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1.
Zhonghua Bing Li Xue Za Zhi ; 49(11): 1152-1157, 2020 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-33152821

RESUMO

Objective To understand the effects and clinical significance of the 2019 guidelines for the human epidermal growth factor receptor 2 (HER2) detection. Methods: According to the 2014 guidelines, 548 cases of invasive breast cancer with equivocal HER2 (2+) detected by immunohistochemistry (IHC) in Taizhou Enze Medical Center, Zhejiang Province, China from 2013 to 2019 were selected. The results of IHC and HER2/CEPl7 double-probe were reevaluated and divided into groups according to the 2019 guidelines for the comparative analysis. Results: Among the 548 IHC HER2 (2+) invasive breast cancers, the number of positive, equivocal and negative cases for HER2 were 96 (17.52%), 81 (14.78%) and 371 (67.70%), respectively, according to the 2014 guidelines. However, according to the 2019 guidelines, 10 cases (1.82%) were reclassified as IHC 1+, 2 cases in the group 2 were reclassified as negative, and all the originally equivocal cases in group 4 were reclassified as negative. Finally, the total number of positive and negative cases for HER2 were 94 (17.15%) and 454 (82.85%), respectively. Conclusions: After applying the 2019 guidelines, the number of IHC 2+ cases decreases, and the positive rate for HER2 also decreases slightly due to the reevaluation change in groups 2 and 4, leading to reclassification of the cases that were deemed equivocal according to the 2014 guidelines. In general, the new 2019 guidelines are more reasonable and easier to use.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Biomarcadores Tumorais , Neoplasias da Mama/diagnóstico , China , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Receptor ErbB-2/genética
2.
Zhonghua Bing Li Xue Za Zhi ; 49(11): 1169-1173, 2020 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-33152824

RESUMO

Objective: To explore the relationship between the expression of human epidermal growth factor receptor 2 (HER2) in core needle biopsy (CNB) specimens before neoadjuvant chemotherapy (NAC) and post NAC Residual Cancer Burden (RCB) classification in breast cancer. Methods: This retrospective study included 150 patients with CNB proven invasive breast carcinoma in the Fourth Hospital of Hebei Medical University from January 2013 to January 2014. Immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) was used to detect the expression of HER2 in the CNB specimens. RCB was used to assess the chemotherapy response of patients. SPSS 21.00 and GraphPad Prism 8.0.1 were used for data statistics; Chi square test and Fisher's exact test for correlation analysis, and Cox regression for survival analysis. P<0.05 was considered statistically significant. Results: Among the 150 patients, there were 38 RCB-0, 12 RCB-Ⅰ, 61 RCB-Ⅱ and 39 RCB-Ⅲ post NAC. RCB-0 meant pathological complete response (PCR). Statistical analysis found that the pre NAC HER2 expression was related to PCR and RCB classification after surgery (r1=‒0.217,r2=‒0.282;P<0.05). Further analysis demonstrated that in the HER2-positive group, PCR was associated with prolonged OS and DFS (HR=2.939, 2.359; P<0.05); the differences of OS and DFS in RCB classifications were more significant (P<0.05) in the HER2 positive than HER2 negative groups. Conclusion: There is a correlation between pre NAC HER2 expression and PCR and RCB classification after treatment. In HER2-positive patients, the prognostic stratification of RCB classification is more obvious, suggesting that pre NAC HER2 overexpression combined with RCB classification after surgery can more accurately predict the prognosis.


Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Humanos , Hibridização in Situ Fluorescente , Neoplasia Residual , Prognóstico , Receptor ErbB-2/genética , Estudos Retrospectivos , Resultado do Tratamento
3.
Nat Commun ; 11(1): 5017, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024122

RESUMO

The survival and recurrence of residual tumor cells following therapy constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during relapse. We use cellular barcoding to monitor clonal dynamics during tumor recurrence in vivo. We find that clonal diversity decreases during tumor regression, residual disease, and recurrence. The recurrence of dormant residual cells follows several distinct routes. Approximately half of the recurrent tumors exhibit clonal dominance with a small number of subclones comprising the vast majority of the tumor; these clonal recurrences are frequently dependent upon Met gene amplification. A second group of recurrent tumors comprises thousands of subclones, has a clonal architecture similar to primary tumors, and is dependent upon the Jak/Stat pathway. Thus the regrowth of dormant tumors proceeds via multiple routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities.


