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1.
Breast Cancer Res Treat ; 206(1): 67-76, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38568368

RESUMO

PURPOSE: We compared 21-gene recurrence score (RS) distribution and expression of the single-gene/gene groups within this assay between BC patients with pathogenic variants (PV) in BRCA1/2 vs the general 21-gene-tested BC population. METHODS: This retrospective study included consecutive 21-gene-tested female ER + HER2-negative BC patients with germline PVs in BRCA1/2. RS/gene expression data were compared to a previously described commercial use database (CDB, N = 799,986). Chi-square and 1-sample t test were used to compare RS distribution and single-gene/gene group scores between the study group and the CDB. RESULTS: Study group patients (N = 81) were younger and their RS results were higher compared to the CDB (age: median [IQR], 56 [47-61.5] vs 60 [51-67] years; p < 0.001; proportion of patients with RS ≥ 26: 49.4% vs 16.4%, p < 0.001). Expression of 12/16 cancer genes in the assay and the ER, proliferation, and invasion gene group scores differed significantly between the study group and the CDB, all in a direction contributing to higher RS. The differences between the study group and the CDB were mostly retained, upon stratifying the patients by menopausal status. CONCLUSION: BC patients with PVs in BRCA1/2 have higher RS results that stem from distinct gene expression profiles in the majority of genes in the 21-gene assay.


Assuntos
Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Proteína BRCA2/genética , Proteína BRCA1/genética , Idoso , Estudos Retrospectivos , Biomarcadores Tumorais/genética , Mutação em Linhagem Germinativa , Mutação , Heterozigoto , Adulto , Predisposição Genética para Doença
2.
BJU Int ; 2024 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-38953550

RESUMO

OBJECTIVES: To evaluate the utility of the 17-gene Genomic Prostate Score® (GPS; MDxHealth, Irvine, CA, USA) performed on prostate cancer at the positive margin of the radical prostatectomy (RP) for its association with risk of subsequent biochemical recurrence (BCR). PATIENTS AND METHODS: We designed a case-cohort for the outcome of BCR, selecting 223 from a cohort of 813 RP patients treated at Johns Hopkins from 2008 to 2017 with positive margins and available clinical data; of these, 213 had available tissue and clinical data. RNA was isolated from formalin-fixed paraffin-embedded tumour tissue adjacent to the positive surgical margin and the GPS was evaluable in 203 of these patients with a score ranging from 0 to 100, with higher scores indicating higher risk. All patients underwent RP with or without adjuvant radiation therapy (ART). The statistical analysis employed Cox proportional hazards regression models for outcome of BCR weighted for case-cohort design. RESULTS: In univariable analysis, every 20-unit increase in the GPS was associated with a nearly threefold increase in risk of BCR (hazard ratio [HR] per 20 units 2.82, P < 0.001). In a multivariable Cox model adjusted for age, race, Cancer of the Prostate Risk Assessment Postsurgical score, Grade Group at the positive margin, and ART, the GPS was significantly associated with BCR (HR 1.56 per 20 units; 95% confidence interval 1.11-2.19; P = 0.011). The study is limited by its retrospective and single institution design. CONCLUSIONS: The GPS at the positive surgical margin could help stratify prognosis and inform clinical decision-making regarding adjuvant therapy after RP.

3.
Breast Cancer Res ; 24(1): 74, 2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36320066

RESUMO

BACKGROUND: The United States Food and Drug Administration recently approved a Ki-67 immunohistochemistry (IHC) assay to identify patients with early breast cancer at high disease recurrence risk. The Oncotype Dx Breast Recurrence Score® assay has been validated in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) invasive breast cancer (IBC) to predict chemotherapy benefit and distant recurrence risk, regardless of nodal status. This study assessed the correlation between Recurrence Score® (RS) results and the Ki-67 IHC MIB-1 pharmDx assay. METHODS: HR+, HER2-, N1 IBC samples with RS results were examined by Ki-67 IHC; 311 specimens were collected, including 275 without regard to RS ("unselected RS") and 36 more with RS 26-100; 12 were lymph node negative upon pathology report review, and one had no Ki-67 score, leaving 262 unselected RS and 298 total samples. Spearman rank correlation was calculated using the unselected samples and a weighted rank correlation using all samples. A receiver operating characteristic (ROC) curve for predicting high RS (26-100) from Ki-67 was constructed. RESULTS: The Spearman rank correlation between Ki-67 and RS results was moderately positive (unselected RS samples: 0.396; 95% confidence interval [CI] 0.288-0.493; all samples: 0.394; 95% CI 0.294-0.486). While 71% of samples with RS 26-100 had Ki-67 ≥ 20%, 75% with RS 0-25 had Ki-67 < 20%. ROC area under the curve was 0.792 (95% CI 0.725-0.859). CONCLUSIONS: The moderately positive correlation is consistent with previous analyses suggesting the Oncotype Dx® assay and Ki-67 IHC MIB-1 assay should not be used interchangeably in clinical practice.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Imuno-Histoquímica , Prognóstico , Recidiva Local de Neoplasia/patologia , Curva ROC , Biomarcadores Tumorais/metabolismo
4.
J Surg Oncol ; 122(4): 611-618, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32497318

