Triple-Negative Breast Cancer Time to Slice and Dice? Carsten Denkert, MD Charité University Hospital Berlin, Germany
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1 Triple-Negative Breast Cancer Time to Slice and Dice? Carsten Denkert, MD Charité University Hospital Berlin, Germany
2 Triple-Negative Breast Cancer (TNBC) 2018 Presentation Outline The molecular heterogeneity and clinical diversity of TNBC Pathologic and molecular characteristics of both hereditary and nonhereditary subtypes of the disease Different approaches for subtyping Potential prognostic biomarkers and therapeutic targets in TNBC PD-L1 and other immunologic biomarkers Androgen-receptor signaling The relevance of deficiencies in DNA repair Current technologies for evaluating defects in DNA repair
3 The Simple View Three Subtypes of Breast Cancer Triple-negative (15%) HR-positive (70%) HER2-positive (15%) Chemotherapy Endocrine therapy Anti-HER2 therapy HER2, human epidermal growth factor receptor 2; HR, hormone receptor
4 The Simple View Extended Subtypes of TNBC (?) Triple-negative (15%) Stem-like AR-pos Mesenchymal Immune Basallike 2 Basallike 1 Challenges to define TNBC subtypes: Different subgroups Mixture of tumor-cell features and tumor-microenvironment Subtypes are overlapping No established diagnostic assay AR, androgen receptor positive; pos, positive
5 Molecular Model for TNBC Biologic Features of a Heterogeneous Disease HRD, homologous recombination deficiency; METABRIC, Molecular Taxonomy of Breast Cancer International Consortium; TIL, tumor-infiltrating lymphocytes; TCGA, The Cancer Genome Atlas Denkert C, et al. Lancet. 2017;389(10087):
6 TNBC Pathologic Characteristics The classical histology High-grade IDC Triple-Negative High nuclear grade Mitoses Solid growth Event-Free Survival, % pcr no pcr High proliferation Time Since Randomization, Years 33% pcr rate IDC, invasive ductal carcinoma; pcr, pathologic complete response Cortazar P, et al. Lancet. 2014;384(9938):
7 TNBC Special Situations The classical histology High-grade IDC Salivary gland like tumors better prognosis, not real TNBC High nuclear grade Mitoses Solid growth Medullary BC immune activation Observed in other TNBCs as well No clearly defined entity High proliferation Minimal ER expression (1% to 9%) Borderline between luminal and TN tumors BC, breast cancer; TN, triple-negative Rakha EA, et al. J Clin Oncol. 2008;26(15):
8 Different Approaches to Molecular Subtyping of TNBC Lehmann BD, et al. J Clin Invest. 2011;121(7): Analysis restricted to the TNBC group. Sørlie T, et al. Proc Natl Acad Sci U S A. 2001;98(19): Comparison of all breast cancer subtypes. Burstein et al. Clin Cancer Res. 2015;21(7): Analysis restricted to the TNBC group. 6 groups: Basal-like 1 Basal-like 2 Immunomodulatory Mesenchymal-like Mesenchymal stem-like Luminal/AR 2 groups: basal-like claudin-low 4 groups: Basal-like immuno suppressed Basal-like immune activated Mesenchymal Luminal/AR Overlapping signatures in different approaches Currently no standardized diagnostic test for molecular subtyping Reduction of 2188-gene algorithm (Lehmann) to a 101-gene algorithm was successful (Ring BZ, et al. BMC Cancer. 2016;16:143.) Consistent molecular motives: Luminal/AR Immune-activated Two types of basallike tumors Mesenchymal Basis for molecular targeted therapy of TNBC
9 TNBC Subtypes Have Different Therapy Response Rates Lehmann groups groups: Basal-like 1; Basal-like 2 Immunomodulatory; Mesenchymal-like Mesenchymal-stem-like; Luminal/AR UNS BL1 BL2 IM M MSL LAR P<.04 pcr, % P<.01 pcr, % P<.011 pcr, % Lehmann BD, et al. PLoS One. 2016;11(6):e Highest response rate: Lowest response rate: BL1 BL2; Luminal/AR
