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BACKGROUND: The heterogeneous behavior of patients with melanoma makes prognostication challenging. To address this, a gene expression profile (GEP) test to predict metastatic risk was previously developed. This study evaluates the GEP's prognostic accuracy in an independent cohort of cutaneous melanoma patients. METHODS: This multi-center study analyzed primary melanoma tumors from 523 patients, using the GEP to classify patients as Class 1 (low risk) and Class 2 (high risk). Molecular classification was correlated to clinical outcome and assessed along with AJCC v7 staging criteria. Primary endpoints were recurrence-free (RFS) and distant metastasis-free (DMFS) survival. RESULTS: The 5-year RFS rates for Class 1 and Class 2 were 88% and 52%, respectively, and DMFS rates were 93% versus 60%, respectively (P < 0.001). The GEP was a significant predictor of RFS and DMFS in univariate analysis (hazard ratio [HR] = 5.4 and 6.6, respectively, P < 0.001 for each), along with Breslow thickness, ulceration, mitotic rate, and sentinel lymph node (SLN) status (P < 0.001 for each). GEP, tumor thickness and SLN status were significant predictors of RFS and DMFS in a multivariate model that also included ulceration and mitotic rate (RFS HR = 2.1, 1.2, and 2.5, respectively, P < 0.001 for each; and DMFS HR = 2.7, 1.3 and 3.0, respectively, P < 0.01 for each). CONCLUSIONS: The GEP test is an objective predictor of metastatic risk and provides additional independent prognostic information to traditional staging to help estimate an individual's risk for recurrence. The assay identified 70% of stage I and II patients who ultimately developed distant metastasis. Its role in consideration of patients for adjuvant therapy should be examined prospectively.
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Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica , Melanoma/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Perfilación de la Expresión Génica/estadística & datos numéricos , Humanos , Estimación de Kaplan-Meier , Metástasis Linfática , Melanoma/patología , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/patología , Adulto JovenRESUMEN
BACKGROUND: A significant proportion of patients with American Joint Committee on Cancer (AJCC)-defined early-stage cutaneous melanoma have disease recurrence and die. A 31-gene expression profile (GEP) that accurately assesses metastatic risk associated with primary cutaneous melanomas has been described. OBJECTIVE: We sought to compare accuracy of the GEP in combination with risk determined using the web-based AJCC Individualized Melanoma Patient Outcome Prediction Tool. METHODS: GEP results from 205 stage I/II cutaneous melanomas with sufficient clinical data for prognostication using the AJCC tool were classified as low (class 1) or high (class 2) risk. Two 5-year overall survival cutoffs (AJCC 79% and 68%), reflecting survival for patients with stage IIA or IIB disease, respectively, were assigned for binary AJCC risk. RESULTS: Cox univariate analysis revealed significant risk classification of distant metastasis-free and overall survival (hazard ratio range 3.2-9.4, P < .001) for both tools. In all, 43 (21%) cases had discordant GEP and AJCC classification (using 79% cutoff). Eleven of 13 (85%) deaths in that group were predicted as high risk by GEP but low risk by AJCC. LIMITATIONS: Specimens reflect tertiary care center referrals; more effective therapies have been approved for clinical use after accrual. CONCLUSIONS: The GEP provides valuable prognostic information and improves identification of high-risk melanomas when used together with the AJCC online prediction tool.
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Melanoma/genética , Melanoma/secundario , Recurrencia Local de Neoplasia/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Transcriptoma , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Tasa de Supervivencia , Adulto JovenRESUMEN
The transforming growth factor beta (TGFB) protein family is renowned for its diverse roles in developmental biology including reproduction. Gremlin is a member of the differential screening-selected gene aberrative in neuroblastoma (DAN)/cerberus family of bone morphogenetic protein (BMP) antagonists. Recent studies on gremlin focus on its involvement in embryonic skeletal, lung, and kidney development. To define the role of gremlin (Grem1) in female reproduction, we analyzed postnatal folliculogenesis using global and conditional knockout (cKO) mice for gremlin. Grem1(-/-) mice die within 48 h after birth, and ovaries collected from neonatal Grem1(-/-) mice demonstrated reduced oocyte numbers and delayed primordial follicle development. Transplanting Grem1(-/-) neonatal ovaries showed that folliculogenesis proceeded to large antral follicle stage, but Grem1(-/-) ovaries contained corpora lutea-like structures not found in control-transplanted ovaries. However, Grem1 cKO mice had comparable fertility to control mice. These data suggest that gremlin plays a previously uncharacterized role in the regulation of oocyte numbers and the timing of primordial follicle development, but either it is not required for later folliculogenesis or its loss is possibly compensated by other BMP antagonists.