RESUMO

BACKGROUND AND OBJECTIVE: Recent COVID-19 pandemic guidelines recommend genomic assessment of core biopsies to help guide treatment decisions in estrogen receptor (ER)-positive early-stage breast cancer. Herein we characterize biopsy and excisional breast cancer specimens submitted for 21-gene testing. METHODS: US samples submitted to Genomic Health for 21-gene testing (01/2004-04/2020) were assessed by pathologists and analyzed by a standardized quantitative reverse transcription-polymerase chain reaction. Predefined cutoffs were: ESR1 (positive ≥6.5), PGR (positive ≥5.5), and ERBB2 (negative <10.7). ER status by immunohistochemistry (IHC) and lymph node status were determined locally. Median and interquartile range were reported for continuous variables, and total and percent for categorical variables. Distributions were assessed overall, by age, and by nodal involvement. RESULTS: Of 919 701 samples analyzed, 13% were biopsies and 87% were excisions. Initial assay success rates were 94.5% (biopsies) and 97.3% (excisions). ER IHC concordance with central ESR1 was 96.8% (biopsies) and 97.6% (excisions). Biopsy and excisional medians were: Recurrence Score results 16 (each); ESR1 10.2 (each); PGR 7.7 and 7.6; ERBB2 9.4 and 9.2, respectively. CONCLUSIONS: Biopsy submissions for 21-gene testing are common and consistently generate results that are very similar to the experience with excisions. The 21-gene test can be performed reliably on core biopsies.

5.
Breast Cancer Res Treat ; 177(3): 611-618, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302854

RESUMO

PURPOSE: Adjuvant therapy decisions may in part be based on results of Oncotype DX Breast Recurrence Score® (RS) testing of primary tumors. When necessary, lymph node metastases may be considered as a surrogate. Here we evaluate the concordance in gene expression between primary breast cancers and synchronous lymph node metastases, based on results from quantitative RT-PCR-based RS testing between matched primary tumors and synchronous nodal metastases. METHODS: This retrospective, exploratory study included patients (≥ 18 years old) treated at our center (2005-2009) who had ER+ , HER2-negative invasive breast cancer and synchronous nodal metastases with available tumor blocks from both sites. Paired tissue blocks underwent RS testing, and RS and single-gene results for ER, PR, and HER2 were explored between paired samples. RESULTS: A wide distribution of RS results in tumors and in synchronous nodal metastases were modestly correlated between 84 paired samples analyzed (Pearson correlation 0.69 [95% CI 0.55-0.78]). Overall concordance in RS group classification between samples was 63%. ER, PR, and HER2 by RT-PCR between the primary tumor and lymph node were also modestly correlated (Pearson correlation [95% CI] 0.64 [0.50-0.75], 0.64 [0.49-0.75], and 0.51 [0.33-0.65], respectively). Categorical concordance (positive or negative) was 100% for ER, 77% for PR, and 100% for HER2. CONCLUSIONS: There is modest correlation in continuous gene expression, as measured by the RS and single-gene results for ER, PR, and HER2 between paired primary tumors and synchronous nodal metastases. RS testing for ER+ breast cancer should continue to be based on analysis of primary tumors.


