Download Immune Targeting in Breast Cancer

3/27/2017
International Society of Breast Pathology
“Molecular diagnostics in breast cancer”
USCAP 2017 Annual Meeting
Immune Targeting in Breast Cancer
Ashley Cimino‐Mathews, MD
Associate Professor of Pathology and Oncology
The Johns Hopkins Hospital
March 5, 2017
Speaker Disclosures
• No relevant disclosures or conflicts of interest.
Disclosure of Relevant
Financial Relationships
USCAP requires that all planners (Education Committee) in a position to influence or control the content of CME disclose any relevant financial relationship WITH COMMERCIAL INTERESTS which they or their spouse/partner have, or have had, within the past 12 months, which relates to the content of this educational activity and creates a conflict of interest. OBJECTIVES
1. DEFINE THE TUMOR MICROENVIRONMENT
2. EXAMINE THE ROLE OF TILS (TUMOR INFILTRATING LYMPHOCYTES)
AS PROGNOSTIC AND PREDICTIVE MARKERS
3. DISCUSS THE USE OF IMMUNE CHECKPOINT
INHIBITION IN BREAST CANCER
What are the elements of the tumor immune microenvironment?
The components of the tumor microenvironment are:
1) the cells
2) the proteins they express and secrete
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These cells participate in
cancer immune surveillance
The cells of the inflamed tumor microenvironment
Cytotoxic granules
Tumor elimination
CD8+ Cytotoxic T lymphocyte
Macrophage
FoxP3+ Regulatory T lymphocyte
Cytokines
Tertiary lymphoid structure
CD20+ B lymphocyte
CD8+ T cell Th1 T cell
Immune evasion
Innate M1 immune macrophage cells
Equilibrium
INHIBITORY “IMMUNE CHECKPOINT” SIGNALS
PD‐1
‐
CTLA4
PD‐1
‐
+
Signal 1 TCR
INHIBITORY “IMMUNE CHECKPOINT” SIGNALS
‐
CD80/86
MHC Class I/II
‐
Cytokines
Adapted from: Cimino‐Mathews A. Oncology (Williston Park) 2015;29:375‐85.
M2 macrophage
Proteins expressed by tumor and immune cells can stimulate or inhibit the anti‐tumor immune response.
PD‐L1
Antigen Presenting Cell
Anti‐tumor T cell response
Th2 T cell
Tumor cells gain immune resistance mechanisms and immune cells shift to pro‐
tumorigenic milieu
Immune system recognizes tumor neo‐antigens as “foreign”
Adapted from: Cimino‐Mathews A. Oncology (Williston Park) 2015;29:375‐85.
Proteins expressed by tumor and immune cells can stimulate or inhibit the anti‐tumor immune response.
FoxP3+ Treg
CHECKPOINT Anti‐tumor INHIBITORS: T cell Result in anti‐tumor response
T cell activation
+
CTLA4
PD‐L1
CD80/86
Antigen Presenting Cell
‐
Signal 1 TCR
MHC Class I/II
‐
Cytokines
Adapted from: Cimino‐Mathews A. Oncology (Williston Park) 2015;29:375‐85.
TILs are emerging as a promising biomarker in breast cancer.
What do we already know about tumor infiltrating lymphocytes (TILs) and breast carcinomas?
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Medullary Breast Carcinoma
HER2+ Carcinoma with brisk lymphocyte infiltrate (TIL)
ER+ Carcinoma with minimal lymphocyte infiltrate (TIL)
Triple negative (TNBC) and HER2+ carcinomas are more immunogenic than luminal (ER+) carcinomas:
‐ increased TIL infiltrate
‐ increased “immune” gene signatures
[1] Clin Cancer Res, 2014; 20:2773‐82. [2] Hum Pathol. 2013; 44: 2494‐500. [3] Hum Pathol. 2016;47(1):52‐63. [4] Clin Cancer Res, 2008; 15:5158‐65. [5] Breast Cancer Res, 2009; 11:R15. Cancer. 1949;2:635‐42.
“Weak” infiltrate
~500 patients overall “Dense” infiltrate
Improved recurrence free survival & breast cancer survival
Eur J Cancer.
1992; 28A:859‐64.
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How should we score TILs in breast carcinoma?
