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BACKGROUND: Lymph node invasion is associated with poor outcome in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with RCC within a single center from 2001 to 2018 were retrospectively obtained from the Chang Gung Research Database. Patient gender, physical status, Charlson Comorbidity Index, tumor side, histology, age at diagnosis, and body mass index (BMI) were compared. The overall survival (OS) and cancer-specific survival (CSS) of each group were estimated using the Kaplan-Meier method. Log-rank tests were used to compare between the subgroups. RESULTS AND CONCLUSIONS: A total of 335 patients were enrolled, of whom 76 had pT3N0M0, 29 had pT1-3N1M0, 104 had T1-4N0M1, and 126 had T1-4N1M1 disease. Significant OS difference was noted between pT3N0M0 and pT1-3N1M0 groups with 12.08 years [95% confidence interval (CI), 8.33-15.84] versus 2.58 years (95% CI, 1.32-3.85), respectively (P < 0.005). No significant difference was observed in OS between pT1-3N1M0 and T1-4N0M1 groups with 2.58 years (95% CI, 1.32-3.85) versus 2.50 years (95% CI, 1.85-3.15, P = 0.72). The OS of N1M1 group was worse than that of N0M1 group with 1.00 year (95% CI, 0.74-1.26) versus 2.50 years (95% CI, 1.85-3.15, P < 0.05). Similar results were also observed in CSS. In summary, we claim that RCC with lymph node (LN) invasion should be reclassified as stage IV disease in terms of survival outcome.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/cirurgia , Neoplasias Renais/cirurgia , Estudos Retrospectivos , Prognóstico , Linfonodos/cirurgia , Linfonodos/patologia , Estadiamento de NeoplasiasRESUMO
Immune checkpoint blockade (ICB) has revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by immune-related adverse events (irAEs). Limited understanding of irAE mechanisms hampers development of approaches to mitigate their damage. To address this, we examined whether mice gained sensitivity to anti-CTLA-4 (αCTLA-4)-mediated toxicity upon disruption of gut homeostatic immunity. We found αCTLA-4 drove increased inflammation and colonic tissue damage in mice with genetic predisposition to intestinal inflammation, acute gastrointestinal infection, transplantation with a dysbiotic fecal microbiome, or dextran sodium sulfate administration. We identified an immune signature of αCTLA-4-mediated irAEs, including colonic neutrophil accumulation and systemic interleukin-6 (IL-6) release. IL-6 blockade combined with antibiotic treatment reduced intestinal damage and improved αCTLA-4 therapeutic efficacy in inflammation-prone mice. Intestinal immune signatures were validated in biopsies from patients with ICB colitis. Our work provides new preclinical models of αCTLA-4 intestinal irAEs, mechanistic insights into irAE development, and potential approaches to enhance ICB efficacy while mitigating irAEs.
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Colite , Interleucina-6 , Camundongos , Animais , Qualidade de Vida , Colite/patologia , Imunoterapia , InflamaçãoRESUMO
A stem cell theory of cancer considers genetic makeup in the proper cellular context. It is a unified theory of cancer that unites the genome with the epigenome, links the intracellular with the extracellular, and connects the cellular constituents and compartments with the microenvironment. Although it allies with genomic medicine, it is better aligned with integrated medicine. In this perspective, we focus on translational research in cancer care. We expose some intrinsic fallacies in translational research when it relates to the basic principles of the scientific method in the care of patients with genomic medicine versus integrated medicine. We postulate that genomic medicine may be at the root of many failed efforts in drug development and data reproducibility. We propose an alternate heuristic approach that may expedite the development of safe and effective treatments and minimize the generation of unproductive pharmaceutical products and nonreproducible experimental results. Importantly, a heuristic approach emphasizes the role of a pertinent scientific theory and distinguishes therapy development from drug development, such that we discover not only useful drugs but also better ways to use them in order to optimize patient care and maximize clinical outcomes.
