Profili Genici e Personalizzazione del trattamento adiuvante nel carcinoma mammario G. RICCIARDI UOC Oncologia Medica, A.O. Papardo, Messina Dir. Prof. V. Adamo
BREAST CANCER Brain Adjuvant Medical Therapies Lung Liver Bone Localized Disease Curable But risk of: Overtreatment Undertreatment Wrog treatment Suboptimal treatment Generalized Disease Very difficult to cure Adapted by M. Piccart AACR 2016
Treatment Individualization 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
St Gallen Definition Risk Low G1, T 2, N -; ER & PgR + HER2 ; LVI Absent Only 20% of patienst! R I S k Intermedie High Age <35, G2-3; T>2, Node or Node + (1-3), ER & PgR+, HER2 - Node + (1-3), HER2+, Node + (>4) Most difficult group for CT decision! R I S k
Adjuvant Chemotherapy in Early Breast Cancer: Benefit/Risk Balance 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
The Road To Treatment Individualization QUESTION WHO CAN BE SPARED TREATMENT? WHO SHOULD RECEIVE TREATMENT? CLINICAL PROBLEM AVOID UNNECESSARY Tx MAXIMIZE BENEFIT TOOL PROGNOSTIC MARKERS PREDICTIVE MARKERS INDIVIDUALIZED TREATMENT CHOICE
Evaluation of Gene-Expression Profiles Analytic Validity Clinical validity Correlation of score with outcome 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 Clinical utility 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 Kwa M, Nat Rev Clin Oncol 2017
Most Common Commercially Available Prognostic Gene Signatures for Breast Cancer *FDA Approval: Mammaprint & PAM50 ROR Kwa M, Nat Rev Clin Oncol 2017
Early Breast Cancer HR+/HER2- We can identify a subset of patients who do not require adjuvant chemotherapy? YES!
Predicting Baseline Prognosis All tests have at least level IB evidence for HR+/HER2-, T1-2 and N0-1 early BC MammaPrint OncotypeDX PAM50 ROR EndoPredict Vijver NEJM 2002 Paik NEJM 2006 Dowsett JCO 2013 Filipits CCR 2011 DATA FROM PROSPECTIVE RANDOMIZED TRIALS (include tumor size+nodal status) Analytical Validation of Decentralized Gene Expression-based tests (only EndoPredict and PROSIGNA)
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), intermediaterisk (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
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) Sparano JA et al. N Engl J Med 2015
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) 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. 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 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 formalinfixed, 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
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 YES NO INTERMEDIATE HIGH MODERATE STRONG HR+/HER2-neg and NODE-positive MINDACT : MammaPrint assay may be used in those with high clinical risk INDICATION Evidence Quality Recommendation Strenght OncotypeDX NO INTERMEDIATE MODERATE PAM50 ROR NO INTERMEDIATE MODERATE EndoPredict NO INSUFFICIENT MODERATE MammaPrint NO INTERMEDIATE MODERATE *could be considered in low burden nodal status. 1.Harris L. J Clin Oncol 2016; 2. Krop I., J Clin Onco 2017
Early Breast Cancer HR+/HER2- we can identify with the Ki-67 a low-risk group that does not need chemotherapy? NO
Confusion Regarding Ki67 Scoring in the Clinical Setting St Gallen 2009 Ki67 was not taken into account Goldhirsch A, Ann of Oncol 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 St Gallen 2015 Coates A, Ann of Oncol 2015 St Gallen 2017 Curigliano G, Ann of Oncol 2017 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 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 assay
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 J Clin Oncol 2016
What if the Prognostic Gene Signatures are inserted into clinical practice? Changes the choice of adjuvant treatment?
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
Early Breast Cancer HR+/HER2- Can we safely identify patients who do not need endocrine therapy beyond 5 years?
Predicting Late Recurrence 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 PAM50 ROR EndoPredic t Sestak JCO 2015 Sestak JNCI 2013 Dubsky BJC 2013 (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
Multigene Tests: Summary of Evidence 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
GRAZIE!