Assuntos
Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Genômica , Linfonodos/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Genômica/métodos , Humanos , Metástase Linfática , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Estudos Retrospectivos , Adulto Jovem
6.
Breast Cancer Res Treat ; 168(1): 69-77, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29128898

RESUMO

BACKGROUND: The 21-gene recurrence score (RS) predicts outcome and benefit from adjuvant chemotherapy benefit in breast cancer patients treated with adjuvant endocrine therapy. In the NSABP B-28 study, we evaluated the 21-gene RS for its prognostic impact and its ability to predict benefit from paclitaxel (P) in node-positive, estrogen receptor-positive (ER+) breast cancer patients treated with adjuvant chemotherapy plus tamoxifen. METHODS: The B-28 trial compared doxorubicin/cyclophosphamide (AC) with AC followed by P in 3060 patients. Tamoxifen for 5 years was also given to patients > 50 years and those < 50 years with ER+ and/or progesterone receptor-positive (PR+) tumors. The present study includes 1065 ER-positive, tamoxifen-treated patients with RS assessment. Median follow-up time was 11.2 years. RESULTS: In univariate analyses, RS was a significant predictor of outcome. In multivariate analyses, RS remained a significant independent predictor of outcome beyond clinico-pathologic factors, age, and type of surgery (p < 0.001). In the study population (n = 1065), the disease-free survival (DFS) hazard ratio (HR) with adding P to AC was 0.87 (95% CI 0.72-1.05; p = 0.14). RS was not a significant predictor of P benefit: for DFS, HRs for adding P to AC in RS low, intermediate, and high subgroups were 1.01 (95% CI 0.69-1.47; p = 0.99), 0.84 (95% CI 0.62-1.14; p = 0.26), and 0.81 (95% CI 0.60-1.10; p = 0.21), respectively (interaction p = 0.64). Similar findings were observed for the other study endpoints. CONCLUSIONS: RS maintains significant prognostic impact in ER-positive, node-positive patients treated with adjuvant chemotherapy plus tamoxifen. However, RS did not significantly predict benefit from adding paclitaxel to AC chemotherapy. (Trial Registration: PDQ: NSABP-B-28).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Ciclofosfamida/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Seguimentos , Testes Genéticos/métodos , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática/patologia , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Paclitaxel/uso terapêutico , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/uso terapêutico
7.
BMC Cancer ; 18(1): 526, 2018 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-29728098

RESUMO

BACKGROUND: The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m2) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). METHODS: The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). RESULTS: There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p <  0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p <  0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79). CONCLUSIONS: After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. TRIAL REGISTRATION: Not applicable.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Testes Genéticos/métodos , Recidiva Local de Neoplasia/diagnóstico , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ensaios Clínicos Fase III como Assunto , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/genética , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
8.
Breast Cancer Res Treat ; 159(1): 71-8, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27447876

RESUMO

Clinical variables and several gene signature profiles have been investigated for the prediction of (distant) recurrence in several trials. These molecular markers are significantly correlated with overall and late distant recurrences. Here, we retrospectively explore whether age and body mass index (BMI) affect the prediction of these molecular scores for distant recurrence in postmenopausal women with hormone receptor-positive breast cancer in the transATAC trial. 940 postmenopausal women for whom the Clinical Treatment Score (CTS), immunohistochemical markers (IHC4), Oncotype Recurrence Score (RS), and the Prosigna Risk of Recurrence Score (ROR) were available were included in this retrospective analysis. Conventional BMI groups were used (N = 865), and age was split into equal tertiles (N = 940). Cox proportional hazard models were used to determine the effect of a molecular score for the prediction of distant recurrence according to BMI and age groups. In both the univariate and bivariate analyses, the effect size of the IHC4 and RS was strongest in women aged 59.8 years or younger. Trends tests for age were significant for the IHC4 and RS, but not for the CTS and ROR, for which most prognostic information was added in women aged 60 years or older. The CTS and ROR scores added significant prognostic information in all three BMI groups. In both the univariate and bivariate analyses, the IHC4 provided the most prognostic information in women with a BMI lower than 25 kg/m(2), whereas the RS did not add prognostic information for distant recurrence in women with a BMI of 30 kg/m(2) or above. Molecular scores are increasingly used in women with breast cancer to assess recurrence risk. We have shown that the effect size of the molecular scores is significantly different across age groups, but not across BMI groups. The results from this retrospective analysis may be incorporated in the identification of women who may benefit most from the use of these molecular scores, but our findings need further evaluation before these scores can be used in clinical decision making.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/terapia , Recidiva Local de Neoplasia/terapia , Fatores Etários , Idoso , Antineoplásicos Hormonais/uso terapêutico , Índice de Massa Corporal , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ensaios Clínicos como Assunto , Feminino , Humanos , Histerectomia , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Pós-Menopausa , Prognóstico , Radioterapia , Estudos Retrospectivos , Tamoxifeno/uso terapêutico
9.
Breast Cancer Res ; 17(1): 133, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26429296