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BACKGROUND: Recently, we showed that melanoma brain metastases (MBMs) are characterized by increased utilization of the oxidative phosphorylation (OXPHOS) metabolic pathway compared to melanoma extracranial metastases (ECMs). MBM growth was inhibited by a potent direct OXPHOS inhibitor, but observed toxicities support the need to identify alternative therapeutic strategies. Thus, we explored the features associated with OXPHOS to improve our understanding of the pathogenesis and potential therapeutic vulnerabilities of MBMs. METHODS: We applied an OXPHOS gene signature to our cohort of surgically resected MBMs that had undergone RNA-sequencing (RNA-seq) (n = 88). Clustering by curated gene sets identified MBMs with significant enrichment (High-OXPHOS; n = 21) and depletion (Low-OXPHOS; n = 25) of OXPHOS genes. Clinical data, RNA-seq analysis, and immunohistochemistry were utilized to identify significant clinical, molecular, metabolic, and immune associations with OXPHOS in MBMs. Preclinical models were used to further compare melanomas with High- and Low-OXPHOS and for functional validation. RESULTS: High-OXPHOS MBMs were associated with shorter survival from craniotomy compared to Low-OXPHOS MBMs. High-OXPHOS MBMs exhibited an increase in glutamine metabolism, and treatment with the glutaminase inhibitor CB839 improved survival in mice with MAPKi-resistant, High-OXPHOS intracranial xenografts. High-OXPHOS MBMs also exhibited a transcriptional signature of deficient immune activation, which was reversed in B16-F10 intracranial tumors with metformin treatment, an OXPHOS inhibitor. CONCLUSIONS: OXPHOS is associated with distinct clinical, molecular, metabolic, and immune phenotypes in MBMs. These associations suggest rational therapeutic strategies for further testing to improve outcomes in MBM patients.
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Although genetic changes may be pivotal in the origin of cancer, cellular context is paramount. This is particularly relevant in a progenitor germ cell tumor and its differentiated mature teratoma counterpart when it concerns tumor heterogeneity and cancer dormancy in subsequent second malignancies (subsequent malignant neoplasms (SMNs)). From our tumor registry database, we identified 655 testicular germ cell tumor (TGCT) patients who developed SMNs between January 1990 and September 2018. Of the 113 solid organ SMNs, 42 had sufficient tumor tissue available for fluorescence in situ hybridization (FISH) analysis of isochromosome 12p [i(12p)]. We identified seven additional patients for targeted DNA and RNA sequencing of teratomas and adjacent somatic transformation. Finally, we established cell lines from freshly resected post-chemotherapy teratomas and evaluated the cells for stemness expression by flow cytometry and by the formation of teratomas in a xenograft model. In our cohort, SMNs comprising non-germ cell tumors occurred about 18 years after a diagnosis of TGCT. Of the 42 SMNs examined, 5 (12%) contained i(12p) and 16 (38%) had 12p gain. When comparing a teratoma and adjacent somatic transformation, targeted DNA and RNA sequencing demonstrated high concordance. Studies of post-chemotherapy teratoma-derived cell lines revealed cancer-initiating cells expressing multipotency as well as early differentiation markers. For the first time, we demonstrated the prevalence of i(12p) in SMNs and the presence of progenitor cells embedded within mature teratomas after chemotherapy. Our findings suggest a progenitor stem-like cell of origin in SMN and TGCT and highlight the importance of cellular context in this disease.
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Elevated serum lactate dehydrogenase (sLDH) is associated with poor clinical outcomes in patients with stage IV metastatic melanoma (MM). It is currently unknown if sLDH elevation correlates with distinct molecular, metabolic, or immune features of melanoma metastases. The identification of such features may identify rational therapeutic strategies for patients with elevated sLDH. Thus, we obtained sLDH levels for melanoma patients with metastases who had undergone molecular and/or immune profiling. Our analysis of multi-omics data from independent cohorts of melanoma metastases showed that elevated sLDH was not significantly associated with differences in immune cell infiltrate, point mutations, DNA copy number variations, promoter methylation, RNA expression, or protein expression in melanoma metastases. The only significant association observed for elevated sLDH was with the number of metastatic sites of disease. Our data support that sLDH correlates with disease burden, but not specific molecular or immunological phenotypes, in metastatic melanoma.
