Triple negatif meme karsinomlarında PD-L1 ekspresyonunun ve tümörü infiltre eden lenfosit yoğunluğunun prognoz üzerine etkilerinin değerlendirilmesi
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Dosyalar
Tarih
2021
Yazarlar
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Yayıncı
Ege Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Meme karsinomları tüm dünyada ve ülkemizde en sık görülen malignitelerden birini oluşturmaktadır. Hormon reseptörlerine yönelik endokrin tedavi ve Human Epidermal Growth Factor Receptor 2'ye yönelik hedef tedaviler ile bu malignitelerde sağkalım üzerine başarılı sonuçlar elde edilmiş olmakla birlikte, immünhistokimyasal olarak triple negatif fenotipe sahip tümörler için henüz standartlaşmış bir hedefe yönelik tedavi bulunmamaktadır. Tüm meme karsinomlarının yaklaşık %20'sini oluşturan bu grup diğerlerine göre belirgin kötü prognozla ilerlemektedir. Melanomlarda yüz güldürücü sonuçlar alınmasıyla birlikte başlayan immünoterapi seçeneği pek çok solid tümörde denenmiş ve başarılı sonuçlar alınmıştır. İmmünoterapide asıl amaç tümörü tanıması farklı mekanizmalarla inhibe olmuş immün hücrelere bu yeteneği geri kazandırmaktır. PD-1 (Programmed Cell Death 1) ve ligandı olan PD-L1 (Programmed Cell Death Ligand 1) immün sistemin baskılanmasını sağlayan mekanizmalardan birini oluşturmaktadır. Sağlıklı dokuda PD-1 ve PD-L1 immün sistemin aşırı aktivasyonu nedeniyle konağa zararını engellemekteyken, pek çok malignitede gösterilen artmış seviyelerinin tümörlerin de bu mekanizma ile immün sistemden kaçabildiğini göstermiştir. PD-1 ve PD-L1 blokajına yönelik tedavilerden fayda görecek hasta popülasyonunu seçmek için ise tümörlerdeki PD-1 ve PD-L1 ekspresyonunun değerlendirilmesi ile belirlenebileceği düşünülmektedir. Tümör infiltre lenfositler terimi tümör mikroçevresindeki mononükleer hücreleri temsil etmektedir. Malignitelerin büyük kısmında iyi prognostik bir belirteç olduğu gösterilmiştir. Meme karsinomlarında da tümör infiltre lenfosit oranının belirlenmesine yönelik konsensüs oluşturulmuş ve bu konuda öneriler yapılmıştır. Yakın gelecekte bu oranı patoloji raporlarında belirtmek bir zorunluluk haline gelecek gibi görünmektedir. Çalışmamıza 2011 ve 2017 yılları arasında immünhistokimyasal olarak triple negatif fenotip sergileyen 104 olgu dahil edilmiştir. PD-L1 ve tümör infiltre lenfosit oranını değerlendirdiğimiz olgularda bu parametrelerin klinikopatolojik bulgulara ve sağkalıma etkisini araştırdık. Ortalama takip süremiz 61,5±31,51 aydı. PD-L1 ekspresyonu ile p53 oranının pozitif bir ilişkide olduğu saptandı (p=0,001). PD-L1 değerlendirmesinde yeni bir pencere olarak ≥%1 PD-L1 ekspresyonuna sahip tümörlerdeki intraepitelyal PD-L1 pozitif boyanan immün hücrelerin varlığı not edildi. Tümör infiltre lenfositler ile klinikopatolojik bulgular arasında istatistiksel olarak anlamlı bir fark saptanmamakla birlikte tümör infiltre lenfosit oranındaki artış ile PD-L1 ekspresyonu arasında pozitif bir korelasyon izlendi (p=0,001). Sağkalım verilerine bakıldığında PD-L1 ekspresyonunun varlığının bu yönde istatistiksel olarak anlamlı bir fark göstermemesiyle birlikte PD-L1 pozitif olgularda intraepitelyal PD-L1 pozitif tümör infiltre immün hücrelerin bulunmasının genel sağkalım süresini arttırdığını saptadık (p=0,006). Tümör infiltre lenfosit oranının artışı ile ise hem genel hem de uzak metastazsız sağkalıma pozitif bir etki yaratmaktaydı (p=0,040 ve p=0,006). Buna göre intraepitelyal PD-L1 pozitif tümör infiltre immün hücresi bulunmayan olgularda ölüm riski bulunanlara göre 5,18 kat (p=0,013) artmış bulundu. Tümör infiltre lenfosit oranı ≤%10 olanlarda >%40 olanlara göre ölüm riski 5,40 kat (p=0,024); uzak metastaz riski 11,95 kat artmış olarak hesaplandı. Çalışmamızda tümör infiltre lenfosit oranının prognozu daha kötü olan triple negatif meme karsinomlarında sağkalım üzerine istatistiksel olarak anlamlı fark yarattığı sonucuna ulaşılmıştır. PD-L1 pozitifliği (≥%1) sağkalım sürelerini uzatsa da bu fark istatistiksel olarak anlamlı olmamakla birlikte, PD-L1 pozitif olgularda intraepitelyal PD-L1 pozitif tümör infiltre immün hücrelerin bulunması istatistiksel olarak anlamlı bir şekilde sağkalımı uzatmıştır. Tümör infiltre lenfosit oranının değerli prognostik bilgi vermesi sebebiyle patoloji raporlarında yer alması gerektiğine inanıyoruz. İntratümöral PD-L1 pozitif immün hücrelerin varlığının prognoz üzerine etkisinin aydınlatılması için ise daha ileri çalışmalara ihtiyaç duyulmaktadır.