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Fertilidad , Péptidos y Proteínas de Señalización Intercelular/fisiología , Folículo Ovárico/crecimiento & desarrollo , Animales , Animales Recién Nacidos , Citocinas , Femenino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovario/citología , Ovario/metabolismo , Proteínas/metabolismoRESUMEN
Targeted disruption of the inhibin alpha gene (Inha(-)(/)(-)) in mice results in an ovarian phenotype of granulosa cell tumors that renders the animals infertile. Little is known about the reproductive defects prior to tumor development. Here, we report novel data on early follicle dynamics in Inha(-)(/)(-) mice, which demonstrate that inhibin alpha has important consequences upon follicle development. Morphological changes in both germ and somatic cells were evident in postnatal day 12 ovaries, with Inha(-/-) mice exhibiting numerous multilayered follicles that were far more advanced than those observed in age-matched controls. These changes were accompanied by alterations in follicle dynamics such that Inha(-/-) ovaries had fewer follicles in the resting pool and more committed in the growth phase. Absence of inhibin alpha resulted in advanced follicular maturation as marked by premature loss of anti-Müllerian hormone (AMH) in secondary follicles. Additionally, gene expression analysis revealed changes in factors known to be vital for oocyte and follicle development. Together, these data provide key evidence to suggest that regulation of the inhibin/activin system is essential for early folliculogenesis in the prepubertal mouse ovary.
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Tumor de Células de la Granulosa/genética , Células de la Granulosa/patología , Inhibinas/deficiencia , Oocitos/patología , Folículo Ovárico/patología , Neoplasias Ováricas/genética , Factores de Edad , Animales , Aromatasa/biosíntesis , Aromatasa/genética , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/genética , Femenino , Hormona Folículo Estimulante/sangre , Regulación de la Expresión Génica , Tumor de Células de la Granulosa/patología , Inhibinas/genética , Inhibinas/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Folículo Ovárico/fisiopatología , Neoplasias Ováricas/patología , Receptores de HFE/biosíntesis , Receptores de HFE/genética , Maduración SexualRESUMEN
BACKGROUND: We report the performance of a gene expression profile test to classify the recurrence risk of cutaneous melanoma tumors of the head and neck as low-risk Class 1 or high-risk Class 2. METHODS: Of note, 157 primary head and neck cutaneous melanoma tumors were identified. Survival analyses were performed using Kaplan-Meier and Cox methods. RESULTS: Gene expression profile class and node status stratified tumors into significantly different 5-year survival groups by Kaplan-Meier method (P < .0001 for all end points), and both were independent predictors of recurrence in multivariate analysis. Overall, 74% of distant metastases and 88% of melanoma-specific deaths had Class 2 risk. CONCLUSION: The gene expression profile test identifies cases at increased risk for metastasis and death independent of a clinically or pathologically negative nodal status, suggesting that incorporation of this molecular tool could improve clinical management of patients with head and neck cutaneous melanoma, especially in those with a negative sentinel lymph node biopsy.
