Department of Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Deparment of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Centers, VU University, Amsterdam, the Netherlands.
JCO Precis Oncol. 2021 Nov 17;5. doi: 10.1200/PO.21.00223. eCollection 2021.
Somatic mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the mutation variant. mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in G12, G13, Q61, K117, or A146.
A total of 419 patients with colorectal cancer with initially unresectable liver-limited metastases, who participated in a multicenter prospective trial, were evaluated for tumor tissue mutation status. For the subgroup of patients who carried a mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N = 156), pretreatment circulating tumor DNA levels were analyzed, and total tumor volume (TTV) was quantified on the pretreatment computed tomography images.
Most patients carried a G12 mutation (N = 112), followed by mutations in G13 (N = 15), A146 (N = 12), Q61 (N = 9), and K117 (N = 5). High plasma circulating tumor DNA levels were observed for patients carrying a A146 mutation versus those with a G12 mutation, with median mutant allele frequencies of 48% versus 19%, respectively. Radiologic TTV revealed this difference to be associated with a higher tumor load in patients harboring a A146 mutation (median TTV 672 cm [A146] 74 cm [G12], = .036). Moreover, A146 mutation carriers showed inferior overall survival compared with patients with mutations in G12 (median 10.7 26.4 months; hazard ratio = 2.5; = .003).
Patients with mCRC with a A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all mutations in routine clinical care.
大约一半的转移性结直肠癌（mCRC）患者存在体细胞突变。基于突变变体，肿瘤的生物学特征存在差异。已知突变会影响患者的预后，并被用作治疗决策的预测生物标志物。本研究分析了伴有 G12、G13、Q61、K117 或 A146 体细胞突变的 mCRC 患者的临床特征。
对参加多中心前瞻性试验的 419 例初始不可切除的肝转移局限型结直肠癌患者进行肿瘤组织突变状态评估。对携带突变且接受贝伐珠单抗联合双药或三药化疗的 156 例患者亚组，分析了治疗前循环肿瘤 DNA 水平，并对治疗前 CT 图像进行了总肿瘤体积（TTV）定量分析。
大多数患者携带 G12 突变（N=112），其次是 G13 突变（N=15）、A146 突变（N=12）、Q61 突变（N=9）和 K117 突变（N=5）。携带 A146 突变的患者的血浆循环肿瘤 DNA 水平较高，突变等位基因频率中位数分别为 48%和 19%。影像学 TTV 显示，携带 A146 突变的患者肿瘤负荷更高（中位 TTV 672cm3[ A146] 74cm3[G12]，=.036）。此外，与 G12 突变患者相比，携带 A146 突变的患者总生存时间更差（中位 10.7 26.4 个月；风险比=2.5；=.003）。
伴有 A146 突变的 mCRC 患者代表了一个具有更高肿瘤负荷和更差临床结局的独特分子亚群，可能受益于更强化的治疗。这些结果强调了在常规临床护理中检测所有结直肠癌突变的重要性。