Breast carcinomas constitute one of the most common malignancies all over the world and in our country. Although successful results on survival have been obtained in these malignancies with endocrine therapy for hormone receptors and targeted therapies for Human Epidermal Growth Factor Receptor 2, there is no standardized targeted therapy for tumors with a triple negative phenotype immunohistochemically. This group, which constitutes approximately 20% of all breast carcinomas, progresses with a significantly worse prognosis compared to others. The immunotherapy option, which started with satisfactory results in melanomas, has been tried in many solid tumors and successful results have been obtained. The main purpose of immunotherapy is to restore tumor recognition ability of immune cells whose this ability has been inhibited by different mechanisms. PD-1 (Programmed Cell Death 1) and its ligand PD-L1 (Programmed Cell Death Ligand 1) constitute one of the mechanisms that provide suppression of the immune system. While PD-1 and PD-L1 in healthy tissue prevent damage to the host due to over-activation of the immune system, it has been shown that tumors can escape from the immune system with this mechanism, with their increased levels shown in many malignancies. It is thought that PD-1 and PD-L1 expression in tumors can be determined by evaluating the expression of PD-1 and PD-L1 in tumors to select the patient population that will benefit from treatments for PD-1 and PD-L1 blockade. The term tumor infiltrating lymphocytes represents mononuclear cells in the tumor microenvironment. It has been shown to be a good prognostic marker in the majority of malignancies. Consensus was formed for the determination of tumor infiltrating lymphocyte ratio in breast carcinomas and recommendations were made in this regard. It seems that it will become a necessity to indicate this rate in pathology reports in the near future. Overall 104 cases with immunohistochemically triple negative phenotype were included in our study between 2011 and 2017. In cases where we evaluated PD-L1 and tumor infiltrating lymphocyte ratio, we investigated the effects of these parameters on clinicopathological findings and survival. Our mean follow-up period was 61.5±31.51 months. A positive correlation was found between PD-L1 expression and p53 ratio (p=0.001). The presence of intraepithelial PD-L1 positive staining immune cells in tumors with ≥1% PD-L1 expression was noted as a new parameter for PD-L1 evaluation. Although there was no statistically significant difference between tumor infiltrating lymphocytes and clinicopathological findings, a positive correlation was observed between the increase in tumor infiltrating lymphocyte rate and PD-L1 expression (p=0.001). Considering the survival data, we determined that the presence of intraepithelial PD-L1 positive tumor infiltrating immune cells in PD-L1 positive cases increased the overall survival, although the presence of PD-L1 expression did not show a statistically significant difference in this direction (p=0.006). The increase in tumor infiltrating lymphocyte ratio had a positive effect on both overall and distant metastasis-free survival (p=0.040 and p=0.006). Accordingly, it was found that the risk of death was increased 5.18 times (p=0.013) in patients without intraepithelial PD-L1 positive tumor infiltrating immune cells. The risk of death in patients with tumor infiltrating lymphocyte rate ≤10% was 5.40 times compared to those with >40% (p=0.024); The risk of distant metastasis was calculated as 11.95 times increased. In our study, it was concluded that the ratio of tumor infiltrating lymphocytes made a statistically significant difference on survival in triple negative breast carcinomas which have a worse prognosis. Although PD-L1 positivity (≥1%) prolongs survival, this difference is not statistically significant. The presence of intraepithelial PD-L1 positive tumor-infiltrating immune cells in PD-L1 positive cases prolonged survival in a statistically significant way. We believe that tumor infiltrating lymphocyte ratio should be included in pathology reports as it provides valuable prognostic information. Further studies are needed to elucidate the effect of the presence of intratumoral PD-L1 positive immune cells on prognosis.
