RESUMO
We used a noninvasive electrochemical quantitative assay for IgG Abs to SARS-CoV-2 S1 Ag in saliva to investigate the kinetics of Ab response in a community-based population that had received either the Pfizer or Moderna mRNA-based vaccine. Samples were received from a total of 97 individuals, including a subset of 42 individuals who collected samples twice weekly for 3 mo or longer. In all, >840 samples were collected and analyzed. In all individuals, salivary SARS-CoV-2 S1 IgG Ab levels rose sharply in the 2-wk period after their second vaccination, with peak Ab levels seen at 10-20 d after vaccination. We observed that 20%, 10%, and 2.4% of individuals providing serial samples had a 90%, 95%, and 99% drop, respectively, from peak levels during the duration of monitoring, and in two patients, Abs fell to prevaccination levels (5%). The use of noninvasive quantitative salivary Ab measurement can allow widespread, cost-effective monitoring of vaccine response.
Assuntos
Vacina de mRNA-1273 contra 2019-nCoV/imunologia , Anticorpos Antivirais/metabolismo , Vacina BNT162/imunologia , COVID-19/imunologia , Imunoglobulina G/metabolismo , SARS-CoV-2/fisiologia , Saliva/metabolismo , Adulto , Fatores Etários , Pesquisa Participativa Baseada na Comunidade , Feminino , Humanos , Masculino , VacinaçãoRESUMO
BACKGROUND: The National Comprehensive Cancer Network recommends that women who carry gene variants that confer substantial risk for breast cancer consider risk-reduction strategies, that is, enhanced surveillance (breast magnetic resonance imaging and mammography) or prophylactic surgery. Pathogenic variants can be detected in women with a family history of breast or ovarian cancer syndromes by multigene panel testing. OBJECTIVES: To investigate whether using a seven-gene test to identify women who should consider risk-reduction strategies could cost-effectively increase life expectancy. METHODS: We estimated effectiveness and lifetime costs from a payer perspective for two strategies in two hypothetical cohorts of women (40-year-old and 50-year-old cohorts) who meet the National Comprehensive Cancer Network-defined family history criteria for multigene testing. The two strategies were the usual test strategy for variants in BRCA1 and BRCA2 and the seven-gene test strategy for variants in BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, and PALB2. Women found to have a pathogenic variant were assumed to undergo either prophylactic surgery or enhanced surveillance. RESULTS: The incremental cost-effectiveness ratio for the seven-gene test strategy compared with the BRCA1/2 test strategy was $42,067 per life-year gained or $69,920 per quality-adjusted life-year gained for the 50-year-old cohort and $23,734 per life-year gained or $48,328 per quality-adjusted life-year gained for the 40-year-old cohort. In probabilistic sensitivity analysis, the seven-gene test strategy cost less than $100,000 per life-year gained in 95.7% of the trials for the 50-year-old cohort. CONCLUSIONS: Testing seven breast cancer-associated genes, followed by risk-reduction management, could cost-effectively improve life expectancy for women at risk of hereditary breast cancer.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Detecção Precoce de Câncer/economia , Perfilação da Expressão Gênica/economia , Testes Genéticos/economia , Custos de Cuidados de Saúde , Expectativa de Vida , Anos de Vida Ajustados por Qualidade de Vida , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/economia , Neoplasias da Mama/terapia , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Detecção Precoce de Câncer/métodos , Feminino , Predisposição Genética para Doença , Hereditariedade , Humanos , Imageamento por Ressonância Magnética/economia , Mamografia/economia , Mastectomia/economia , Pessoa de Meia-Idade , Modelos Econômicos , Seleção de Pacientes , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Conduta Expectante/economiaRESUMO
Classification of breast cancer into molecular subtypes maybe important for the proper selection of therapy, as tumors with seemingly similar histopathological features can have strikingly different clinical outcomes. Herein, we report the development of a molecular subtyping profile (BluePrint), that enables rationalization in patient selection for either chemotherapy or endocrine therapy prescription. An 80-Gene Molecular Subtyping Profile (BluePrint) was developed using 200 breast cancer patient specimens and confirmed on four independent validation cohorts (n = 784). Additionally, the profile was tested as a predictor of chemotherapy response in 133 breast cancer patients, treated with T/FAC neoadjuvant chemotherapy. BluePrint classification of a patient cohort that was treated with neoadjuvant chemotherapy (n = 133) shows improved distribution of pathological Complete Response (pCR), among molecular subgroups compared with local pathology: 56% of the patients had a pCR in the Basal-type subgroup, 3% in the MammaPrint Low-risk, Luminal-type subgroup, 11% in the MammaPrint High-risk, Luminal-type subgroup, and 50% in the HER2-type subgroup. The group of genes identifying Luminal-type breast cancer is highly enriched for genes having an Estrogen Receptor binding site proximal to the promoter-region, suggesting that these genes are direct targets of the Estrogen Receptor. Implementation of this profile may improve the clinical management of breast cancer patients, by enabling the selection of patients who are most likely to benefit from either chemotherapy or from endocrine therapy.
Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Estudos de Coortes , Interpretação Estatística de Dados , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Modelos Biológicos , Análise de Sequência com Séries de Oligonucleotídeos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Transdução de Sinais/genética , Resultado do TratamentoRESUMO
Multigene assays have been developed and validated to determine the prognosis of breast cancer. In this study, we assessed the additional predictive value of the 70-gene MammaPrint signature for chemotherapy (CT) benefit in addition to endocrine therapy (ET) from pooled study series. For 541 patients who received either ET (n = 315) or ET + CT (n = 226), breast cancer-specific survival (BCSS) and distant disease-free survival (DDFS) at 5 years were assessed separately for the 70-gene high and low risk groups. The 70-gene signature classified 252 patients (47%) as low risk and 289 (53%) as high risk. Within the 70-gene low risk group, BCSS was 97% for the ET group and 99% for the ET + CT group at 5 years with a non-significant univariate hazard ratio (HR) of 0.58 (95% CI 0.07-4.98; P = 0.62). In the 70-gene high risk group, BCSS was 81% (ET group) and 94% (ET + CT group) at 5 years with a significant HR of 0.21 (95% CI 0.07-0.59; P < 0.01). DDFS was 93% (ET) versus 99% (ET + CT), respectively, in the 70-gene low risk group, HR 0.26 (95% CI 0.03-2.02; P = 0.20). In the high risk group DDFS was 76 versus 88%, HR of 0.35 (95% CI 0.17-0.71; P < 0.01). Results were similar in multivariate analysis, showing significant survival benefit by adding CT in the 70-gene high risk group. A significant and clinically meaningful benefit was observed by adding chemotherapy to endocrine treatment in 70-gene high risk patients. This benefit was not significant in low risk patients, who were at such low risk for recurrence and cancer-related death, that adding CT does not appear to be clinically meaningful.
Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Adenocarcinoma/radioterapia , Adenocarcinoma/cirurgia , Adulto , Idoso , Antraciclinas/administração & dosagem , Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Terapia Combinada , Feminino , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Metástase Neoplásica/genética , Proteínas de Neoplasias/biossíntese , Estadiamento de Neoplasias , Valor Preditivo dos Testes , Radioterapia Adjuvante , Medição de Risco , Taxoides/administração & dosagem , Carga TumoralRESUMO
The diagnosis of unknown primary carcinoma is often the result of the failure of light microscopy and immunohistochemistry to elucidate the origin of adenocarcinoma or poorly differentiated carcinoma. Recent advances in gene expression profiling using either reverse transcription polymerase chain reaction (RT-PCR) or microarray have enabled researchers to develop expression profiles unique to a wide variety of well-characterized primary cancers and to compare these unique signatures with those from unknown primary cancers. As the gene expression profile is frequently conserved when the tumor metastasizes, it is often possible to analyze a biopsy specimen and genomically identify its tissue of origin. In fact, the overall accuracy of genomic cancer classification in patients with known primary cancers is 80% to 90%. This new system of molecular classification might be considered as "genomic taxonomy." The genomic classification is then available to the pathologist and clinician to aid in both the patient's diagnosis and treatment planning. The impact of this new technology on patient outcomes is currently under study.