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Biomarcadores Tumorais/sangue , L-Lactato Desidrogenase/sangue , Melanoma/sangue , Neoplasias Cutâneas/sangue , Biomarcadores Tumorais/genética , Bases de Dados de Ácidos Nucleicos , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Melanoma/genética , Melanoma/imunologia , Melanoma/secundário , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Análise Serial de Tecidos , Regulação para CimaRESUMO
There is a critical need to improve our understanding of the pathogenesis of melanoma brain metastases (MBM). Thus, we performed RNA sequencing on 88 resected MBMs and 42 patient-matched extracranial metastases; tumors with sufficient tissue also underwent whole-exome sequencing, T-cell receptor sequencing, and IHC. MBMs demonstrated heterogeneity of immune infiltrates that correlated with prior radiation and post-craniotomy survival. Comparison with patient-matched extracranial metastases identified significant immunosuppression and enrichment of oxidative phosphorylation (OXPHOS) in MBMs. Gene-expression analysis of intracranial and subcutaneous xenografts, and a spontaneous MBM model, confirmed increased OXPHOS gene expression in MBMs, which was also detected by direct metabolite profiling and [U-13C]-glucose tracing in vivo. IACS-010759, an OXPHOS inhibitor currently in early-phase clinical trials, improved survival of mice bearing MAPK inhibitor-resistant intracranial melanoma xenografts and inhibited MBM formation in the spontaneous MBM model. The results provide new insights into the pathogenesis and therapeutic resistance of MBMs. SIGNIFICANCE: Improving our understanding of the pathogenesis of MBMs will facilitate the rational development and prioritization of new therapeutic strategies. This study reports the most comprehensive molecular profiling of patient-matched MBMs and extracranial metastases to date. The data provide new insights into MBM biology and therapeutic resistance.See related commentary by Egelston and Margolin, p. 581.This article is highlighted in the In This Issue feature, p. 565.
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Neoplasias Encefálicas/secundário , Linfócitos do Interstício Tumoral/imunologia , Melanoma/imunologia , Melanoma/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/metabolismo , Estudos de Coortes , Modelos Animais de Doenças , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma/tratamento farmacológico , Melanoma/patologia , Análise do Fluxo Metabólico , Metaboloma , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Fosforilação Oxidativa , Análise de Sequência de RNA/métodos , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Background: Bone is the most common site of metastasis of breast cancer. Biological mechanisms of metastasis to bone may be different from mechanisms of metastasis to non-bone sites, and identification of distinct signaling pathways and somatic mutations may provide insights on biology and rational targets for treatment and prevention of bone metastasis. The aims of this study were to compare and contrast somatic mutations, clinicopathologic characteristics, and survival in breast cancer patients with bone-only versus non-bone sites of first metastasis. Methods: Primary tumor samples were collected before treatment from 389 patients with untreated primary breast cancer and distant metastasis at diagnosis. In each sample, 46 or 50 cancer-related genes were analyzed for mutations by AmpliSeq Ion Torrent next-generation sequencing. Fisher's exact test was used to identify somatic mutations associated with bone-only first metastasis. Logistic regression models were used to identify differences in detected somatic mutations, clinicopathologic characteristics, and survival between patients with bone-only first metastasis and patients with first metastasis in non-bone sites only ("other-only first metastasis"). Results: Among the 389 patients, 72 (18.5%) had bone-only first metastasis, 223 (57.3%) had other-only first metastasis, and 94 (24.2%) had first metastasis in both bone and non-bone sites. The most commonly mutated genes were TP53 (N=103), PIK3CA (N=79), AKT (N=13), and PTEN (N=2). Compared to patients with other-only first metastasis, patients with bone-only first metastasis had higher rates of hormone-receptor-positive disease, non-triple-negative subtype, and lower grade (grade 1 or 2; Nottingham grading system) (all three comparisons, p<0.001); had a lower ratio of cases of invasive ductal