BC Cancer, University of British Columbia, Vancouver, BC, Canada.
Canadian Cancer Trials Group, Kingston, ON, Canada.
JCO Precis Oncol. 2024 Aug;8:e2400031. doi: 10.1200/PO.24.00031.
In metastatic colorectal cancer (mCRC), mutations drive resistance to anti-epidermal growth factor receptor antibodies. It is unclear whether mutations ever become clonally undetectable.
CO.26 was a phase II clinical trial that assessed durvalumab + tremelimumab in heavily pretreated mCRC. mutation status was tracked over time using circulating tumor DNA (ctDNA) sequencing at baseline, week 8, and on progression.
Among the 95 patients with mutations in their archival tumor tissue, 6.3% (6/95) had undetectable mutations in ctDNA collected at baseline or week 8 of the CO.26 study. Of these, 67% (4/6) of disappearances were transient, with the same mutation reappearing with progressive disease. In three cases, the simultaneous persistence of other preexisting CRC-associated truncal mutations could not be demonstrated, suggestive of low tumor shedding of ctDNA, leaving the incidence of true clonal reversion to -wildtype (WT) possibly as low as 3.2% (3/95). Fewer patients in the neo--WT group (33%) had greater than four lesions at trial baseline compared with patients with persistent mutations (75%), = .046. The likelihood of synchronous metastases at cancer diagnosis (33% 63%; = .15) or liver metastases at trial baseline (50% 68.5%; = .17) was not significantly different between patients with disappearing versus persistent mutations. Overall survival from stage IV diagnosis (hazard ratio, 0.77 [95% CI, 0.35 to 1.72]; = .52) was not significantly different between those with disappearing versus persistent mutations. The disappearance of mutations was not associated with primary tumor sidedness ( = .41), archival -mutant status ( = .16/1.00/.09), nor baseline ctDNA amplifications ( = 1.00).
We identified a 3.2%-6.3% prevalence of the neo--WT phenomenon in the CO.26 trial. However, 67% of apparent cases were transient with subsequent re-emergence.
在转移性结直肠癌（mCRC）中， 突变导致抗表皮生长因子受体抗体耐药。目前尚不清楚 突变是否曾经变得克隆性不可检测。
CO.26 是一项评估 durvalumab + tremelimumab 在 mCRC 患者中的疗效和安全性的 II 期临床试验。在基线、第 8 周和疾病进展时，通过循环肿瘤 DNA（ctDNA）测序来跟踪 突变状态。
在 95 例存档肿瘤组织中存在 突变的患者中，有 6.3%（6/95）在 CO.26 研究的基线或第 8 周的 ctDNA 中检测不到 突变。其中，67%（4/6）的消失是短暂的，随着疾病进展，相同的突变再次出现。在三种情况下，不能证明其他先前存在的 CRC 相关主干突变同时存在，提示 ctDNA 的肿瘤脱落量低，使真正的克隆性向野生型（WT）的逆转发生率可能低至 3.2%（3/95）。在新的 WT 组（33%）中，与持续存在 突变的患者相比（75%），更多患者在试验基线时具有大于 4 个病灶， =.046。在诊断时同步转移（33% 63%； =.15）或试验基线时肝转移（50% 68.5%； =.17）的可能性在消失和持续 突变的患者之间没有显著差异。从 IV 期诊断开始的总生存（危险比，0.77 [95%CI，0.35 至 1.72]； =.52）在消失和持续 突变的患者之间没有显著差异。 突变的消失与原发肿瘤侧别（ =.41）、存档 -突变状态（ =.16/1.00/.09）或基线 ctDNA 扩增（ = 1.00）无关。
我们在 CO.26 试验中发现了新的 WT 现象的患病率为 3.2%-6.3%。然而，67%的明显病例是短暂的，随后再次出现。