Assuntos
Neoplasias Primárias Desconhecidas/classificação , Neoplasias Primárias Desconhecidas/genética , Perfilação da Expressão Gênica , HumanosRESUMO
OBJECTIVE: To determine whether a next-generation sequencing (NGS) panel of 34 cancer-associated genes would cost-effectively aid in the treatment selection for patients with metastatic melanoma, compared with a single-site BRAF V600 mutation test. METHODS: A decision model was developed to estimate the costs and health outcomes of the two test strategies. The cost effectiveness of these two strategies was analyzed from a payer perspective over a 2-year time horizon with model parameters taken from the literature. RESULTS: In the base case, the gene sequencing panel strategy resulted in a cost of US$120,022 and 0.721 quality-adjusted life years (QALYs) per patient, whereas the single-site mutation test strategy resulted in a cost of US$128,965 and 0.704 QALYs. Thus, the gene sequencing panel strategy cost US$8943 less per patient and increased QALYs by 0.0174 per patient. Sensitivity analyses showed that, compared with the single-site mutation test strategy, the gene sequencing panel strategy had a 90.9% chance of having reduced costs and increased QALYs, with the cost of the gene sequencing panel test having minimal effect on the incremental cost. CONCLUSION: Compared with the single-site mutation test, the use of an NGS panel of 34 cancer-associated genes as an aid in selecting therapy for patients with metastatic melanoma reduced costs and increased QALYs. If the base-case results were applied to the 8900 patients diagnosed with metastatic melanoma in the USA each year, the gene sequencing panel strategy could result in an annual savings of US$79.6 million and a gain of 155 QALYs.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/economia , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Análise de Sequência de DNA/economia , Análise Custo-Benefício , Técnicas de Apoio para a Decisão , Predisposição Genética para Doença , Gastos em Saúde , Humanos , Melanoma/economia , Modelos Econômicos , Mutação , Metástase Neoplásica , Anos de Vida Ajustados por Qualidade de Vida , Sensibilidade e EspecificidadeRESUMO
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary colon cancer syndrome and is responsible for as many as 10% of all colorectal cancers. Hereditary nonpolyposis colorectal cancer is autosomally dominant with a prevalence of 1 in 200-2000 and exhibits incomplete penetrance. Affected individuals have an approximately 70% lifetime risk of colon cancer with a mean age of onset of 44 years and an approximately 40% lifetime risk of endometrial cancer. At least 5 mismatch repair genes (MLH1, MSH2, MSH6, PMS1, PMS2) have been implicated in HNPCC; however, no predominant mutations were found in these genes. Mutation detection by direct sequencing has proven to be the most sensitive method. We have developed high-throughput full-length sequencing assays of the MLH1, MSH2, and MSH6 genes. These 3 genes account for approximately 90% of all germline mutations found in HNPCC. In our assays, 19 exons of MLH1, 16 exons of MSH2, 10 exons of MSH6, and the adjacent splice sites were amplified using polymerase chain reaction and loaded onto a capillary sequencing machine. Results were analyzed using sequence analysis software and stored in a relational database. Our assay method was validated using 15 affected patients and normal controls. It is anticipated that our high-throughput assay technique will provide accurate diagnoses for patients at risk for HNPCC and thereby facilitate early curative intervention.