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Perfilación de la Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Ganglios Linfáticos/patología , Melanoma/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Supervivencia sin Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Humanos , Estimación de Kaplan-Meier , Escisión del Ganglio Linfático/métodos , Ganglios Linfáticos/cirugía , Metástasis Linfática , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica/patología , Estadificación de Neoplasias , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Medición de Riesgo , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Análisis de Supervivencia , Estados UnidosRESUMEN
BACKGROUND: The DecisionDx-Melanoma test provides prognostic information for patients with cutaneous melanoma (CM). Using formalin-fixed paraffin-embedded primary tumor tissue, the RT-PCR-based test classifies patients into a low- (Class 1) or high-risk (Class 2) category for recurrence based on expression of 31 genes. The current study was designed to assess the analytical validity of this test. METHODS: Inter-assay, inter-instrument, and inter-operator studies were performed to evaluate reliability of the 31-gene expression test results, sample stability and reagent stability. From March 2013 through June 2016, the gene expression test was performed on 8244 CM tumors. De-identified data from Pathology Reports were used to assess technical success. RESULTS: Robust sample and reagent stability was observed. Inter-assay concordance on 168 specimens run on 2 consecutive days was 99% and matched probability scores were significantly correlated (R2 = 0.96). Inter-instrument concordance was 95%, and probability scores had a correlation R2 of 0.99 (p < 0.001). From 8244 CM specimens submitted since 2013, 85% (7023) fulfilled pre-specified tumor content parameters. In these samples with sufficient tumor requirements, the technical success of the test was 98%. CONCLUSION: DecisionDx-Melanoma is a robust gene expression profile test that demonstrates strong reproducibility between experiments and has high technical reliability on clinical samples.
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Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Melanoma/genética , Metástasis de la Neoplasia/genética , Perfilación de la Expresión Génica/métodos , Humanos , Melanoma/patología , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Factores de Riesgo , Transcriptoma/genéticaRESUMEN
BACKGROUND: A 31-gene expression profile (GEP) test that provides risk classification of cutaneous melanoma (CM) patients has been validated in several retrospective studies. The objective of the reported study was a prospective evaluation of the GEP performance in patients enrolled in two clinical registries. METHODS: Three-hundred twenty two CM patients enrolled in the EXPAND (NCT02355587) and INTEGRATE (NCT02355574) registries met the criteria of age ≥ 16 years, successful GEP result and ≥1 follow-up visit for inclusion in this interim analysis. Primary endpoints were recurrence-free (RFS), distant metastasis-free (DMFS), and overall survival (OS). RESULTS: Median follow-up was 1.5 years for event-free patients. Median age for subjects was 58 years (range 18-87) and median Breslow thickness was 1.2 mm (range 0.2-12.0). Eighty-eight percent (282/322) of cases had stage I/II disease and 74% (237/322) had a SLN biopsy. Seventy-seven percent (248/322) had class 1 molecular profiles. 1.5-year RFS, DMFS, and OS rates were 97 vs. 77%, 99 vs. 89%, and 99 vs. 92% for class 1 vs. class 2, respectively (p < 0.0001 for each). Multivariate Cox regression showed Breslow thickness, mitotic rate, and GEP class to significantly predict recurrence (p < 0.01), while tumor thickness was the only significant predictor of distant metastasis and overall survival in this interim analysis. CONCLUSIONS: Interim analysis of patient outcomes from a combined prospective cohort supports the 31-gene GEP's ability to stratify early-stage CM patients into two groups with significantly different metastatic risk. RFS outcomes in this real-world cohort are consistent with previously published analyses with retrospective specimens. GEP testing complements current clinicopathologic features and increases identification of high-risk patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02355574 and NCT02355587.
