RESUMEN
Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, the tumors demonstrated multinodular growth of cytologically uniform, ovoid-to-epithelioid, occasionally short spindled cells with delicate intratumoral vasculature and frequent myxoid stroma. Mitotic activity ranged from 0 to 8 mitoses/2 mm2 (mean 2). Lymphovascular invasion/protrusion of tumor cells into endothelial-lined vascular spaces was present or suspected in 6 cases. Necrosis, significant nuclear pleomorphism, or well-developed, fascicular spindle-cell growth were absent. Half demonstrated features of the newly proposed subset, "distinctive nested glomoid neoplasm." Tumors were consistently positive for CD56 (n = 5/5). A subset was stained with S100 protein (n = 7/13), SMA (n = 6/13), keratin (n = 2/9), EMA (n = 3/7), and CD99 (n = 2/6). Tumors harbored ACTB::GLI1 (n = 15) or PTCH1::GLI1 (n = 1) fusions. The assays used did not capture cases defined by GLI1 amplification. We also identified recurrent cytogenetic gains (1q, 5, 7, 8, 12, 12q13.2-ter, 21, and X). For patients with available clinical follow-up (n = 8), half were disease free. Half demonstrated distant metastases (lungs, bone, or soft tissue). Of cases without follow-up (n = 8), 2 were known recurrences, and 1 was presumed metastasis. Our results imply a more aggressive biological potential than currently reported. Given the possibility for metastasis and disease progression, even in cytologically bland, nested tumors, close clinical surveillance, akin to that for sarcoma management, may be indicated. The term GLI1-altered mesenchymal tumor with malignant potential is proposed.
Asunto(s)
Neoplasias de los Tejidos Conjuntivo y Blando , Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Proteína con Dedos de Zinc GLI1/genética , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/patología , Proteínas S100 , Sarcoma/patología , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisisRESUMEN
Activation of the tyrosine kinase receptor IGF1R is targetable with existing tyrosine kinase inhibitors (TKIs) and monoclonal antibodies, but mutations in IGF1R have not been systematically characterized. Pan-cancer analysis of 326,911 tumors identified two distinct, activating non-frameshift insertion hotspots in IGF1R, which were significantly enriched in adenoid cystic carcinomas (ACCs). IGF1R alterations from 326,911 subjects were analyzed by variant effect prediction class, position within the gene, and cancer type. 6502 (2.0%) samples harbored one or more alterations in IGF1R. Two regions were enriched for non-frameshift insertions: codons 663-666 at the hinge region of the fibronectin type 3 domain and codons 1034-1049 in the tyrosine kinase domain. Hotspot insertions were highly enriched in ACCs (27.3-fold higher than in the remainder of the pan-cancer dataset; P = 2.3 × 10-17). Among salivary gland tumors, IGF1R hotspot insertions were entirely specific to ACCs. IGF1R alterations were most often mutually exclusive with other ACC drivers (9/15, 60%). Tumors with non-frameshift hotspot IGF1R insertions represent a novel, potentially targetable subtype of ACC. Additional studies are needed to determine whether these patients respond to existing IGF1R inhibitors.
Asunto(s)
Carcinoma Adenoide Quístico , Neoplasias de las Glándulas Salivales , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Fibronectinas , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Inhibidores de Proteínas Quinasas , Anticuerpos Monoclonales , Receptor IGF Tipo 1/genéticaRESUMEN
BACKGROUND: Trastuzumab with cisplatin and fluoropyrimidine is the standard treatment in metastatic HER2-positive gastric or gastroesophageal (GE) junction adenocarcinoma; however, there is limited data on the efficacy of trastuzumab in combination with a three-drug regimen in this setting. We examined the efficacy and safety of modified docetaxel, cisplatin and 5 fluorouracil (mDCF) plus trastuzumab in a single-arm multicenter phase II trial. METHODS: Previously untreated patients with HER2-positive metastatic gastric or GE junction adenocarcinoma were treated with mDCF and trastuzumab every 2 weeks. The primary endpoint was 6-month progression-free survival (PFS); secondary endpoints included objective response rate, overall survival (OS), and toxicity. RESULTS: We enrolled 26 patients with metastatic HER2-positive gastric or GE junction adenocarcinoma between February 2011 and June 2015. The median age of patients was 62 years; 96% had a Karnofsky performance status equal to or greater than 80%. With a median follow-up of 25.4 months, the 6-month PFS was 73% (95% CI 51-86%). The objective response rate was 65%, the median PFS was 13 months (95% CI 6.4-20.7) and the median OS was 24.9 months (95% CI 14.4-42.5). Grade 3/4 toxicities included neutropenia (42%), fatigue (23%), and hypophosphatemia (15%). There were no episodes of febrile neutropenia. CONCLUSION: The combination of mDCF and trastuzumab is effective and safe in patients with metastatic HER2-positive gastric or GE junction adenocarcinoma and can be considered as an option for selected patients. This trial is registered at ClinicalTrials.gov, number NCT00515411.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Trastuzumab/administración & dosificación , Adenocarcinoma/mortalidad , Adulto , Anciano , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Docetaxel/administración & dosificación , Docetaxel/efectos adversos , Unión Esofagogástrica/patología , Femenino , Fluorouracilo/administración & dosificación , Humanos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Receptor ErbB-2/biosíntesis , Neoplasias Gástricas/mortalidad , Trastuzumab/efectos adversosRESUMEN
