Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Cancer Program, Broad Institute of MIT and Harvard, Cambridge, Massachusetts; Pritzker School of Medicine, Biological Sciences Division, The University of Chicago, Chicago, Illinois.
J Thorac Oncol. 2021 Jul;16(7):1176-1187. doi: 10.1016/j.jtho.2021.03.024.
The SWItch/Sucrose Nonfermentable (SWI/SNF) chromatin remodeling complex acts as a regulatory component of transcription, and inactivating mutations (muts) within the complex are implicated in genomic instability, higher tumor mutational burden, and an aggressive cancer phenotype. Whether SMARCA4 and other SWI/SNF alterations are independent prognostic factors or associated with clinical outcomes to immune checkpoint inhibitors (ICIs) in NSCLC remains unclear.
We collected clinicopathologic and genomic data from patients with NSCLC who underwent targeted next-generation sequencing at the Dana-Farber Cancer Institute. Tumors were characterized on the basis of the presence or absence of muts across a set of six SWI/SNF genes (ARID1A, ARID1B, ARID2, PBRM1, SMARCA4, and SMARCB1).
Of 2689 patients with NSCLC, 20.6% (N = 555) had SWI/SNF genomic alterations. Compared with SWI/SNF wild-type (wt) NSCLC, patients with SWI/SNF-mutant NSCLCs had a lower prevalence of concurrent targetable driver muts (33.2% versus 22.2%; p < 0.001), a higher tumor mutational burden (median 8.5 versus 12.2 muts/megabase; p < 0.001), and a shorter median overall survival (mOS) from the time of advanced disease diagnosis (25.0 versus 19.3 mo, p = 0.01); the detrimental effect in OS seemed to be largely driven by SMARCA4 muts (mOS: 25.0 for SMARCA4 wt versus 15.6 mo for SMARCA4 mutant; p < 0.001). Among 532 patients who received ICIs, 25.5% (N = 136) harbored SWI/SNF muts. From the start of immunotherapy, there was no difference in objective response rate (ORR = 19.9% versus 25.0%, p = 0.2), median progression-free survival (mPFS = 3.0 versus 3.0 mo, hazard ratio [HR] = 0.96 [95% confidence interval [CI] = 0.77-1.18], p = 0.7), or mOS (13.1 versus 9.5 mo, HR = 0.81 [95% CI: 0.64-1.02], p = 0.07) in SWI/SNF-wt versus SWI/SNF-mutant NSCLC, respectively. Nevertheless, among KRAS-mutant NSCLCs treated with ICIs (N = 176), a concurrent SWI/SNF mut (N = 39) conferred a numerically lower ORR (21.9% versus 12.8%, p = 0.2), a significantly shorter mPFS (4.1 versus 1.8 mo, HR = 0.57 [95% CI: 0.38-0.84], p = 0.005), and a significantly shorter mOS (15.5 versus 8.2 mo, HR = 0.56 [95% CI: 0.36-0.86], p = 0.008). The deleterious effect on immunotherapy outcomes in KRAS-mutant NSCLC was most pronounced in the SMARCA4-mutant subset (N = 17), with a lower ORR (22% versus 0%, p = 0.03), a significantly shorter mPFS (4.1 versus 1.4 mo, HR = 0.25 [95% CI: 0.14-0.42], p < 0.001), and a significantly shorter mOS (15.1 versus 3.0 mo, HR = 0.29 [95% CI: 0.17-0.50], p < 0.001) compared with SMARCA4-wt KRAS-mutant NSCLCs.
Although there were no associations between SWI/SNF mut status and immunotherapy efficacy in the overall NSCLC cohort, the presence of a SMARCA4 alteration may confer a worse outcome to immunotherapy among KRAS-mutant NSCLCs.
SWItch/Sucrose Nonfermentable（SWI/SNF）染色质重塑复合物作为转录的调节成分发挥作用，复合物内的失活突变（mutations，muts）与基因组不稳定性、更高的肿瘤突变负担和侵袭性癌症表型有关。在非小细胞肺癌（NSCLC）中，SMARCA4 和其他 SWI/SNF 改变是否是独立的预后因素，还是与免疫检查点抑制剂（ICI）的临床结局相关，目前尚不清楚。
我们从在丹娜-法伯癌症研究所接受靶向下一代测序的 NSCLC 患者中收集了临床病理和基因组数据。根据一组六个 SWI/SNF 基因（ARID1A、ARID1B、ARID2、PBRM1、SMARCA4 和 SMARCB1）中是否存在 muts，对肿瘤进行了特征描述。
在 2689 例 NSCLC 患者中，20.6%（N=555）存在 SWI/SNF 基因改变。与 SWI/SNF 野生型（wt）NSCLC 相比，SWI/SNF 突变型 NSCLC 患者同时存在靶向驱动 muts 的频率较低（33.2%与 22.2%；p<0.001），肿瘤突变负担更高（中位值 8.5 与 12.2 突变/兆碱基；p<0.001），晚期疾病诊断后总生存期（overall survival，OS）的中位数更短（25.0 与 19.3 个月，p=0.01）；OS 的这种不良影响似乎主要是由 SMARCA4 muts 引起的（OS：SMARCA4 wt 为 25.0 个月，SMARCA4 突变型为 15.6 个月；p<0.001）。在 532 例接受 ICI 治疗的患者中，25.5%（N=136）存在 SWI/SNF muts。从免疫治疗开始，客观缓解率（objective response rate，ORR）无差异（19.9%与 25.0%，p=0.2），无进展生存期（progression-free survival，PFS）的中位数也无差异（3.0 与 3.0 个月，风险比[hazard ratio，HR]0.96 [95%置信区间[confidence interval，CI]0.77-1.18]，p=0.7），总生存期（OS）的中位数也无差异（13.1 与 9.5 个月，HR 0.81 [95% CI 0.64-1.02]，p=0.07），分别在 SWI/SNF-wt 与 SWI/SNF-mut 型 NSCLC 中。然而，在接受 ICI 治疗的 KRAS 突变型 NSCLC 患者（N=176）中，同时存在 SWI/SNF mut（N=39）的患者的 ORR 较低（21.9%与 12.8%，p=0.2），PFS 的中位数较短（4.1 与 1.8 个月，HR 0.57 [95% CI 0.38-0.84]，p=0.005），OS 的中位数也较短（15.5 与 8.2 个月，HR 0.56 [95% CI 0.36-0.86]，p=0.008）。在 KRAS 突变型 NSCLC 中，SMARCA4 mut 的存在对免疫治疗结局的不良影响最为明显（N=17），ORR 较低（22%与 0%，p=0.03），PFS 的中位数较短（4.1 与 1.4 个月，HR 0.25 [95% CI 0.14-0.42]，p<0.001），OS 的中位数也较短（15.1 与 3.0 个月，HR 0.29 [95% CI 0.17-0.50]，p<0.001），与 SMARCA4-wt KRAS 突变型 NSCLC 相比。
尽管在整体 NSCLC 队列中，SWI/SNF mut 状态与免疫治疗疗效之间没有关联，但 SMARCA4 改变的存在可能会使 KRAS 突变型 NSCLC 患者的免疫治疗结局更差。
