Heterogeneidad tumoral. Federico Rojo

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1 Heterogeneidad tumoral Federico Rojo

2 Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?

3 Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?

4 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 s ER, PR and HER 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

5 Evidencesof breastcancer heterogeneity

6 Evidencesof breastcancer heterogeneity

7 Breast cancer is a complex disease characterized by morphologic and molecular heterogeneity: From the clinic: HER2 heterogeneity HER2

8 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

9 Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?

10 Intertumorheterogeneity: Luminal A tumors are molecularly different Ciriello, C et al. AACR 2015

11 Intertumorheterogeneity HER2 tumors are clinically different pcr rate in HER2 breast tumors treated with dual blockade Loi, S and Savas, P. J ClinOncol2016

12 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

13 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

14 Intertumorheterogeneity TN breast cancer is heterogeneous Bianchini, G et al. NatRevClinOncol2016

15 Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity Clinical implications of tumor heterogeneity. Can it be overcome?

16 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

17 Temporal intratumorheterogeneity Evolution may occur during the course of breast cancer progression Yates, LR et al. Nat Med 2015

18 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

19 Consequences in clinical setting of temporal heterogeneity 48 studies, 4200 cases Discrepancies: 20% ER, 33% PgR, 8% HER2 Aurilio, G et al. EurJ Cancer2014

20 Temporal intratumorheterogeneity: Consequences in clinical setting GEICAM/ _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 Positive to negative Negative to positive PR No conversion Positive to negative Negative to positive HER2 No conversion Positive to negative Negative to positive Martínez de Dueñas, E et al. BreastCan Res Treat2013

21 Temporal intratumorheterogeneity: Consequences in clinical setting GEICAM/ _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

22 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

23 Temporal intratumorheterogeneity: Consequences in molecular alterations Non-conserved driver alterations are significantly more frequent in discordant tumors Discordant tumors Concordant tumors p<0.001

24 Temporal intratumorheterogeneity: Consequences in molecular alterations and the effect is due to lost primary driver alterations Discordant tumors Concordant tumors p<0.001

25 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 TNBC DI = 0.7 PD-L1 IC Her2 + BC DI = PDL1 IHC 3 PRIMARY ER + BC METASTASES DI = PRIMARY ER + Her2 + BC METASTASES DI = 0.7 PD-L1 IC 2 1 PD-L1 IC PRIMARY METASTASES PRIMARY METASTASES

26 Temporal intratumorheterogeneity: Consequences in molecular alterations GEICAM/ _ConvertHER trial Active Fibroblasts Fibroblasts TGFB response Notch Pathway Innate Inflammation Downregulated in Metastases Name Pvalue SMAD protein signal transduction negative regulation of protein autophosphorylation mature B cell differentiation involved in immune response mature B cell differentiation positive regulation of interferon-alpha production MDA-5 signaling pathway antimicrobial humoral response antibacterial humoral response regulation of cardiac muscle contraction cardiac muscle contraction regulation of striated muscle contraction release of sequestered calcium ion into cytosol by sarcoplas sarcoplasmic reticulum calcium ion transport cytoplasmic pattern recognition receptor signaling pathway Ras GTPase activator activity response to mineralocorticoid membrane depolarization insulin receptor binding insulin-like growth factor binding Rho GTPase activator activity positive regulation of lipid catabolic process positive regulation of steroid biosynthetic process positive regulation of steroid metabolic process response to corticosterone negative regulation of Ras protein signal transduction negative regulation of small GTPase mediated signal transdu axon regeneration negative regulation of myeloid cell apoptotic process neuron projection regeneration negative regulation by host of viral transcription negative regulation of viral transcription regulation of protein autophosphorylation regulation of monocyte differentiation glial cell migration positive regulation of type I interferon-mediated signaling p macrophage apoptotic process cellular response to dsrna

27 Outline of the presentation Definition and evidences Intertumor heterogeneity Spatial and temporal intratumor heterogeneity How can tumor heterogeneity be overcome?

28 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

29 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)

30 Role of stroma in tumor biology and outcome of patients 5. Cuál debe de ser el planteamiento futuro en el diagnóstico morfológico?

31 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

32 Evidencesof breastcancer heterogeneity

33 Spatial intratumor heterogeneity: Genetic variation across different locations within a single tumor: Biopsies of different areas may produce different results

34 Evidencesof breastcancer heterogeneity

35 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