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Perfilación de la Expresión Génica/métodos , Melanoma/genética , Neoplasias Cutáneas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Humanos , Masculino , Melanoma/mortalidad , Melanoma/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Pronóstico , Estudios Prospectivos , Sistema de Registros , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Adulto Joven , Melanoma Cutáneo MalignoRESUMEN
Uveal melanoma management is challenging due to its metastatic propensity. DecisionDx-UM is a prospectively validated molecular test that interrogates primary tumor biology to provide objective information about metastatic potential that can be used in determining appropriate patient care. To evaluate the continued clinical validity and utility of DecisionDx-UM, beginning March 2010, 70 patients were enrolled in a prospective, multicenter, IRB-approved study to document patient management differences and clinical outcomes associated with low-risk Class 1 and high-risk Class 2 results indicated by DecisionDx-UM testing. Thirty-seven patients in the prospective study were Class 1 and 33 were Class 2. Class 1 patients had 100% 3-year metastasis-free survival compared to 63% for Class 2 (log rank test p = 0.003) with 27.3 median follow-up months in this interim analysis. Class 2 patients received significantly higher-intensity monitoring and more oncology/clinical trial referrals compared to Class 1 patients (Fisher's exact test p = 2.1 × 10(-13) and p = 0.04, resp.). The results of this study provide additional, prospective evidence in an independent cohort of patients that Class 1 and Class 2 patients are managed according to the differential metastatic risk indicated by DecisionDx-UM. The trial is registered with Clinical Application of DecisionDx-UM Gene Expression Assay Results (NCT02376920).
RESUMEN
OBJECTIVE: DecisionDx-Melanoma * is a 31-gene expression profile test that predicts the risk of metastasis in patients with primary cutaneous melanoma (CM). This study was designed to ascertain clinical management changes determined by the test outcome, which classifies CM patients being at low (Class 1) or high (Class 2) risk for recurrence. RESEARCH DESIGN AND METHODS: Medical charts were reviewed from 156 CM patients from six institutions (three dermatology and three surgical oncology practices) who were consecutively tested between May 2013 and December 2015. Clinical management data that were compiled and compared before and after receipt of the 31-gene expression test result included frequency of physical exams, frequency and modality of imaging, and referrals to surgical and medical oncologists. RESULTS: Forty-two percent of patients were Stage I, 47% were Stage II and 8% were Stage III. Overall, 95 patients (61%) were Class 1 and 61 (39%) were Class 2. Documented changes in management were observed in 82 (53%) patients, with the majority of Class 2 patients (77%) undergoing management changes compared to 37% of Class 1 patients (p < 0.0001 by Fisher's exact test). The majority (77/82, 94%) of these changes were concordant with the risk indicated by the test result (p < 0.0001 by Fisher's exact test), with increased management intensity for Class 2 patients and reduced management intensity for Class 1 patients. CONCLUSIONS: Molecular risk classification by gene expression profiling has clinical impact and influences physicians to direct clinical management of CM patients. The vast majority of the changes implemented after the receipt of test results were reflective of the low or high recurrence risk associated with the patient's molecular classification. Because follow-up data was not collected for this patient cohort, the study is limited for the assessment of the impact of gene expression profile based management changes on healthcare resource utilization and patient outcome.
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Perfilación de la Expresión Génica/métodos , Melanoma , Técnicas de Diagnóstico Molecular/métodos , Neoplasias Cutáneas , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/epidemiología , Melanoma/genética , Melanoma/metabolismo , Melanoma/patología , Persona de Mediana Edad , Estudios Prospectivos , Riesgo , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología , Melanoma Cutáneo MalignoRESUMEN
BACKGROUND: Clinical outcomes of patients with chronic myeloid leukemia (CML) treated in clinical trials, including response to therapy, may not be representative of those treated in a community setting. Thus, we sought to determine the real-world effectiveness of first-line tyrosine kinase inhibitors in CML by evaluating response rates, all-cause discontinuation, and adherence. Response monitoring patterns were also analyzed. PATIENTS AND METHODS: This retrospective observational study, using the McKesson Specialty Health/US Oncology Network (MSH/USON) iKnowMed electronic health record database and medical charts, identified newly diagnosed CML patients who received first-line imatinib, dasatinib, or nilotinib from July 2007 to March 2011, and were then followed for ≥ 18 months. RESULTS: Three hundred patients met study criteria (222 imatinib-treated, 34 dasatinib-treated, and 44 nilotinib-treated in the first-line). Molecular and cytogenetic response assessments were conducted less frequently than recommended (40% never had cytogenetic or molecular monitoring at any time). Patients treated with either dasatinib or nilotinib experienced higher response rates by 6, 12, and 18 months, faster time to major molecular response, and a significantly lower rate of all-cause treatment discontinuation within 18 months relative to imatinib-treated patients. Approximately 56% of all patients were adherent to tyrosine kinase inhibitor therapy. CONCLUSION: Dasatinib and nilotinib were more effective than imatinib as first-line therapy for CML in a community setting, as observed in descriptive and univariate analyses. The frequency of cytogenetic and molecular monitoring was lower than that recommended by current guidelines, including patients with no molecular or cytogenetic assessments during the 18-month follow-up. Therefore, MSH/USON is working toward improving compliance with response monitoring guidelines.
