Meme Kanserinde PD-1/PD-L1 Hedefli Tedaviler

Yıl 2023, Cilt: 4 Sayı: 2, 55 - 61, 30.04.2023

Güneş Özen Eroğlu , İlham Yaylım Uğur Gezer , Dürdane Serap Kuruca

Öz

Meme kanseri, kadınlarda en yaygın görülen kanserlerden biridir ve
dünyadaki en yüksek insidansa sahip kanser türüdür. Meme kanseri
gelişiminde cinsiyet, yaş, östrojen düzeyi, aile öyküsü, gen mutasyonları
ve sağlıksız yaşam tarzı gibi çok sayıda risk faktörü bulunmaktadır.
Mevcut tedavi seçenekleri cerrahi, radyoterapi, hormonal tedaviler,
kemoterapi ve hedefe yönelik tedavilerdir. Hedefe yönelik tedavilerin
içinde immünoterapi son yıllarda oldukça yaygın bir tedavi stratejisi
olarak karşımıza çıkmaktadır.
Meme kanseri immün sistemden bağımsız bir kanser olduğu düşüncesinin
aksine, artık meme kanserinin immün temelli bir kanser türü
olduğu bilinmektedir. Bu kapsamda diğer kanser türlerinde olduğu
gibi, meme kanserinde de immünoterapinin hedeflediği moleküllerden
programlanmış hücre ölümü-1 (PD-1) ve programlanmış hücre
ölümü ligandı-1 (PD-L1) ile yapılan çok sayıda çalışma bulunmaktadır.
PD-1 ve PD-L1 hedefli tedaviler günümüzde meme kanseri tedavisinde
uygulanmaktadır. Meme kanseri alt tipleri olarak ele alındığında;
farklı alt tipler arasında heterojen bir dağılım olmakla birlikte tümör
hücrelerinde artmış PD-L1 ekspresyonu gözlenmektedir. Ayrıca, PDL1
ekspresyonu, genç yaş, ileri evre, tümör infiltre eden lenfositlerin
(TIL’ler) varlığı ve agresif moleküler alt tipler ile pozitif korelasyon göstermektedir.
Şimdilik sadece üçlü negatif meme kanserinin (TNMK)
tedavisinde yer alan immünoterapi, yapılacak daha fazla araştırma sonucunda,
diğer meme kanseri alt tiplerinde de kombinasyon ya da tek
tedavi olarak yer alabilecektir.
Meme kanseri tedavisinde, PD-1 ve PD-L1 düzenlemesinin ayrıntılı
mekanizmasını anlamak; tedavilere direncin üstesinden gelinmesi ve
daha iyi klinik sonuçlara ulaşılması açısından büyük önem taşımaktadır.
Bu derlemede meme kanserinde PD-1 ve PD-L1 hedefli tedavilerin
incelenmesi hedeflenmiştir.

Anahtar Kelimeler

meme kanseri, PD-1, PD-L1, immünoterapi

PD-1/PD-L1 Targeted Therapies in Breast Cancer

Öz

Breast cancer is one of the most common cancers among women and has
the highest incidence globally. Many risk factors for breast cancer progression include gender, age, estrogen level, family history, gene mutations,
and unhealthy lifestyle. Besides, current treatment options are surgery, radiotherapy, hormonal treatments, chemotherapy, and targeted therapies.
Among the targeted therapies, Immunotherapy has emerged as a very
common treatment strategy in recent years. Contrary to the thought that
breast cancer is an immune system-independent cancer, it is presently acknowledged that breast cancer is an immune-based cancer type. In this
context—as in other cancer types—many studies are conducted with programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1)
molecules targeted by Immunotherapy in breast cancer. PD-1 and PD-L1
targeted therapies are currently used to treat breast cancer. Although there
is a heterogeneous distribution among different subtypes, increased PD-L1
expression is observed in tumor cells—when considering breast cancer
subtypes. Moreover, PD-L1 expression correlates positively with young age,
advanced stage, presence of tumor-infiltrating lymphocytes (TILs), and aggressive molecular subtypes. Therefore, Immunotherapy, which is currently
only used in the treatment of triple-negative breast cancer (TNBC), may be
used as a combination of treatment or single treatment procedure in other
breast cancer subtypes—after further research. To better understand the
detailed mechanism of PD-1 and PD-L1 regulation in breast cancer treatment, overcoming resistance to treatments and achieving better clinical
outcomes is important. This review aims to investigate PD-1 and PD-L1
targeted therapies in breast cancer.

