Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burden (> 50 mutations per megabase; 19 functional alterations in tissue next-generation sequencing (NGS; 315 genes)) as well as PDL1/PDL2/JAK2 amplification (as determined by both tissue NGS and by analysis of plasma-derived cell-free DNA). The latter was performed using technology originally developed for the genome-wide detection of sub-chromosomal copy-number alterations (CNAs) in noninvasive prenatal testing and showed numerous CNAs including amplification of the 9p24.3-9p22.2 region containing PD-L1, PD-L2 and JAK2. Of interest, PD-L1, PD-L2 and JAK2 amplification is a characteristic of Hodgkin lymphoma, which is exquisitely sensitive to nivolumab. In conclusion, selected SMO antagonist-resistant metastatic basal cell carcinomas may respond to nivolumab based on underlying molecular genetic mechanisms that include PD-L1 amplification and high tumour mutational burden.

中文翻译：

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带有PD-L1扩增的转移性基底细胞癌：对抗PD1治疗的异常反应。

转移性基底细胞癌是罕见的恶性肿瘤，具有SMO拮抗剂（vismodegib / sonidegib）靶向的Hedgehog途径改变。我们首次描述了使用nivolumab（抗PD1抗体）实现了快速的肿瘤消退（4个月即将完全缓解）的Hedgehog抑制剂耐药的转移性基底细胞癌患者的分子遗传学和反应。他具有多种抗PD1反应的特征，包括高突变负担（每兆碱基> 50个突变；组织下一代测序中的19种功能改变（NGS； 315个基因））以及PDL1 / PDL2 / JAK2扩增（两者均确定）组织NGS和通过血浆来源的无细胞DNA的分析）。后者是使用最初为在非侵入性产前检测中全基因组范围内检测亚染色体拷贝数变化（CNA）而开发的技术进行的，并显示了许多CNA，包括扩增包含PD-L1的9p24.3-9p22.2区， PD-L2和JAK2。有趣的是，PD-L1，PD-L2和JAK2扩增是霍奇金淋巴瘤的特征，它对nivolumab非常敏感。总之，基于包括PD-L1扩增和高肿瘤突变负担在内的潜在分子遗传机制，选择的对SMO拮抗剂具有抗性的转移性基底细胞癌可能对nivolumab有反应。PD-L2和JAK2扩增是霍奇金淋巴瘤的特征，它对nivolumab非常敏感。总之，基于包括PD-L1扩增和高肿瘤突变负担在内的潜在分子遗传机制，选择的对SMO拮抗剂耐药的转移性基底细胞癌可能对nivolumab有反应。PD-L2和JAK2扩增是霍奇金淋巴瘤的特征，它对nivolumab非常敏感。总之，基于包括PD-L1扩增和高肿瘤突变负担在内的潜在分子遗传机制，选择的对SMO拮抗剂耐药的转移性基底细胞癌可能对nivolumab有反应。