10 Immune Activation Is Observed in Many TNBC Subtypes Lehmann groups groups: Basal-like 1; Basal-like 2 Immunomodulatory; Mesenchymal-like Mesenchymal-stem-like; Luminal/AR UNS BL1 BL2 IM M MSL LAR Lehmann BD, et al. PLoS One. 2016;11(6):e Lehmann BD, et al. J Clin Invest. 2011;121(7):
11 Immune Activation Is Observed in Many TNBC Subtypes Lehmann groups groups: Basal-like 1; Basal-like 2 Immunomodulatory; Mesenchymal-like Mesenchymal-stem-like; Luminal/AR UNS BL1 BL2 IM M MSL LAR Lehmann groups groups: Basal-like 1; Basal-like 2 Mesenchymal-like; Luminal/AR BL1 BL2 M LAR excluded 2016 IM = presence of immune cells MSL = presence stromal cells Immune activation TILs Lehmann BD, et al. PLoS One. 2016;11(6):e Lehmann BD, et al. J Clin Invest. 2011;121(7): immune genes
12 Immune Gene Signature: Correlation With TIL Morphology and Chemotherapy Response in GeparSixto cold hot intermediate PDL1 IDO1 PD1 CTLA4 pcr Rate, % CXCL9 10 CD8A CCL5 CXCL Immune-A Immune-B Immune-C Immune-type A C B Denkert C, et al. J Clin Oncol. 2015;33(9): IGKC CD21 FOXP3 CD80 HR+ HRstrLy (%) LPBC n=481 LPBC Cases, % P< Immune-A Immune-B Immune-C
13 TILs and Increased Chemotherapy Response Rates in Breast Cancer Combined Analysis of 6 Neoadjuvant Trials (N = 3771) 62.5 P<.0005 P<.0005 P<.0005 P<.0005 pcr Rate, % Low (0% to 10%) Intermediate (11% to 59%) High ( 60%) n= All Patients Lum/HER2- HER2+ TNBC pcr: ypt0ypn0 Denkert C, et al. Lancet Oncol. 2018;19(1):40-50.
14 Univariate analysis Multivariate analysis all baseline parameters Multivariate analysis all baseline parameters and pcr Prognosis: High TILs Improved Survival in HER2+ and TNBC high TILs = better survival Disease-Free Survival low TILs = better survival HR per 10% P value All tumors 1.02 ns TNBC HER Lum/HER ns All tumors TNBC HER Lum/HER ns All tumors TNBC 0.95 ns HER Lum/HER ns high TILs = better surival Overall Survival low TILs = better survival HR per 10% P value All tumors 1.01 ns TNBC HER ns Lum/HER All tumors 0.96 ns TNBC HER Lum/HER All tumors 0.99 ns TNBC 0.95 ns HER ns Lum/HER Denkert C, et al. Lancet Oncol. 2018;19(1): ns, not significant
15 TNBC Strata: -TILs (low/med/ high) N = 174 R GeparNuevo Study Design Window of opportunity Durvalumab Placebo 2 weeks Window phase stopped after patient 117 (request of IDMC) Core biopsy nab-pac +Durvalumab nab-pac +Placebo 12 weeks Clinical response ECx4 +Durvalumab ECx4 +Placebo 8 weeks Samples* Samples** Samples** Samples** Surgery Primary endpoint: - pcr ypt0 ypn0 Secondary biomarker endpoints: - TILs - Ki-67 - Immune mrna marker - PD-L1 *Tissue: FFPE, fresh frozen; Liquid biopsies: full blood; plasma, serum **Tissue: FFPE, fresh frozen; Liquid biopsies: plasma, serum
16 GeparNuevo: Complete Cohort and Window Cohort - pcr ypt0, ypn0 80% 70% 60% 50% 40% Complete cohort n=174 (primary endpoint) Window subcohort (exploratory) n= % P =.287* Adjusted** OR 1.53 [95%CI ] P = % 80% 70% 60% 50% 40% 61.0% P = % 30% 20% 10% 0% Durvalumab Placebo N = 88 N = 86 Loibl S, et al. J Clin Oncol. 2018;36(suppl): Abstract % 20% 10% 0% Durvalumab Placebo N = 59 N = 58 * Continuous corrected χ² test ** For stratification factor (TIL groups)
17 GeparNuevo: Subgroup Analysis GeparNuevo preliminary conclusion: Timing of immunotherapy might be important Ongoing translational research Validation in additional trials Loibl S, et al. J Clin Oncol. 2018;36(suppl): Abstract 104.
