Research Article

Hubungan antara Stromal Tumor Infiltrating Lymphocytes (TIL) dengan ekspresi Programmed Death-Ligand 1 (PD-L1) pada karsinoma payudara invasif tipe tidak spesifik subtipe Human Epidermal Growth Factor Receptor-2 (HER-2) enriched di RSUP Sanglah, Bali, Ind

Popi Imelda Margareth Sitompul , Herman Saputra, Luh Putu Iin Indrayani Maker, I Gusti Ayu Sri Mahendra Dewi, Ni Putu Sriwidyani, I Made Muliarta

Popi Imelda Margareth Sitompul
Departemen Patologi Anatomi, Fakultas Kedokteran, Universitas Udayana, RSUP Sanglah, Bali, Indonesia. Email: poppyimsitompul@gmail.com

Herman Saputra
Departemen Patologi Anatomi, Fakultas Kedokteran, Universitas Udayana, RSUP Sanglah, Bali, Indonesia

Luh Putu Iin Indrayani Maker
Departemen Patologi Anatomi, Fakultas Kedokteran, Universitas Udayana, RSUP Sanglah, Bali, Indonesia

I Gusti Ayu Sri Mahendra Dewi
Departemen Patologi Anatomi, Fakultas Kedokteran, Universitas Udayana, RSUP Sanglah, Bali, Indonesia

Ni Putu Sriwidyani
Departemen Patologi Anatomi, Fakultas Kedokteran, Universitas Udayana, RSUP Sanglah, Bali, Indonesia

I Made Muliarta
Departemen Fisiologi, Fakultas Kedokteran, Universitas Udayana, Bali, Indonesia
Online First: August 10, 2021 | Cite this Article
Sitompul, P., Saputra, H., Maker, L., Dewi, I., Sriwidyani, N., Muliarta, I. 2021. Hubungan antara Stromal Tumor Infiltrating Lymphocytes (TIL) dengan ekspresi Programmed Death-Ligand 1 (PD-L1) pada karsinoma payudara invasif tipe tidak spesifik subtipe Human Epidermal Growth Factor Receptor-2 (HER-2) enriched di RSUP Sanglah, Bali, Ind. Intisari Sains Medis 12(2): 543-550. DOI:10.15562/ism.v12i2.1021


Background: Breast cancer is the most common malignancy cancer in women. This malignancy is molecularly heterogeneous, where overexpression of the HER-2 growth factor receptor generally has a more aggressive nature. The role of immune system interaction, namely Tumor Infiltrating Lymphocytes (TIL) and Programmed Death-Ligand 1 (PD-L1) expression, is associated with prognostic and predictive factors. Therefore, this study aims to investigate the association between stromal TIL with PD-L1 expression in invasive breast carcinoma non-specific type HER-2 enriched subtype.

Methods: This study was an observational analytical study with cross-sectional design from January 1st 2015 to December 31st 2019. The samples were taken from a paraffin block of patients with invasive breast carcinoma non-specific type, that has performed histopathological examination, ER, PR, HER-2 and FISH/CISH immunohistochemistry examination at the Anatomical Pathology Laboratory of Sanglah Hospital Denpasar. The samples obtained were stained with PD-L1 immunohistochemistry. The preparation was evaluated to assess TIL. Data were analyzed using SPSS version 20 for Windows.

Results: The study found a statistically significant association between stromal TIL with PD-L1 expression in tumor cells (p = 0.018).  There is statistically significant association between stromal TIL with PD-L1 expression in TIL (p = 0.001). There is statistically significant association between stromal TIL with PD-L1 expression in total tumor cells and TIL (p = 0.007) in invasive breast carcinoma non-specific type HER-2 enriched subtype at Sanglah Hospital, Denpasar.

Conclusion: In conclusion, there is an association between stromal TIL with the expression of PD-L1 in tumor cells and TIL in invasive breast carcinoma non-specific type HER-2 enriched subtype. 