CONTEXT.: Multiple procedural techniques can be used to obtain tissue to create a formalin-fixed, paraffin-embedded specimen for comprehensive genomic profiling (CGP) in lung cancer. The literature is mixed on whether the procedure affects CGP success. OBJECTIVE.: To examine whether biopsy procedure affects lung cancer CGP success. DESIGN.: This was a cross-sectional study of all patients with lung cancer whose specimens were submitted for CGP between January and February 2020. Multiple quality control metrics were used to determine whether cases were successfully profiled. RESULTS.: In all, 3312 samples were identified. Overall, 67.5% (2236 of 3312) of samples were obtained from biopsies, 13.0% (432 of 3312) from fine-needle aspirations (FNAs), 9.7% (321 of 3312) from resections, 5.3% (174 of 3312) from fluid cytology cell blocks, and 4.5% (149 of 3312) from bone biopsies. Overall, 70.1% (2321 of 3312) of cases passed CGP, 15.4% (510 of 3312) of cases were released as qualified reports, and 14.5% (481 of 3312) of cases failed CGP. Resection samples were the most likely to be successfully sequenced, failing in only 2.8% (9 of 321) of instances, while fluid cytology specimens were the least likely, failing in 23.0% (40 of 174) of instances. Biopsy (14.5% [324 of 2236]), FNA (18.5% [80 of 432]), and bone biopsy (18.8% [28 of 149]) specimens failed at intermediate frequencies. On multivariate logistic regression analysis of CGP success on specimen type, fluid cytology (odds ratio [OR], 0.08; 95% CI, 0.03-0.19), biopsy (OR, 0.25; 95% CI, 0.11-0.52), FNA (OR, 0.14; 95% CI, 0.06-0.32), and bone biopsy (OR, 0.07; 95% CI, 0.03-0.17) specimens had decreased odds of CGP success relative to resection samples. Among patients with successfully sequenced samples, 48.0% were eligible for at least 1 therapy, based on a companion diagnostic or National Comprehensive Cancer Network biomarker. CONCLUSIONS.: The method of tissue acquisition was an important preanalytic factor that determined whether a sample would be successfully sequenced and whether a clinically actionable genomic alteration would be detected.
Asunto(s)
Neoplasias Pulmonares , Humanos , Estudios Transversales , Neoplasias Pulmonares/diagnóstico , Biopsia con Aguja Fina , Genómica , CitodiagnósticoRESUMEN
Neuroblastoma evolution, heterogeneity, and resistance remain inadequately defined, suggesting a role for circulating tumor DNA (ctDNA) sequencing. To define the utility of ctDNA profiling in neuroblastoma, 167 blood samples from 48 high-risk patients were evaluated for ctDNA using comprehensive genomic profiling. At least one pathogenic genomic alteration was identified in 56% of samples and 73% of evaluable patients, including clinically actionable ALK and RAS-MAPK pathway variants. Fifteen patients received ALK inhibition (ALKi), and ctDNA data revealed dynamic genomic evolution under ALKi therapeutic pressure. Serial ctDNA profiling detected disease evolution in 15 of 16 patients with a recurrently identified variant-in some cases confirming disease progression prior to standard surveillance methods. Finally, ctDNA-defined ERRFI1 loss-of-function variants were validated in neuroblastoma cellular models, with the mutant proteins exhibiting loss of wild-type ERRFI1's tumor-suppressive functions. Taken together, ctDNA is prevalent in children with high-risk neuroblastoma and should be followed throughout neuroblastoma treatment. SIGNIFICANCE: ctDNA is prevalent in children with neuroblastoma. Serial ctDNA profiling in patients with neuroblastoma improves the detection of potentially clinically actionable and functionally relevant variants in cancer driver genes and delineates dynamic tumor evolution and disease progression beyond that of standard tumor sequencing and clinical surveillance practices. See related commentary by Deubzer et al., p. 2727. This article is highlighted in the In This Issue feature, p. 2711.
Asunto(s)
ADN Tumoral Circulante , Neuroblastoma , Niño , Humanos , ADN Tumoral Circulante/genética , Mutación , Genómica/métodos , Neuroblastoma/genética , Progresión de la Enfermedad , Proteínas Tirosina Quinasas Receptoras/genética , Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
PURPOSE: Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC. EXPERIMENTAL DESIGN: Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT-targeted sequencing, outcomes were correlated with tumor genomic features. RESULTS: One-hundred sixty-one patients were treated with ICIs (110 with anti-PD-1/PD-L1 antibodies and 51 with anti-CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1-positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed. CONCLUSIONS: In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.