Heterogeneidad tumoral Federico Rojo
Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?
Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?
Evolution in breast cancer classification 1890s >3500 y First identification of breast cancer Heterogeneity in prognosis Identification of hormone dependent breast cancer 1900s Clinical staging 1920s Histological classification 1960-1990s ER, PR and HER2 2000 Intrinsic subtype 2000s TCGA 21st century Next? Sorlie, T et al. PNAS, 2001 Perou, CM et al. Nature, 2000 Perreard, L et al. Breast Cancer Res, 2006 EBCTCG. Lancet 2011
Evidencesof breastcancer heterogeneity
Evidencesof breastcancer heterogeneity
Breast cancer is a complex disease characterized by morphologic and molecular heterogeneity: From the clinic: HER2 heterogeneity HER2
Breast cancer is a complex disease characterized by morphologic and molecular heterogeneity: From the clinic: heterogeneity in proliferation Buckley, NE et al. ScienRep2016 Besusparis, J. Diag Pathol 2016
Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?
Intertumorheterogeneity: Luminal A tumors are molecularly different Ciriello, C et al. AACR 2015
Intertumorheterogeneity HER2 tumors are clinically different pcr rate in HER2 breast tumors treated with dual blockade Loi, S and Savas, P. J ClinOncol2016
Intertumorheterogeneity HER2 tumors are clinically different Neoadjuvantpaclitaxelplus trastuzumab with or without lapatinib, CALGB40601 Intrinsicsubtypeand reponsein N9831 trial pcrrates: 36% (luminala) vs 70% (HER2-E) Carey, LA et al. J ClinOncol2016 Perez, EA et al. JNCI 2017
Intertumorheterogeneity HER2 tumors are clinically different Alternative driver mutations in heterogeneous HER2 gene amplified breast cancer Ng, CKY et al. Gen Biol2015 BRF2 and DSN1 driver amplification in HER2 negative tumor cells at HER2 gene amplified breast cancer
Intertumorheterogeneity TN breast cancer is heterogeneous Bianchini, G et al. NatRevClinOncol2016
Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?
Spatial intratumor heterogeneity: Genetic variation across different locations within a single tumor: Biopsies of different areas may produce different results Yates, LR et al. Nat Med 2015
Temporal intratumorheterogeneity Evolution may occur during the course of breast cancer progression Yates, LR et al. Nat Med 2015
Temporal intratumorheterogeneity Evolution may occur during the course of breast cancer progression The ESR1 mutation example in breast cancer Schiavon, G et al. ScienceTransMed2015 Toy, W et al. NatGenetics2013 Robinson, DR et al. Nat Genetics 2013 Polyak, K. Nature Medicine 2014
Consequences in clinical setting of temporal heterogeneity 48 studies, 4200 cases Discrepancies: 20% ER, 33% PgR, 8% HER2 Aurilio, G et al. EurJ Cancer2014
Temporal intratumorheterogeneity: Consequences in clinical setting GEICAM/2009-03_ConvertHER trial: analysis of clinical phenotypes in paired primary and metastatic breast tumors (n=160) Overall HR positive Her2 amplified TN N % N % N % N % ER No conversion 126 79 94 82 18 60 14 93 0.032 Positive to negative 14 9 7 6 6 20 1 7 Negative to positive 20 12 14 12 6 20 0 0 PR No conversion 102 65 66 59 21 72 15 100 0.021 Positive to negative 34 22 28 25 6 21 0 0 Negative to positive 20 13 18 16 2 7 0 0 HER2 No conversion 117 84 78 80 26 93 13 93 0.322 Positive to negative 9 6 8 8 0 0 1 7 Negative to positive 14 10 12 12 2 7 0 0 Martínez de Dueñas, E et al. BreastCan Res Treat2013
Temporal intratumorheterogeneity: Consequences in clinical setting GEICAM/2009-03_ConvertHER trial: analysis of PAM50 phenotypes in paired primary and metastatic breast tumors Primary Tumor Metastatic Site Basal-like HER2-E LumA LumB Basal-like 12 (92%) 1 (8%) 0 0 HER2-E 2 (15%) 10 (77%) 1 (8%) 0 LumA 1 (2%) 6 (13%) 21 (46%) 18 (39%) LumB 0 4 (13%) 5 (17%) 21 (70%) Subtype Concordance = 63% 54% of primary Luminal A tumors become non-luminal A 13% of primary Luminal A/B become HER2-E Cejalvo, JM et al. CancerRes 2017
Temporal intratumorheterogeneity: Consequences in molecular alterations 1340 mutations in 156 genes and 888 CNA in 171 genes Mutations and CNA were less frequent in HR-/HER2+ Primary tumor Metastasis Martínez de Dueñas, E et al. SEOM 2015
Temporal intratumorheterogeneity: Consequences in molecular alterations Non-conserved driver alterations are significantly more frequent in discordant tumors Discordant tumors Concordant tumors p<0.001
Temporal intratumorheterogeneity: Consequences in molecular alterations and the effect is due to lost primary driver alterations Discordant tumors Concordant tumors p<0.001
