Predicting Response to Neoadjuvant Chemotherapy in Muscle-invasive Bladder Cancer

Официальное название

The Impact of Tumor Microenvironment and Clinicopathological Features in Predicting Response to Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer

Обзор

Bladder cancer (BC) is the 10th most commonly diagnosed cancer worldwide and the second most common cancer among Egyptian males. The mainstay of treatment of muscle-invasive BC( MIBC) is neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) or bladder preservation(BP) using maximal transurethral resection of the bladder tumor followed by chemoradiation. The rationale to use NAC before RC or BP is to eradicate micro-metastasis and to downstage the primary tumor. The 5-year cancer-specific survival for responders to NAC is 90%, in contrast to 30-40% for those not obtaining an objective response. Drawbacks of NAC are disappointing delay of surgery in non-responders and the potential toxicity. So, predictors of response to NAC are necessary to identify patients who may achieve pathologic complete response and will benefit from BP, and the others who may not respond to NAC and spare them NAC toxicity and RC delay. Tumor microenvironment (TME), including neutrophil extracellular traps (NETs), and CD8+ T lymphocytes is a promising predictor of response to NAC in MIBC. NETs are reticulated DNA structures decorated with various protein substances (e.g., histones, myeloperoxidase, neutrophil elastase).NETs are involved in tumor growth, metastasis, and treatment resistance. Moreover, NETs can inhibit T cell responses, thereby promoting tumor growth. On the other hand, immune cells that are present in the TME play a major role in slowing down tumor progression. CD8+T lymphocytes play a central role in immune-mediated control of cancer . Also, they have been found to be a prognostic tool for advanced BC.

Подробное описание

Formalin fixed paraffin embedded tissue specimen of the baseline TUR of MIBC will be obtained from pathology laboratory, Pathology Department, Assiut University.

* Histological diagnosis of H\&E stained sections will be confirmed. * Immunohistochemical staining for Citrullinated histone H3 (H3Cit) antibody as a hallmark of NETs, and CD8 antibody to quantity density of NETs and CD8 expression, then calculate NETs/CD8 ratio. * Baseline clinicopathological features of MIBC patients who received neoadjuvant chemotherapy will be collected from patients' records. * Correlation between NETs expression, CD8 expression, NETs/CD8 ratio, and the baseline clinicopathological features with the response to neoadjuvant chemotherapy. * develop a risk score based on the significant predictors of response to identify patients who may achieve pathologic complete response and will benefit from BP, and the others who may not respond to NAC and spare them NAC toxicity and RC delay.

Вмешательства

• Комбинированный продукт neoadjuvant chemotherapy
  platinum-based chemotherapy before radical cystectomy or bladder preservation

Первичные конечные точки

• Evaluation of the expression of NETs and CD8 in paraffin-embedded TUR biopsies [Срок оценки: 6 months]
• - Response to platinum-based chemotherapy in localized MIBC in relation to: NETs expression, CD8 expression, NET/CD8 ratio and baseline clinicopathological features [Срок оценки: 6 months]

Вторичные конечные точки (1)

• Local recurrence-free survival (RFS) [Срок оценки: 2 years]

Критерии участия

Критерии включения

• Pathologically proven pure urothelial carcinoma, or morphologic variant of urothelial carcinoma.
• Patients with ≥T2, N0-1, M0, according to American Joint Committee on Cancer (AJCC) TNM Staging System for Bladder Cancer 8th ed., 2017.
• Patients who received platinum-based neoadjuvant chemotherapy before RC or BP.
• Available paraffin-embedded TUR specimens for Immunohistochemistry (IHC).

Критерии исключения

• Non urothelial carcinoma.
• Not muscle invasive < T2.
• Metastatic bladder cancer.
• No available paraffin-embedded TUR specimens for IHC.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Публикации

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• Zhao J, Jin J. Neutrophil extracellular traps: New players in cancer research. Front Immunol. 2022 Aug 19;13:937565. doi: 10.3389/fimmu.2022.937565. eCollection 2022. PMID 36059520
• Kaltenmeier C, Yazdani HO, Morder K, Geller DA, Simmons RL, Tohme S. Neutrophil Extracellular Traps Promote T Cell Exhaustion in the Tumor Microenvironment. Front Immunol. 2021 Nov 24;12:785222. doi: 10.3389/fimmu.2021.785222. eCollection 2021. PMID 34899751

Идентификаторы

NCT: NCT06325423 · response to NAC in MIBC

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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