Utilité clinique des prédicteurs moléculaires pour la décision de chimiothérapie adjuvante Fabrice ANDRE Institut Gustave Roussy Question posée • Est‐il licite d’utiliser des tests moléculaires pour ne pas faire de chimiothérapie adjuvante ? • Chimiothérapie adjuvante: 10% bénéfice • Raison pour ne pas donner de chimio: – Bon pronostic – Résistance • Très efficace dans les RH‐ ou Her2+; question: quelles patientes avec RH+/Her2‐ peuvent éviter la chimio ? Question clinique ER-negatif Meta‐analyse: 1ere/2e generation: ER‐ / 50‐69 ans: 0.75 (SD 0.06) 3e versus 2e generation: ER‐/PR‐: 0.77 (SD:0.06) Her2+++ HR rechute (A vs Est‐ce que des patientes autre) RE+/Her2‐ peuvent ne Her2+ 0.71 (0.61‐0.83) pas recevoir de chimiothérapie Her2‐ 1.00 (0.9‐1.11) Adjuvante ? Gennari, JNCI, 2008 + Haute sensibilité Synergie taxanes / trastuzumab Chimio T>5mm Chimio T>5mm RE+/Her2- Chimiothérapie (sauf exceptions) Plan • Niveau de preuve biomarqueurs • Signatures multigéniques • Ki67 • Recommandations pratique clinique ANALYTICAL VALIDITY A test’s ability to accurately and reliably measure biomarker of interest (includes reproducibility, robustness (e.g., resistance to small changes in pre‐ analytic or analytic variables) and quality control) CLINICAL VALIDITY A test’s ability to accurately and reliably identify or predict a relevant breast cancer survival endpoint (= “significativité statistique”) CLINICAL UTILITY Treatment decision based on a genomic test results in improved clinical outcome Simon & Hayes Level of Evidence Scale Simon, JNCI, 2009 Simon & Hayes Level of Evidence Scale Simon, JNCI, 2009 Take home message I: level of evidence scale Two different level of evidence scales: EGAPP: requires randomized trials to validate clinical utility of biomarkers Simon / Hayes : does not require randomized trials to reach level I evidence Most of the discrepancies about biomarker use in the world is coming from lack of Standardization about LOE Plan • Niveau de preuve biomarqueurs • Signatures multigéniques • Ki67 • Recommandations pratique clinique EVALUATED SIGNATURES 1. 2. 3. 4. 5. 6. 21-gene Recurrence Score (Oncotype Dx®) GENE70 (MammaPrint ®) Genomic Grade Index (GGI, MapQuant Dx®) Breast Cancer Index (BCI) EndoPredict (EP) PAM50 (ROR-S) LITERATURE SEARCH • Cross-referencing was performed of identified articles • Exclusion criteria – Cost-benefit studies (healthcare dependent) – Neoadjuvant studies (different sampling procedure, addresses prediction not prognosis) – In-silico analyses (approximate version, uses data from datasets previously analyzed) ELIGIBLE ARTICLES Gene Signature Articles Oncotype Dx 21 1 15 5 2 2 EndoPredict MammaPrint GGI PAM50 (ROR-S) BCI Unique Patients Samples from randomized trials (n) 6,033 5* 2,666 2 ** 2,440 0 1,841 0 1,496 0 853 1 *** * ECOGE2197, SWOG8814, NSABP-B20, NSABP-B14, ATAC ** ABCSG-6, ABCSG-8 ** * Stockholm Breast Cancer Study Group randomized phase III trial Mammaprint 70 genes signature Associated with high risk of metastatic relapse Validation I: retrospective analysis samples from NKI Van de Vijvers, NEJM, 2002 Validation II: retrospective analysis samples from 5 European centers Buyse, JNCI, 05 Prospective validation of Mammaprint: EORTC‐BIG MINDACT TRIAL Onco type DX ™ 21‐Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki ‐67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 CD68 REFERENCE Beta ‐actin GAPDH RPLPO GUS TFRC RS = + 0.47 x HER2 Group Score ‐ 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 ‐ 0.08 x GSTM1 ‐ 0.07 x BAG1 Category RS (0 ‐100) Low risk RS <18 Int risk RS >18 and <31 High risk RS >31 8 Validation I: ER-positive disease (NSABP-B14) Oncotype DX identifies a group of patients with a low risk of metastatic relapse Paik NEJM 2004 Validation II: Retrospective analysis of NSABP-B20 trial (CMF vs No chemo) RS<18 18<RS<31 RS>31 Interaction test, p=0.038 Oncotype DX identifies a group of patients: 1. with low risk of relapse 2. with less sensitivity to 1st generation adjuvant chemotherapy Paik, JCO, 2006 Validation prospective du bon pronostic des RS faibles (<11) / N0 Sparano JA et al. N Engl J Med 2015;373:2005-2014. Oncotype: Summary of data • Prospective clinical trial (TAILORx) • >3000 patients analyzed (4 from randomized trials) – NSABP-B14 (NEJM, 04), NSABP-B20 (JCO, 06), Kaiser studies (Breast Cancer Res), SWOG-8814 (Lancet Oncol, 2009), Trans ATAC (SABCS, 08), Japanese study (ASCO breast, 09)… • Concordant data: – Prognostic parameter – Risk of metastatic relapse <10% if RS<18 and N0 – Predictive parameter for the efficacy of suboptimal chemotherapy • Missing data: – Comparison with optimal IHC score (only one study) – Predictive value in Node positive disease (only one study) – Efficacy of taxanes in RS<18 not evaluated (no study with predictive value reported) – Prospective validation (ongoing TAILORx, RxPONDER) Endopredict 8 cancer-related genes Filiptis, Clin Cancer Res, 2012 ROR: PAM50 gene classifier Nielsen, Clin Cancer Res, 2010 Breast Cancer Index (BCI) Molecular grade index 5 genes Grade / proliferation (Ma, Clin Cancer Res, 2008) HOXB13/IL17R (Ma, Cancer Cell, 2004) Breast Cancer Index RT‐PCR, FFPE Central lab Biomarker studies assessing BCI as prognostic marker Dataset Test n Result Reference TransATAC (randomized trial) BCI 665 HR: 2.30 (1.62–3.27) Sgroi, Lancet Oncol, 2013 Sestak et al, A532 MA17 trial (randomized trial) H/I 249 (case control) Late recurrences OR= 0.35; 0.16 to 0.75 Sgroi, JNCI, 2013 Kaiser cohort BCI 608 (case‐control) Tam treated: RR: 3.3 (1.1‐10.3) Untreated: RR: 2 (0.8‐4.9) Habel, BCR, 2013 University of Pittsburgh BCI 265 HR: 5.3 (2.18‐13.1) Jankowitz, BCR, 2011 Stockholm trial (randomized trial) BCI 588 (n=236 Tam) HR: 7.5 (2.4–23.6) Jerevall, BJC, 2011 MGH / Oxford BIC 323 HR: 7.9 (2.2‐28.2) (n=89) Ma, Clin Cancer Res, 2008 NCCTG 89‐30‐52 H/I 211 HR: 1.63 (1.05‐2.53) Goetz, Clin Cancer Res, 2006 >10 studies, three from retrospective analyses of randomized trials Studies excluded: Jansen, JCO, 2006 , Ma, JCO, 2007 , Ma, Cancer Cell, 2004 Recommendations/ Year Signatures Guidelines Evaluated Statement ASCO 2007 2007 Oncotype MammaPrint Rotterdam GS Breast cancer gene expression ratio ‐ Oncotype CAN be used for prognosis in ER+ N0, Tam treated BC ‐ MAY be used for CT utility ‐Other GS under investigation for prognosis and utility French 2013 Oncotype MammaPrint uPA‐PAI‐1 Oncotype pas validé EGAPP 2009 Oncotype MammaPrint H:I ratio test ‐ Inadequate analytic validity “all” ‐ Adequate clinical validity “Oncotype” ‐ Inadequate clinical utility “all” St Gallen 2011 Oncotype MammaPrint ‐Oncotype MAY be used to predict CT utility ‐Mammaprint‐ insufficient data NICE (draft guidelines) 2012 Oncotype MammaPrint Mammastrat IHC4 ‐Oncotype remboursé Plan • Niveau de preuve biomarqueurs • Signatures multigéniques • Ki67 • Recommandations pratique clinique Ki67 • Marqueur de prolifération • Quelle valeur dans les cancers RH+/Her2‐ ? Prognostic value in ER+ disease: IBCSG VIII/IX 30% of the ER+ / grade I‐II have high Ki67 HR for relape:1.5 Modest prognostic value Viale, JNCI, 2008 Prognostic value of Ki67 expression: BIG1‐98 Total: 171 / 1324 (13%) Modest prognostic value Viale, J Clin Oncol, 2008 3rd generation 2nd generation 1st generation Ki67 and efficacy of adjuvant chemotherapy Trials n method Interaction test Viale G JNCI 2008 IBCSG VIII and IX 1521 IHC p=0.90 (IX) p=0.45 (VIII) Paik S JCO 2006 NSABP‐B20 651 RT‐PCR p=0.17 1941 IHC p=0.95 PACS01 700 IHC p=0.10 BCIRG001 1350 IHC Non significant Bartlett Lancet Oncol 2010 Penault‐llorca F JCO 2009 Dumontet Clin Cancer Res 2011 NEAT / BR9601 Ki67 : Summary • Modest prognostic value • Peut être un critère de décision lorsque très faible (<10%) ou très fort (>25%) chez les patientes N-/RH+/Her2-/taille faibleintermédiaire • NO evidence that it could be a predictive biomarker for the efficacy of adjuvant chemotherapy Plan • Niveau de preuve biomarqueurs • Signatures multigéniques • Ki67 • Recommandations pratique clinique Conclusion • Ki67 : – valeur pronostique modeste – pas de valeur prédictive démontrée – Pas de démonstration de l’utilité clinique – Mauvais outil de décision « per se » • Signatures génomiques: – valeur pronostique retrospective et prospective En France, 2016 : N537 Signature d'expression génique dans le cancer du sein AHC/BHN 6850 Indications: (i) évaluation de la probabilité de récidive à distance à dix ans (évaluation 1 849,50 pronostique), (ii) évaluation du bénéfice anticipé € de la chimiothérapie adjuvante (évaluation prédictive), (iii) la classification moléculaire de la tumeur Perspectives • TAILORx / MINDACT : résultats sous peu • Nécessité de bâtir de nouveaux modèles d’implémentation de biomarqueurs (cohortes avec remboursement conditionnel) • Endopredict / ROR : prometteurs • IHC4: prometteur mais en cours de validation • Nécessité de QUANTIFIER le bénéfice attendu de ne pas faire de chimiothérapie : coût , toxicités , qualité de vie (CANTO)