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1.
Clin Cancer Res ; 2021 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-34862246

RESUMO

PURPOSE: Accurate response assessment during neoadjuvant systemic treatment (NST) poses a clinical challenge. Therefore, a minimally-invasive assessment of tumor response based on cell-free circulating tumor DNA (ctDNA) may be beneficial to guide treatment decisions. EXPERIMENTAL DESIGN: We profiled 93 genes in tissue from 193 early breast cancer patients. Patient-specific assays were designed for 145 patients to track ctDNA during NST in plasma. ctDNA presence and levels were correlated with complete pathological response (pCR), residual cancer burden (RCB) as well as clinicopathologic characteristics of the tumor to identify potential proxies for ctDNA release. RESULTS: At baseline, ctDNA could be detected in 63/145 (43.4%) patients and persisted in 25/63 (39.7%) patients at mid-therapy (MT) and 15/63 (23.8%) patients at the end of treatment. ctDNA detection at MT was significantly associated with higher RCB (OR 0.062, 95% CI 0.01-0.48, P=0.0077).Out of 31 patients with detectable ctDNA at MT, 30 patients (96.8%) were non-responders (RCB II, n=8; RCB III, n=22) and only one patient responded to the treatment (RCB I). Considering all 145 patients with baseline (BL) plasma, none of the patients with RCB 0 and only 6.7% of patients with RCB I had ctDNA detectable at MT, while 30.6% and 29.6% of patients with RCB II/III, respectively, had a positive ctDNA result. CONCLUSION: Overall, our results demonstrate that the detection and persistence of ctDNA at MT may have the potential to negatively predict response to neoadjuvant treatment and identify patients who will not achieve pCR or be classified with RCB II/III.

2.
Exp Mol Pathol ; 123: 104685, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34560086

RESUMO

Detection of EGFR mutations from blood plasma represents a gentle, non-invasive alternative to rebiopsy and can therefore be used for therapy monitoring of non-small-cell lung cancer (NSCLC) patients. The aim of this project was to investigate whether the Reveal ctDNA™ 28 NGS assay (ArcherDX, Boulder, CO), has a comparable sensitivity and specificity to droplet digital PCR (ddPCR, gold-standard) and is therefore suitable for therapy monitoring of progressing lung cancer patients. First, we validated the NGS assay with a commercially available reference material (SeraCare, Massachusetts, US). Using an input of 22 ng, a sensitivity of 96% and a specificity of 100% could be achieved for variant allele frequencies (VAF) of 0.5%. For variants at a VAF of 0.1% the sensitivity was substantially reduced. Next, 28 plasma samples from 16 patients were analyzed and results were compared to existing ddPCR data. This comparative analysis of patient samples revealed a concordance of 91% between NGS and ddPCR. These results confirm that the Reveal ctDNA™ 28 NGS assay can be used for therapy monitoring of patients under TKI therapy. However, due to the slightly superior sensitivity of ddPCR, a combination of NGS (with broad coverage of a large number of genomic loci) and ddPCR (with targeted highly sensitive detection of specific mutations) might be the ideal approach.

3.
Clin Cancer Res ; 27(21): 5931-5938, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34380638

RESUMO

PURPOSE: To validate the clinical performance of the OncoMasTR Risk Score in the biomarker cohort of Austrian Breast and Colorectal Cancer Study Group (ABCSG) Trial 8. EXPERIMENTAL DESIGN: We evaluated the OncoMasTR test in 1,200 formalin-fixed, paraffin-embedded (FFPE) surgical specimens from postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative primary breast cancer with 0 to 3 involved lymph nodes in the prospective, randomized ABCSG Trial 8. Time to distant recurrence (DR) was analyzed by Cox models. RESULTS: The OncoMasTR Risk Score categorized 850 of 1,087 (78.2%) evaluable patients as "low risk". At 10 years, the DR rate for patients in the low-risk group was 5.8% versus 21.1% for patients in the high-risk group (P < 0.0001, absolute risk reduction 15.3%). The OncoMasTR Risk Score was highly prognostic for prediction of DR in years 0 to 10 in all patients [HR 1.91, 95% confidence interval (CI) 1.62-2.26, P < 0.0001; C-index 0.73], in patients that were node negative (HR 1.79, 95% CI, 1.43-2.24, P < 0.0001; C-index 0.72), and in patients with 1 to 3 involved lymph nodes (HR 1.93, 95% CI, 1.44-2.58, P < 0.0001; C-index 0.71). The OncoMasTR Risk Score provided significant additional prognostic information beyond clinical parameters, Ki67, Nottingham Prognostic Index, and Clinical Treatment Score. CONCLUSIONS: OncoMasTR Risk Score is highly prognostic for DR in postmenopausal women with ER-positive, HER2-negative primary breast cancer with 0 to 3 involved lymph nodes. In combination with prior validation studies, this fully independent validation in ABCSG Trial 8 provides level 1B evidence for the prognostic capability of the OncoMasTR Risk Score.

