Sehdev Amikar, Cramer Harvey M, Ibrahim Ashley A M, Younger Anne E, O'Neil Bert H
Division of Hematology/Oncology, Department of Medicine, Indiana University, Indianapolis, IN 46202, USA.
Department of Pathology and Laboratory Medicine, Indiana University, Indianapolis, IN 46202, USA.
Discov Med. 2016 May;21(117):341-7.
Mismatch repair (MMR) and BRAF mutation status are established independent prognostic factors for colorectal cancer (CRC). MMR deficient tumors are considered to have better prognosis whereas BRAF mutation is associated with poor prognosis. Studies evaluating the combined effect of BRAF and MMR status suggest MSI-high and BRAF mutant patients have a poorer prognosis as compared to MSI-high and BRAF wild type patients. Emerging evidence suggests MMR status predicts the immune response to anti-PD-1 therapy in CRC patients; however little is known about combined MMR and BRAF mutation status in this context. Therefore, it is important to identify whether there is a differential response to anti-PD-1 therapy based on BRAF status in the subset of MSI-high CRC patients.
We report the first case of MSI-high, BRAF mutant metastatic CRC that had an excellent response (pathologic complete response) to anti-PD-1 therapy. We take this opportunity to review the similar cases in literature and discuss combined MMR and BRAF status as a potential biomarker for anti-PD-1 therapy.
The case presented illustrates that anti-PD-1 therapy can be effectively used to treat CRC patients with MSI-high and BRAF mutant status which is usually considered a poor prognostic category as opposed to MSI-high and BRAF wild type tumors. Future studies with anti-PD-1 therapy distinguishing these molecular subgroups will improve our knowledge of whether BRAF status can add to MMR status as a predictive biomarker for anti-PD-1 therapy in patients with metastatic CRC.
错配修复（MMR）和BRAF突变状态是已确定的结直肠癌（CRC）独立预后因素。MMR缺陷型肿瘤被认为预后较好，而BRAF突变与预后不良相关。评估BRAF和MMR状态联合作用的研究表明，与微卫星高度不稳定（MSI-高）且BRAF野生型患者相比，MSI-高且BRAF突变型患者预后较差。新出现的证据表明，MMR状态可预测CRC患者对抗程序性死亡蛋白1（PD-1）治疗的免疫反应；然而，在这种情况下，关于MMR和BRAF突变状态联合情况的了解甚少。因此，确定MSI-高的CRC患者亚组中基于BRAF状态对抗PD-1治疗是否存在差异反应很重要。
我们报告了首例MSI-高、BRAF突变的转移性CRC患者，其对抗PD-1治疗有出色反应（病理完全缓解）。我们借此机会回顾文献中的类似病例，并讨论MMR和BRAF联合状态作为抗PD-1治疗潜在生物标志物的情况。
所呈现的病例表明，抗PD-1治疗可有效用于治疗MSI-高且BRAF突变状态的CRC患者，与MSI-高且BRAF野生型肿瘤相比，这种情况通常被认为是预后不良类别。未来区分这些分子亚组的抗PD-1治疗研究将增进我们对于BRAF状态能否作为转移性CRC患者抗PD-1治疗预测生物标志物补充MMR状态的认识。