carcinoma to cases of invasive lobular carcinoma (p=0.002); and tended to have a higher 5-year overall survival (OS) rate (78.2% [95% confidence interval (CI), 68.6%-89.0%] vs 55.0% [95% CI, 48.1%-62.9%]; p=0.051). However, in the subgroup of patients with TP53 mutation and in the subgroup of patients with PIK3CA mutation, OS did not differ between patients with bone-only and other-only first metastasis (p=0.49 and p=0.68, respectively). In univariate analysis, the rate of TP53 mutation tended to be lower in patients with bone-only first metastasis than in those with other-only first metastasis (15.3% vs 29.1%; p=0.051). In multivariate analysis, TP53 mutation was not significantly associated with site of first metastasis (p=0.54) but was significantly associated with hormone-receptor-negative disease (p<0.001). Conclusions: We did not find associations between somatic mutations and bone-only first metastasis in patients with untreated breast cancer. Patients with bone-only first metastasis tend to have longer OS than patients with other-only first metastasis. More comprehensive molecular analysis may be needed to further understand the factors associated with bone-only metastatic disease in breast cancer.
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PURPOSE: Initiatives such as The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) have generated high-quality, multi-platform molecular data from thousands of frozen tumor samples. While these initiatives have provided invaluable insight into cancer biology, a tremendous potential resource remains largely untapped in formalin-fixed, paraffin-embedded (FFPE) samples that are more readily available, but which can present technical challenges due to crosslinking of fragile molecules such as RNA. MATERIALS AND METHODS: We extracted RNA from FFPE primary melanomas and assessed two gene expression platforms -- genome-wide RNA sequencing (RNA-seq) and targeted NanoString -- for their ability to generate coherent biological signals. To do so, we generated an improved approach to quantifying gene expression pathways, in which we refine pathway scores through correlation-guided gene subsetting. We also make comparisons to the TCGA and other publicly available melanoma datasets. RESULTS: Comparison of the gene expression patterns to each other, to established biological modules, and to clinical and immunohistochemical data confirmed the fidelity of biological signals from both platforms using FFPE samples to known biology. Moreover, correlations with patient outcome data were consistent with previous frozen-tissue-based studies. CONCLUSION: FFPE samples from previously difficult-to-access cancer types - such as small primary melanomas - represents a valuable and previously unexploited source of analyte for RNA-seq and NanoString platforms. This work provides an important step towards the use of such platforms to unlock novel molecular underpinnings and inform future biologically-driven clinical decisions.
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BACKGROUND: Understanding the biology of breast cancer is important for guiding treatment strategies and revealing resistance mechanisms. Our objectives were to investigate the relationship between previous systemic therapy exposure and mutational spectrum in metastatic breast cancer and to identify clinicopathological factors associated with identified frequent somatic mutations. METHODS: Archival tissues of patients with metastatic breast cancer were subjected to hotspot molecular testing by next-generation sequencing. The variables that significantly differed (P < 0.05) in univariate analysis were selected to fit multivariate models. Logistic models were fit to estimate the association between mutation status and clinical variables of interest. Five-fold cross-validation was performed to estimate the prediction error of each model. RESULTS: A total of 922 patients were included in the analysis. In multivariate analysis, previous systemic treatment before molecular testing (N = 186) was associated with a significantly higher rate of TP53 and PIK3CA mutations compared with the lack of systemic treatment (P < 0.001 for both). CONCLUSION: Systemic treatment exposure is an independent risk factor for high rates of TP53 and PIK3CA mutation, which suggests the importance of testing samples after systemic therapy to accurately assess mutations. It is worth testing the gene profile when tumours become resistant to systemic treatments.