Assuntos
Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Animais , Linhagem Celular Tumoral , Crizotinibe/farmacologia , Doxiciclina/farmacologia , Transição Epitelial-Mesenquimal/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Camundongos Nus , Recidiva Local de Neoplasia/tratamento farmacológico , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-met/genética , Receptor ErbB-2/genética , Análise de Célula Única , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Crit Rev Oncol Hematol ; 155: 103094, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33027724

RESUMO

Triple-negative breast cancer (TNBC) is a heterogeneous and complex disease characterized by the absence of immunohistochemical expression of estrogen receptor, progesterone receptor and HER2. These breast tumors present an aggressive biology and offer few opportunities to be treated with targeted therapy resulting in bad disease outcomes. The epidemiology of TNBC is intriguing where the understanding of its biology has progressed quickly. One of the peculiarities of this type of cancer is a high prevalence in Afrodescendants and Hispanic patients compared to Caucasian women. In this review we describe some features of TNBC, focusing in the Hispanic population, such as epidemiological, clinicopathological features and molecular features and the correlation between TNBC prevalence and the human development index.


Assuntos
Neoplasias de Mama Triplo Negativas , Feminino , Hispano-Americanos , Humanos , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Neoplasias de Mama Triplo Negativas/epidemiologia
5.
Am J Chin Med ; 48(6): 1475-1489, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32907364

RESUMO

Inadequate responses to traditional chemotherapeutic agents in cholangiocarcinoma (CCA) emphasize a requirement for new effective compounds for the treatment of this malignancy. This study aimed to investigate the antiproliferative property of cucurbitacin B on KKU-100 CCA cells. The determination of underlying molecular mechanisms was also carried out. The results revealed that cucurbitacin B suppressed growth and replicative ability to form colonies of CCA cells, suggesting the antiproliferative effect of this compound against the cells. Flow cytometry analysis demonstrated that the interfering effect of cucurbitacin B on the CCA cell cycle at the G2/M phase was accountable for its antiproliferation property. Accompanied with cell cycle disruption, cucurbitacin B altered the expression of proteins involved in the G2/M phase transition including downregulation of cyclin A, cyclin D1, and cdc25A, and upregulation of p21. Additional molecular studies demonstrated that cucurbitacin B suppressed the activation of focal adhesion kinase (FAK) which consequently resulted in inhibition of its kinase-dependent and kinase-independent downstream targets contributing to the regulation of cell proliferation including PI3K/PDK1/AKT and p53 proteins. In this study, the transient knockdown of FAK using siRNA was employed to ascertain the role of FAK in CCA cell proliferation. Finally, the effect of cucurbitacin B on upstream receptor tyrosine kinases regulating FAK activation was elucidated. The results showed that the inhibitory effect of cucurbitacin B on FAK activation in CCA cells is mediated via interference of EGFR and HER2 expression. Collectively, cucurbitacin B might be a promising drug for CCA treatment by targeting FAK protein.


Assuntos
Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Colangiocarcinoma/genética , Colangiocarcinoma/patologia , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Quinase Piruvato Desidrogenase (Transferência de Acetil)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Triterpenos/farmacologia , Proteína Supressora de Tumor p53/metabolismo , Neoplasias dos Ductos Biliares/dietoterapia , Linhagem Celular Tumoral , Colangiocarcinoma/tratamento farmacológico , Receptores ErbB/genética , Receptores ErbB/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Terapia de Alvo Molecular , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Triterpenos/uso terapêutico
6.
Lancet Oncol ; 21(10): 1296-1308, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32919527

