Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Cancer Res. 2024 Jun 14;30(12):2672-2683. doi: 10.1158/1078-0432.CCR-23-4005.
Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance.
We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT).
All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases.
Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.
针对转移性结直肠癌患者的靶向治疗已经改善了患者的预后，但由于耐药性的迅速出现，其效果受到了限制。我们假设，对介导治疗耐药性的潜在遗传机制和内在肿瘤特征的了解，将指导新的治疗策略，并最终能够预防耐药性。
我们收集了 52 名接受 EGFR（n = 17）、BRAF V600E（n = 17）、KRAS G12C（n = 15）或扩增 HER2（n = 3）靶向治疗的患者的配对预处理和进展样本，以鉴定与治疗时间（TOT）相关的分子和临床因素。
所有患者均因进展而停止治疗，且不同致癌驱动因素的 TOT 无差异（P = 0.5）。基线疾病负担（≥3 个部位与<3 个部位，P = 0.02）、肝转移的存在（P = 0.02）和基线组织上的基因扩增（P = 0.03）均与较短的 TOT 相关。我们发现，基线 MAPK 通路扩增的患者和获得性基因扩增的患者在进展时存在染色体不稳定性（CIN）的证据。在耐药时，拷贝数变化（P = 0.008）和获得性改变的高数量（≥5 个，P = 0.04）与较短的 TOT 相关。肝转移的患者在耐药时表现出更高数量的新出现的改变，并且富集了涉及受体酪氨酸激酶的突变。
我们的基因组分析表明，高基线 CIN 或在靶向治疗下有效诱导增强的突变是快速进展的基础。较长的反应似乎是由于潜在癌症中基因组或染色体不稳定性的逐渐获得，或者是新耐药性改变的偶然事件。