 

Latar Belakang: Kanker payudara merupakan keganasan tersering pada wanita. Keganasan ini bersifat  heterogen ditinjau dari aspek molekuler, dimana overekspresi HER-2 umumnya memiliki sifat yang lebih agresif. Peranan sistem imun, yakni ekspresi Tumor Infiltrating Lymphocytes (TIL) dan Programmed Death-Ligand 1 (PDL-1) dihubungkan dengan faktor prognostik. Oleh karena itu, penelitian ini bertujuan untuk mengevaluasi hubungan antara stromal TIL dengan ekspresi PD-L1 pada karsinoma payudara invasif tipe tidak spesifik subtipe HER-2 enriched.

Metode: Penelitian ini merupakan penelitian observasional analitik dengan rancangan studi potong lintang mulai dari 1 Januari 2015 sampai 31 Desember 2019. Sampel adalah blok parafin penderita karsinoma payudara invasif tipe tidak spesifik yang telah dilakukan pemeriksaan histopatologi, imunohistokimia ER, PR, HER-2 dan FISH/CISH  di Laboratorium Patologi Anatomi RSUP Sanglah Denpasar. Sampel yang diperoleh dilakukan pulasan imunohistokimia PD-L1 Preparat sampel digunakan untuk menilai TIL. Data dianalisis dengan SPSS versi 20 untuk Windows.

Hasil: Pada penelitian ditemukan hubungan yang signifikan secara statistik antara stromal TIL dengan ekspresi PD-L1 pada sel tumor (p=0,018). Terdapat hubungan yang signifikan secara statistik  antara stromal TIL dengan ekspresi PD-L1 pada TIL (p=0,001). Terdapat hubungan yang signifikan secara statistik antara stromal TIL dengan ekspresi PD-L1 pada total sel tumor dan TIL (p=0,007) pada karsinoma payudara invasif tipe tidak spesifik subtipe HER-2 enriched di RSUP Sanglah Denpasar.

Kesimpulan: Hasil penelitian ini menunjukkan terdapat hubungan bermakna antara stromal TIL dengan ekspresi PD-L1 sel tumor dan TIL pada karsinoma payudara invasif tipe tidak spesifik subtipe HER-2 enriched

References

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.

Kemenkes RI. Balitbang Kemenkes RI. Riset kesehatan dasar. 2013.

Rao C, Shetty J, Prasad K. Immunohistochemical Profile and Morphology in Triple-Negative Breast Cancer. J Clin Diagn Resp. 2013;7(7):1361-5.

Rakha EA, Allison KH, Ellis IO, Horii R, Masuda S, Penault-Llorca F, et al. Invasive breast carcinoma: general overview. In WHO Classification of Tumor Editorial Board. World Health Organization Classification of Tumours WHO Classification of Tumours of the Breast. 5th ed. Lyon: International Agency for Research on Cancer. 2019:82-101.

Evangelou Z, Papoudou-Bai A, Karpathiou G, Kourea H, Kamina S, Goussia A, et al. PD-L1 Expression and Tumor-infiltrating Lymphocytes in Breast Cancer: Clinicopathological Analysis in Women Younger than 40 Years Old. 2020;34(2):639-47.

Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell. 2011;144(5):646-674.

Karpathiou G, Casteillo F, Giroult JB, Forest F, Fournel P, Monaya A, et al. Prognostic impact of immune microenvironment in laryngeal and pharyngeal squamous cell carcinoma: Immune cell subtypes, immuno-suppressive pathways and clinicopathologic characteristics. Oncotarget. 2017; 8(12):19310-19322

Lee MC, Buitrago DH, Kadota K, Ujiie H, Woo K, Sima CS, et al. The tumor immune microenvironment in octogenarians with stage I non-small cell lung cancer. Oncoimmunology 2014;3(11):e967142.

Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Francoise VE, et al. Prognostic and significance value of tumor infiltrating lymphocyte in phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860-67.

Fulawka L, Halon A. Ki-67 evaluation in breast cancer: The daily diagnostic practice. Indian J PatholMicrobiol. 2017;60(2):177-84.

Gannon LM, Cotter MB, Quinn CM. The Classification Invasive Carcinoma of The Breast. Expert Rev Anticancer Ther. 2013;13(8):941-54.

Denkert C, Loibl S, Noske A, Roller M, Muller B, Komor M, et al. Tumor-associated lymphocytes as an independent predictor response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28(1):105-113.

