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1.
Lancet ; 402(10409): 1251-1260, 2023 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-37805216

RESUMO

BACKGROUND: Multicancer early detection (MCED) blood tests can detect a cancer signal from circulating cell-free DNA (cfDNA). PATHFINDER was a prospective cohort study investigating the feasibility of MCED testing for cancer screening. METHODS: In this prospective cohort study done in oncology and primary care outpatient clinics at seven US health networks, a convenience sample of adults aged 50 years or older without signs or symptoms of cancer consented to MCED testing. We collected blood, analysed cfDNA, and returned results to participants' doctors. If a methylation signature indicative of cancer was detected, predicted cancer signal origin(s) informed diagnostic assessment. The primary outcome was time to, and extent of, diagnostic testing required to confirm the presence or absence of cancer. This trial is registered at ClinicalTrials.gov, NCT04241796, and is completed. FINDINGS: Between Dec 12, 2019, and Dec 4, 2020, we recruited 6662 participants. 4204 (63·5%) of 6621 participants with analysable results were women, 2417 (36·5%) were men, and 6071 (91·7%) were White. A cancer signal was detected in 92 (1·4%) of 6621 participants with analysable results. 35 (38%) participants were diagnosed with cancer (true positives) and 57 (62%) had no cancer diagnosis (false positives). Excluding two participants whose diagnostic assessments began before MCED test results were reported, median time to diagnostic resolution was 79 days (IQR 37-219): 57 days (33-143) in true-positive and 162 days (44-248) in false-positive participants. Most participants had both laboratory tests (26 [79%] of 33 with true-positive results and 50 [88%] of 57 with false-positive results) and imaging (30 [91%] of 33 with true-positive results and 53 [93%] of 57 with false-positive results). Fewer procedures were done in participants with false-positive results (17 [30%] of 57) than true-positive results (27 [82%] of 33) and few had surgery (one with a false-positive result and three with a true-positive result). INTERPRETATION: This study supports the feasibility of MCED screening for cancer and underscores the need for further research investigating the test's clinical utility. FUNDING: GRAIL.


Assuntos
Ácidos Nucleicos Livres , Neoplasias , Masculino , Humanos , Feminino , Estudos Prospectivos , Detecção Precoce de Câncer , Testes Hematológicos , Neoplasias/diagnóstico
2.
Cancers (Basel) ; 13(14)2021 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-34298717

RESUMO

To examine the extent of the evaluation required to achieve diagnostic resolution and the test performance characteristics of a targeted methylation cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test, ~6200 participants ≥50 years with (cohort A) or without (cohort B) ≥1 of 3 additional specific cancer risk factors will be enrolled in PATHFINDER (NCT04241796), a prospective, longitudinal, interventional, multi-center study. Plasma cfDNA from blood samples will be analyzed to detect abnormally methylated DNA associated with cancer (i.e., cancer "signal") and a cancer signal origin (i.e., tissue of origin). Participants with a "signal detected" will undergo further diagnostic evaluation per guiding physician discretion; those with a "signal not detected" will be advised to continue guideline-recommended screening. The primary objective will be to assess the number and types of subsequent diagnostic tests needed for diagnostic resolution. Based on microsimulations (using estimates of cancer incidence and dwell times) of the typical risk profiles of anticipated participants, the median (95% CI) number of participants with a "signal detected" result is expected to be 106 (87-128). Subsequent diagnostic evaluation is expected to detect 52 (39-67) cancers. The positive predictive value of the MCED test is expected to be 49% (39-58%). PATHFINDER will evaluate the integration of a cfDNA-based MCED test into existing clinical cancer diagnostic pathways. The study design of PATHFINDER is described here.

3.
Nat Commun ; 10(1): 4182, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519911

RESUMO

Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.


Assuntos
Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Carcinoma Ductal de Mama/metabolismo , Mutação/genética , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal de Mama/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proliferação de Células/fisiologia , Feminino , Imunofluorescência , Mutação em Linhagem Germinativa/genética , Humanos , Imuno-Histoquímica , Camundongos , Fator 1 de Transcrição de Linfócitos T/genética , Fator 1 de Transcrição de Linfócitos T/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo
4.
Cancer Discov ; 7(10): 1098-1115, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28652380

RESUMO

To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. ©2017 AACR.See related commentary by Speiser and Verdeil, p. 1062This article is highlighted in the In This Issue feature, p. 1047.


Assuntos
Neoplasias da Mama/imunologia , Carcinoma Ductal de Mama/imunologia , Carcinoma Intraductal não Infiltrante/imunologia , Perfilação da Expressão Gênica/métodos , Linfócitos T/imunologia , Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Complexo CD3/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal não Infiltrante/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Antígenos Comuns de Leucócito/genética , Receptor ErbB-2/genética , Microambiente Tumoral
5.
Fam Cancer ; 12(4): 651-6, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23584879

RESUMO

We evaluated the feasibility of an automated tablet computer application providing a family and personal history based cancer risk assessment for hereditary breast, ovarian, endometrial and colorectal cancers. 1,002 women presenting for screening mammography and 1,000 presenting for ultrasound were offered screening. The application calculated the risk of BRCA mutations using BRCAPRO, Myriad and Tyrer-Cuzick risk assessment models. Lifetime risk of breast and ovarian cancer was assessed with the BRCAPRO, Claus and Tyrer-Cuzick models. Colorectal and endometrial cancer risk was calculated via the MMRpro model. Patients were identified as high-risk based on thresholds 10% or greater risk for carrying genetic mutations or 20% or greater lifetime risk of breast or ovarian cancer. The percent of women found to be high-risk by a single risk assessment tool ranged from 0.5 to 5.3%. Combining assessment tools found 9.3% of women to be high-risk. The risk assessments performed similarly for the mammography and ultrasound cohorts with yields (combining assessment tools) of 9.2 and 9.4% respectively. The average ages of all the high-risk women were 45.8 and 39.6 years for the mammography and ultrasound cohorts respectively. Difficulties encountered included a need for software upgrade, wireless network unreliability and hardware theft. Automated family history screening can identify women probably at high-risk for hereditary cancers efficiently. The number of women identified is increased by employing multiple risk assessment models simultaneously. Surveying women in conjunction with ultrasound identified women at increased risk as effectively and at a younger age than with screening mammography.


Assuntos
Biomarcadores Tumorais/genética , Predisposição Genética para Doença , Mamografia , Síndromes Neoplásicas Hereditárias/diagnóstico , Autoavaliação (Psicologia) , Ultrassonografia , Adulto , Estudos de Coortes , Detecção Precoce de Câncer , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Síndromes Neoplásicas Hereditárias/genética , Prognóstico , Fatores de Risco
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