Novel SLC12A2-ROS1 Fusion in Non-Small Cell Lung Cancer with a Significant Response to Crizotinib: The Importance of Choosing the Appropriate Next-Generation Sequencing Assay

Abstract

Identifying the druggable target is crucial for patients with non-squamous advanced non-small-cell lung cancer (NSCLC). This case report adds to the spectrum of ROS1 fusion cases described in NSCLC. We describe a novel SLC12A2-ROS1 rearrangement that has not been previously reported in other cancers, a fusion that has clinical and radiological sensitivity to crizotinib. We detected the SLC12A2-ROS1 fusion by FISH and it was confirmed through hybrid capture-based next-generation sequencing; however, the fusion could not be detected by amplicon-based assay. The success of implementing next-generation sequencing into routine clinical practice depends on the accuracy of testing. The test's methodological features should then be considered because they significantly affect the results.

Unique SLC12A2-ROS1 fusion is associated with marked response to crizotinib in lung adenocarcinoma

“… 3 , 5 , 8 , 16 The present case provides the second report in the literature that NSCLCs harboring SLC12A2-ROS1 fusions can respond to second-line crizotinib as well, with our patient remaining progression-free for 21 months now. 17 …”

“…Although it is unknown whether SLC12A2-ROS1 fusion occurs more frequently in this subgroup of patients, our report reinforces the concept that not only this fusion is oncogenic but also confers sensitivity to ROS1 TKIs, which could theoretically contribute to tailor clinical decision for individuals diagnosed with lung tumors harboring this alteration. 17 , 19 Interestingly, the case reported by Rodriguez-Antolin and colleagues displays some intriguing similarities with our case, for instance, (1) very young age of diagnosis (21 vs 26 years old, which could contribute to delay the diagnosis), (2) symptomatic and high-volume lung involvement at diagnosis of advanced disease, (3) refractoriness to frontline chemoimmunotherapy with subsequent clinical deterioration, as well as (4) fast and deep response to crizotinib. In this specific case, the ROS1 fusion breakpoint occurred in exon 36, as opposed to our case and Li et al’s 19 description (introns 35 and 34, respectively).…”

“…In this specific case, the ROS1 fusion breakpoint occurred in exon 36, as opposed to our case and Li et al’s 19 description (introns 35 and 34, respectively). 17 Importantly, based on the recent identification of SLC12A2-ROS1 fusion in a head and neck inflammatory myofibroblastic tumor, it is reasonable to consider that this fusion can also act as important oncogenic event in other solid tumors. 20 …”

“…3,5,8,16 The present case provides the second report in the literature that NSCLCs harboring SLC12A2-ROS1 fusions can respond to second-line crizotinib as well, with our patient remaining progression-free for 21 months now. 17 Although the incidence of CNS metastasis in advanced ROS1 + NSCLCs is described as a frequent event, the precise proportion of patients with secondary involvement is conflicting, ranging from nearly 20%-40% in treatmentnaïve patients to 50%-56% in crizotinib-pretreated patients according to data from prospective trials. 8 This CNS tropism, along with an inferior blood-brain barrier penetration of crizotinib (when compared to other newer-generation multikinase inhibitors), and the paucity of therapeutic options for crizotinib-resistant tumors, prompted the study of these modern TKIs in the context of ROS1 + malignancies.…”

From targeted therapy to a novel way: Immunogenic cell death in lung cancer

“…The (c-ros oncogene1) ROS1 rearrangements, which drive malignant transformation of NSCLC, affect approximately 0.7-1.7% NSCLC patients (91). The fusion partners include CD74, SLC34A2, FIG, TPM3, SLC12A2, CCDC6, and SDC4, while CD74-ROS1 fusion is the most prevalent phenotype in NSCLC (92,93). Gou et al demonstrated that CD74-ROS1 mutation could lead to EMT and enhance the NSCLC invasion and migration ability by upregulating Twist1 (94).…”