液体活检驱动的西妥昔单抗再挑战策略在分子筛选的转移性结直肠癌患者中的应用
Liquid Biopsy-Driven Cetuximab Rechallenge Strategy in Molecularly Selected Metastatic Colorectal Cancer Patients.
作者信息
Mariani Stefano, Puzzoni Marco, Giampieri Riccardo, Ziranu Pina, Pusceddu Valeria, Donisi Clelia, Persano Mara, Pinna Giovanna, Cimbro Erika, Parrino Alissa, Spanu Dario, Pretta Andrea, Lai Eleonora, Liscia Nicole, Lupi Alessio, Giglio Enrica, Palomba Grazia, Casula Milena, Pisano Marina, Palmieri Giuseppe, Scartozzi Mario
机构信息
Azienda Ospedaliera Universitaria (AOU) Cagliari, University Hospital and University of Cagliari, Cagliari, Italy.
Medical Oncology Unit, University Hospital and Università Politecnica delle Marche, Ancona, Italy.
出版信息
Front Oncol. 2022 Apr 21;12:852583. doi: 10.3389/fonc.2022.852583. eCollection 2022.
BACKGROUND
Rechallenge with EGFR inhibitors represents a promising strategy for patients with RAS wild type (WT) colorectal cancer (CRC) but definitive selection criteria are lacking. Recently, the RAS WT status on circulating tumor DNA (ct-DNA) emerged as a potential watershed for this strategy. Our study explored the liquid biopsy-driven cetuximab rechallenge in a RAS and BRAF WT selected population.
METHODS
CRC patients with RAS and BRAF WT both on tumor tissue and on ct-DNA at baseline receiving rechallenge with cetuximab were eligible for our analysis. Ct-DNA was analyzed for RAS-BRAF mutations with pyro-sequencing and nucleotide sequencing assays. Real-time PCR and droplet digital PCR were performed to confirm the RAS-BRAF mutational status.
RESULTS
A total of 26 patients were included in our analysis. In the global population, RR was 25.0%, median overall survival (mOS) was 5.0 months, and median progression-free survival (mPFS) was 3.5 months. Previous response to anti-EGFR was associated with improved mPFS (5.0 vs. 2.0 months, HR: 0.26, = 0.048); anti-EGFR free interval > 14 months and anti-EGFR free interval > 16 months were associated with improved mPFS (respectively 7.0 vs. 3.0 months, HR: 0.27, = 0.013 and not reached vs. 3.0 months, HR: 0.20, = 0.002) and with improved mOS (respectively 13.0 vs. 5.0 months, HR: 0.27, = 0.013 and 13.0 vs. 5.0 months, HR: 0.20, = 0.002). Previous lines >2 were correlated with improved mPFS (4.0 vs. 1.0 month, HR: 0.05, = 0.041) and with improved mOS (7.0 vs. 1.0 month, HR: 0.045, = 0.034). In a multiple logistic regression model, only the anti-EGFR free interval was confirmed to be a significant predictor for mOS and mPFS.
CONCLUSIONS
Liquid biopsy-driven cetuximab rechallenge was confirmed to be effective. The clinical outcome was consistent with available results from phase II studies. In addition to the molecular selection through the analysis of ct-DNA for RAS, the long anti-EGFR free interval is confirmed as a prospective selection criterion for this therapeutic option.
背景
对于RAS野生型（WT）结直肠癌（CRC）患者，再次使用表皮生长因子受体（EGFR）抑制剂是一种有前景的策略，但缺乏明确的选择标准。最近，循环肿瘤DNA（ct-DNA）上的RAS WT状态成为该策略潜在的分水岭。我们的研究在RAS和BRAF WT的选定人群中探索了液体活检驱动的西妥昔单抗再次使用情况。
方法
基线时肿瘤组织和ct-DNA上RAS和BRAF均为WT且接受西妥昔单抗再次治疗的CRC患者符合我们的分析标准。采用焦磷酸测序和核苷酸测序分析ct-DNA的RAS-BRAF突变。进行实时聚合酶链反应（PCR）和数字液滴PCR以确认RAS-BRAF突变状态。
结果
共有26例患者纳入我们的分析。在总体人群中，缓解率（RR）为25.0%，中位总生存期（mOS）为5.0个月，中位无进展生存期（mPFS）为3.5个月。既往对抗EGFR治疗有反应与mPFS改善相关（5.0个月对2.0个月，风险比[HR]：0.26，P = 0.048）；抗EGFR无治疗间隔>14个月和抗EGFR无治疗间隔>16个月与mPFS改善相关（分别为7.0个月对3.0个月，HR：0.27，P = 0.013；未达到对3.0个月，HR：0.20，P = 0.002）且与mOS改善相关（分别为13.0个月对5.0个月，HR：0.27，P = 0.013；13.0个月对5.0个月，HR：0.20，P = 0.002）。既往治疗线数>2与mPFS改善相关（4.0个月对1.0个月，HR：0.05，P = 0.041）且与mOS改善相关（7.0个月对1.0个月，HR：0.045，P = 0.034）。在多因素逻辑回归模型中，仅抗EGFR无治疗间隔被确认为mOS和mPFS的显著预测因素。
结论
液体活检驱动的西妥昔单抗再次使用被证实有效。临床结果与II期研究的现有结果一致。除了通过分析ct-DNA进行RAS分子选择外，长抗EGFR无治疗间隔被确认为该治疗方案的前瞻性选择标准。
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