Anahtar Kelimeler

breast cancer, PD-1, PD-L1, immunotherapy

Kaynakça

• 1. GLOBOCAN 2020. Erişim adresi: https://gco.iarc.fr/today/data/factsheets/ populations/900-world-fact-sheets.pdf Erişim tarihi: 30.11.2022
• 2. Sun YS, Zhao Z, Yang ZN, Xu F, Lu HJ, Zhu ZY,et al. Risk factors and preventions of breast cancer. International journal of biological sciences. 2017;13(11):1387.
• 3. Zhang M, Sun H, Zhao S, Wang Y, Pu H, Zhang Q. Expression of PD-L1 and prognosis in breast cancer: a meta-analysis. Oncotarget. 2017;8(19):31347.
• 4. Kazemi T, Younesi V, Jadidi-Niaragh F, Yousefi M. Immunotherapeutic approaches for cancer therapy: an updated review. Artificial cells, nanomedicine, and biotechnology. 2016;44(3):769-79.
• 5. Nikkhoo A, Rostami N, Hojjat‐Farsangi M, Azizi G, Yousefi B, Ghalamfarsa G, et al. Smac mimetics as novel promising modulators of apoptosis in the treatment of breast cancer. Journal of Cellular Biochemistry. 2019;120(6):9300-14.
• 6. Perou CM, Sørlie T, Eisen MB, Van De Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747-52.
• 7. Dai X, Li T, Bai Z, Yang Y, Liu X, Zhan J, et al. Breast cancer intrinsic subtype classification, clinical use and future trends. American journal of cancer research. 2015;5(10):2929.
• 8. Gao JJ, Swain SM. Luminal A breast cancer and molecular assays: A review. The oncologist. 2018;23(5):556-65.
• 9. Onitilo AA, Engel JM, Greenlee RT, Mukesh BN. Breast cancer subtypes based on ER/PR and Her2 expression: comparison of clinicopathologic features and survival. Clinical medicine & research. 2009;7(1-2):4-13.
• 10. https://www.drozdogan.com/immunoterapiler-ve-kanser-asilari/ Erişim tarihi: 7.12.2022
• 11. Ljunggren HG, Jonsson R, Höglund P. Seminal immunologic discoveries with direct clinical implications: The 2018 Nobel Prize in Physiology or Medicine honours discoveries in cancer immunotherapy. Scandinavian Journal of Immunology. 2018;88(6):e12731.
• 12. Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. International immunology. 2007;19(7):813-24.
• 13. Bryan LJ, Gordon LI. Blocking tumor escape in hematologic malignancies: the anti-PD-1 strategy. Blood reviews. 2015;29(1):25-32.
• 14. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annual review of immunology. 2008;26(1):677-704.
• 15. Ren Y, Song J, Li X, Luo N. Rationale and Clinical Research Progress on PD-1/PD-L1-Based Immunotherapy for Metastatic Triple-Negative Breast Cancer. International Journal of Molecular Sciences. 2022;23(16):8878.
• 16. Boussiotis VA. Molecular and biochemical aspects of the PD-1 checkpoint pathway. New England Journal of Medicine. 2016;375(18):1767-78.
• 17. Chocarro de Erauso L, Zuazo M, Arasanz H, Bocanegra A, Hernandez C, Fernandez G, et al. Resistance to PD-L1/PD-1 blockade immunotherapy. A tumor-intrinsic or tumor-extrinsic phenomenon?. Frontiers in Pharmacology. 2020;11:441.
• 18. Zhang X, Schwartz JC, Guo X, Bhatia S, Cao E, Chen L, et al. Structural and functional analysis of the costimulatory receptor programmed death-1. Immunity. 2004;20(3):337-47.
• 19. Lin DY, Tanaka Y, Iwasaki M, Gittis AG, Su HP, Mikami B, et al. The PD-1/ PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors. Proceedings of the National Academy of Sciences. 2008;105(8):3011-6.