4.
Transl Lung Cancer Res ; 10(4): 1594-1607, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34012777

RESUMO

Background: Programmed cell death 1/programmed death ligand 1 (PD-1/PD-L1) immune-checkpoint blockade is a promising new therapeutic strategy in cancer. However, expression patterns and prognostic significance of PD-L1 and PD-1 are still controversial in human malignant pleural mesothelioma (MPM). Methods: Formalin-fixed paraffin-embedded (FFPE) tumor samples from 203 MPM patients receiving standard treatment without immunotherapy were collected from 5 European centers. PD-L1 and PD-1 expression of tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) were measured by immunohistochemistry and correlated with clinical parameters and long-term outcome. Results: High (>10%) PD-L1 TC and PD-1 TILs expressions were found in 18 (8%) and 39 (24%) patients, respectively. PD-L1 was rarely expressed by TILs [≥1%, n=13 (8%); >10%, n=1]. No significant associations were found between the PD-L1 or PD-1 expression of TCs or TILs and clinicopathological parameters such as stage or histological subtype. Notably, patients with high (>10%) TC-specific PD-L1 expression exhibited significantly worse median overall survival (OS) (6.3 vs. 15.1 months of those with low TC PD-L1 expression; HR: 2.51, P<0.001). In multivariate cox regression analysis adjusted for clinical parameters, high TC PD-L1 expression (>10%) proved to be an independent negative prognostic factor for OS (HR: 2.486, P=0.005). There was no significant correlation between PD-L1 or PD-1 expression of TILs and OS. Conclusions: In this multicenter cohort study, we demonstrate that high (>10%) PD-L1 expression of TCs independently predicts worse OS in MPM. Further studies are warranted to investigate the value of PD-L1/PD-1 expression as a marker for treatment response in MPM patients receiving immunotherapy.

5.
Biomolecules ; 11(5)2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919291

RESUMO

BACKGROUND: To assess the clinical relevance of genome-wide somatic copy-number alterations (SCNAs) in plasma circulating tumor DNA (ctDNA) from advanced epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma patients. METHODS: We included 43 patients with advanced EGFR T790M-positive lung adenocarcinoma who were treated with osimertinib after progression under previous EGFR-TKI therapy. We performed genomic profiling of ctDNA in plasma samples from each patient obtained pre-osimertinib and after patients developed resistance to osimertinib. SCNAs were detected by shallow whole-genome plasma sequencing and EGFR mutations were assessed by droplet digital PCR. RESULTS: SCNAs in resistance-related genes (rrSCNAs) were detected in 10 out of 31 (32%) evaluable patients before start of osimertinib. The presence of rrSCNAs in plasma before the initiation of osimertinib therapy was associated with a lower response rate to osimertinib (50% versus 81%, p = 0.08) and was an independent predictor for shorter progression-free survival (adjusted HR 3.33, 95% CI 1.37-8.10, p = 0.008) and overall survival (adjusted HR 2.54, 95% CI 1.09-5.92, p = 0.03). CONCLUSIONS: Genomic profiling of plasma ctDNA is clinically relevant and affects the efficacy and clinical outcome of osimertinib. Our approach enables the comprehensive assessment of SCNAs in plasma samples of lung adenocarcinoma patients and may help to guide genotype-specific therapeutic strategies in the future.


