improving patients outcome, but data are emerging