RESUMO

BACKGROUND: Circulating tumour DNA (ctDNA) testing might provide a current assessment of the genomic profile of advanced cancer, without the need to repeat tumour biopsy. We aimed to assess the accuracy of ctDNA testing in advanced breast cancer and the ability of ctDNA testing to select patients for mutation-directed therapy. METHODS: We did an open-label, multicohort, phase 2a, platform trial of ctDNA testing in 18 UK hospitals. Participants were women (aged ≥18 years) with histologically confirmed advanced breast cancer and an Eastern Cooperative Oncology Group performance status 0-2. Patients had completed at least one previous line of treatment for advanced breast cancer or relapsed within 12 months of neoadjuvant or adjuvant chemotherapy. Patients were recruited into four parallel treatment cohorts matched to mutations identified in ctDNA: cohort A comprised patients with ESR1 mutations (treated with intramuscular extended-dose fulvestrant 500 mg); cohort B comprised patients with HER2 mutations (treated with oral neratinib 240 mg, and if oestrogen receptor-positive with intramuscular standard-dose fulvestrant); cohort C comprised patients with AKT1 mutations and oestrogen receptor-positive cancer (treated with oral capivasertib 400 mg plus intramuscular standard-dose fulvestrant); and cohort D comprised patients with AKT1 mutations and oestrogen receptor-negative cancer or PTEN mutation (treated with oral capivasertib 480 mg). Each cohort had a primary endpoint of confirmed objective response rate. For cohort A, 13 or more responses among 78 evaluable patients were required to infer activity and three or more among 16 were required for cohorts B, C, and D. Recruitment to all cohorts is complete and long-term follow-up is ongoing. This trial is registered with ClinicalTrials.gov, NCT03182634; the European Clinical Trials database, EudraCT2015-003735-36; and the ISRCTN registry, ISRCTN16945804. FINDINGS: Between Dec 21, 2016, and April 26, 2019, 1051 patients registered for the study, with ctDNA results available for 1034 patients. Agreement between ctDNA digital PCR and targeted sequencing was 96-99% (n=800, kappa 0·89-0·93). Sensitivity of digital PCR ctDNA testing for mutations identified in tissue sequencing was 93% (95% CI 83-98) overall and 98% (87-100) with contemporaneous biopsies. In all cohorts, combined median follow-up was 14·4 months (IQR 7·0-23·7). Cohorts B and C met or exceeded the target number of responses, with five (25% [95% CI 9-49]) of 20 patients in cohort B and four (22% [6-48]) of 18 patients in cohort C having a response. Cohorts A and D did not reach the target number of responses, with six (8% [95% CI 3-17]) of 74 in cohort A and two (11% [1-33]) of 19 patients in cohort D having a response. The most common grade 3-4 adverse events were raised gamma-glutamyltransferase (13 [16%] of 80 patients; cohort A); diarrhoea (four [25%] of 20; cohort B); fatigue (four [22%] of 18; cohort C); and rash (five [26%] of 19; cohort D). 17 serious adverse reactions occurred in 11 patients, and there was one treatment-related death caused by grade 4 dyspnoea (in cohort C). INTERPRETATION: ctDNA testing offers accurate, rapid genotyping that enables the selection of mutation-directed therapies for patients with breast cancer, with sufficient clinical validity for adoption into routine clinical practice. Our results demonstrate clinically relevant activity of targeted therapies against rare HER2 and AKT1 mutations, confirming these mutations could be targetable for breast cancer treatment. FUNDING: Cancer Research UK, AstraZeneca, and Puma Biotechnology.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , DNA Tumoral Circulante/sangue , Terapia de Alvo Molecular , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/antagonistas & inibidores , Receptor alfa de Estrogênio/genética , Feminino , Fulvestranto/uso terapêutico , Genótipo , Humanos , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Estudos Prospectivos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Quinolinas/uso terapêutico , Receptor ErbB-2/genética , Receptores Estrogênicos/antagonistas & inibidores , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Resultado do Tratamento
7.
Medicine (Baltimore) ; 99(33): e20996, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32871976