Morphology, definitions, biological and diagnostic relevance of the different immune
infiltrates found in breast cancer.
Stromal TILs vs. Intratumoral TILs
R. Salgado et al. Ann Oncol 2015;26:259-271
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical
Oncology. All rights reserved. For permissions, please email: [email protected].
R. Salgado et al. Ann Oncol 2015;26:259-271
Standardized approach for TILs evaluation in breast cancer.
“Intratumoral TIL”
“Stromal TIL”
R. Salgado et al. Ann Oncol 2015;26:259-271
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical
Oncology. All rights reserved. For permissions, please email: [email protected].
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Standardized approach for TILs evaluation in breast cancer.
R. Salgado et al. Ann Oncol 2015;26:259-271
Standardized approach for TILs evaluation in breast cancer.
Standardized approach for TILs evaluation in breast cancer.
R. Salgado et al. Ann Oncol 2015;26:259-271
Standardization and guidelines for TILs assessment.
R. Salgado et al. Ann Oncol 2015;26:259-271
R. Salgado et al. Ann Oncol 2015;26:259-271
“Lymphocyte‐predominant breast cancer” © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical
Oncology. All rights reserved. For permissions, please email: [email protected].
“Lymphocyte‐predominant breast cancer” • In studies, most look at TIL in deciles • Use cut‐off of > 50‐60% TIL for “lymphocyte predominant breast carcinoma” (LPBC) (i.e., more TIL than carcinoma cells)
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Can TIL be reliably assessed on core needle biopsy?
What is the role of TILs as a prognostic
biomarker?
The presence of TIL and tertiary lymphoid structures are associated with improved survival in TNBC and HER2+ carcinomas:
‐ independent prognostic factor for overall survival, “T and B lymphocytes show more heterogeneity across … a single section than between different sections ... This observation suggests that the average lymphocyte score from a single biopsy of a tumor is reasonably representative of the whole cancer.”
Medullary carcinomas have a favorable prognosis… but what is the association of TIL with survival in invasive ductal carcinomas?
Disease free survival
Distant‐disease free survival
~900 patients
Overall survival
decreased metastasis, and increased metastasis free survival in TNBC [1‐6] ‐ improved overall survival in HER2+ carcinomas [1]
[1] J Clin Oncol, 2014; 32:2959‐67. [2] Ann Oncol, 2014; 25:1544‐50. [3] Breast Cancer Res, 2007; 9:R65. [4] Ann Oncol. 2015 Aug;26(8):1698‐704 [5] Oncoimmunology. 2015 Jul 27;4(9):e985930. [6] Ann Oncol. 2016 Feb;27(2):249‐56
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Table 3 Adjuvant trials in which TILs have been assessed
Table 3 Adjuvant trials in which TILs have been assessed
Savas, P. et al. (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.215
Savas, P. et al. (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.215
What is the role of TILs as a prognostic biomarker in residual disease after neoadjuvant therapy?
The presence of TIL in the tumor bed after
neoadjuvant chemotherapy is favorable, primarily in TNBC:
– improved recurrence‐free survival
– improved overall survival [1] Ann Oncol, 2014; 25:611‐8. [2] Clin Cancer Res, 2008; 14: 2413‐20. [3] J Pathol, 2011; 224: 389‐400.
~300 patients
Tumors with high TIL have improved survival
High TIL (> 60%)
Low TIL (< 60%)
Metastasis‐free survival
High TIL (> 60%)
What is the role of TILs as a predictive
biomarker?
Low TIL (< 60%)
Overall survival
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LPBC have highest pCR
The presence of TIL predicts a favorable response to neoadjuvant therapy, particularly in TNBC and HER2+ tumors.
41.7%
Increased TIL
Lacking TIL
12.8%
All cases
[1] Clin Cancer Res, 2014: 20:5995‐6005. [2] J Clin Oncol, 2010; 28:105‐13. [3] J Clin Oncol. 2015;33:983‐91. Table 4 Neoadjuvant trials that have assessed TILs
~1000 patients
LPBC
Table 4 Neoadjuvant trials that have assessed TILs
Reference: Issa‐Nummer/Denkert. PLoS
One. 2013; 8:e79755.