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Antineoplásicos/uso terapéutico , Dasatinib/uso terapéutico , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Adolescente , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Leucemia Mielógena Crónica BCR-ABL Positiva/mortalidad , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Inhibin-α knockout (Inha-/-) female mice develop sex cord-stromal ovarian cancer with complete penetrance and previous studies demonstrate that the pituitary gonadotropins (FSH and LH) are influential modifiers of granulosa cell tumor development and progression in inhibin-deficient females. Recent studies have demonstrated that Inha-/- ovarian follicles develop precociously to the early antral stage in prepubertal mice without any increase in serum FSH. These studies suggest that in the absence of inhibins, granulosa cells differentiate abnormally and thus at sexual maturity may undergo an abnormal response to gonadotropin signaling contributing to tumor development. To test this hypothesis, we stimulated immature wild-type and Inha-/- female mice with gonadotropin analogs prior to tumor formation and subsequently examined gonadotropin-induced ovarian follicle development as well as preovulatory and human chorionic gonadotropin-induced gene expression changes in granulosa cells. We find that at 3 wk of age, inhibin-deficient ovaries do not show further antral development or undergo cumulus expansion. In addition, there are widespread alterations in the transcriptome of gonadotropin-treated Inha-/- granulosa cells, with significant changes in genes involved in extracellular matrix and cell-cell communication. These data indicate the gonadotropins initiate an improper program of cell differentiation prior to tumor formation in the absence of inhibins.
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Regulación de la Expresión Génica/efectos de los fármacos , Gonadotropinas/farmacología , Células de la Granulosa/efectos de los fármacos , Inhibinas/genética , Folículo Ovárico/efectos de los fármacos , Folículo Ovárico/fisiología , Animales , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Femenino , Perfilación de la Expresión Génica , Células de la Granulosa/metabolismo , Inhibinas/deficiencia , Ratones , Ratones Noqueados , Análisis de Secuencia por Matrices de Oligonucleótidos , Folículo Ovárico/metabolismo , Ovario/crecimiento & desarrollo , Ovario/metabolismo , Ovulación/efectos de los fármacos , Ovulación/genética , Ovulación/metabolismo , Ovulación/fisiología , Estudios de Validación como AsuntoRESUMEN
Granulosa cell tumors (GCTs) of the ovary are rare sex cord stromal tumors. Although generally indolent, GCTs recur, and if not diagnosed and treated in early stages, survival rates are significantly shortened. Very little is known regarding GCT etiology. Because of the low incidence of cases and lack of standard diagnostics, mouse models for granulosa cell tumors are a valuable tool for studying GCTs and provide models for developing diagnostic and treatment strategies. We recently developed a novel mouse model of metastatic granulosa cell tumors by genetic deletion of the bone morphogenetic protein signaling transcription factors (SMADs) in granulosa cells of the ovary. Histological and serum hormone analyses reveal that this mouse model most closely resembles the juvenile form of GCT. We further analyzed samples of human juvenile GCT (JGCT) for expression of anti-Müllerian hormone and activation of two major signaling pathways: TGFbeta/SMAD2/3 and wingless-related mouse mammary tumor virus integration site (Wnt)/beta-catenin. The TGFbeta family is active in mouse Smad1-Smad5 double knockout tumors, and here we show that this pathway, but not the beta-catenin pathway, is activated in samples of human JGCT. These data suggest that the SMAD family, possibly through disruption of SMAD1/5 or activation of SMAD2/3 may contribute to the pathogenesis of JGCT in humans.