Assuntos
Adenocarcinoma de Pulmão/genética , DNA Tumoral Circulante/genética , Acrilamidas/uso terapêutico , Adenocarcinoma/patologia , Adenocarcinoma de Pulmão/metabolismo , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/uso terapêutico , Biomarcadores Farmacológicos/sangue , Carcinoma Pulmonar de Células não Pequenas/patologia , Ácidos Nucleicos Livres/sangue , Ácidos Nucleicos Livres/genética , Variações do Número de Cópias de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Biópsia Líquida/métodos , Pulmão/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico
7.
Clin Med Insights Oncol ; 15: 1179554921993072, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33642890

RESUMO

Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. Methods: Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

8.
Br J Cancer ; 124(11): 1795-1802, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33762716

RESUMO

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

9.
Target Oncol ; 16(1): 77-84, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33270169

RESUMO

BACKGROUND: The allele frequency of epidermal growth factor receptor (EGFR) mutations could be a potential molecular biomarker for the outcome of osimertinib therapy. OBJECTIVE: The purpose of our study was to assess the clinical relevance of the allele frequency of EGFR mutations in plasma-based circulating tumor DNA (ctDNA) before starting osimertinib therapy in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC) who had progressed under treatment with EGFR tyrosine kinase inhibitors (TKIs). PATIENTS AND METHODS: We enrolled 141 patients with advanced EGFR T790M-positive NSCLC who underwent second-line osimertinib treatment. Plasma ctDNA was tested for EGFR-activating mutations (EGFR deletions in exon 19, L858R, L861Q, S768I) and T790M by means of droplet digital polymerase chain reaction (ddPCR). RESULTS: The allele frequency of EGFR-activating mutations in plasma ctDNA before osimertinib initiation ranged from 0 to 81,543 copies/ml and was independently associated with progression-free survival (PFS) and overall survival (OS) after adjusting for known clinicopathological risk factors (PFS: adjusted hazard ratio [HR] 1.26, 95% confidence interval [CI] 1.15-1.39, P < 0.0001; OS: adjusted HR 1.32, 95% CI 1.18-1.47, P < 0.0001). The allele frequency of T790M in plasma ctDNA before starting osimertinib therapy ranged from 0 to 38,092 copies/ml. Multivariate analyses showed that a higher T790M allele frequency was associated with a trend towards a shorter PFS (adjusted HR 1.19, 95% CI 0.99-1.42, P = 0.05) and a significantly shorter OS (adjusted HR 1.25, 95% CI 1.02-1.53, P = 0.03) of the patients. CONCLUSION: A higher allele frequency of EGFR mutations, particularly EGFR-activating mutations, in plasma ctDNA is a poor prognostic marker. Further studies on the clinical utility of liquid biopsy are needed.


Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Frequência do Gene/genética , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Acrilamidas/farmacologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Compostos de Anilina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Receptores ErbB/metabolismo , Feminino , Genótipo , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Mutação , Inibidores de Proteínas Quinases/farmacologia , Análise de Sobrevida
10.
Anticancer Res ; 40(11): 6229-6236, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109560

RESUMO

BACKGROUND/AIM: To compare the GeneXpert® O6-methylguanine DNA methyltransferase (MGMT) methylation prototype (GX MGMT) assay with pyrosequencing in glioblastomas. MATERIALS AND METHODS: The MGMT methylation status was retrospectively assessed in formalin-fixed paraffin embedded (FFPE) tumor blocks from 262 glioblastoma patients obtained from three independent cohorts using either a standard of care pyrosequencing laboratory developed test or the GX MGMT assay. RESULTS: The concordance rate was 92.1% (58/63) for Oregon Health and Science University (OSHU) samples, 91.7% (88/96) for Medical University of Vienna (MUV) samples, and 82.5% (85/103) for Kepler University Hospital (KUH) samples. Patients with MGMT promoter hypermethylation assessed by pyrosequencing or the GX MGMT test had a significantly longer overall survival compared to patients without hypermethylation (HR=0.43, 95%CI=0.26-0.72, p=0.001 and HR=0.51, 95%CI=0.31-0.84, p=0.008, respectively). CONCLUSION: Standardized, simplified, and on-demand testing of MGMT promoter methylation by the GX MGMT assay is feasible.


