The Value of Tumor‐Infiltrating Lymphocytes(TILs)and CD 8...
Transcript of The Value of Tumor‐Infiltrating Lymphocytes(TILs)and CD 8...
The Value of Tumor‐Infiltrating Lymphocytes (TILs) and CD 8 as a Predictor of Response to Anthracycline‐based
Neoadjuvant Chemotherapyin Invasive Ductal Carcinoma Mammae
Upik A. Miskad, Rizky A. Rifai, Syarifuddin Wahid
DEPARTEMENT OF PATHOLOGYFACULTY OF MEDICINE
HASANUDDIN UNIVERSITYMAKASSAR, SOUTH SULAWESI INDONESIA
• Breast Cancer (BC): most common malignancy with highest mortality in women worldwide.
• Breast Cancer remains a heterogeneous disease, a range of clinical pattern, pathological characteristics, prognostic factors and responses to different types of treatment.
INTRODUCTION
• Many studies showed the existence of tumor‐infiltrating lymphocytes (TILs)related with the better prognosis of breast cancer (in terms of disease free survival (DFS), responses to chemotheraphy) (Denkert et al., 2010, 2015; Li et al., 2016; Loi et al., 2014; Salgado, 2015; West et al., 2011; Yamaguchi et al., 2012).
INTRODUCTION
Tumor Immunology
The major mechanism of immune protection to tumour cells iseradication by CD8 cytotoxic T cells (Abbas et al., 2017)
INTRODUCTION
However, incomplete tumor elimination may lead to tumor progression andthen can not be controlled by immune system.
Breast Cancer Treatment
Neoadjuvant Chemotheraphy• Recomended for locally advanced breast cancer (Stage IIB & III).
• Benefits: reduce surgical procedure radicality & enabling in vivo evaluation of chemotheraphy responses.
INTRODUCTION
• Breast cancer patients with same stadium and given same regimen were not always showed same results.
• Clinicians were can not always predict individual response to certain chemotheraphy regimen, so it is crucial to identify predictive factors for better tailor theraphy.
INTRODUCTION
• To evaluate the value of TILs and CD 8 expression as a predictor of anthracycline‐based neoadjuvant chemotherapy in invasive ductal carcinoma mammae?
AIM
• There were 75 pre‐treatment biopsy samples diagnosed as Invasive Ductal Carcinoma Mammae, and the patients were given anthracycline‐based neoadjuvant chemotherapyin Wahidin Hospital, Makassar.
• The TILs were evaluated in percentage as a semiquantitative parameter using recommendations of International TILs Working Group 2014, categorized as > 10 % and ≤ 10 %.
Materials and Methods
• CD8 expression assess by semi quantitative analysis. Cytotoxic T CD8 cells count manually in 4 HPF (Obj. 40x) in hot spot area with maximum lymphocyte infiltrats. Hemorraghic and necrosis areas were excluded.
• The mean value of the total 4 High Power Field (HPF)classified as: ‘high expression’ if > median value and ‘low expression’ if ≤ median value(Al‐Saleh et al., 2017).
Materials and Methods
• The chemotherapy responses were evaluatedafter 3/4 cycles of chemotherapy, right before mastectomy using RECIST criteria.
• Complete and Partial response were categorized as chemosensitive samples, while
• Stable and Progressive disease were categorized as chemoresistance samples.
Materials and Methods
• Define area for TILS Evaluation, area within tumor borders, do not include immune infiltrate outside the tumor, do not include large areas of central necrosis and fibrosis.
• Focus on stromal TILS (scan tumor with Low Magnification).
• Determine type of inflammatory infiltrate only mononuclear infiltrate (lymphocytes and plasma cells).
• Report the average of stromal area, do not focus on hotspot. Report percentage of Stromal Lymphocytes.
TILs EVALUATION on BREAST CANCER
Minimal TILs on Stroma (≤ 10 %)
Results : TILS Evaluation
Medium TILs on Stroma (20 %)
75 % of TILs (Obj. 40x)High TILs on Stroma (75 %)
Low CD 8 expression ≤ median value (20) (Obj. 40x)
RESULTS: CD8 Expression by IHC
High CD 8 expression >median value (20)
Table 1: characteristic of sampleClinicopathological Characteristic n %
Age < 40 15 20.0
≥ 40 60 80.0
Grading Low Grade 6 8.0
Moderate Grade 57 76.0
High Grade 12 16.0
CD 8 expression (median: 20) High 35 46.7
Low 40 53.3
TILs > 10 % 41 54.6
≤ 10 % 34 46.4
Chemotheraphy responses Chemosensitive 46 61.3
Chemoresistance 29 38.7
Results & Discussion
Results & Discussion
Chemotheraphy Responses p value OR
CI 95%
Chemo‐sensitive
Chemo‐resistance Min Max
TILs >10% 31 10 0.011 3.93 1.47 10.49
≤10% 15 19
CD8 Expression
High 27 8 0.017 3.73 1.37 10.18
Low 19 21
Total 46 29
Table 2: Prediction of Neoadjuvant Chemotheraphyaccording to TILs and CD8 expression
• Higher TILs and CD 8 expression were more responsive to anthracycline‐based chemotheraphy compared to low TILs and Low CD 8 expression.
• consistent with the previous study, West et al., 2011 and Mahmoud et al., 2011).
Results & Discussion
Immunomodulation by Anthracycline
Immune System contributing to Anthracycline mediated antitumor effect. Anthracycline induced Immunogenic Cell Death (ICD) which can modulate immune response and induce activation of Cytotoxic CD8 T cells.
Discussion
Immunomodulation by Anthracycline
•Antracycline (doxorubicin) selectively can eliminate Myeloid Derived Suppressor cells (MDSCs) in lymph nodes, bloods, and tumour areas.• MDSCs has ability to suppress T cells responses.Remaining MDSCs have abnormal immunosupressive function.
Alizadeh et al., 2014
Immunomodulation by Anthracycline
•Previous study: Depletion of CD8α T cells and Neutralization of IFN‐γ with mAbadministration, immediately prior to Anthracycline therapy, severely decrease antitumor effect of the drug. •Anthracycline (doxorubicin) needs CD8 cytotoxic T cells and IFN‐γ when work to eliminate cancer cells
Mattarollo S. et al
Conclusions
• TILs number and CD 8 expresions might be used to predict response to anthracycline‐based neoadjuvantchemotherapy in invasive ductal carcinoma mammae.