Breast carcinomas constitute one of the most common malignancies all over the world and in our country. Although successful results on survival have been obtained in these malignancies with endocrine therapy for hormone receptors and targeted therapies for Human Epidermal Growth Factor Receptor 2, there is no standardized targeted therapy for tumors with a triple negative phenotype immunohistochemically. This group, which constitutes approximately 20% of all breast carcinomas, progresses with a significantly worse prognosis compared to others. The immunotherapy option, which started with satisfactory results in melanomas, has been tried in many solid tumors and successful results have been obtained. The main purpose of immunotherapy is to restore tumor recognition ability of immune cells whose this ability has been inhibited by different mechanisms. PD-1 (Programmed Cell Death 1) and its ligand PD-L1 (Programmed Cell Death Ligand 1) constitute one of the mechanisms that provide suppression of the immune system. While PD-1 and PD-L1 in healthy tissue prevent damage to the host due to over-activation of the immune system, it has been shown that tumors can escape from the immune system with this mechanism, with their increased levels shown in many malignancies. It is thought that PD-1 and PD-L1 expression in tumors can be determined by evaluating the expression of PD-1 and PD-L1 in tumors to select the patient population that will benefit from treatments for PD-1 and PD-L1 blockade. The term tumor infiltrating lymphocytes represents mononuclear cells in the tumor microenvironment. It has been shown to be a good prognostic marker in the majority of malignancies. Consensus was formed for the determination of tumor infiltrating lymphocyte ratio in breast carcinomas and recommendations were made in this regard. It seems that it will become a necessity to indicate this rate in pathology reports in the near future. Overall 104 cases with immunohistochemically triple negative phenotype were included in our study between 2011 and 2017. In cases where we evaluated PD-L1 and tumor infiltrating lymphocyte ratio, we investigated the effects of these parameters on clinicopathological findings and survival. Our mean follow-up period was 61.5±31.51 months. A positive correlation was found between PD-L1 expression and p53 ratio (p=0.001). The presence of intraepithelial PD-L1 positive staining immune cells in tumors with ≥1% PD-L1 expression was noted as a new parameter for PD-L1 evaluation. Although there was no statistically significant difference between tumor infiltrating lymphocytes and clinicopathological findings, a positive correlation was observed between the increase in tumor infiltrating lymphocyte rate and PD-L1 expression (p=0.001). Considering the survival data, we determined that the presence of intraepithelial PD-L1 positive tumor infiltrating immune cells in PD-L1 positive cases increased the overall survival, although the presence of PD-L1 expression did not show a statistically significant difference in this direction (p=0.006). The increase in tumor infiltrating lymphocyte ratio had a positive effect on both overall and distant metastasis-free survival (p=0.040 and p=0.006). Accordingly, it was found that the risk of death was increased 5.18 times (p=0.013) in patients without intraepithelial PD-L1 positive tumor infiltrating immune cells. The risk of death in patients with tumor infiltrating lymphocyte rate ≤10% was 5.40 times compared to those with >40% (p=0.024); The risk of distant metastasis was calculated as 11.95 times increased. In our study, it was concluded that the ratio of tumor infiltrating lymphocytes made a statistically significant difference on survival in triple negative breast carcinomas which have a worse prognosis. Although PD-L1 positivity (≥1%) prolongs survival, this difference is not statistically significant. The presence of intraepithelial PD-L1 positive tumor-infiltrating immune cells in PD-L1 positive cases prolonged survival in a statistically significant way. We believe that tumor infiltrating lymphocyte ratio should be included in pathology reports as it provides valuable prognostic information. Further studies are needed to elucidate the effect of the presence of intratumoral PD-L1 positive immune cells on prognosis.
Açıklama
Anahtar Kelimeler
Triple Negative Breast Cancer (Triple Negatif Meme Kanseri), Tumor Infiltrating Lymphocyte (Tümör İnfiltre Lenfosit), Programmed Cell Death 1 (Proglamlanmış Hücre Ölümü 1), Programmed Cell Death Ligand 1 (Programlanmış Hücre Ölümü Ligandı 1), Immune Checkpoint Blockade (İmmün Kontrol Noktası Blokajı), Triple Negative Breast Cancer, Tumor Infiltrating Lymphocyte, Programmed Cell Death 1, Programmed Cell Death Ligand 1, Immune Checkpoint Blockade