• 20. Collins M, Ling V, Carreno BM. The B7 family of immune-regulatory ligands. Genome biology. 2005;6(6):1-7.
• 21. Gato-Cañas M, Zuazo M, Arasanz H, Ibañez-Vea M, Lorenzo L, Fernandez- Hinojal G, et al. PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity. Cell reports. 2017;20(8):1818- 29.
• 22. Yamazaki T, Akiba H, Iwai H, Matsuda H, Aoki M, Tanno Y, et al. Expression of programmed death 1 ligands by murine T cells and APC. The Journal of Immunology. 2002;169(10):5538-45.
• 23. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends in molecular medicine. 2015;21(1):24-33.
• 24. Schwartz RH. T cell anergy. Annual review of immunology. 2003;21:305.
• 25. Baram T, Oren N, Erlichman N, Meshel T, Ben-Baruch A. Inflammation- Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer. Cancers. 2022;14(14):3513.
• 26. Gatalica Z, Snyder C, Maney T, Ghazalpour A, Holterman DA, Xiao N, et al. Programmed cell death 1 (PD-1) and its ligand (PD-L1) in common cancers and their correlation with molecular cancer type. Cancer epidemiology, biomarkers & prevention. 2014;23(12):2965-70.
• 27. Li X, Wetherilt CS, Krishnamurti U, Yang J, Ma Y, Styblo TM, et al. Stromal PD-L1 expression is associated with better disease-free survival in triple-negative breast cancer. American Journal of Clinical Pathology. 2016;146(4):496-502.
• 28. Teng MW, Ngiow SF, Ribas A, Smyth MJ. Classifying cancers based on T-cell infiltration and PD-L1. Cancer research. 2015;75(11):2139-45.
• 29. 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 research and treatment. 2014;146(1):15-24.
• 30. Bailly C, Thuru X, Quesnel B. Combined cytotoxic chemotherapy and Immunotherapy of cancer: modern times. NAR cancer. 2020;2(1):zcaa002.
• 31. Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR et al. Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 2015;6(7):5449.
• 32. Matikas A, Zerdes I, Lövrot J, Richard F, Sotiriou C, Bergh J, et al. Prognostic implications of PD-L1 expression in breast cancer: systematic review and meta-analysis of immunohistochemistry and pooled analysis of transcriptomic data. Clinical Cancer Research. 2019;25(18):5717-26.
• 33. Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, et al. PD-L1 expression in triple-negative breast cancer. Cancer immunology research. 2014;2(4):361-70.
• 34. Tsang J, Au WL, Lo KY, Ni YB, Hlaing T, Hu J, et al. PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients. Breast cancer research and treatment. 2017;162(1):19-30.
• 35. Qin T, Zeng YD, Qin G, Xu F, Lu JB, Fang WF, et al. High PD-L1 expression was associated with poor prognosis in 870 Chinese patients with breast cancer. Oncotarget. 2015;6(32):33972.
• 36. Ali HR, Glont SE, Blows FM, Provenzano E, Dawson SJ, Liu B, et al. PDL1 protein expression in breast cancer is rare, enriched in basal-like tumours and associated with infiltrating lymphocytes. Annals of Oncology. 2015;26(7):1488-93.
• 37. Baptista MZ, Sarian LO, Derchain SF, Pinto GA, Vassallo J. Prognostic significance of PD-L1 and PD-L2 in breast cancer. Human pathology. 2016;47(1):78-84.
• 38. Wang Z, Wu X. Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker. Cancer medicine.