18 Genomics of TNBC: Number of Mutations in Breast Cancer Mutational Burden (Whole-Exome NGS Sequencing) P = 1.4e-14 P = 1.4e number of mutated genes number of mutated genes G1 G2 G3 HR+ HER2+ HER2+ TNBC HER2- HR+ HR- Budczies J, et al. J Pathol Clin Res. 2015;1(4):
19 Mutational Burden, Therapy Response, and Prognosis MDACC cohort, n = 29 TCGA cohort, n = 101 P =.05 P =.029 Jiang T, et al. PLoS Med, 2016;13(12): e
20 BRCA Mutations in TNBC The majority of hereditary breast cancers show a TN-phenotype (75% to 80%) But still, most TNBC are nonhereditary BCs BRCA mutations are relevant for response to PARP-inhibitors and/or platin-therapy BRCAness : there are tumors that show a homologous recombination deficiency (HRD) without a BRCA mutation these might also respond to PARP-inhibitors/platin-therapy
21 HRD - Biomarker Strategies and Tumor Heterogeneity Different Assays Identify Overlapping Populations Methods for HR deficiency: NGS sequencing for BRCA In normal cells (germline) In tumor cells HDR score Genomic scars Different methods Different cutpoints HRDetect HRD based on WES GeparSixto: 19.8% gbrca mutant 30.3% tbrca mutant 66.8% HRD score high 70.5% any HR deficiency von Minckwitz G, et al. Cancer Res. 2017; 77(4 Suppl): Abstract P
22 Additional Options HRDetect Somatic mutational signatures (=mutation patterns) Physiologic readout of the DNA damage and DNA repair processes that have occurred through tumorigenesis Measured by whole-genome sequencing 98.7% sensitivity for BRCA1/2-mutated tumors Davies H, et al. Nat Med. 2017;23(4):
23 HRD and BRCA As Biomarkers in Clinical Trials GeparSixto Trial (neoadjuvant, early BC): Increased overall CTX response with gbrca1 mutations No carboplatin difference with gbrca1 mutations Positive carbo effect in BRCA wildtype (Increased pcr with HRD, no additional carbo effect) TNT Trial (advanced/metastatic BC): Increased carboplatin response with gbrca1 mutations (No difference with HRD assay) Vn Minckwitz G et al ASCO 2104 Von Minckwitz G, et al. J Clin Oncol. 2014;32(5s):Abstract Updated by Hahnen E, in press Tutt A, et al. Nat Med. 2018;24(5):
24 Mina A, et al. Onco Targets Ther. 2017;10: Parker JS, et al. J Clin Oncol. 2015;33(15 suppl): Vera-Badillo FE, et al. J Natl Cancer Inst. 2014;106(1):djt319. Additional Biomarkers: Androgen Receptors in TNBC AR is present in 13% to 37% of TNBC Detectable by immunohistochemistry Gene expression analysis under development Target for anti-androgenic therapy AR positive TNBC: Better prognosis (Consider AR testing in low-proliferative TNBC)
25 Additional Biomarkers PD-L1 Expression in Breast Cancer Study n %PD-L1 Positive Wang ZQ, et al. Oncotarget. 2017;8(31): Muenst S, et al. Breast Cancer Res Treat. 2014;146(1): Bertucci F, et al. Oncotarget. 2015;6(15): Ali HR, et al. Ann Oncol. 2015;26(7): % all tumors 35.4% in TNBC % all tumors % of inflammatory BCs 3916 PD-L1 immune cells 6% PD-L1 tumor cells 1.7% Membranous staining; associated with better RFS in TNBC Membranous or cytoplasmic staining; associated with worst survival in all subtypes Staining compared to normal breast tissue; Correlation with increased pcr rate Evaluation on TMAs Open questions: Best cutpoints Tumor cells vs TILs Role in immunotherapy trials Currently not a biomarker for clinical practice
26 Take-Home Message TNBC TNBC is a clinical term, not a defined disease entity Molecular features of TNBC include: High immune infiltrate AR expression BRCA mutations / BRCAness Mesenchymal and stem-like features Basal-like phenotype Increased mutational load Each molecular alteration is found only in a subset of TNBC; there is overlap between subtypes They cannot be used for stable subtyping of TNBC, but they are the basis for new therapeutic options Denkert C, et al. Lancet. 2017;389(10087):
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