RESUMO

INTRODUCTION: The N9831 trial demonstrated the efficacy of adjuvant trastuzumab for patients with human epidermal growth factor receptor 2 (HER2) locally positive tumors by protein or gene analysis. We used the 21-gene assay to examine the association of quantitative HER2 messenger RNA (mRNA) gene expression and benefit from trastuzumab. METHODS: N9831 tested the addition of trastuzumab to chemotherapy in stage I-III HER2-positive breast cancer. For two of the arms of the trial, doxorubicin and cyclophosphamide followed by paclitaxel (AC-T) and doxorubicin and cyclophosphamide followed by paclitaxel and trastuzumab concurrent chemotherapy-trastuzumab (AC-TH), recurrence score (RS) and HER2 mRNA expression were determined by the 21-gene assay (Oncotype DX®) (negative <10.7, equivocal 10.7 to <11.5, and positive ≥11.5 log2 expression units). Cox regression was used to assess the association of HER2 expression with trastuzumab benefit in preventing distant recurrence. RESULTS: Median follow-up was 7.4 years. Of 1,940 total patients, 901 had consent and sufficient tissue. HER2 by reverse transcriptase polymerase chain reaction (RT-PCR) was negative in 130 (14 %), equivocal in 85 (9 %), and positive in 686 (76 %) patients. Concordance between HER2 assessments was 95 % for RT-PCR versus central immunohistochemistry (IHC) (>10 % positive cells = positive), 91 % for RT-PCR versus central fluorescence in situ hybridization (FISH) (≥2.0 = positive) and 94 % for central IHC versus central FISH. In the primary analysis, the association of HER2 expression by 21-gene assay with trastuzumab benefit was marginally nonsignificant (nonlinear p = 0.057). In hormone receptor-positive patients (local IHC) the association was significant (p = 0.002). The association was nonlinear with the greatest estimated benefit at lower and higher HER2 expression levels. CONCLUSIONS: Concordance among HER2 assessments by central IHC, FISH, and RT-PCR were similar and high. Association of HER2 mRNA expression with trastuzumab benefit as measured by time to distant recurrence was nonsignificant. A consistent benefit of trastuzumab irrespective of mHER2 levels was observed in patients with either IHC-positive or FISH-positive tumors. Trend for benefit was observed also for the small groups of patients with negative results by any or all of the central assays. TRIAL REGISTRATION: Clinicaltrials.gov NCT00005970 . Registered 5 July 2000.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Recidiva Local de Neoplasia/metabolismo , Receptor ErbB-2/metabolismo , Trastuzumab/farmacologia , Adolescente , Adulto , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Expressão Gênica , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/prevenção & controle , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trastuzumab/uso terapêutico , Resultado do Tratamento , Adulto Jovem
10.
Breast Cancer Res Treat ; 152(2): 389-98, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26119102

RESUMO

Validated biomarkers are needed to improve risk assessment and treatment decision-making for women with ductal carcinoma in situ (DCIS) of the breast. The Oncotype DX DCIS Score (DS) was shown to predict the risk of local recurrence (LR) in individuals with low-risk DCIS treated by breast-conserving surgery (BCS) alone. Our objective was to confirm these results in a larger population-based cohort of individuals. We used an established population-based cohort of individuals diagnosed with DCIS treated with BCS alone from 1994 to 2003 with validation of treatment and outcomes. Central pathology assessment excluded cases with invasive cancer, DCIS < 2 mm or positive margins. Cox model was used to determine the relationship between independent covariates, the DS (hazard ratio (HR)/50 Cp units (U)) and LR. Tumor blocks were collected for 828 patients. Final evaluable population includes 718 cases, of whom 571 had negative margins. Median follow-up was 9.6 years. 100 cases developed LR following BCS alone (DCIS, N = 44; invasive, N = 57). In the primary pre-specified analysis, the DS was associated with any LR (DCIS or invasive) in ER+ patients (HR 2.26; P < 0.001) and in all patients regardless of ER status (HR 2.15; P < 0.001). DCIS Score provided independent information on LR risk beyond clinical and pathologic variables including size, age, grade, necrosis, multifocality, and subtype (adjusted HR 1.68; P = 0.02). DCIS was associated with invasive LR (HR 1.78; P = 0.04) and DCIS LR (HR 2.43; P = 0.005). The DCIS Score independently predicts and quantifies individualized recurrence risk in a population of patients with pure DCIS treated by BCS alone.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Mastectomia Segmentar , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Carcinoma Intraductal não Infiltrante/epidemiologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Ontário/epidemiologia , Vigilância da População , Medição de Risco
11.
Cancer Cell ; 10(6): 515-27, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17157791