Gajewski TF. The Next Hurdle in Cancer Immunotherapy: Overcoming the Non–T-Cell–Inflamed Tumor Microenvironment. Semin Oncol. 2016;42(4):663-71.

Kim A, Lee SJ, Kim YK, Perk WY, Park DY, Kim JY, et al. Programmed death-ligand 1 (PD-L1) expression in tumour cell and tumour infiltrating lymphocytes of HER2-positive breast cancer and its prognostic value. Scientific Reports. 2017;7(1):11671.

Muenst S, Schaerli AR, Gao F, Däster S, Trella E, Droeser RA, et al. Expression of programmed death ligand 1 (PD-L1) is associated with poor prognosis in human breast cancer. Breast Cancer Res Treat. 2014;146(1):15-24.

Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum Pathol. 2016;47(1):78-84.

Campbell MJ, Julious SA. Statistics in Medicine: citations of papers in the first ten years. Stat Med. 1994;13(1):3-10.

Salgado R, Denkert C, Campbell C, Savas P, Nuciforo P, Aura C, et al. Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO Trial. JAMA oncology. 2015;1(4):448–454.

Lee HJ, Kim JY, Park IA, Song IH, Yu JH, Ahn JH, et al. Prognostic Significance of Tumor-Infiltrating Lymphocytes and the Tertiary Lymphoid Structures in HER2-Positive Breast Cancer Treated With Adjuvant Trastuzumab. American journal of clinical pathology. 2015;144(2):278–288.

Sugie T, Sato E, Miyashita M, Yamaguchi R, Sakatani T, Kozuka Y, et al. Multispectral quantitative immunohistochemical analysis of tumor-infiltrating lymphocytes in relation to programmed death-ligand 1 expression in triple-negative breast cancer. Breast cancer (Tokyo, Japan). 2020;27(4):519–526.

Kurozumi S, Inoue K, Matsumoto H, Fujii T, Horiguchi J, Oyama T, et al. Prognostic Utility Of Tumor-Infiltrating Lymphocytes In Residual Tumor After Neoadjuvant Chemotherapy With Trastuzumab For HER2-Positive Breast Cancer. Scientific Reports. 2019 ;9(1):1583.

Zekri J, Saadeddin A, Alharbi H. Frequency and clinical characteristics of HER2 overexpressed breast cancer in Saudi Arabia: a retrospective study. BMC womens health. 2021;21(1):10.

Stanton SE, Adams S, Disis ML. Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review. JAMA oncology. 2016;2(10):1354–1360.

Nuciforo, P, Prat A, Llombart A, Fasani R, Paré L, Pascual T, et al, Holgado E. Tumor-infiltrating lymphocytes (TILs) in HER2-positive (HER21) early breast cancer treated with neoadjuvant lapatinib and trastuzumab without chemotherapy in the PAMELA Trial. Annals of Oncology. 2017;28 (suppl_5):v43-v67.

Savas P, Salgado R, Denkert C, Sotiriou C, Darcy PK, Smyth MJ, et al. Clinical relevance of host immunity in breast cancer: from TILs to the clinic. Nrclinonc. 2016;13(4):228-41.

Francisco ML, Sage TP, Sharpe AH. The PD-1 pathway in tolerance and autoimmunity. Immunological Reviews. 2010;236:219–42.

Chen J, Jiang CC, Jin L, Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol. 2015;27(3):409–416.

Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol. 2018;71(3):189-194.

Cao Y, Zhang L, Kamimura Y, Ritprajak P, Hashiguchi M, Hirose S, et al. B7 H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. Cancer Research. 2011;71(4):1235-43.

Chen DS., Irving BA, Hodi FS. Molecular Pathways: Next Generation Immunotherapy-Inhibiting Programmed Death-Ligand-1 and Programmed Death-1. Clin Cancer Res. 2012;18(24):6580-7.

Lee SJ, Hwang CS, Kim YK, Lee HJ, Ahn SJ, Shin N, et al. Expression of Myxovirus Resistance A (MxA) Is Associated with Tumor-Infiltrating Lymphocytes in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancers. Cancer Res Treat. 2017;49(2):313-321.


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