Assuntos
Bioensaio/métodos , Neoplasias Encefálicas/genética , Metilação de DNA/genética , Metilases de Modificação do DNA/genética , Enzimas Reparadoras do DNA/genética , Glioblastoma/genética , Reação em Cadeia da Polimerase/métodos , Regiões Promotoras Genéticas , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Adulto Jovem
11.
ESMO Open ; 5(5): e000905, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32948629

RESUMO

BACKGROUND: Patients with metastatic breast cancer (MBC) have a considerable symptom burden and may require extensive care for a long period of time. Palliative care (PC) has the potential to improve their quality of care and reduce their use of medical services. However, the role of specialised PC (SPC) in patients with MBC remains unclear. PATIENTS AND METHODS: We performed a retrospective analysis of the medical records of patients diagnosed with breast cancer (BC) from 2008 to 2018 at an university-based referral centre to examine the extent of early and late integration of SPC services for patients with MBC. A descriptive analysis of the patients was also established. RESULTS: In all, 932 patients were diagnosed with BC from 2008 to 2018; 225 of these patients had or developed metastases related to their BC. In addition, 132 patients received SPC (58.7%) and 93 patients did not receive SPC (41.3%). The median probability of overall survival (OS) for patients who did not receive SPC services was 3.6 years (95% CI 2.0 to 5.1) and 1.8 years (95% CI 1.3 to 2.3) (p<0.0001) for patients who did receive SPC. In multivariate analysis, referral to SPC services was independently associated with OS (HR 1.60, 95% CI 1.16 to 2.22, p=0.004). CONCLUSION: Patients who received SPC lived significantly shorter amounts of time than patients not referred for SPC services at our hospital. We concluded that the referral to SPC services was often too late and should be implemented earlier in the course of the disease. We suggest that patients with MBC should participate in a consultation by a SPC team ≤60 days after the start of systemic palliative anticancer therapy in addition to endocrine treatment. Larger prospective studies are needed to evaluate the benefit of the early integration of SPC services for patients with MBC.


Assuntos
Neoplasias da Mama , Cuidados Paliativos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Feminino , Humanos , Prevalência , Encaminhamento e Consulta , Estudos Retrospectivos
12.
Eur J Cancer ; 134: 99-106, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32502940

RESUMO

BACKGROUND: Neoadjuvant chemotherapy (NaCT) and neoadjuvant endocrine therapy (NET) can reduce pre-operative tumour burden in patients with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early-stage breast cancer. This prospective translational study assessed the ability of a 12-gene molecular score (MS; EndoPredict®) to predict response to NaCT or NET within the ABCSG-34 trial. PATIENTS AND METHODS: Hormone receptor (HR)-positive, HER2-negative samples from patients in the ABCSG-34 randomized phase II trial were selected and EndoPredict testing was performed to generate a 12-gene MS. ABCSG-34 patients were assigned to receive either NaCT or NET based on menopausal status, HR expression, grade and Ki67. Response was measured by residual cancer burden (RCB). RESULTS: Patients selected for NaCT generally had high-risk disease by 12-gene MS (125/134), while slightly more patients treated with NET had low-risk disease (44/83). Low-risk NaCT-treated and high-risk NET-treated tumours responded poorly (NPV 100% [95% CI 66.4%-100%] and NPV 92.3% [95% CI 79.1%-98.4%], respectively]. The 12-gene MS significantly predicted treatment response for NaCT (AUC 0.736 [95% CI 0.63-0.84]) and NET (AUC 0.726 [95% CI 0.60-0.85]). CONCLUSIONS: The 12-gene MS predicted RCB after treatment with neoadjuvant therapies for patients with HR-positive, HER2-negative early-stage breast cancer. Tumours with low MS were unlikely to benefit from NaCT, whereas a high MS predicted resistance to NET. This additional biologic information can aid personalized treatment selection in daily practice and builds a strong rationale to use EndoPredict in biomarker-driven studies in the neoadjuvant setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos
13.
Cancers (Basel) ; 12(6)2020 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-32575418