RESUMO

Recent studies suggest that thousands of genes may contribute to breast cancer pathophysiologies when deregulated by genomic or epigenomic events. Here, we describe a model "system" to appraise the functional contributions of these genes to breast cancer subsets. In general, the recurrent genomic and transcriptional characteristics of 51 breast cancer cell lines mirror those of 145 primary breast tumors, although some significant differences are documented. The cell lines that comprise the system also exhibit the substantial genomic, transcriptional, and biological heterogeneity found in primary tumors. We show, using Trastuzumab (Herceptin) monotherapy as an example, that the system can be used to identify molecular features that predict or indicate response to targeted therapies or other physiological perturbations.


Assuntos
Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Genômica , Humanos , Proteínas de Neoplasias/análise
12.
Diagnostics (Basel) ; 14(9)2024 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-38732326

RESUMO

Circulating tumor DNA (ctDNA) holds promise as a biomarker for predicting clinical responses to therapy in solid tumors, and multiple ctDNA assays are in development. However, the heterogeneity in ctDNA levels prior to treatment (baseline) across different cancer types and stages and across ctDNA assays has not been widely studied. Friends of Cancer Research formed a collaboration across multiple commercial ctDNA assay developers to assess baseline ctDNA levels across five cancer types in early- and late-stage disease. This retrospective study included eight commercial ctDNA assay developers providing summary-level de-identified data for patients with non-small cell lung cancer (NSCLC), bladder, breast, prostate, and head and neck squamous cell carcinoma following a common analysis protocol. Baseline ctDNA levels across late-stage cancer types were similarly detected, highlighting the potential use of ctDNA as a biomarker in these cancer types. Variability was observed in ctDNA levels across assays in early-stage NSCLC, indicative of the contribution of assay analytical performance and methodology on variability. We identified key data elements, including assay characteristics and clinicopathological metadata, that need to be standardized for future meta-analyses across multiple assays. This work facilitates evidence generation opportunities to support the use of ctDNA as a biomarker for clinical response.

13.
NEJM Evid ; 3(8): EVIDoa2300267, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-39041867

RESUMO

BACKGROUND: The 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown. METHODS: A patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry. RESULTS: RSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92). CONCLUSIONS: The 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.).


Assuntos
Neoplasias da Mama , Recidiva Local de Neoplasia , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Feminino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Pessoa de Meia-Idade , Idoso , Adulto , Fatores de Risco
14.
J Natl Cancer Inst ; 2024 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-39423142

RESUMO

BACKGROUND: There are currently no molecular tests to identify individual breast cancers where radiotherapy (RT) offers no benefit. Profile for the Omission of Local Adjuvant Radiotherapy (POLAR) is a 16-gene molecular signature developed to identify low risk cancers where RT will not further reduce recurrence rates. METHODS: An individual participant data meta-analysis was performed in 623 cases of node-negative ER+/HER2-negative early breast cancer enrolled in three RT randomized trials for whom primary tumor material was available for analysis. A Cox proportional hazards model on time to locoregional recurrence (LRR) was used to test the interaction between POLAR score and RT. RESULTS: 429 (69%) patients' tumors had a high POLAR score and 194 (31%) had a low score. Patients with high POLAR score had, in the absence of RT, a 10-year cumulative incidence of LRR: 20% (15%-26%) vs 5% (2%-11%) for those with a low score. Patients with a high POLAR score had a large benefit from RT (hazard ratio [HR] for RT vs no RT: 0.37 [0.23-0.60], p < .001). In contrast, there was no evidence of benefit from RT for patients with a low POLAR score (HR: 0.92 [0.42-2.02], p = .832). The test for interaction between RT and POLAR was statistically significant (p = .022). CONCLUSIONS: POLAR is not only prognostic for locoregional recurrence but also predictive of benefit from radiotherapy in selected patients. Patients ≥ 50 years with ER+/HER2-negative disease and a low POLAR score could consider omitting adjuvant RT. Further validation in contemporary clinical cohorts is required.