Assuntos
Neoplasias Colorretais Hereditárias sem Polipose/genética , Análise Mutacional de DNA/métodos , Testes Genéticos , Reação em Cadeia da Polimerase/métodos , Pareamento Incorreto de Bases/genética , Instabilidade Cromossômica/genética , Análise Custo-Benefício , Análise Mutacional de DNA/economia , Reparo do DNA/genética , Mutação em Linhagem Germinativa/genética , Humanos , Repetições de Microssatélites/genética , Proteínas de Neoplasias/genéticaRESUMO
One of the critical gaps in the clinical diagnostic space is the lack of quantitative proteomic methods for use on formalin-fixed, paraffin-embedded (FFPE) tissue. Herein, we describe the development of a quantitative, multiplexed, mass spectrometry-based selected reaction monitoring (SRM) assay for four therapeutically important targets: epidermal growth factor receptor, human EGF receptor (HER)-2, HER3, and insulin-like growth factor-1 receptor. These assays were developed using the Liquid Tissue-SRM technology platform, in which FFPE tumor tissues were microdissected, completely solubilized, and then subjected to multiplexed quantitation by SRM mass spectrometry. The assays were preclinically validated by comparing Liquid Tissue-SRM quantitation of FFPE cell lines with enzyme-linked immunosorbent assay/electrochemiluminescence quantitation of fresh cells (R(2) > 0.95). Clinical performance was assessed on two cohorts of breast cancer tissue: one cohort of 10 samples with a wide range of HER2 expression and a second cohort of 19 HER2 IHC 3+ tissues. These clinical data demonstrate the feasibility of quantitative, multiplexed clinical analysis of proteomic markers in FFPE tissue. Our findings represent a significant advancement in cancer tissue analysis because multiplexed, quantitative analysis of protein targets in FFPE tumor tissue can be tailored to specific oncological indications to provide the following: i) complementary support for anatomical pathological diagnoses, ii) patient stratification to optimize treatment outcomes and identify drug resistance, and iii) support for the clinical development of novel therapies.
Assuntos
Neoplasias da Mama/genética , Receptores ErbB/isolamento & purificação , Receptor ErbB-2/isolamento & purificação , Receptor ErbB-3/isolamento & purificação , Receptor IGF Tipo 1/isolamento & purificação , Receptores de Somatomedina/isolamento & purificação , Biomarcadores Tumorais/isolamento & purificação , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Ensaio de Imunoadsorção Enzimática , Receptores ErbB/biossíntese , Feminino , Formaldeído , Humanos , Espectrometria de Massas , Inclusão em Parafina , Receptor ErbB-2/biossíntese , Receptor ErbB-3/biossíntese , Receptor IGF Tipo 1/biossíntese , Receptores de Somatomedina/biossíntese , Fixação de TecidosRESUMO
The hepatic isoform 1A1 of uridine diphosphate glucuronosyltransferase is responsible for glucuronidation and detoxification of SN-38, the active metabolite of irinotecan. The presence of an additional TA repeat in the TATA sequence of the UGT1A1 promoter leads to a significant decrease in SN-38 glucuronidation. Patients with the UGT1A1 (TA)7 allele are more likely to experience severe neutropenia and diarrhea following irinotecan chemotherapy. We assessed the distribution of the UGT1A1 (TA)n polymorphism in healthy male and female US residents of European and Asian descent. We used a fluorescent polymerase chain reaction-based assay to detect UGT1A1 (TA)n polymorphisms in 138 healthy volunteers (56 Caucasians, 37 Chinese, 37 Filipino and eight Japanese) between the ages of 18 and 65 years. The chi-test was used to assess between-group differences in the distribution of UGT1A1 (TA)n genotypes. The UGT1A1 (TA)6/6 genotype was significantly more common in Asians than in Caucasians (76 vs. 46%), whereas the (TA)6/7 (39 vs. 20%) and (TA)7/7 (13 vs. 5%) genotypes were more common in Caucasians than in Asians. Genotype distributions did not differ significantly between men and women in either group. The UGT1A1 (TA)5/5 genotype was detected in one Caucasian woman. In conclusion, consistent with previous reports, the UGT1A1 (TA)7/7 genotype was significantly more common in Caucasians than in Asians. UGT1A1 (TA)n/n genotype distribution did not vary with sex in individuals of European or Asian descent.
