Background Recognition of rare molecular subgroups is a challenge for precision oncology and may lead to tissue-agnostic approval of targeted agents. Here we aimed to comprehensively characterize the clinical, pathological and molecular landscape of RET rearranged metastatic colorectal cancer (mCRC). Patients and methods In this case series, we compared clinical, pathological and molecular characteristics of 24 RET rearranged mCRC patients with those of a control group of 291 patients with RET negative tumors. RET rearranged and RET negative mCRCs were retrieved by systematic literature review and by taking advantage of three screening sources: (i) Ignyta's phase 1/1b study on RXDX-105 (NCT01877811), (ii) cohorts screened at two Italian and one South Korean Institutions and (iii) Foundation Medicine Inc. database. Next-generation sequencing data were analyzed for RET rearranged cases. Results RET fusions were more frequent in older patients (median age of 66 versus 60 years, P = 0.052), with ECOG PS 1-2 (90% versus 50%, P = 0.02), right-sided (55% versus 32%, P = 0.013), previously unresected primary tumors (58% versus 21%, P < 0.001), RAS and BRAF wild-type (100% versus 40%, P < 0.001) and MSI-high (48% versus 7%, P < 0.001). Notably, 11 (26%) out of 43 patients with right-sided, RAS and BRAF wild-type tumors harbored a RET rearrangement. At a median follow-up of 45.8 months, patients with RET fusion-positive tumors showed a significantly worse OS when compared with RET-negative ones (median OS 14.0 versus 38.0 months, HR: 4.59; 95% CI, 3.64-32.66; P < 0.001). In the multivariable model, RET rearrangements were still associated with shorter OS (HR: 2.97; 95% CI, 1.25-7.07; P = 0.014), while primary tumor location, RAS and BRAF mutations and MSI status were not. Conclusions Though very rare, RET rearrangements define a new subtype of mCRC that shows poor prognosis with conventional treatments and is therefore worth of a specific management.

中文翻译：

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RET融合在一小部分晚期大肠癌中有被忽视的风险。

背景技术稀有分子亚群的识别对于精确肿瘤学是一个挑战，可能导致靶向药物的组织不可知批准。在这里，我们旨在全面表征RET重排的转移性结直肠癌（mCRC）的临床，病理和分子学特征。患者和方法在本病例系列中，我们比较了24例RET重排的mCRC患者与291例RET阴性肿瘤对照组的临床，病理和分子特征。RET重排和RET阴性的mCRCs通过系统的文献综述并利用三个筛查来源进行检索：（i）Ignyta对RXDX-105（NCT01877811）进行的1 / 1b研究，（ii）在两个意大利人和一个韩国人中筛选的队列机构和（iii）Foundation Medicine Inc.数据库。分析了下一代测序数据中的RET重排病例。结果RET融合在老年患者中更为常见（中位年龄为66岁vs 60岁，P = 0.052），其中ECOG PS 1-2（90％vs 50％，P = 0.02），右侧（55％vs 32％） ，P = 0.013），先前未切除的原发肿瘤（58％比21％，P <0.001），RAS和BRAF野生型（100％比40％，P <0.001）和MSI高（48％比7％）， P <0.001）。值得注意的是，在43例右侧，RAS和BRAF野生型肿瘤患者中，有11例（占26％）具有RET重排。在中位随访45.8个月时，与RET阴性的患者相比，RET融合阳性的肿瘤患者的OS显着降低（中位OS 14.0 vs 38.0个月，HR：4.59； 95％CI，3.64-32.66； P <0.001）。在多变量模型中，RET重排仍与较短的OS有关（HR：2.97; 95％CI，1.25-7.07; P = 0.014），而原发肿瘤的位置，RAS和BRAF突变以及MSI状态则不相关。结论尽管RET重排非常罕见，但它定义了mCRC的一种新亚型，该亚型在常规治疗中预后较差，因此值得进行特殊治疗。