RESUMO

Cancer cells activate a telomere maintenance mechanism like telomerase in order to proliferate indefinitely. Telomerase can be reactivated by gain-of-function Telomerase Reverse Transcriptase (TERT) promoter mutations (TPMs) that occur in several cancer subtypes with high incidence and association with diagnosis, prognosis and epigenetics. However, such information about TPMs in sporadic pancreatic neuroendocrine neoplasms (pNENs) including tumor (pNET) and carcinoma (pNEC) is less well defined. We have studied two hot spot TPMs and telomere length (TL) in pNEN and compared the results with clinicopathological information and proliferation-associated miRNA/HDAC expression profiles. DNA was isolated from formalin-fixed paraffin-embedded (FFPE) tissue of 58 sporadic pNEN patients. T allele frequency of C250T and C228T TPM was analyzed by pyrosequencing, relative TL as telomeric content by qPCR. In total, five pNEN cases (9%) including four pNETs and one pNEC were identified with TPMs, four cases with exclusive C250T as predominant TPM and one case with both C250T and C228T. T allele frequencies of DNA isolated from adjacent high tumor cell content FFPE tissue varied considerably, which may indicate TPM tumor heterogeneity. Overall and disease-free survival was not associated with TPM versus wild-type pNEN cases. Binary category analyses indicated a marginally significant relationship between TPM status and longer telomeres (p = 0.086), and changes in expression of miR449a (p = 0.157), HDAC4 (p = 0.146) and HDAC9 (p = 0.149). Future studies with larger patient cohorts are needed to assess the true clinical value of these rare mutations in pNEN.

14.
Clin Cancer Res ; 26(17): 4682-4687, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32561662

RESUMO

PURPOSE: Invasive lobular carcinoma (ILC) accounts for approximately 5%-15% of all invasive breast cancer cases. Most of the correlations between multigene assays and patient outcome were derived from studies based on patients with invasive ductal carcinoma (IDC) or without distinction between the subtypes. Here, we investigate the prognostic value of EndoPredict (EPclin) in a large cohort of ILCs pooled from three phase III randomized trials (ABCSG-6, ABCSG-8, TransATAC). EXPERIMENTAL DESIGN: The primary objective of this analysis was to determine the prognostic value of EPclin for distant recurrence (DR) in years 0-10 in postmenopausal women with ILC. The primary outcome was DR. RESULTS: 470 women (17.9%) presented with ILC, 1,944 (73.9%) with IDC, and 216 (8.2%) with other histologic types. EPclin was highly prognostic in women with ILC [HR = 3.32 (2.54-4.34)] and provided more prognostic value than the Clinical Treatment Score [CTS; HR = 2.17 (1.73-2.72)]. 63.4% of women were categorized into the low EPclin risk group and they had a 10-year DR of 4.8% (2.7-8.4) compared with 36.6% of women in the high-risk group with a 10-year DR risk of 26.6% (20.0-35.0). EPclin also provided highly prognostic information in women with node-negative disease [HR = 2.56 (1.63-4.02)] and node-positive disease [HR = 3.70 (2.49-5.50)]. CONCLUSIONS: EPclin provided highly significant prognostic value and significant risk stratification for women with ILC. Ten-year DR risk in the EPclin low-risk groups were similar between ILC and IDC. Our results show that EPclin is informative in women with ILC and suggest that it is equally valid in both histologic subtypes.


Assuntos
Neoplasias da Mama/mortalidade , Mama/patologia , Carcinoma Lobular/mortalidade , Recidiva Local de Neoplasia/epidemiologia , Idoso , Antineoplásicos Hormonais/uso terapêutico , Mama/cirurgia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Carcinoma Lobular/terapia , Quimioterapia Adjuvante/métodos , Ensaios Clínicos Fase III como Assunto , Conjuntos de Dados como Assunto , Intervalo Livre de Doença , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Estimativa de Kaplan-Meier , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/análise , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/análise , Receptores de Progesterona/metabolismo , Medição de Risco/métodos
15.
Clin Cancer Res ; 26(21): 5682-5688, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32546648