Assuntos
Asiático/genética , Frequência do Gene , Glucuronosiltransferase/genética , Polimorfismo Genético , População Branca/genética , Adolescente , Adulto , Idoso , Antineoplásicos Fitogênicos/farmacocinética , Camptotecina/análogos & derivados , Camptotecina/farmacocinética , China/etnologia , Feminino , Genótipo , Humanos , Irinotecano , Japão/etnologia , Masculino , Taxa de Depuração Metabólica/genética , Pessoa de Meia-Idade , Filipinas/etnologia , Estados UnidosRESUMO
PURPOSE: We previously identified three genes, HOXB13, IL17BR and CHDH, and the HOXB13:IL17BR ratio index in particular, that strongly predicted clinical outcome in breast cancer patients receiving tamoxifen monotherapy. Confirmation in larger independent patient cohorts was needed to fully validate their clinical utility. PATIENTS AND METHODS: Expression of HOXB13, IL17BR, CHDH, estrogen receptor (ER) and progesterone receptor (PR) were quantified by real-time polymerase chain reaction in 852 formalin-fixed, paraffin-embedded primary breast cancers from 566 untreated and 286 tamoxifen-treated breast cancer patients. Gene expression and clinical variables were analyzed for association with relapse-free survival (RFS) by Cox proportional hazards regression models. RESULTS: ER and PR mRNA measurements were in close agreement with immunohistochemistry. In the entire cohort, expression of HOXB13 was associated with shorter RFS (P = .008), and expression of IL17BR and CHDH was associated with longer RFS (P < .0001 for IL17BR and P = .0002 for CHDH). In ER+ patients, the HOXB13:IL17BR index predicted clinical outcome independently of treatment, but more strongly in node-negative patients. In multivariate analysis of the ER+ node-negative subgroup including age, PR status, tumor size, S phase fraction, and tamoxifen treatment, the two-gene index remained a significant predictor of RFS (hazard ratio = 3.9; 95% CI, 1.5 to 10.3; P = .007). CONCLUSION: This tumor bank study demonstrated HOXB13:IL17BR index is a strong independent prognostic factor for ER+ node-negative patients irrespective of tamoxifen therapy.
Assuntos
Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Receptores de Interleucina/biossíntese , Receptores de Interleucina/genética , Idoso , Colina Desidrogenase/biossíntese , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Interleucina-17 , Receptores de Progesterona/metabolismo , Tamoxifeno/farmacologiaRESUMO
5-Fluorouracil (5-FU) has been used for more than 40 years in the treatment of neoplastic disease, and remains the standard first-line treatment for colorectal cancer in combination with irinotecan and leucovorin. Previous studies indicated that measurement of dihydropyrimidine dehydrogenase (DPD) gene expression before treatment was valuable in determining the potential benefit of and toxicity to 5-FU treatment. In this study, we investigated the association between intratumoral DPD gene expression and the adjacent normal tissue DPD gene expression and DPD mRNA expression level in non-paired colon tumor and normal colon tissue specimens. In addition, we have compared the difference of DPD gene expression at three different RNA concentrations from the same specimen (180, 100 and 5 ng/reaction, respectively). DPD expression was measured by quantitative RT-PCR using a LightCycler instrument in a total of 31 specimens. Gene expression values were expressed as a ratio of target gene (DPD) to the internal reference gene (G6PDH). Our study revealed no statistically significant difference (p=0.23) between tumor tissues and matched normal tissue in DPD expression. In contrast, the data on DPD mRNA expression in non-paired colon tumor and normal tissue specimens revealed a significant difference (p=0.0004) between the tumor group and the normal group. In the three RNA concentration groups, there was no significant difference (p=0.55) in gene expression at the different RNA concentrations from the same donor. These results demonstrate that intratumoral gene expression levels of DPD do not correlate with tumor cell percentage or with RNA concentration. Thus, DPD mRNA expression appears to be a valid sensitivity test for 5-FU in spite of a varying density of tumor cells and RNA yield in specimens submitted for analysis.