Bouchahda Mohamed, Saffroy Raphael, Karaboué Abdoulaye, Hamelin Jocelyne, Innominato Pasquale, Saliba Faouzi, Lévi Francis, Bosselut Nelly, Lemoine Antoinette
Medical Oncology Department, Paul Brousse Hospital, Villejuif, France.
Medical Oncology Unit, Clinique du Mousseau, Evry, France.
JCO Precis Oncol. 2020 Sep 16;4. doi: 10.1200/PO.19.00400. eCollection 2020.
Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with wild-type (-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with mutation (-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was -wt.
The occurrence of Kirsten rat sarcoma viral oncogene homolog (), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (), and mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed -mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with -wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with -mt ctDNA were treated with the oncologist's choice of therapy.
Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified -mt in seven patients (44%) and -wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with -wt ctDNA and 17.9% for those with -mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.
Patients with -mt mCRC whose plasma biopsies contained -wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.
将西妥昔单抗与化疗联合应用可为60%的野生型（-wt）转移性结直肠癌（mCRC）患者带来临床获益。这项初步研究调查了以西妥昔单抗为基础的化疗方案在原发肿瘤存在突变（-mt）但其循环肿瘤DNA（ctDNA）为野生型的患者样本（40%）中的疗效。
通过一种基于质谱检测的新型超灵敏分析方法，在ctDNA中检测 Kirsten大鼠肉瘤病毒癌基因同源物（KRAS）、神经母细胞瘤大鼠肉瘤病毒癌基因同源物（NRAS）、V-raf鼠肉瘤病毒癌基因同源物B1（BRAF）和PIK3CA突变的发生情况。所有已确认原发肿瘤为KRAS突变型（-mt）的mCRC且同意参与研究的患者，在之前不含抗表皮生长因子受体（EGFR）的化疗中均出现疾病进展。ctDNA为野生型的患者接受西妥昔单抗 + 氟尿嘧啶、亚叶酸钙和伊立替康（FOLFIRI）治疗，而ctDNA为突变型的患者则接受肿瘤学家选择的治疗方案。
16名登记患者中，11名男性，5名女性。年龄在48至81岁之间，患有无法切除的结肠（n = 11）或直肠（n = 5）转移性腺癌，转移部位中位数为2个。他们之前接受化疗方案的中位数为3个。血浆基因分型显示7名患者（44%）为KRAS突变型，9名患者（56%）为野生型。在ctDNA为野生型的患者中，客观肿瘤缓解率为50.0%，包括1例完全缓解和4例部分缓解，接受西妥昔单抗 + FOLFIRI治疗的疗程中位数为6个（范围为1至16个疗程）。9名患者中有2名病情稳定，2名病情进展。未出现3至4级毒性反应。ctDNA为野生型的患者1年生存率为60.0%，ctDNA为突变型的患者为17.9%。总生存时间中位数分别未达到和为4.7个月。
血浆活检显示ctDNA为野生型的KRAS突变型mCRC患者可能从以西妥昔单抗为基础的治疗中获益，这一假设有待在前瞻性随机试验中进行验证。
