Loaiza-Bonilla Arturo, Jensen Christopher E, Shroff Stuti, Furth Emma, Bonilla-Reyes Paula A, Deik Andres F, Morrissette Jennifer
Medicine, Hematology and Oncology, Abramson Cancer Center of the University of Pennsylvania.
Department of Medicine, The Hospital of the University of Pennsylvania.
Cureus. 2016 Feb 3;8(2):e478. doi: 10.7759/cureus.478.
This is the case of an 84-year-old woman diagnosed with Stage IVb colon adenocarcinoma (CRC) metastatic to the liver, retroperitoneum, anastomotic site, and distal rectal sigmoid colon. She experienced intolerable side effects to systemic chemotherapy with 5-fluorouracil and bevacizumab, as well as disease progression. Next generation sequencing of her tumor was ordered, and further discussion of her malignancy's genomic information took place at a multidisciplinary molecular tumor board. The patient had mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) which made her ineligible for epidermal growth factor receptor (EGFR) inhibitors; however, a KDR p.R961W c.2881C>T mutation was noted as a variant of unknown significance (VUS). KDR (kinase insert domain receptor) is the human gene encoding for vascular endothelial growth factor receptor 2 (VEGFR-2). She was then considered a suitable candidate for regorafenib, which she could only tolerate at a low dose of 40 mg daily, with the intent of prolonging her survival and to optimize her quality of life. We report her excellent tolerance and exceptional response to low dose regorafenib, including symptomatic, tumor marker, and sustained partial metabolic radiological improvement. In the largest Phase III trial of regorafenib in CRC, only five patients (1%) of 760 experienced a partial response (versus one patient, 0.4%, receiving placebo). KDR R961W mutation has been described but no functional data has been reported. This mutation occurs in the tyrosine kinase domain of the VEGFR-2. Regorafenib targets VEGFR-2 (KDR). Hereby we hypothesize KDR mutation as a novel predictive biomarker to exceptional response to regorafenib in metastatic colorectal cancer. To our knowledge, this is the first reported case of the potential correlation between KDR mutation and regorafenib use for the successful management of a patient with advanced CRC, leading to what is considered an exceptional response. Further studies based on this preliminary data are warranted.
这是一位84岁女性的病例，她被诊断为IVb期结肠腺癌（CRC），已转移至肝脏、腹膜后、吻合口部位以及直肠乙状结肠远端。她对5-氟尿嘧啶和贝伐单抗的全身化疗出现了无法耐受的副作用，且疾病进展。于是对她的肿瘤进行了二代测序，并在多学科分子肿瘤委员会对其恶性肿瘤的基因组信息进行了进一步讨论。该患者存在KRAS（ Kirsten大鼠肉瘤病毒癌基因同源物）突变，这使得她不符合使用表皮生长因子受体（EGFR）抑制剂的条件；然而，发现一个KDR p.R961W c.2881C>T突变，其意义不明（VUS）。KDR（激酶插入结构域受体）是编码血管内皮生长因子受体2（VEGFR-2）的人类基因。随后她被认为是瑞戈非尼的合适候选者，她仅能耐受每日40mg的低剂量，目的是延长生存期并优化生活质量。我们报告了她对低剂量瑞戈非尼具有良好耐受性和显著反应，包括症状改善、肿瘤标志物变化以及代谢和影像学持续部分缓解。在瑞戈非尼治疗CRC的最大规模III期试验中，760例患者中只有5例（1%）出现部分缓解（相比之下，接受安慰剂的患者中有1例，占0.4%）。KDR R961W突变已有报道，但尚未有功能数据。该突变发生在VEGFR-2的酪氨酸激酶结构域。瑞戈非尼靶向VEGFR-2（KDR）。因此，我们假设KDR突变是转移性结直肠癌对瑞戈非尼显著反应的一种新型预测生物标志物。据我们所知，这是首次报道KDR突变与瑞戈非尼用于成功治疗晚期CRC患者之间潜在相关性的病例，从而导致了被认为是显著反应的情况。基于这些初步数据的进一步研究是必要的。