RESUMO

INTRODUCTION: Pure mucinous carcinoma is a rare type of breast carcinoma, but it usually has a favorable prognosis. Tumors of pure mucinous carcinoma are typically positive for both estrogen receptor (ER) and progesterone receptor (PR), and they do not commonly overexpress human epidermal growth factor receptor 2 (HER2). However, when tumors have HER2 overexpression and are progesterone receptor negative, the prognosis is worse. PATIENT CONCERNS: A 59-year-old female reported a slow growth mass of 3 years, which was radiologically diagnosed as fibroadenoma at another institution. The patient came to our institution for treatment and follow-up. She had no salient past history. DIAGNOSIS: Excisional biopsy revealed a pure mucinous breast carcinoma that was ER (100%, moderate-strong intensity), PR(-), 5% Ki-67 (+), and HER2(3+) by immunohistochemistry. The HER2 gene was found to be amplified by fluorescence in situ hybridization (FISH). The clinical staging was T2N0M0, with pathological grade I, subtype luminal B. INTERVENTIONS: After a modified radical mastectomy, she received four 21-day cycles of intravenous docetaxel (75 mg/m), intravenous cyclophosphamide (600 mg/m), and intravenous trastuzumab (8 mg/kg) (loading dose) on day 1 followed by 6 mg/kg every 3 weeks to complete a full year of treatment. She then received 2.5 mg of letrozole daily for 5 years. OUTCOMES: After following up for 2 years, the patient's outcome was survival without recurrence. Cardiac ultrasounds were performed every 3 months and there was no change in the left ventricular ejection fraction (LEVF). CONCLUSION: It is essential to correctly diagnose the ER(+), PR(-) HER2(+) subtype in mucinous carcinoma. This type should be treated with chemotherapy and anti-HER2 therapy, as well as aromatase inhibitor endocrine therapy.


Assuntos
Adenocarcinoma Mucinoso/genética , Adenocarcinoma Mucinoso/terapia , Neoplasias da Mama/genética , Neoplasias da Mama/terapia , Receptor ErbB-2/genética , Adenocarcinoma Mucinoso/diagnóstico , Adenocarcinoma Mucinoso/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Receptores Estrogênicos/genética , Receptores de Progesterona/genética
8.
Anticancer Res ; 40(10): 5557-5566, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988879

RESUMO

BACKGROUND/AIM: E- and P-cadherin (E-cadh, P-cadh) control tumor cell invasion, metastatic or stemness potential and chemotherapy resistance. The study aimed to assess E- and P-cadherin expression in breast cancer molecular subtypes. MATERIALS AND METHODS: Immunohistochemistry for E-cadh and P-cadh was performed for 97 breast cancer cases. Membrane (M), cytoplasmic (C) or mixed (MC) patterns of E-cadh and P-cadh were considered in our evaluation. RESULTS: E-cadh and P-cadh C pattern was significantly correlated in the HER2 subtype (p=0.031). P-cadh M pattern was highly specific for the HER2 subtype (p=0.002). Only P-cadh C characterized the triple negative breast cancer subtype (p=0.015). For Luminal B/HER2 cases, P-cadh M pattern was strongly coexpressed with the E-cadh MC pattern (p=0.012). Progesterone receptor (PR) expression influenced E-cadh M pattern in the Luminal B/HER2 subtype (p=0.042). CONCLUSION: E- and P-cadherins define distinct subgroups within breast cancer molecular subtypes. Our findings support the inclusion of E- and P-cadherin into breast cancer molecular classification.


Assuntos
Antígenos CD/genética , Biomarcadores Tumorais/genética , Caderinas/genética , Neoplasias de Mama Triplo Negativas/genética , Movimento Celular/genética , Proliferação de Células/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Invasividade Neoplásica/patologia , Células-Tronco Neoplásicas/metabolismo , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética , Neoplasias de Mama Triplo Negativas/classificação , Neoplasias de Mama Triplo Negativas/patologia
9.
Anticancer Res ; 40(10): 5649-5657, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988889

RESUMO

BACKGROUND: In recent years, GATA-binding protein 3 (GATA3) has been indicated as a marker showing good prognosis in breast cancer. In luminal breast cancer, which has good a prognosis, it shows more significant elevation in small-sized and low-grade tumors. In contrast, Ki-67 is defined as a poor prognostic factor. The aim of this study was to emphasise the prognostic importance of GATA3 and the inverse relationship with Ki-67. MATERIALS AND METHODS: In our study, 90 patients with invasive ductal breast cancer were immunohistochemically evaluated for Ki-67 and GATA3 expression. The relationship between GATA3 and Ki-67 expression was examined. In addition, the relationship between these two factors with estrogen, progesterone, human epidermal growth factor 2 receptor antibodies and other prognostic parameters such as disease-free survival and local recurrence was investigated. We accepted the level of ≥5% nüclear reaction as positive for GATA 3. A Ki-67 cut-off value of 20% was accepted as positive. RESULTS: In GATA3 positive breast cancers, good prognostic parameters were seen including high estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, small tumor size and low histological grade as well as low Ki-67 expression. In breast cancers showing high Ki-67 expression, ER, PR, and GATA3 positivity were lower and there was higher human epidermal growth factor receptor 2 (HER2) positivity and high histological grade while the tumor size was larger. CONCLUSION: Our study has revealed that GATA3 has an inverse relationship with Ki-67, whereas it has a positive releationship with good prognostic factors.


