Department of Surgery, Faculty of Medicine, CHU de Québec-Université Laval.
Department of Pathology, Faculty of Medicine, CHU de Québec-Université Laval.
Urol Oncol. 2021 May;39(5):303.e1-303.e8. doi: 10.1016/j.urolonc.2021.02.014. Epub 2021 Mar 5.
Chemotherapy for testicular germ cell tumors (GCT) is highly effective, with few patients who do not respond. Clinical studies to evaluated novel treatments are challenging given the rarity of these patients. Therefore, we sought to evaluate PD-L1 staining on metastatic and postchemotherapy viable testicular GCTs as a surrogate for potential benefit for immunotherapy targeting the PD-1/PD-L1 axis.
Ethics research committee approval for this retrospective study was obtained by four participating institutions (CHU de Québec, St. Joseph's Health Care, Halifax Health Science Centre, Johannes Gutenberg University). Patients with viable metastatic testicular GCTs pathology samples were included. Patients with pure teratoma were excluded. PD-L1 staining with the 22C3 clone was evaluated on samples with >100 viable tumor cells using the combined positive score (CPS).
From 51 patients identified at participating institutions, 24 postchemotherapy and 18 chemotherapy-naive metastatic samples were available for PD-L1 staining, with 9 matched prechemotherapy samples and 7 matched orchiectomy pathology samples, respectively. The median CPS score was 55.6 (IQR 16-100) for all metastatic samples, 44.9 (IQR 13-100) for postchemotherapy metastatic samples, and 68.8 (IQR 38-100) for chemotherapy-naïve metastatic samples, with the median number of viable tumor cells at 545, 500, and 550, respectively. Differences were not significant between chemotherapy-naïve and postchemotherapy samples (P = 0.07), though among non-seminoma GCT metastatic samples, CPS scores were significantly lower postchemotherapy (P = 0.02). Significant differences among postchemotherapy metastatic tumors were also seen according to predominant subtype, with lower CPS scores for predominant yolk sac and higher values for predominant seminoma and choriocarcinoma. In 7 patients with matched specimens pre- and postchemotherapy, a significant increase in CPS was observed for seminoma (26.7 vs. 81.7, P = 0.045), but not nonseminoma GCTs. Comparing all chemotherapy naïve-samples, PD-L1 expression was higher in metastatic samples versus testicular samples (mean CPS 68.8 vs. 39.8, P = 0.02). This was also seen in matched chemotherapy-naïve samples (mean CPS 77.9 vs. 33.1, P = 0.01).
Our results suggest that most patients with refractory GCTs postchemotherapy will not benefit from PD-1/PD-L1 immunotherapy. However, the high PD-L1 expression in patients with predominant or pure seminoma post-chemotherapy suggests this may represent a subgroup for whom further trials may be considered.
化疗治疗睾丸生殖细胞肿瘤（GCT）非常有效，很少有患者没有反应。鉴于这些患者的罕见性，评估新治疗方法的临床研究具有挑战性。因此，我们试图评估转移性和化疗后存活的睾丸 GCT 中的 PD-L1 染色，作为针对 PD-1/PD-L1 轴的免疫治疗潜在获益的替代标志物。
四家参与机构（魁北克大学附属医院、圣约瑟夫医疗保健中心、哈利法克斯健康科学中心、约翰内斯古腾堡大学）的伦理研究委员会批准了这项回顾性研究。纳入有存活转移性睾丸 GCT 病理样本的患者。排除单纯畸胎瘤患者。使用 22C3 克隆进行 PD-L1 染色，评估 >100 个存活肿瘤细胞的联合阳性评分（CPS）。
在参与机构确定的 51 名患者中，有 24 名化疗后和 18 名化疗初治转移性样本可用于 PD-L1 染色，分别有 9 个匹配的化疗前样本和 7 个匹配的睾丸切除术病理样本。所有转移性样本的中位 CPS 评分分别为 55.6（IQR 16-100）、化疗后转移性样本为 44.9（IQR 13-100）和化疗初治转移性样本为 68.8（IQR 38-100），分别有 545、500 和 550 个存活肿瘤细胞。化疗初治和化疗后样本之间的差异无统计学意义（P=0.07），但在非精原细胞瘤 GCT 转移性样本中，化疗后 CPS 评分显著降低（P=0.02）。化疗后转移性肿瘤的亚组之间也存在显著差异，以卵黄囊为主型的 CPS 评分较低，以精原细胞瘤和绒毛膜癌为主型的 CPS 评分较高。在 7 名有化疗前和化疗后匹配标本的患者中，观察到精原细胞瘤的 CPS 显著增加（26.7 比 81.7，P=0.045），而非精原细胞瘤 GCT 则没有。比较所有化疗初治样本，转移性样本的 PD-L1 表达高于睾丸样本（平均 CPS 分别为 68.8 和 39.8，P=0.02）。在匹配的化疗初治样本中也观察到这种情况（平均 CPS 分别为 77.9 和 33.1，P=0.01）。
我们的结果表明，大多数化疗后难治性 GCT 患者不会从 PD-1/PD-L1 免疫治疗中获益。然而，化疗后以精原细胞瘤为主或单纯精原细胞瘤患者的 PD-L1 表达较高，提示这可能代表一个可能需要进一步试验的亚组。
