International Society of Breast Pathology. Immune Targeting in Breast Cancer. USCAP 2017 Annual Meeting

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1 International Society of Breast Pathology USCAP 2017 Annual Meeting Immune Targeting in Breast Cancer Ashley Cimino-Mathews, MD Assistant Professor of Pathology and Oncology The Johns Hopkins Hospital March 5, 2017

2 Pre-meeting materials for online distribution

3 Speaker Disclosures No relevant disclosures or conflicts of interest.

4 Pre-meeting Material Outline Introduce the components of the tumor microenvironment Discuss tumor infiltrating lymphocytes (TILs) and their roles as: Prognostic biomarkers Predictive biomarkers Biomarkers of residual disease Present the use of immune checkpoint inhibitors in breast carcinoma Ask: what are the pathologic predictors of response to the immune checkpoint inhibitors?

5 Pre-meeting Material Outline Introduce the components of the tumor microenvironment Discuss tumor infiltrating lymphocytes (TILs) and their roles as: Prognostic biomarkers Predictive biomarkers Biomarkers of residual disease Present the use of immune checkpoint inhibitors in breast carcinoma Ask: what are the pathologic predictors of response to the immune checkpoint inhibitors?

6 The elements of the tumor microenvironment are: 1) the cells 2) the proteins they express and secrete

7 Who are these tumor infiltrating lymphocytes (TIL), and how do we assess them??

8 Figure 1. The inflamed tumor microenvironment. CD8+ Cytotoxic T lymphocyt e PD-1/PD-L1 Macrophage/ Antigenpresenting cell FoxP3+ Regulatory T lymphocyte CD20+ B lymphocyte FoxP3+ Regulatory T lymphocyte CD8+ Cytotoxic T lymphocyte LEGEND CD20+ B lymphocyte Stromal myofibroblast Carcinoma cell PD-1 PD-L1 Cytokines Cytotoxic granules Adapted from: Cimino-Mathews A. Oncology (Williston Park) 2015;29:

9 Cancer immune surveillance Tumor elimination Immune evasion CD8+ T cell Th1 T cell Innate M1 immune macrophage cells Immune system recognizes tumor neo-antigens as foreign tumor elimination Equilibrium FoxP3+ Treg Th2 T cell M2 macrophage Tumor cells gain immune resistance mechanisms and induce immune tolerance and the immune milieu shifts to pro-tumorigenic tumor survival

10 - + Inhibitory interactions between antigen presenting cells and T cells dampen the T cell immune response - PD-1 CTLA4 PD-L1 CD80/86 CD80/86 CD137L Signal 1 TCR MHC Class I/II MHC Class I/II TCR Signal CYTOKINES IL-1, IL-6, IL-10, IL- 12, IL-18, TGF- + Antigen Presenting Cell OX40L CYTOKINES IL-1, IL-6, IL-10, IL- 12, IL-18, TGF- Adapted from: Cimino-Mathews A. Oncology (Williston Park) 2015;29: B7RP1 Stimulatory signals from T cells activate antigen presenting cells CD137 CD28 ICOS OX40 +

11 In breast carcinoma, we can evaluate the tumor microenvironment on the basis of these cell types and immune protein expression

12 What do we know about tumor infiltrating lymphocytes (TIL) and breast carcinomas?

13 Medullary carcinoma The classic histologic criteria used to define medullary carcinomas: Syncytial growth pattern in >75% tumor Cytologically atypical cells with prominent nucleoli and abundant cytoplasm Lack of tubule formation Circumscribed/pushing border Prominent and diffuse lymphoplasmacytic inflammation Medullary carcinomas have relatively favorable prognosis

14 Medullary Breast Carcinoma

15 Cancer. 1949;2:

16 Questions that arise from observations about medullary carcinomas Why do some tumors have TIL and others don t? Is the presence of TIL good or bad? Can we harness the good (anti-tumor) TIL and block the inhibitory checkpoints of the bad (pro-tumor) TIL for therapy?

17 How do we score TILs in breast carcinoma?

18

19 Stromal TIL Intratumoral TIL

20 Triple negative (TNBC) and HER2+ carcinomas are more immunogenic than luminal (ER+) carcinomas.

21 HER2+ Carcinoma with brisk lymphocyte infiltrate ( TIL )

22 ER+ Carcinoma with minimal lymphocyte infiltrate ( TIL )

23 Medullary carcinomas have a favorable prognosis but what is the association of TIL with survival in invasive ductal carcinomas?

