Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Houston, TX.
Department of Investigational Cancer Therapeutics (Phase 1 Program), The University of Texas MD Anderson Cancer Center, Houston, TX.
JCO Precis Oncol. 2024 Nov;8:e2400419. doi: 10.1200/PO-24-00419. Epub 2024 Nov 22.
PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.
From January 2016 to December 2021, 15,701 patients with solid tumors received NGS covering the MMR genes, and 4,994 patients had both IHC and NGS. Sequencing results were analyzed for mutations in MMR genes, tumor type distribution, and concordance with IHC results when available.
Six hundred and ninety-eight (4.4%) of 15,701 patients had mutations in one of the MMR genes. Mutations were found across tumor types. Three hundred and seventeen (6.3%) of 4,994 patients displayed IHC loss for at least one MMR protein. 33.8% patients (110/325) patients with MMR mutations had dMMR, compared with just 4.4% (207/4,669) patients without mutations ( < .001); dMMR rate varied by mutation type.
Mutations in MMR genes are found in multiple tumor types where IHC testing is not routine. Reflex IHC testing of patients carrying MMR gene mutations, especially those known or inferred to be inactivating, may identify more patients with dMMR and matched treatment options. However, dedicated IHC screening is needed to capture majority of the patients.
程序性死亡受体-1（PD-1）抑制剂在错配修复缺陷（dMMR）的实体瘤患者中具有肿瘤不可知的疗效。然而，并非所有肿瘤类型都常规进行免疫组织化学（IHC）检测 dMMR。相比之下，针对体细胞基因组改变的下一代测序（NGS）在各种肿瘤类型中经常进行。我们假设 NGS 可以识别存在错配修复（MMR）基因改变的患者，并且这些患者的 IHC 检测会显示更高比例的 MMR 蛋白缺失。这将支持 NGS 后进行 IHC 反射性检测的效用，并有可能与批准的治疗方案相匹配。
从 2016 年 1 月至 2021 年 12 月，15701 例实体瘤患者接受了涵盖 MMR 基因的 NGS 检测，其中 4994 例患者同时进行了 IHC 和 NGS 检测。分析了测序结果中 MMR 基因的突变、肿瘤类型分布以及与 IHC 结果的一致性（如有）。
在 15701 例患者中，有 698 例（4.4%）存在 MMR 基因中的一种突变。突变存在于各种肿瘤类型中。在 4994 例患者中，有 317 例（6.3%）至少有一种 MMR 蛋白的 IHC 检测缺失。与没有突变的患者（4669 例中的 207 例，4.4%）相比，MMR 基因突变的患者中有 33.8%（325 例中的 110 例）具有 dMMR（<0.001）；dMMR 率因突变类型而异。
在不常规进行 IHC 检测的多种肿瘤类型中发现了 MMR 基因的突变。对携带 MMR 基因突变的患者进行 IHC 反射性检测，特别是那些已知或推断为失活的突变，可能会识别出更多具有 dMMR 和匹配治疗选择的患者。然而，需要进行专门的 IHC 筛查来捕捉大多数患者。