Assuntos
Carcinoma Ductal de Mama/genética , Fator de Transcrição GATA3/genética , Antígeno Ki-67/genética , Recidiva Local de Neoplasia/genética , Adulto , Biomarcadores Tumorais , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/patologia , Intervalo Livre de Doença , Estrogênios/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Progesterona/genética , Prognóstico , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética
10.
Anticancer Res ; 40(10): 5883-5893, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988919

RESUMO

BACKGROUND/AIM: Somatic mutations were investigated in 21 patients with postmenopausal estrogen receptor (ER)-positive and human epidermal growth factor receptor-2 (HER-2)-positive (ER+HER2+) breast cancer (BC) treated with neoadjuvant letrozole and lapatinib, to identify their distinct molecular landscape. PATIENTS AND METHODS: We used tissue samples of 21 patients from phase II Neo ALL-IN cohort, and somatic alterations were examined using targeted exome sequencing performed in Foundation Medicine, Inc. (FMI). RESULTS: TP53 (61.9%) and PIK3CA (57.1%) were the two most frequently mutated genes that were inter-correlated (p=0.026). They were associated with unfavorable clinical outcomes, particularly when accompanying PIK3CA mutations at exon 9 in helical domains. Meanwhile, MLL2 alteration was negatively associated with mutations of TP53 or PIK3CA, and it tended to be present in patients with low KI-67 levels and no initial nodal involvement. Moreover, patients with MLL2 mutations numerically showed more favorable overall response rates (ORR) (80% vs. 56.2%) and better 5-year event-free survival (EFS) rates (100% vs. 87.5%) compared to the wild-type. CONCLUSION: Mutations in TP53 and PIK3CA hotspot at exon 9 may be potential negative predictors of ER+HER2+ BC treated with neoadjuvant letrozole and lapatinib, while MLL2 inactivating mutation might confer therapeutic benefit in these patients.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/genética , Proteínas de Ligação a DNA/genética , Proteínas de Neoplasias/genética , Proteína Supressora de Tumor p53/genética , Idoso , Biomarcadores Tumorais/genética , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Lapatinib/administração & dosagem , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Mutação/genética , Intervalo Livre de Progressão , Receptor ErbB-2/genética
11.
PLoS One ; 15(8): e0236580, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32756609

RESUMO

Lung cancer is generally treated with conventional therapies, including chemotherapy and radiation. These methods, however, are not specific to cancer cells and instead attack every cell present, including normal cells. Personalized therapies provide more efficient treatment options as they target the individual's genetic makeup. The goal of this study was to identify the frequency of causal genetic mutations across a variety of lung cancer subtypes in the earlier stages. 833 samples of non-small cell lung cancer from 799 patients who received resection of their lung cancer, were selected for molecular analysis of six known mutations, including EGFR, KRAS, BRAF, PIK3CA, HER2 and ALK. A SNaPshot assay was used for point mutations and fragment analysis searched for insertions and deletions. ALK was evaluated by IHC +/- FISH. Statistical analysis was performed to determine correlations between molecular and clinical/pathological patient data. None of the tested variants were identified in most (66.15%) of cases. The observed frequencies among the total samples vs. only the adenocarcinoma cases were notable different, with the highest frequency being the KRAS mutation (24.49% vs. 35.55%), followed by EGFR (6.96% vs. 10.23%), PIK3CA (1.20% vs. 0.9%), BRAF (1.08% vs. 1.62%), ALK (0.12% vs. 0.18%), while the lowest was the HER2 mutation (0% for both). The statistical analysis yielded correlations between presence of a mutation with gender, cancer type, vascular invasion and smoking history. The outcome of this study will provide data that helps stratify patient prognosis and supports development of more precise treatments, resulting in improved outcomes for future lung cancer patients.


