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Background RET (rearranged during transfection) fusions have been reported in 1% to 2% of lung adenocarcinoma (LADC) cases. In contrast, KIF5B-RET and CCDC6-RET fusion genes have been identified in 70% to 90% and 10% to 25% of tumors, respectively. The natural history and management of RET-rearranged LADC are still being delineated. Materials and Methods We present a series of 14 patients with RET-rearranged LADC. The response to therapy was assessed by the clinical response and an avatar model in 2 cases. Patients underwent chemotherapy, targeted therapy, and immunotherapy. Results A total of 14 patients (8 women; 10 never smokers; 4 light smokers; mean age, 57 years) were included. KIF5B-RET and CCDC6-RET variants were diagnosed in 10 and 4 cases, respectively. Eight patients had an early disseminated manifestation, seven with KIF5B-RET rearranged tumor. The features of this subset included bilateral miliary lung metastases, bone metastases, and unusual early visceral abdominal involvement. One such patient demonstrated an early and durable complete response to cabozantinib for 7 months. Another 2 patients treated with cabozantinib experienced a partial response, with rapid significant clinical improvement. Four patients with tumors harboring CCDC6-RET and KIF5B-RET fusions showed pronounced and durable responses to platinum-based chemotherapy that lasted for 8 to 15 months. Two patients' tumors showed programmed cell death ligand 1-positive staining but did not respond to pembrolizumab. The median overall survival was 22.8 months. Conclusion RET-rearranged LADC in our series tended to occur as bilateral disease with early visceral involvement, especially with KIF5B fusion. Treatment with cabozantinib achieved responses, including 1 complete response. However, further studies are required in this group of patients.

Background Next-generation sequencing is available for assessing genomic alterations in non–small-cell lung cancer (NSCLC), although the performance characteristics and clinical utility has not been well characterized. This technique can be used to sequence hundreds of known cancer-associated genes. Our aim was to investigate the diagnostic success and clinically relevant results of extensive sequencing in NSCLC patients. Patients and Methods A case series of 49 NSCLC patients was used to determine the success of extended next-generation sequencing, record genomic alterations, and evaluate clinical utility. Data were collected in a retrospective review. Sequencing was performed using a hybridization capture of 3320 exons from 236 cancer-related genes and 47 introns of 19 genes applied to ≥50 ng of DNA and sequenced to high, uniform coverage of 622 times. Results Sequencing was successful in 29 of 32 (91%) surgical/excisional specimens, and 12 of 17 (71%) nonsurgical specimens including an endoscopic forceps biopsy, core needle biopsies, fine-needle aspirates, and effusion cytologies. All 5 transthoracic core needle biopsies failed. A total of 179 genomic alterations (average 4.37 per tumor) were found. A total of 63 were clinically relevant (average 1.54 per tumor). The most frequently mutated genes were tumor protein p53, cyclin-dependent kinase inhibitor 2A, megalencephalic leukoencephalopathy with subcortical cysts 1, rapamycin-insensitive companion of mammalian target of rapamycin, epithelial growth factor receptor, SWI/SNF Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A, Member 4, cyclin-dependent kinase inhibitor 2B, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α, Kirsten rat sarcoma viral oncogene homolog, Erb-B2 receptor tyrosine kinase 2, Serine/Threonine Kinase 11, and NK2 Homeobox 1. Sequencing results led to a change in management in 7 of 49 cases (14.3%). Conclusion Extended next-generation sequencing was performed successfully in 41 (83.7%) cases of NSCLC using a range of pathology specimens. Testing had the potential to affect treatment decisions in selected patients.

The ability to reliably distinguish synchronous primary non-small-cell lung cancer (NSCLC) from intrapulmonary metastatic spread affects staging and treatment decisions in resected NSCLC. Adjuvant therapy for early-stage NSCLC is complicated and recommendations are primarily based on older data from trials that used now-outdated staging systems. Patients found to have 2 tumors with similar morphology in the same lobe are currently staged as pathologic T3 (pT3) but such cases represent a minority of patients in adjuvant lung cancer trials. Potentially more precise than tumor morphology alone, comprehensive genomic profiling technologies have the power to discriminate whether tumors in the same lobe represent 2 separate primary lesions or localized spread of a single lesion. In addition to lineage insights, tumor profiling simultaneously provides information on actionable genomic alterations. In this review we discuss the data that support the ability of molecular technologies to distinguish synchronous primary tumors from intrapulmonary metastases and discuss the use of molecular assays as an adjunct to current staging systems. Two cases are presented to highlight the potential immediate clinical implications of comprehensive genomic profiling.