Lægedag Syd 2011 Biomarkører ved brystkræft -fra primær tumor til metastase Jeanette Dupont Jensen MD Onkologisk Afdeling, Odense Universitets Hospital Forskningsenheden for Onkologi, Klinisk Institut, Sundhedsvidenskabeligt Fakultet, SDU Lægedag Syd 2011
Biomarkør definition 1 : "a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention Prognostisk 2 : Prædiktiv mht. prognose (risiko for recidiv/død), uafhængig af behandling (dvs. forudsiger sygdomsforløb, -om pt. ska tilbydes adj. beh.) Prædiktiv 2 : Forudsiger forskellig gavn (følsomhed/resistens) af en bestemt behandling afhængig af markørstatus (dvs. hvilken behandling) Mål: optimere individualiseret terapi 1 Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther 69:89-95, 2001 2 Hayes et al., Breast Caner Res Treat 1998; 52: 305-319 Definitioner
Lav risiko i henhold til DBCG Acta Oncologica 2008; 47:506-524 Baggrund
DBCG 2010, adjuverende behandlings allokering www.dbcg.dk/mammaskema Baggrund
Primær tumor vs. metastase Biomarkører: primær tumor vs. metastase? Ca. 30% får recidiv Valg af beh. ved recidiv baseres på markører udtrykt i primær tumor idet stabilitet antages På trods af: Størstedelen har modtaget adj. beh (kemoterapi, biologisk beh., endokrin beh.) - beh. selektion? -klonal selektion under sgd progression? Ofte mange år ml. primær sygdom og tilbagefald Heterogenicitet i primær tumor Behandlingsmålet er tilbagefalds sygdommen Baggrund
Formål Formål
Tidligere studier ER diskrepans: 12 29%, oftest med tab af receptoren HER2 diskrepans: 6 20%, oftest med erhvervelse af HER2+ TOP2A/PIK3CA kun i et studie Begrænsninger: Mange studier ikke lavet re-analyse af primær tumor prøver (metode forskellighed) Sammenlignet med synkrone lymfeknude eller loko-regional recidiv, få studier rapporteret om mange fjernmetastaser (n<20) Få prospektive studier: -Biopsi havde behandlingskonsekvens hos 15-20% -Benign sygdom/anden malignitet hos 14% Baggrund
Materiale & metoder IHC Eksklusion: Non-bryst karcinom recidiv eller ikke repræsentativ biopsi Insufficient metastatisk væv til yderligere analyse eller primære vævsblokke ikke til rådighed hos patienter med brystkræft recidiv FISH Primer extension metode: (SNaPshot TM assay) E542K CISH E545K H1047L H1047R Materiale & metoder
Biopsi lokalisation, asynkrone metastaser Resultater Dupont Jensen et al, Breast Cancer Res Treat 2011 in press
Biopsi resultater, patienter med formodet recidiv af brystkræft, Onkologisk Afd., Odense Universitets Hospital 2007-2010 Biopsy results from patients with suspected relapse (N=81) % of patients (n) Recurrence of breast cancer carcinoma 80 % (65/81) Other malignancies (NSCLC (2) and lymphoma (1)) 4 % (3/81) Benign conditions (haemangioma, cyst, reactive lymph nodes, non-malignant sclerotic bones, non-malignant scar alterations)* 7 % (6/81) Non-representative biopsy, recurrent breast carcinoma assumed** 9 % (7/81) *Patients have not been diagnosed with recurrent disease at follow-up (january 2011) **Assumed recurrent disease as some had a later confirmatory biopsy, died form metastatic disease, or had unambiguous diagnostic imaging indicating recurrent disease. Resultater Dupont Jensen et al, Breast Cancer Res Treat 2011 in press
Parret ER, HER2 & TOP2A status Asynchronous metastasis Primary tumor ER Negative Positive Total Concordant Negative 19 4 23 104/118 = 88 % Positive 10 85 95 Discordant Total 29 89 118 14/118 = 12 % Asynchronous metastasis Primary tumor HER2 Negative Positive Total Concordant Negative 96 8 104 104/114 = 91 % Positive 2 8 10 Discordant Total 98 16 114 10/114 = 9 % Asynchronous metastasis Primary tumor TOP2A Normal Aberration* Total Concordant Normal 55 7 62 58/75=77 % Aberration* 10 3 13 Discordant Total 65 10 75 17/75=23 % Axillary nodal status not included. McNemar s exact test, p=0.2, p=0.1, and p=0.6, respectively Resultater Dupont Jensen et al, Breast Cancer Res Treat 2011 in press
PIK3CA status, primær tumor vs. metastase PIK3CA status (exon 9 and/or exon 20) Metastasis (asynchronous) EXON 9/20 Wildtype Mutant Total Primary tumor Wildtype 35 21 56 Mutant 11 33 44 Total 46 54 100 PIK3CA status, combined exon 9 and/or exon 20 mutations in 100 patients with paired results available. Nodal status not included. McNemar s paired test, p=0.08 Resultater Dupont Jensen et al, Clin Cancer Research 2011;17:667-77.
Heterogenicitet, PIK3CA status i primær BC Primary breast cancer, different invasive areas were laser captured and subsequent mutation analysis showed heterogeneity. A: Full section. B: Area with exon 20 mutation (H1047R). C: Area with wildtype (Wt). D: Area with exon 9 mutation (E542K). Overall the status was a double mutation exon 9/exon 20 from the core analysis. Resultater Dupont Jensen et al, Clin Cancer Research 2011;17:667-77.
Korrelation, biomarkør diskordance & lokalisation, adj. beh, og tidlig/sent recidiv Resultater Dupont Jensen et al, Breast Cancer Res Treat 2011 in press
Biomarker discordance True tumor biological changes? BC exhibit intra & intertumoral heterogeneity Clonal selection, selective effect of prior adj. treatment, increased genetic instability during progression, long time interval between events Heterogeneity (pheno- and genotypic) detected by several methods (IHC, FISH, NGS, CGH, and gene expression analyzes) OR Methodological inconsistencies No re-staining/re-analysis (different metods, different times & settings several years between analysis) Interobserver variability (several observers/institutions) IHC vs. ICC, FNA vs. CNB IHC (lack of reproducibility): -changed antigenecity: variation in tissue fixation (time to fixation, type, duration), different staining/hier/antibodies methodology, sample size, age, and quality, decalcification techniques Discussion, Study I & II
Konklusion Ændret geno/fænotype med diskordance, ER (12%), HER2 (9%), PIK3CA (32%), og TOP2A (23%) status, mere ens status mellem primær tumorer og synkrone axillære lymfeknuder Intratumoral heterogenicitet af PIK3CA status in primær tumor Ingen association ml biomarkør ændringer og tidligere adj. beh. 80% havde recidiv af brystkræft -hvis muligt, bør formodet recidiv biopteres dels for at verificere tilbagefald af c. mammae og dels for at optimere efterfølgende targeteret behandling Konklusion
Perspektiv: -biopsi ved formodet recidiv? Perspektiv