Assuntos
Adenocarcinoma/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Predisposição Genética para Doença , Prognóstico , Adenocarcinoma/classificação , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quinase do Linfoma Anaplásico/genética , Carcinoma Pulmonar de Células não Pequenas/classificação , Carcinoma Pulmonar de Células não Pequenas/epidemiologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Receptores ErbB/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptor ErbB-2/genética
12.
PLoS One ; 15(8): e0236896, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745119

RESUMO

Single-stranded DNA binding protein 2 (SSBP2) is ubiquitously expressed, with several studies reporting it to be a tumor suppressor. We investigated SSBP2 expression and its clinicopathological significance in gastric cancer. SSBP2 expression was examined by immunohistochemistry in 539 gastric cancer sections. The cases were divided into three subtypes, namely, Epstein-Barr virus-associated (EBV), microsatellite unstable, and others (microsatellite stable and EBV negative), based on the molecular classification of The Cancer Genome Atlas (TCGA). Cases were also divided into two subgroups according to the amplification status of human epidermal growth factor receptor 2 (HER2). Most cases showed SSBP2 positivity, and only 24 (4.5%) cases displayed negative nuclear expression. Loss of nuclear expression correlated significantly with high pT category (P = 0.001), nodal metastasis (P = 0.002), and stage of progression (P = 0.005), with no correlation between molecular characteristics and SSBP2 expression. All HER2 amplification cases displayed positive SSBP2 expression. Negative SSBP2 cases showed significantly shorter recurrence-free survival (RFS) compared to positive SSBP2 cases (P = 0.008). Loss of nuclear expression of SSBP2 was significantly associated with shorter RFS in the microsatellite stable and EBV negative groups (P = 0.002), as well as the HER2 negative group (P = 0.007). However, there were no statistically significant differences in multivariate analyses. Loss of nuclear expression of SSBP2 was a poor prognostic factor, associated with stage of progression and recurrence, and showed no significant difference in molecular characteristics, including TCGA subtype and HER2 status.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Receptor ErbB-2/genética , Neoplasias Gástricas , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Núcleo Celular/metabolismo , Proteínas de Ligação a DNA/genética , Feminino , Expressão Gênica , Herpesvirus Humano 4/isolamento & purificação , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/classificação , Neoplasias Gástricas/patologia , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
13.
Medicine (Baltimore) ; 99(32): e21457, 2020 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-32769873

RESUMO

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) gene amplification and mutations have emerged as oncogenic drivers and therapeutic targets not limited to breast and gastric cancers, but also in a variety of cancers. However, even if an actionable gene alteration is found, the incidence of HER2 amplification in these cancers is less than 5%. It is too difficult to conduct a conventional randomized, controlled trial in a rare fraction. Therefore, we have designed a organ-agnostic basket study, which covers a variety of solid cancers harboring HER2 amplification, in 1 study protocol. METHODS/DESIGN: This trial is a multicenter, single-arm, basket phase 2 study in Japan. Patients with solid cancers harboring HER2 amplification that have progressed with standard treatment, or rare cancers for which there is no standard treatment, will be eligible. Target cancers include bile duct, urothelial, uterine, ovarian, and other solid cancers where HER2 amplification is detected by comprehensive genomic profiling using next-generation sequencing technology. A total of 38 patients will be treated with combination therapy with trastuzumab and pertuzumab every 3 weeks until disease progression, unmanageable toxicity, death, or patient refusal. The primary endpoint is the objective response rate, and secondary endpoints are progression-free survival, overall survival, and duration of response. DISCUSSION: The aim of this trial is to evaluate the safety and efficacy of combination therapy with trastuzumab and pertuzumab in patients with locally advanced or metastatic, solid cancers harboring HER2 amplification. Instead of focusing on 1 organ type, our trial design uses a basket study focusing on HER2 amplification, regardless of the site or origin of the cancer. The results of our study will advance clinical and scientific knowledge concerning the treatment of locally advanced, rare solid cancers harboring HER2 amplification, using the combination of trastuzumab and pertuzumab. TRIAL REGISTRATION: This trial was registered in Japan Registry of Clinical Trials (jCRT) on February 25, 2019, as jRCT2031180150.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/genética , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Quimioterapia Combinada , Humanos , Japão , Estudos Multicêntricos como Assunto , Neoplasias/patologia
14.
APMIS ; 128(11): 573-582, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32860265