15.
J Clin Oncol ; 41(20): 3565-3575, 2023 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-37406456

RESUMO

PURPOSE: The 21-gene recurrence score (RS) assay quantifies the likelihood of distant recurrence in women with estrogen receptor-positive, lymph node-negative breast cancer treated with adjuvant tamoxifen. The relationship between the RS and chemotherapy benefit is not known. METHODS: The RS was measured in tumors from the tamoxifen-treated and tamoxifen plus chemotherapy-treated patients in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B20 trial. Cox proportional hazards models were utilized to test for interaction between chemotherapy treatment and the RS. RESULTS: A total of 651 patients were assessable (227 randomly assigned to tamoxifen and 424 randomly assigned to tamoxifen plus chemotherapy). The test for interaction between chemotherapy treatment and RS was statistically significant (P = .038). Patients with high-RS (≥ 31) tumors (ie, high risk of recurrence) had a large benefit from chemotherapy (relative risk, 0.26; 95% CI, 0.13 to 0.53; absolute decrease in 10-year distant recurrence rate: mean, 27.6%; SE, 8.0%). Patients with low-RS (< 18) tumors derived minimal, if any, benefit from chemotherapy treatment (relative risk, 1.31; 95% CI, 0.46 to 3.78; absolute decrease in distant recurrence rate at 10 years: mean, -1.1%; SE, 2.2%). Patients with intermediate-RS tumors did not appear to have a large benefit, but the uncertainty in the estimate can not exclude a clinically important benefit. CONCLUSION: The RS assay not only quantifies the likelihood of breast cancer recurrence in women with node-negative, estrogen receptor-positive breast cancer, but also predicts the magnitude of chemotherapy benefit.

16.
JCO Precis Oncol ; 7: e2200543, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37027813

RESUMO

PURPOSE: Circulating tumor DNA (ctDNA) has been validated across multiple indications in the adjuvant and surveillance settings. We evaluated whether targeted digital sequencing (TARDIS) may distinguish a partial response (PR) from a complete response (CR) among patients with metastatic renal cell carcinoma (mRCC) receiving immune checkpoint inhibitor (ICI) therapy. MATERIALS AND METHODS: Eligible patients had mRCC that yielded a PR or CR to ICI therapy. Peripheral blood was obtained at a single time point for ctDNA analysis. TARDIS was used for quantification of average variant allele fractions (VAFs). Our primary objective was to determine the association between VAFs and depth of response (PR v CR). A secondary objective was to determine whether VAFs were associated with disease progression. RESULTS: Twelve patients were analyzed, nine of whom achieved a PR (75%). Patients received either nivolumab monotherapy (50%) or nivolumab plus ipilimumab (50%). ctDNA analysis incorporated an average of 30 patient-specific mutations (range, 19-35); average coverage depth was 103,342 reads per target. TARDIS quantified a significant difference in VAFs between PR and CR (median, 0.181% [IQR, 0.077%-0.420%] v 0.007% [IQR, 0.0%-0.028%], respectively [P = .014]). Of the 12 patients in the series, six patients demonstrated radiographic progression subsequent to ctDNA assessment. Patients who progressed on subsequent scans had significantly higher ctDNA than those who maintained their response (median, 0.362% [IQR, 0.181%-2.71%] v 0.033% [IQR, 0.007%-0.077%], respectively [P = .026]). CONCLUSION: In this pilot study, TARDIS accurately differentiated PR from CR among patients with mRCC receiving immunotherapy, and also prospectively identified patients at risk for subsequent progression. Given these findings, we envision subsequent studies that validate these results and investigate the utility of this assay to discern appropriate candidates for discontinuation of immunotherapy.


