The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Oncologist. 2021 Feb;26(2):e270-e278. doi: 10.1002/onco.13601. Epub 2020 Dec 3.
Genomic biomarkers that predict response to anti-PD1 therapy in prostate cancer are needed. Frameshift mutations are predicted to generate more neoantigens than missense mutations; therefore, we hypothesized that the number or proportion of tumor frameshift mutations would correlate with response to anti-PD1 therapy in prostate cancer.
To enrich for response to anti-PD1 therapy, we assembled a multicenter cohort of 65 men with mismatch repair-deficient (dMMR) prostate cancer. Patient characteristics and outcomes were determined by retrospective chart review. Clinical somatic DNA sequencing was used to determine tumor mutational burden (TMB), frameshift mutation burden, and frameshift mutation proportion (FSP), which were correlated to outcomes on anti-PD1 treatment. We subsequently used data from a clinical trial of pembrolizumab in patients with nonprostatic dMMR cancers of various histologies as a biomarker validation cohort.
Nineteen of 65 patients with dMMR metastatic castration-resistant prostate cancer were treated with anti-PD1 therapy. The PSA response rate was 65%, and the median progression-free survival (PFS) was 24 (95% confidence interval 16-54) weeks. Tumor FSP, more than overall TMB, correlated most strongly with prolonged PFS and overall survival (OS) on anti-PD1 treatment and with density of CD8+ tumor-infiltrating lymphocytes. High FSP similarly identified patients with longer PFS as well as OS on anti-PD1 therapy in a validation cohort.
Tumor FSP correlated with prolonged efficacy of anti-PD1 treatment among patients with dMMR cancers and may represent a new biomarker of immune checkpoint inhibitor sensitivity.
Given the modest efficacy of immune checkpoint inhibition (ICI) in unselected patients with advanced prostate cancer, biomarkers of ICI sensitivity are needed. To facilitate biomarker discovery, a cohort of patients with DNA mismatch repair-deficient (dMMR) prostate cancer was assembled, as these patients are enriched for responses to ICI. A high response rate to anti-PD1 therapy in these patients was observed; however, these responses were not durable in most patients. Notably, tumor frameshift mutation proportion (FSP) was identified as a novel biomarker that was associated with prolonged response to anti-PD1 therapy in this cohort. This finding was validated in a separate cohort of patients with nonprostatic dMMR cancers of various primary histologies. This works suggests that FSP predicts response to anti-PD1 therapy in dMMR cancers, which should be validated prospectively in larger independent cohorts.
需要基因组生物标志物来预测前列腺癌对抗 PD1 治疗的反应。移码突变预计会产生比错义突变更多的新抗原；因此，我们假设肿瘤移码突变的数量或比例与前列腺癌对抗 PD1 治疗的反应相关。
为了富集对抗 PD1 治疗的反应，我们组建了一个由 65 名错配修复缺陷（dMMR）前列腺癌患者组成的多中心队列。通过回顾性病历审查确定患者特征和结局。临床体细胞 DNA 测序用于确定肿瘤突变负担（TMB）、移码突变负担和移码突变比例（FSP），并将其与抗 PD1 治疗的结果相关联。随后，我们使用了一项 pembrolizumab 治疗各种组织学来源的非前列腺 dMMR 癌症患者的临床试验数据作为生物标志物验证队列。
在 65 名患有 dMMR 转移性去势抵抗性前列腺癌的患者中，有 19 名接受了抗 PD1 治疗。PSA 缓解率为 65%，中位无进展生存期（PFS）为 24（95%置信区间 16-54）周。肿瘤 FSP，而不是总 TMB，与抗 PD1 治疗的延长 PFS 和总生存期（OS）以及 CD8+肿瘤浸润淋巴细胞密度相关性最强。在验证队列中，高 FSP 同样可以识别出接受抗 PD1 治疗的患者具有更长的 PFS 和 OS。
肿瘤 FSP 与 dMMR 癌症患者抗 PD1 治疗的疗效延长相关，可能代表免疫检查点抑制剂敏感性的新生物标志物。
鉴于免疫检查点抑制（ICI）在未经选择的晚期前列腺癌患者中的疗效有限，因此需要 ICI 敏感性的生物标志物。为了促进生物标志物的发现，组建了一个 DNA 错配修复缺陷（dMMR）前列腺癌患者队列，因为这些患者对 ICI 反应增强。在这些患者中观察到了抗 PD1 治疗的高缓解率；然而，大多数患者的缓解并不持久。值得注意的是，肿瘤移码突变比例（FSP）被确定为一种新的生物标志物，与该队列中抗 PD1 治疗的延长反应相关。这一发现在另一组不同原发性组织学来源的非前列腺 dMMR 癌症患者中得到了验证。这一研究表明，FSP 预测了 dMMR 癌症对抗 PD1 治疗的反应，这应该在更大的独立队列中进行前瞻性验证。
