Abstract:<p><strong>Objective.</strong> We report a female patient diagnosed with a leiomyosarcoma and who harbored a druggable target as identified by comprehensive genomic profiling in the course of clinical care.</p><p><strong>Case Report.</strong> The patient progressed five years after curative intent surgery and adjuvant treatment. After failure of multiple lines of chemotherapy,she was enrolled in a trial of an ALK inhibitor based on comprehensive genomic profiling (CGP)… Show more
“…An emerging fusion partner of ALK , TNS1 , was recently described in uterine leiomyosarcomas; we observed this fusion in 16 cases (12 cases in uterine and non-uterine LMS) in the current cohort. These results suggest that TNS1-ALK rearrangements are a recurrent fusion in LMS and may require further classification 38 , 39 . Fig.…”
There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas’ molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.
“…An emerging fusion partner of ALK , TNS1 , was recently described in uterine leiomyosarcomas; we observed this fusion in 16 cases (12 cases in uterine and non-uterine LMS) in the current cohort. These results suggest that TNS1-ALK rearrangements are a recurrent fusion in LMS and may require further classification 38 , 39 . Fig.…”
There are more than 70 distinct sarcomas, and this diversity complicates the development of precision-based therapeutics for these cancers. Prospective comprehensive genomic profiling could overcome this challenge by providing insight into sarcomas’ molecular drivers. Through targeted panel sequencing of 7494 sarcomas representing 44 histologies, we identify highly recurrent and type-specific alterations that aid in diagnosis and treatment decisions. Sequencing could lead to refinement or reassignment of 10.5% of diagnoses. Nearly one-third of patients (31.7%) harbor potentially actionable alterations, including a significant proportion (2.6%) with kinase gene rearrangements; 3.9% have a tumor mutational burden ≥10 mut/Mb. We describe low frequencies of microsatellite instability (<0.3%) and a high degree of genome-wide loss of heterozygosity (15%) across sarcomas, which are not readily explained by homologous recombination deficiency (observed in 2.5% of cases). In a clinically annotated subset of 118 patients, we validate actionable genetic events as therapeutic targets. Collectively, our findings reveal the genetic landscape of human sarcomas, which may inform future development of therapeutics and improve clinical outcomes for patients with these rare cancers.
“…The ALK gene partners reported in IMT are TPM3, TPM4, CLTC, RANBP2, SEC31L1, EML4, LMNA, TFG, NF1, PRKAR1A, THBS1, TNS1, NUMA1, LRRFIP1, DCTN1, CARS, KIF5B, and ATIC (3,8,(13)(14)(15)(16)(17)(18). Different ALK fusion detection technologies have their own advantages and disadvantages.…”
BackgroundInflammatory myofibroblastic tumors (IMTs) are rare with distal metastasis. Approximately 50% of patients have anaplastic lymphoma kinase (ALK) fusion. Patients with non-small cell lung cancer with ALK fusion are usually highly sensitive to ALK tyrosine kinase inhibitors (TKIs), but the application of TKI in IMT needs further exploration.Case presentationA 66-year-old man was diagnosed with IMT with bone metastasis, cT4N0M1c, IVB stage. Immunohistochemistry results showed that he was ALK positive, and next-generation sequencing revealed GCC2-ALK fusion in the IMT. The patient was administered first-line ensartinib 225-mg QD, which targeted GCC2-ALK fusion, and denosumab 120-mg Q4w anti-bone metastasis therapy. The patient developed a grade III rash, and the ensartinib dose was reduced to 125 mg QD; consequently, he achieved a partial response (PR), and the side effects significantly reduced. Computed tomography results showed that the patient maintained PR after 7 months of follow-up, and he was still in a state of progression-free survival without obvious side effects after 11 months of follow-up.ConclusionTo our knowledge, this is the first case of the GCC2-ALK fusion type in IMT and the first report showing that the use of ensartinib as a TKI in IMT has clinical benefits.
“…Several cases have been described where a previous diagnosis was revised after discovering an ALK fusion on molecular testing ( Hensley et al, 2020 , Kyi et al, 2021 , Lee et al, 2019 , Zhang et al, 2020 , Testa et al, 2021 ). On review of the literature, this is the third reported case of uterine IMT with an aggressive clinical behavior containing a TNS1-ALK fusion specifically ( Kyi et al, 2021 , Lee et al, 2019 ). This is the second such case treated with alectinib.…”
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