24 TIL as a prognostic biomarker

25 The presence of TIL and lymphoid aggregates are associated with improved survival in select tumor types.

26 Among TIL subtypes, CD8+ cells are favorable and FoxP3+ cells are unfavorable, in select tumor types. CD8+ Cytotoxic T lymphocyte: anti-tumor FoxP3+ Regulatory T lymphocyte: pro-tumor

27 TIL as a predictive biomarker

28 The presence of TIL predicts favorable response to neoadjuvant therapy, in select tumor types.

29 TIL as a biomarker of residual disease

30 The presence of TIL after neoadjuvant therapy is favorable (improved recurrence-free and overall survival), and decreased FoxP3+ cells are seen in patients with pcr, in select tumor types.

31 Pre-meeting Material Outline Introduce the components of the tumor microenvironment Discuss tumor infiltrating lymphocytes (TILs) and their roles as: Prognostic biomarkers Predictive biomarkers Biomarkers of residual disease Present the use of immune checkpoint inhibitors in breast carcinoma Ask: what are the pathologic predictors of response to the immune checkpoint inhibitors?

32 What is the role of immune checkpoint pathways in modulating the immune response in breast carcinoma? The PD-1 Pathway PD-1 is expressed on immune cells. Its ligand PD-L1 is expressed by immune cells and can be induced on tumor cells by inflammatory cytokines or by mutations

33 PD-L1 is expressed by breast carcinoma cells and tumor infiltrating lymphocytes.

34 Understanding these components (cells and immune checkpoint protein expression) enables the development and investigation of immunotherapies.

35 Immunotherapy in breast cancer (1) Clinical trials are investigating immune checkpoint antagonists targeting: PD-1/PD-L1 pathway CTLA4 pathway LAG3 pathway Therapeutic Resulting in anti-tumor T cell Preventative activation Breast Anti-tumor cancer T vaccines cell PD-1 Antigen specific (HER2, MUC-1, htert, survivin, mammaglobin) mmaglobin CD80/86 Cell-based vaccines (dendritic cells, allogeneic tumor cells) CTLA4 Secondary (patients with a history of breast cancer) Primary (patients at risk for developing breast cancer - - Signal 1 - PD-L1 TCR MHC Class I/II Antigen Presenting Cell

36 Immunotherapy in breast cancer (2) Another strategy is breast cancer vaccines, which can be: Therapeutic Antigen specific (HER2, MUC-1, htert, survivin, mammaglobin) Cell-based vaccines (dendritic cells, allogeneic tumor cells) Preventative Secondary (patients with a history of breast cancer) Primary (patients at risk for developing breast cancer Vaccines target tumor antigens on tumor cells, thereby engaging tumor-specific T cells

37 Importance of understanding the tumor microenvironment Identifying targets for immunotherapy (e.g., checkpoint pathways) Identifying patients for whom immunotherapeutic agents could be used Identifying biomarkers for inclusion into trials (potential benefits outweighing potential risk) Identifying biomarkers to predict response Identifying prognostic markers such that microenvironment features may guide treatment algorithm

38 The optimal biomarker to use for immunotherapies is still not clear. The degree tumor infiltrating lymphocytes (TIL)? The number of CD8 versus FoxP3 T cells? The PD-1 or PD-L1 expression by the tumor cells? The PD-1 or PD-L1 expression by the TIL? The ER/PR/HER2 status of the tumor?

39 Understanding the tumor microenvironment characteristics may help guide treatment algorithms and selecting patients for whom immunotherapeutic strategies might be considered.

40 Pre-meeting Material Summary Introduce the components of the tumor microenvironment Discuss tumor infiltrating lymphocytes (TILs) and their roles as: Prognostic biomarkers Predictive biomarkers Biomarkers of residual disease Present the use of immune checkpoint inhibitors in breast carcinoma Ask: what are the pathologic predictors of response to the immune checkpoint inhibitors?

41 References See separately submitted file.

Immune Targeting in Breast Cancer. Ashley Cimino-Mathews, MD Department of Pathology and Oncology The Johns Hopkins Hospital 13 March 2016

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