RESUMO

PURPOSE: To assess the predictive value of molecular breast cancer subtypes in premenopausal patients with hormone receptor-positive early breast cancer who received adjuvant endocrine treatment or chemotherapy. EXPERIMENTAL DESIGN: Molecular breast cancer subtypes were centrally assessed on whole tumor sections by IHC in patients of the Austrian Breast and Colorectal Cancer Study Group Trial 5 who had received either 5 years of tamoxifen/3 years of goserelin or six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF). Luminal A disease was defined as Ki67 <20% and luminal B as Ki67 ≥20%. The luminal B/HER2-positive subtype displayed 3+ HER2-IHC or amplification by ISH. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Cox models adjusted for clinical and pathologic factors. RESULTS: 185 (38%), 244 (50%), and 59 (12%) of 488 tumors were classified as luminal A, luminal B/HER2-negative and luminal B/HER2-positive, respectively. Luminal B subtypes were associated with poor outcome. Patients with luminal B tumors had a significantly shorter RFS [adjusted HR for recurrence: 2.22; 95% confidence interval (CI), 1.41-3.49; P = 0.001] and OS (adjusted HR for death: 3.51; 95% CI, 1.80-6.87; P < 0.001). No interaction between molecular subtypes and treatment was observed (test for interaction: P = 0.84 for RFS; P = 0.69 for OS). CONCLUSIONS: Determination of molecular subtypes by IHC is an independent prognostic factor for recurrence and death in premenopausal women with early-stage, hormone receptor-positive breast cancer but is not predictive for outcome of adjuvant treatment with tamoxifen/goserelin or CMF.See related commentary by Hunter et al., p. 5543.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Receptor ErbB-2/genética , Tamoxifeno/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/classificação , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Gosserrelina/administração & dosagem , Gosserrelina/efeitos adversos , Humanos , Metotrexato/administração & dosagem , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/classificação , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Pré-Menopausa/efeitos dos fármacos , Pré-Menopausa/genética , Intervalo Livre de Progressão , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Tamoxifeno/efeitos adversos
16.
Commun Biol ; 3(1): 252, 2020 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-32444775

RESUMO

Tumors have evolved mechanisms to escape anti-tumor immunosurveillance. They limit humoral and cellular immune activities in the stroma and render tumors resistant to immunotherapy. Sensitizing tumor cells to immune attack is an important strategy to revert immunosuppression. However, the underlying mechanisms of immune escape are still poorly understood. Here we discover Indoleamine-2,3-dioxygenase-1 (IDO1)+ Paneth cells in the stem cell niche of intestinal crypts and tumors, which promoted immune escape of colorectal cancer (CRC). Ido1 expression in Paneth cells was strictly Stat1 dependent. Loss of IDO1+ Paneth cells in murine intestinal adenomas with tumor cell-specific Stat1 deletion had profound effects on the intratumoral immune cell composition. Patient samples and TCGA expression data suggested corresponding cells in human colorectal tumors. Thus, our data uncovered an immune escape mechanism of CRC and identify IDO1+ Paneth cells as a target for immunotherapy.


Assuntos
Neoplasias Colorretais/patologia , Tolerância Imunológica/imunologia , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Neoplasias Intestinais/patologia , Celulas de Paneth/imunologia , Fator de Transcrição STAT1/fisiologia , Animais , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Neoplasias Intestinais/imunologia , Neoplasias Intestinais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Transl Lung Cancer Res ; 9(2): 239-245, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32420063

RESUMO

Background: Osimertinib has become standard therapy of advanced epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients and T790M-mediated resistance. We investigated the clinical utility of EGFR mutation tracking in plasma-based circulating tumor DNA (ctDNA) after start of osimertinib therapy in metastatic, EGFR-mutant NSCLC patients who had progressed on prior therapy with EGFR tyrosine kinase inhibitors (TKIs). Methods: We enrolled 141 patients with advanced EGFR-mutated NSCLC who underwent second-line osimertinib treatment for T790M-positive disease. After initiation of osimertinib, we obtained plasma samples from 108 patients. Plasma ctDNA was tested for EGFR mutations by means of droplet digital PCR and was termed positive if any EGFR mutation was detected. Results: Plasma ctDNA was detected in 58 of 108 (54%) patients after osimertinib initiation and was associated with poor progression-free survival (PFS) [hazard ratio (HR) 4.26, 95% confidence interval (CI): 2.55-7.10, P<0.0001] and overall survival (OS) (HR 3.23, 95% CI: 1.80-5.78, P<0.0001). In multivariable analysis, ctDNA status remained significantly associated with PFS and OS (HR 4.87, 95% CI: 2.81-8.44, P<0.0001; HR 3.49, 95% CI: 1.88-6.50, P<0.0001). Patients with persistence of activating EGFR mutations within eight weeks had shorter durations of PFS (HR 6.17, 95% CI: 3.03-12.56, P<0.0001) and OS (HR 4.83, 95% CI: 2.25-10.36, P<0.0001) than patients with total clearance of the activating EGFR mutation. Persistence of activating EGFR mutations in plasma ctDNA remained an independent predictor of poor PFS and OS in multivariable analyses. Conclusions: Patients with persistence of activating EGFR mutations in plasma ctDNA within eight weeks after osimertinib initiation have worse prognosis and may require the addition of chemotherapy or other treatments in order to achieve better outcome.