Assuntos
Carcinoma de Células Renais , DNA Tumoral Circulante , Neoplasias Renais , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/genética , DNA Tumoral Circulante/genética , Nivolumabe/uso terapêutico , Projetos Piloto , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/genética , Neoplasias Renais/patologia , Imunoterapia/métodos
17.
Breast Cancer Res Treat ; 134(2): 683-92, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22547108

RESUMO

The present study was performed to evaluate the significance of biologic subtype and 21-gene recurrence score relative to local recurrence and local-regional recurrence after breast conservation treatment with radiation. Eastern Cooperative Oncology Group E2197 was a prospective randomized clinical trial that compared two adjuvant systemic chemotherapy regimens for patients with operable breast carcinoma with 1-3 positive lymph nodes or negative lymph nodes with tumor size >1.0 cm. The study population was a subset of 388 patients with known 21-gene recurrence score and treated with breast conservation surgery, systemic chemotherapy, and definitive radiation treatment. Median follow-up was 9.7 years (range = 3.7-11.6 years). The 10-year rates of local recurrence and local-regional recurrence were 5.4 % and 6.6 %, respectively. Neither biologic subtype nor 21-gene Recurrence Score was associated with local recurrence or local-regional recurrence on univariate or multivariate analyses (all P ≥ 0.12). The 10-year rates of local recurrence were 4.9 % for hormone receptor positive, HER2-negative tumors, 6.0 % for triple negative tumors, and 6.4 % for HER2-positive tumors (P = 0.76), and the 10-year rates of local-regional recurrence were 6.3, 6.9, and 7.2 %, respectively (P = 0.79). For hormone receptor-positive tumors, the 10-year rates of local recurrence were 3.2, 2.9, and 10.1 % for low, intermediate, and high 21-gene recurrence score, respectively (P = 0.17), and the 10-year rates of local-regional recurrence were 3.8, 5.1, and 12.0 %, respectively (P = 0.12). For hormone receptor-positive tumors, the 21-gene recurrence score evaluated as a continuous variable was significant for local-regional recurrence (hazard ratio 2.66; P = 0.03). The 10-year rates of local recurrence and local-regional recurrence were reasonably low in all subsets of patients. Neither biologic subtype nor 21-gene recurrence score should preclude breast conservation treatment with radiation.


Assuntos
Adenocarcinoma/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Recidiva Local de Neoplasia/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimiorradioterapia Adjuvante , Terapia Combinada , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Mastectomia Segmentar , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Transcriptoma
18.
Ann Surg Oncol ; 19(3): 1034-42, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21989664

RESUMO

BACKGROUND: The primary objectives of this work are to (1) quantitate tumor burden in sentinel lymph nodes (SLNs), and (2) assess the independent contributions of SLN tumor burden and primary melanoma thickness (PMT) with respect to progression-free survival (PFS) and overall survival (OS). METHODS: Sixty-three patients (41 male and 22 female) with one or more positive SLNs were available for review in this study, with median follow-up of 6.8 years. PMT was measured and SLN metastases were assessed for size, as maximum metastasis size (MMS) in mm, by hematoxylin and eosin (H&E) and immunohistochemistry (S100 and HMB45). PFS and OS were calculated from time of SLN resection until melanoma recurrence or death. Univariate and multivariate analyses and trend test were performed. RESULTS: Kaplan-Meier estimates of PFS and OS differed significantly by MMS (log-rank P = 0.031 for PFS and P = 0.016 for OS) and PMT (log-rank P = 0.036 for PFS and P < 0.001 for OS). After adjusting for age and gender, the hazard ratio (HR) associated with MMS was 1.09 per mm increase (P = 0.05) for PFS, and 6.30 (P = 0.014) and 5.41 (P = 0.048) for OS in patients, respectively, with MMS of 0.6-5.5 mm and MMS ≥5.5 mm compared with those with MMS <0.6 mm. When patients were stratified by their tumor characteristics of PMT, the risk for disease progression and worse OS was substantially higher for the group with PMT ≥ 4.5 mm (HR = 13.10 and P = 0.022 for PFS; HR = 17.26 and P < 0.001 for OS) relative to the baseline group with PMT <1.6 mm. All patients had completion lymph node dissection (CLND) except for four patients. Patients with positive CLND (14, 22.2%) showed significant worse PFS (P = 0.002) and OS (P = 0.0003) than the negative CLND group (45, 71.4%). CONCLUSIONS: PMT and MMS were independently prognostic of PFS and OS in melanoma patients. Patients with negative CLND had significantly better PFS and OS than those with positive CLND.