RESUMO

Human epidermal growth factor receptor 2 (HER2) gene status and overexpression, occurring in ~ 13.6% of primary breast cancers, is essential for identifying patients likely to benefit from biological treatment. In this method of evaluation study, we tested and compared the HER2 gene-protein assay (GPA) with routine HER2 immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The GPA was evaluated using 67 formalin-fixed paraffin-embedded (FFPE) HER2 equivoval IHC (2+) breast cancer tissue samples. Overall, agreement between GPA silver in situ hybridization (SISH) and FISH was 91.9% (57/62). Regression analysis revealed slightly higher, but non-significant difference in HER2/chromosome enumeration probe 17 (CEP17) ratio for GPA as compared to FISH (p = 0.074). Intraclass correlation coefficients (ICCs) of 0.94 and Spearman´s rank correlation coefficients of 0.93 (p < 0.0001) for FISH and GPA SISH suggested strong inter-observer association for methods with one observer counting on average 0.23 significant higher for GPA SISH (p = 0.014). Intra-observer IHC method reproducibility was 52.6% (κ = 0.3122, p = 0.004) and 79.7% (κ = 0.6428, p = 0.9197), suggesting fair significant and substantial non-significant difference between tests for reviewers. Inter-observer reproducibility for IHC methods was 53%. While inter-observer reproducibility for experienced IHC interpretation suggested significant differences (κ = 0.3636, p = 0.0332), unexperienced interpretation of IHC GPA suggested fair non-significant difference between reviewers (κ = 0.3101, p = 0.0747). Using FISH as reference, the diagnostic indices for GPA SISH were as follows: sensitivity 100%, specificity 95% and accuracy 92%. Inaccuracy between tests was in 80% of cases due to ISH categorization as equivocal by one of the methods. IHC results highlight that it may be beneficial with a method for simultaneously visualization of HER2 gene and protein status.


Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma/diagnóstico , Receptor ErbB-2/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma/genética , Carcinoma/patologia , Carcinoma/cirurgia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Metástase Linfática , Variações Dependentes do Observador , Análise Serial de Proteínas , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
15.
Cancer Treat Rev ; 88: 102064, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32622272

RESUMO

The overexpression of human epidermal growth factor receptor-2 (HER2) results in a biologically and clinically aggressive breast cancer (BC) subtype. Since the introduction of anti-HER2 targeted agents, survival rates of patients with HER2-positive metastatic BC have dramatically improved. Currently, although the treatment decision process in metastatic BC is primarily based on HER2 and hormone-receptor (HR) status, a rapidly growing body of data suggests that several other sources of biological heterogeneity may characterize HER2-positive metastatic BC. Moreover, pivotal clinical trials of new anti-HER2 antibody-drug conjugates showed encouraging results in HER2-low metastatic BC, thus leading to the possibility, in the near future, to expand the pool of patients suitable for HER2-targeted treatments. The present review summarizes and puts in perspective available evidence on biomarkers that hold the greatest promise to become potentially useful tools for optimizing HER2-positive metastatic BC patients' prognostic stratification and treatment in the next future. These biomarkers include HER2 levels and heterogeneity, HER3, intrinsic molecular subtypes by PAM50 analysis, DNA mutations, and immune-related factors. Molecular discordance between primary and metastatic tumors is also discussed.


Assuntos
Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Superfície Celular/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/biossíntese , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Feminino , Humanos , Metástase Neoplásica , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-3/biossíntese , Receptor ErbB-3/genética , Receptor ErbB-3/metabolismo
16.
Gene ; 759: 144970, 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-32711101