Temporal intratumorheterogeneity: Consequences in molecular alterations PD-L1 in primary and metastases: TNBC and HER2 are more dynamic Dynamic Index (DI) = # Changing Patients Total Patients PD-L1 IC 3 2 1 TNBC DI = 0.7 PD-L1 IC 3 2 1 Her2 + BC DI = 0.7 0 0 PDL1 IHC 3 PRIMARY ER + BC METASTASES DI = 0.3 3 PRIMARY ER + Her2 + BC METASTASES DI = 0.7 PD-L1 IC 2 1 PD-L1 IC 2 1 0 0 PRIMARY METASTASES PRIMARY METASTASES
Temporal intratumorheterogeneity: Consequences in molecular alterations GEICAM/2009-03_ConvertHER trial Active Fibroblasts Fibroblasts TGFB response Notch Pathway Innate Inflammation Downregulated in Metastases Name Pvalue SMAD protein signal transduction 0.00271869 negative regulation of protein autophosphorylation 0.00271869 mature B cell differentiation involved in immune response 0.00271869 mature B cell differentiation 0.00271869 positive regulation of interferon-alpha production 0.00271869 MDA-5 signaling pathway 0.00271869 antimicrobial humoral response 0.00052652 antibacterial humoral response 0.00788276 regulation of cardiac muscle contraction 0.00788276 cardiac muscle contraction 0.00788276 regulation of striated muscle contraction 0.00788276 release of sequestered calcium ion into cytosol by sarcoplas 0.00788276 sarcoplasmic reticulum calcium ion transport 0.00788276 cytoplasmic pattern recognition receptor signaling pathway 0.00788276 Ras GTPase activator activity 0.00241104 response to mineralocorticoid 0.00244307 membrane depolarization 0.00244307 insulin receptor binding 0.01511404 insulin-like growth factor binding 0.01511404 Rho GTPase activator activity 0.01511404 positive regulation of lipid catabolic process 0.01523899 positive regulation of steroid biosynthetic process 0.01523899 positive regulation of steroid metabolic process 0.01523899 response to corticosterone 0.01523899 negative regulation of Ras protein signal transduction 0.01523899 negative regulation of small GTPase mediated signal transdu0.01523899 axon regeneration 0.01523899 negative regulation of myeloid cell apoptotic process 0.01523899 neuron projection regeneration 0.01523899 negative regulation by host of viral transcription 0.01523899 negative regulation of viral transcription 0.01523899 regulation of protein autophosphorylation 0.01523899 regulation of monocyte differentiation 0.01523899 glial cell migration 0.01523899 positive regulation of type I interferon-mediated signaling p 0.01523899 macrophage apoptotic process 0.01523899 cellular response to dsrna 0.01523899
Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity How can tumor heterogeneity be overcome?
Liquid biopsy might overcome tumor heterogeneity ctdna is a potential source to assess tumor heterogeneity: Capturing repertoire of genetic alterations from discordant primary tumor and/or metastases (all clones are potentially mixed in blood) Longitudinal monitoring of disease Predicting targeted therapy response Tracking secondary resistance (emergence of resistant clones) Murtaza, M et al. NatComm2015
Final remarks Patient selection for therapy is based on the presence of molecular markers and/or actionable genomic alterations Breast tumors have considerable spatial and temporal intratumorgenetic heterogeneity Darwinian rules seem to govern the somatic changes that occur within a tumor Challenges for clinical management: Tumor heterogeneity may affect clinical diagnosis, treatment, and disease recurrence or progression. Analysis of biopsies of different areas within tumors may produce distinct results Tumors may evolve over time (biomarker discordance / therapeutic resistance)
Role of stroma in tumor biology and outcome of patients 5. Cuál debe de ser el planteamiento futuro en el diagnóstico morfológico?
Breast cancer is a complex disease characterized by morphologic and molecular heterogeneity: From the clinic: Estrogen receptor heterogeneity Allot, EH et al. BreastCan Res 2016
Evidencesof breastcancer heterogeneity
Spatial intratumor heterogeneity: Genetic variation across different locations within a single tumor: Biopsies of different areas may produce different results
Evidencesof breastcancer heterogeneity
Temporal intratumorheterogeneity: Consequences in molecular alterations Lost primary driver alterations are significantly different distributed along subtypes: more frequent in luminal B-HER2 and less frequent in HER2 HR+/HER2+ HR+/HER2- HR-/HER2+ p<0.001 TN