Assuntos
Linfonodos/patologia , Melanoma/patologia , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/patologia , Feminino , Humanos , Metástase Linfática , Masculino , Melanoma/mortalidade , Neoplasias Cutâneas/mortalidade , Taxa de Sobrevida
19.
Ann Surg Oncol ; 19(12): 3979-86, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22622474

RESUMO

PURPOSE: Macrophages play a major role in inflammatory processes and have been associated with poor prognosis in a variety of cancers, including breast cancer. Previously, we investigated the relationship of a subset of tumor-associated macrophages (PCNA(+) TAMs) with clinicopathologic characteristics of breast cancer. We reported that high PCNA(+) TAM counts were associated with hormone receptor (HR)-negative, high-grade tumors and early recurrence. To further understand the significance of elevated PCNA(+) TAMs and the functionality of TAMs, we examined the expression of S100A8/S100A9 with the antibody Mac387. The heterodimeric S100A8/S100A9 complex plays a role in inflammation and is increased in several cancer types. METHODS: We performed immunohistochemistry using the Mac387 antibody on 367 invasive human breast cancer cases. Results were compared to previous PCNA(+) TAM counts and were correlated with patient outcomes adjusting for HR status and histologic grade. RESULTS: Like PCNA(+) TAMs, high Mac387 counts were associated with HR negativity, high tumor grade, younger age, and decreased recurrence-free survival. Mac387, however, appears to identify both a subset of macrophages and a subset of tumor cells. The concordance between Mac387 and PCNA(+) TAM counts was low and cases that had both high Mac387 and high PCNA(+) TAMs counts had a stronger association with early recurrence. CONCLUSIONS: The presence of high numbers of PCNA(+) TAMs and Mac387-positive cells in breast cancers with poor outcomes may implicate a subset of TAMs in breast cancer pathogenesis, and may ultimately serve to develop potential cellular targets for therapeutic interventions.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Macrófagos/patologia , Recidiva Local de Neoplasia/mortalidade , Antígeno Nuclear de Célula em Proliferação/metabolismo , Adulto , Anticorpos Monoclonais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Calgranulina A/metabolismo , Calgranulina B/metabolismo , Feminino , Seguimentos , Humanos , Técnicas Imunoenzimáticas , Macrófagos/metabolismo , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida , Análise Serial de Tecidos
20.
J Gastrointest Oncol ; 13(1): 126-136, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35284101

RESUMO

Background: Individualized estimates of the risk of recurrence in colon cancer patients are needed that reflect current medical practice and available treatment options. Methods: Three validation studies of the 12-gene colon recurrence score assay were used with pre-specified patient-specific meta-analysis (PSMA) methods to integrate the 12-gene Oncotype DX Colon Recurrence Score result (RS) with the clinical and pathology risk factors stage, T-stage, mis-match repair (MMR) status, and number of nodes examined to calculate individualized recurrence risk estimates. Baseline risk estimation used the most recent studies, so the risk estimates reflect current medical practice. The effect of fluorouracil (5FU) was estimated with a meta-analysis of two studies. The effect of oxaliplatin was estimated using one of the RS assay validation studies, in which patients were randomized to 5FU with or without oxaliplatin. Results: The RS result and each of the clinical-pathologic factors provided independent prognostic information for recurrence. Among stage II, T3, MMR-proficient patients with ≥12 nodes examined (the most common scenario), patients with RS ≤30 (approximately 48%) have estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-deficient patients with ≥12 nodes examined, patients with RS ≤19 (approximately 14%) have an estimated 5-year recurrence risk ≤10% with surgery alone. Among stage IIIA/B, T3, MMR-proficient patients with ≥12 nodes examined, those with RS ≤14 (approximately 6%) have estimated 5-year recurrence risk ≤10% with 5FU alone. Discussion: The PSMA integrates the 12-gene colon RS result with clinical and pathology factors to provide individualized recurrence risk estimates that reflect current medical practice. The risk estimates are in a range that may help inform treatment decisions for a substantial number of stage II and stage III patients.

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