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Neoplasias da Mama/tratamento farmacológico , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Genes p53 , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-akt/genética , Adulto JovemRESUMO
IMPORTANCE: Potential survival benefits from treating aggressive (Gleason score, ≥7) early-stage prostate cancer are undermined by harms from unnecessary prostate biopsy and overdiagnosis of indolent disease. OBJECTIVE: To evaluate the a priori primary hypothesis that combined measurement of PCA3 and TMPRSS2:ERG (T2:ERG) RNA in the urine after digital rectal examination would improve specificity over measurement of prostate-specific antigen alone for detecting cancer with Gleason score of 7 or higher. As a secondary objective, to evaluate the potential effect of such urine RNA testing on health care costs. DESIGN, SETTING, AND PARTICIPANTS: Prospective, multicenter diagnostic evaluation and validation in academic and community-based ambulatory urology clinics. Participants were a referred sample of men presenting for first-time prostate biopsy without preexisting prostate cancer: 516 eligible participants from among 748 prospective cohort participants in the developmental cohort and 561 eligible participants from 928 in the validation cohort. INTERVENTIONS/EXPOSURES: Urinary PCA3 and T2:ERG RNA measurement before prostate biopsy. MAIN OUTCOMES AND MEASURES: Presence of prostate cancer having Gleason score of 7 or higher on prostate biopsy. Pathology testing was blinded to urine assay results. In the developmental cohort, a multiplex decision algorithm was constructed using urine RNA assays to optimize specificity while maintaining 95% sensitivity for predicting aggressive prostate cancer at initial biopsy. Findings were validated in a separate multicenter cohort via prespecified analysis, blinded per prospective-specimen-collection, retrospective-blinded-evaluation (PRoBE) criteria. Cost effects of the urinary testing strategy were evaluated by modeling observed biopsy results and previously reported treatment outcomes. RESULTS: Among the 516 men in the developmental cohort (mean age, 62 years; range, 33-85 years) combining testing of urinary T2:ERG and PCA3 at thresholds that preserved 95% sensitivity for detecting aggressive prostate cancer improved specificity from 18% to 39%. Among the 561 men in the validation cohort (mean age, 62 years; range, 27-86 years), analysis confirmed improvement in specificity (from 17% to 33%; lower bound of 1-sided 95% CI, 0.73%; prespecified 1-sided P = .04), while high sensitivity (93%) was preserved for aggressive prostate cancer detection. Forty-two percent of unnecessary prostate biopsies would have been averted by using the urine assay results to select men for biopsy. Cost analysis suggested that this urinary testing algorithm to restrict prostate biopsy has greater potential cost-benefit in younger men. CONCLUSIONS AND RELEVANCE: Combined urinary testing for T2:ERG and PCA3 can avert unnecessary biopsy while retaining robust sensitivity for detecting aggressive prostate cancer with consequent potential health care cost savings.
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Antígenos de Neoplasias/genética , Biomarcadores Tumorais/urina , Proteínas de Fusão Oncogênica/genética , Neoplasias da Próstata/urina , RNA/urina , Adulto , Idoso , Idoso de 80 Anos ou mais , Custos e Análise de Custo , Humanos , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/economia , Neoplasias da Próstata/patologia , Urinálise/economiaRESUMO
BACKGROUND: BRAFV600 , NRAS, TP53, and BRAFNon-V600 are among the most common mutations detected in non-acral cutaneous melanoma patients. Although several studies have identified clinical and pathological features associated with BRAFV600 and NRAS mutations, limited data are available regarding the correlates and significance of TP53 and BRAFNon-V600 mutations. METHODS: This study analyzed the patient demographics, primary tumor features, and clinical outcomes of a large cohort of non-acral cutaneous melanoma patients who had undergone clinically indicated molecular testing (n = 926). RESULTS: The prevalence of BRAFV600 , NRAS, TP53, and BRAFNon-V600 mutations was 43%, 21%, 19%, and 7%, respectively. The presence of a TP53 mutation was associated with older age (P = .019), a head and neck primary tumor site (P = .0001), and longer overall survival (OS) from the diagnosis of stage IV disease in univariate (P = .039) and multivariate analyses (P = .015). BRAFNon-V600 mutations were associated with older age (P = .005) but not with primary tumor features or OS from stage IV. Neither TP53 nor BRAFNon-V600 mutations correlated significantly with OS with frontline ipilimumab treatment, and the TP53 status was not significantly associated with outcomes with frontline BRAF inhibitor therapy. Eleven patients with BRAFNon-V600 mutations were treated with a BRAF inhibitor. Three patients were not evaluable for a response because of treatment cessation for toxicities; the remaining patients had disease progression as the best response to therapy. CONCLUSIONS: These results add to the understanding of the clinical features associated with TP53 and BRAFNon-V600 mutations in advanced cutaneous melanoma patients, and they support the rationale for evaluating the prognostic significance of TP53 in other cohorts of melanoma patients. Cancer 2017;123:1372-1381. © 2016 American Cancer Society.