Savas, P. et al. (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.215
Savas, P. et al. (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.215
Understanding the components of the tumor microenvironment enables the development and investigation of immunotherapies. Nat Med. 2015;21:1128‐38.
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Proteins expressed by tumor and immune cells can stimulate or inhibit the anti‐tumor immune response.
In breast carcinomas, the ligand PD‐L1 is expressed by the TIL and
the breast carcinoma cells. The PD‐1 receptor
is expressed on the TIL.
INHIBITORY “IMMUNE CHECKPOINT” SIGNALS
PD‐1
‐
CTLA4
PD‐L1
CD80/86
Antigen Presenting Cell
Anti‐tumor T cell response
‐
+
Signal 1 TCR
MHC Class I/II
‐
Cytokines
Adapted from: Cimino‐Mathews A. Oncology (Williston Park) 2015;29:375‐85.
Triple negative and HER‐2+ carcinomas contain more TIL and are more likely to be PD‐L1+ than luminal (ER+) carcinomas, and thus are the most attractive candidates for immunotherapy.
FDA‐approved* PD‐1/PD‐L1 checkpoint inhibitors in solid organ tumors
•
Nivolumab (Bristol‐Myers Squibb)
– Anti‐PD‐1
– Melanoma, non‐small cell lung carcinoma, renal cell carcinoma, urothelial carcinoma, and head & neck squamous cell carcinoma (and classical Hodgkin lymphoma)
•
Pembrolizumab (Merck)
– Anti‐PD‐1
– Melanoma, non‐small cell lung carcinoma, and head & neck squamous cell carcinoma •
Complementary PD‐L1 diagnostic test (28‐8, Dako, TC)
Companion PD‐L1 diagnostic test (22C3, Dako, TC & stroma)
Atezolizumab (Genentech/Roche)
– Anti‐PD‐L1
– Urothelial carcinoma, NSLCL
Complementary PD‐L1 diagnostic test (SP142, Ventana; TIL & TC)
*as of 02/27/2017
PD‐1/PD‐L1 Blockade in Breast Cancer
Antibody
Avelumab
Pembrolizumab
Atezolizumab
Target
PD‐L1
PD‐1
PD‐L1
Patients
ORR
All
Subtype (all metastatic)
168
4.8%
PD‐L1+ All
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TNBC
58
PD‐L1+ TNBC
PD‐1/PD‐L1 Blockade in Breast Cancer
Patients
ORR
All
168
4.8%
33.3%
PD‐L1+ All
12
33.3%
8.6%
TNBC
58
8.6%
9
44.4%
PD‐L1+ TNBC
9
44.4%
PD‐L1+ TNBC
20
18.5%
PD‐L1+ ER+HER‐2‐
21
12%
PD‐L1+ TNBC
21
19%
References: Dirix L et al SABCS 2015; Nanda R et al JCO 2016;34:2460; Rugo et al SABCS 2015; Emens LA et al AACR 2015
Slide content courtesy of Dr. Leisha Emens, Johns Hopkins Oncology and Immunology
Antibody
Avelumab
Pembrolizumab
Atezolizumab
Target
PD‐L1
PD‐1
PD‐L1
Subtype (all metastatic)
PD‐L1+ TNBC
20
18.5%
PD‐L1+ ER+HER‐2‐
21
12%
PD‐L1+ TNBC
21
19%
References: Dirix L et al SABCS 2015; Nanda R et al JCO 2016;34:2460; Rugo et al SABCS 2015; Emens LA et al AACR 2015
Slide content courtesy of Dr. Leisha Emens, Johns Hopkins Oncology and Immunology
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PD‐1/PD‐L1 Blockade in Breast Cancer
Antibody
Avelumab
Pembrolizumab
Atezolizumab
Target
PD‐L1
PD‐1
PD‐L1
Subtype (all metastatic)
Patients
ORR
All
168
4.8%
PD‐L1+ All
12
33.3%
TNBC
58
8.6%
PD‐L1+ TNBC
9
44.4%
PD‐L1+ TNBC
20
18.5%
PD‐L1+ ER+HER‐2‐
21
12%
PD‐L1+ TNBC
21
19%
References: Dirix L et al SABCS 2015; Nanda R et al JCO 2016;34:2460; Rugo et al SABCS 2015; Emens LA et al AACR 2015
Avelumab (anti‐PD‐L1) activity in unselected patients
Change in Target Lesion Size
• ORR in breast cancer = 4.8%
• 1 CR, 7 PRs, 39 patients with SD; Disease control rate (DCR)= 28%
• Ref: Dirix L et al SABCS 2015
Slide content courtesy of Dr. Leisha Emens, Johns Hopkins Oncology and Immunology
Slide content courtesy of Dr. Leisha Emens, Johns Hopkins Oncology and Immunology
Atezolizumab (anti‐PD‐L1) activity in PD‐L1+ TNBC patients
Change in Target Lesion Size
Combination therapy:
Can we convert a non‐immunogenic tumor into a tumor with an active immune microenvironment?