18.
Virchows Arch ; 477(4): 545-555, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32383007

RESUMO

Reliable determination of Ki67 labeling index (Ki67-LI) on core needle biopsy (CNB) is essential for determining breast cancer molecular subtype for therapy planning. However, studies on agreement between molecular subtype and Ki67-LI between CNB and surgical resection (SR) specimens are conflicting. The present study analyzed the influence of clinicopathological and sampling-associated factors on agreement. Molecular subtype was determined visually by Ki67-LI in 484 pairs of CNB and SR specimens of invasive estrogen receptor (ER)-positive, human epidermal growth factor (HER2)-negative breast cancer. Luminal B disease was defined by Ki67-LI > 20% in SR. Correlation of molecular subtype agreement with age, menopausal status, CNB method, Breast Imaging Reporting and Data System imaging category, time between biopsies, type of surgery, and pathological tumor parameters was analyzed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. CNB had a sensitivity of 77.95% and a specificity of 80.97% for identifying luminal B tumors in CNB, compared with the final molecular subtype determination after surgery. The correlation of Ki67-LI between CNB and SR was moderate (ROC-AUC 0.8333). Specificity and sensitivity for CNB to correctly define molecular subtype of tumors according to SR were significantly associated with tumor grade, immunohistochemical progesterone receptor (PR) and p53 expression (p < 0.05). Agreement of molecular subtype did not significantly impact RFS and OS (p = 0.22 for both). The identified factors likely mirror intratumoral heterogeneity that might compromise obtaining a representative CNB. Our results challenge the robustness of a single CNB-driven measurement of Ki67-LI to identify luminal B breast cancer of low (G1) or intermediate (G2) grade.


Assuntos
Neoplasias da Mama/química , Antígeno Ki-67/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia com Agulha de Grande Calibre , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Proteína Supressora de Tumor p53/análise
19.
Eur J Cancer ; 132: 43-52, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32325419

RESUMO

BACKGROUND: Immune-based strategies represent a promising approach in breast cancer (BC) treatment. The glycoprotein mucin-1 (MUC-1) is overexpressed in more than 90% of BC patients, and is targeted by the cancer vaccine tecemotide. We have investigated the efficacy and safety of tecemotide when added to neoadjuvant standard-of-care (SoC) treatment in early BC patients. PATIENTS AND METHODS: A total of 400 patients with HER2-early BC were recruited into this prospective, multicentre, randomised 2-arm academic phase II trial. Patients received preoperative SoC treatment (chemotherapy or endocrine therapy) with or without tecemotide. Postmenopausal women with oestrogen receptor (ER)+++, or ER++ and Ki67 < 14%, and G1,2 tumours ('luminal A' tumours) received 6 months of letrozole. Postmenopausal patients with triple-negative, ER-/+/++ and Ki67 ≥ 14%, and with G3 tumours, as well as premenopausal patients, received four cycles of epirubicin/cyclophosphamide plus four cycles of docetaxel. Primary end-point was residual cancer burden (RCB; 0/I versus II/III) at surgery. Secondary end-points included pathological complete response (pCR), safety, and quality of life. FINDINGS: We observed no significant difference in RCB 0/I rates between patients with (36.4%) and without (31.9%) tecemotide in the overall study population (p = 0.40) nor in endocrine and chemotherapy-treated subgroups (25.0% versus 13.3%, p = 0.17; 39.6% versus 37.8%, p = 0.75, respectively). The addition of tecemotide did not affect overall pCR rates (22.5% versus 17.4%, p = 0.23), MUC-1 expression, or tumour-infiltrating lymphocytes content. Tecemotide did not increase toxicity when compared to SoC therapy alone. INTERPRETATION: Neoadjuvant tecemotide is safe, but does not improve RCB or pCR rates in patients receiving standard neoadjuvant therapy.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Vacinas Anticâncer/uso terapêutico , Glicoproteínas de Membrana/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Segurança do Paciente , Prognóstico , Estudos Prospectivos , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
20.
Curr Opin Oncol ; 32(1): 68-77, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31714259

RESUMO

PURPOSE OF REVIEW: The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC). RECENT FINDINGS: NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine. SUMMARY: To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.


Assuntos
Neoplasias Pulmonares/diagnóstico , Biópsia/métodos , Heterogeneidade Genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/terapia , Medicina de Precisão/métodos
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