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Melanoma/diagnóstico , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais , Criança , Análise Mutacional de DNA , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Taxa de Mutação , Estadiamento de Neoplasias , Fenótipo , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Carga Tumoral , Adulto Jovem , Melanoma Maligno CutâneoRESUMO
BACKGROUND: While clinical outcomes following immunotherapy have shown an association with tumor mutation load using whole exome sequencing (WES), its clinical applicability is currently limited by cost and bioinformatics requirements. METHODS: We developed a method to accurately derive the predicted total mutation load (PTML) within individual tumors from a small set of genes that can be used in clinical next generation sequencing (NGS) panels. PTML was derived from the actual total mutation load (ATML) of 575 distinct melanoma and lung cancer samples and validated using independent melanoma (n = 312) and lung cancer (n = 217) cohorts. The correlation of PTML status with clinical outcome, following distinct immunotherapies, was assessed using the Kaplan-Meier method. RESULTS: PTML (derived from 170 genes) was highly correlated with ATML in cutaneous melanoma and lung adenocarcinoma validation cohorts (R2 = 0.73 and R2 = 0.82, respectively). PTML was strongly associated with clinical outcome to ipilimumab (anti-CTLA-4, three cohorts) and adoptive T-cell therapy (1 cohort) clinical outcome in melanoma. Clinical benefit from pembrolizumab (anti-PD-1) in lung cancer was also shown to significantly correlate with PTML status (log rank P value < 0.05 in all cohorts). CONCLUSIONS: The approach of using small NGS gene panels, already applied to guide employment of targeted therapies, may have utility in the personalized use of immunotherapy in cancer.
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Adenocarcinoma/genética , Adenocarcinoma/terapia , Imunoterapia/métodos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/terapia , Melanoma/genética , Melanoma/terapia , Mutação , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Adenocarcinoma/imunologia , Adenocarcinoma de Pulmão , Algoritmos , Anticorpos Monoclonais/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Estudos de Coortes , Exoma , Feminino , Humanos , Imunoterapia Adotiva/métodos , Ipilimumab , Neoplasias Pulmonares/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias Cutâneas/imunologia , Linfócitos T/imunologia , Linfócitos T/transplante , Carga Tumoral/genética , Melanoma Maligno CutâneoRESUMO
IMPORTANCE: Combined treatment with dabrafenib and trametinib (CombiDT) achieves clinical responses in only about 15% of patients with BRAF inhibitor (BRAFi)-refractory metastatic melanoma in contrast to the higher response rate observed in BRAFi-naïve patients. Identifying correlates of response and mechanisms of resistance in this population will facilitate clinical management and rational therapeutic development. OBJECTIVE: To determine correlates of benefit from CombiDT therapy in patients with BRAFi-refractory metastatic melanoma. DESIGN, SETTING, AND PARTICIPANTS: Single-center, single-arm, open-label phase 2 trial of CombiDT treatment in patients with BRAF V600 metastatic melanoma resistant to BRAFi monotherapy conducted between September 2012 and October 2014 at the University of Texas MD Anderson Cancer Center. Key eligibility criteria for participants included BRAF V600 metastatic melanoma, prior BRAFi monotherapy, measurable disease (RECIST 1.1), and tumor accessible for biopsy. INTERVENTIONS: Patients were treated with dabrafenib (150 mg, twice daily) and trametinib (2 mg/d) continuously until disease progression or intolerance. All participants underwent a mandatory baseline biopsy, and optional biopsy specimens were