• ORR = 19%
• Median duration of response has not yet been reached (range: 18 to 56+ wks)
• Ref: Emens LA et al, AACR, 2015
Slide content courtesy of Dr. Leisha Emens, Johns Hopkins Oncology and Immunology
“Immunogenic cell death” stimulates an anti‐
tumor T cell response
“Immunogenic cell death” stimulates an anti‐
tumor T cell response
(1) Radiation therapy or chemotherapy
(2) Immune checkpoint inhibition
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Atezolizumab (anti‐PD‐L1) and Nab‐Paclitaxel (taxane) activity in PD‐L1 unselected, metastatic TNBC
Changes in Tumor Burden Over Time 1st line patients: n = 9 (ORR ~ 67%) Summary of Responses to Atezolizumab with Nab‐
Paclitaxel in metastatic TNBC
Best Overall Response
First Line
(n = 9)
Second Line (n = 8)
All Patients
(n = 24)
41.7%
Confirmed ORR
66.7%
25%
28.6%
ORR
88.9%
75%
42.9%
70%
CR
11.1%
0
0
4.2%
PR
77.8%
75%
42.9%
66.7%
SD
11.1%
25%
28.6%
20.8%
PD
0
0
28.6%
Adams S, et al SABCS 2015
Slide content courtesy of Dr. Leisha Emens, Johns Hopkins Oncology and Immunology
> Third Line (n = 7)
8.3%
Adams S, et al, SABCS 2015
Slide content courtesy of Dr. Leisha Emens, Johns Hopkins Oncology and Immunology
The optimal biomarker to use for overall prognosis, prediction and inclusion for immunotherapies is still not clear.
The optimal biomarker to use for overall prognosis, prediction and inclusion 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?
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?
Figure 2 Possible trial design using tumour-infiltrating lymphocytes as a biomarker
Understanding the tumor microenvironment characteristics may help guide treatment algorithms and selecting patients for whom immunotherapeutic strategies might be considered.
Savas, P. et al. (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.215
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Figure 2 Possible trial design using tumour-infiltrating lymphocytes as a biomarker
Savas, P. et al. (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.215
Future considerations
•
•
•
•
•
Is assessing TIL on H&E alone enough information?
What is the role of multiplex assays (CD8, PD‐L1)?
What is the impact of the cancer mutational load?
How do we standardize PD‐L1 assessment?
Is TIL scoring ready for primetime implementation? Figure 2 Possible trial design using tumour-infiltrating lymphocytes as a biomarker
Savas, P. et al. (2015) Clinical relevance of host immunity in breast cancer: from TILs to the clinic
Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2015.215
SUMMARY
1. BREAST CARCINOMAS HAVE ACTIVE TUMOR MICROENVIRONMENTS (ESPECIALLY TNBC AND HER‐2+)
2. TILS ARE PROGNOSTIC AND PREDICTIVE (PARTICULARLY IN TNBC)
3. IMMUNE CHECKPOINT INHIBITORS ARE UNDER CLINICAL INVESTIGATION IN BREAST CANCER, WITH PROMISING EARLY RESULTS
ACKNOWLEDGEMENTS
JHH Oncology and immunology
Leisha Emens, MD PhD
JHH Dermatopathology
Janis Taube, MD
Helen Xu
JHH Pathology
Robert Anders, MD PhD
Pedram Argani, MD
Tamara Lotan, MD PhD
Alan Meeker, PhD
Rajni Sharma, PhD
Elizabeth Thompson, MD PhD
THANK YOU
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