obtained on treatment and at disease progression. Whole-exome sequencing, reverse transcription polymerase chain reaction analysis for BRAF splicing, RNA sequencing, and immunohistochemical analysis were performed on tumor samples, and blood was analyzed for levels of circulating BRAF V600. MAIN OUTCOMES AND MEASURES: The primary end point was overall response rate (ORR). Progression-free survival (PFS) and overall survival (OS) were secondary clinical end points. RESULTS: A total of 28 patients were screened, and 23 enrolled. Among evaluable patients, the confirmed ORR was 10%; disease control rate (DCR) was 45%, and median PFS was 13 weeks. Clinical benefit was associated with duration of prior BRAFi therapy greater than 6 months (DCR, 73% vs 11% for ≤6 months; P = .02) and decrease in circulating BRAF V600 at day 8 of cycle 1 (DCR, 75% vs 18% for no decrease; P = .02) but not with pretreatment mitogen-activated protein kinase (MAPK) pathway mutations or activation. Biopsy specimens obtained during treatment demonstrated that CombiDT therapy failed to achieve significant MAPK pathway inhibition or immune infiltration in most patients. CONCLUSIONS AND RELEVANCE: The baseline presence of MAPK pathway alterations was not associated with benefit from CombiDT in patients with BRAFi-refractory metastatic melanoma. Failure to inhibit the MAPK pathway provides a likely explanation for the limited clinical benefit of CombiDT in this setting. Circulating BRAF V600 is a promising early biomarker of clinical response. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01619774.
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Antineoplásicos/uso terapêutico , Sistema de Sinalização das MAP Quinases/genética , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adulto , Antígeno B7-H1/metabolismo , Antígenos CD8/metabolismo , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Imidazóis/administração & dosagem , Imuno-Histoquímica , Masculino , Melanoma/genética , Melanoma/imunologia , Melanoma/secundário , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Oximas/administração & dosagem , Fosforilação , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Proteína S6 Ribossômica/metabolismo , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
PURPOSE: Given the limited sensitivity and specificity of prostate-specific antigen (PSA), its widespread use as a screening tool has raised concerns for the overdiagnosis of low-risk and the underdiagnosis of high-grade prostate cancer. To improve early-detection biopsy decisions, the National Cancer Institute conducted a prospective validation trial to assess the diagnostic performance of the prostate cancer antigen 3 (PCA3) urinary assay for the detection of prostate cancer among men screened with PSA. PATIENTS AND METHODS: In all, 859 men (mean age, 62 years) from 11 centers scheduled for a diagnostic prostate biopsy between December 2009 and June 2011 were enrolled. The primary outcomes were to assess whether PCA3 could improve the positive predictive value (PPV) for an initial biopsy (at a score > 60) and the negative predictive value (NPV) for a repeat biopsy (at a score < 20). RESULTS: For the detection of any cancer, PPV was 80% (95% CI, 72% to 86%) in the initial biopsy group, and NPV was 88% (95% CI, 81% to 93%) in the repeat biopsy group. The addition of PCA3 to individual risk estimation models (which included age, race/ethnicity, prior biopsy, PSA, and digital rectal examination) improved the stratification of cancer and of high-grade cancer. CONCLUSION: These data independently support the role of PCA3 in reducing the burden of prostate biopsies among men undergoing a repeat prostate biopsy. For biopsy-naive patients, a high PCA3 score (> 60) significantly increases the probability that an initial prostate biopsy will identify cancer.