RESUMO

BACKGROUND: As a critical transcription factor, CBFB (core binding factor subunit ß) is frequently mutated in breast cancer and considered to be of significance in the pathogenesis of cancer. The objective of this study was to investigate CBFB mutation profiles and the relationship between CBFB mutations and clinicopathologic characteristics in breast cancer. METHODS: A total of 671 treatment-naive Chinese patients with invasive breast cancer at Guangdong Provincial People's Hospital (GDPH) were recruited in this study. CBFB mutation status were detected using the method of capture-based targeted sequencing. Correlation between CBFB mutations and clinicopathologic features were analyzed. Then, we compared the results between Chinese and western population by using Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort (n = 1979) and The Cancer Genome Atlas (TCGA) cohort (n = 925). RESULTS: The prevalence of CBFB mutation in GDPH cohort, METABRIC cohort, and TCGA cohort was 4.6% (31/671), 4.6% (92/1979), 2.5% (23/925), respectively. A hotspot mutation due to nucleotide thymine duplication or deletion occurring at the exon2/3 junction was detected in the GDPH and METABRIC cohorts. CBFB mutations were found to be significantly associated with the subtype of HR+/HER2- breast cancer (P = 0.008 in GDPH cohort and P<0.001 in METABRIC cohort), lower tumor grade (P = 0.004 in GDPH cohort and P<0.001 in METABRIC cohort), lower expression of Ki-67 protein (P<0.001 in GDPH cohort), but we didn't find similar results in TCGA cohort. In addition, CBFB in GDPH cohort was observed at a rather high mutation rate in invasive lobular carcinomas (4/18, 22.2%). Further, cox multivariate analysis demonstrated that CBFB was of independent prognosis significance in HR+/HER2- subgroup in METABRIC cohort (HR, 0.562; 95% CI, 0.399-0.790; P = 0.001). CONCLUSION: This study reveals race diversity of CBFB mutation spectrum in breast cancers. CBFB mutations mainly occur in HR+/HER2- breast cancer, and it may be a promising prognostic biomarker in HR+/HER2- subgroup.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Subunidade beta de Fator de Ligação ao Core/genética , Mutação , Adulto , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Receptor ErbB-2/genética
17.
Anticancer Res ; 40(8): 4567-4570, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727787

RESUMO

BACKGROUND/AIM: Historically, breast cancer has been treated according to an evaluation of biomarkers, such as the estrogen receptor and HER2 status. Recently, molecular profiling has been used to detect driver mutations and select anti-cancer treatment strategies. In addition to detecting pathogenic mutations, the total mutation count (tumor mutation burden) has been considered as another biomarker. MATERIALS AND METHODS: We performed molecular profiling of 143 breast cancer tissues obtained from resected tissues via surgical operation. RESULTS: Suspected germline mutations were detected in 10% of the patients with a higher somatic mutation ratio. CONCLUSION: As hypermutated breast cancers are more likely to benefit from certain anti-cancer treatment strategies, molecular profiling can be used as a biomarker.


Assuntos
Neoplasias da Mama/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Mutação em Linhagem Germinativa/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptores Estrogênicos/genética
18.
Proc Natl Acad Sci U S A ; 117(33): 20139-20148, 2020 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-32727899

RESUMO

Lung cancer causes more deaths annually than any other malignancy. A subset of non-small cell lung cancer (NSCLC) is driven by amplification and overexpression or activating mutation of the receptor tyrosine kinase (RTK) ERBB2 In some contexts, notably breast cancer, alternative splicing of ERBB2 causes skipping of exon 16, leading to the expression of an oncogenic ERBB2 isoform (ERBB2ΔEx16) that forms constitutively active homodimers. However, the broader implications of ERBB2 alternative splicing in human cancers have not been explored. Here, we have used genomic and transcriptomic analysis to identify elevated ERBB2ΔEx16 expression in a subset of NSCLC cases, as well as splicing site mutations facilitating exon 16 skipping and deletions of exon 16 in a subset of these lung tumors and in a number of other carcinomas. Supporting the potential of ERBB2ΔEx16 as a lung cancer driver, its expression transformed immortalized lung epithelial cells while a transgenic model featuring inducible ERBB2ΔEx16 specifically in the lung epithelium rapidly developed lung adenocarcinomas following transgene induction. Collectively, these observations indicate that ERBB2ΔEx16 is a lung cancer oncogene with potential clinical importance for a proportion of patients.


Assuntos
Carcinoma/genética , Predisposição Genética para Doença , Neoplasias Pulmonares/genética , Isoformas de Proteínas/genética , Receptor ErbB-2/metabolismo , Animais , Linhagem Celular Tumoral , Feminino , Humanos , Masculino , Camundongos , Ratos , Receptor ErbB-2/genética , Microambiente Tumoral
19.
Proc Natl Acad Sci U S A ; 117(28): 16500-16508, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601199

RESUMO

Despite the implementation of multiple HER2-targeted therapies, patients with advanced HER2+ breast cancer ultimately develop drug resistance. Stromal fibroblasts represent an abundant cell type in the tumor microenvironment and have been linked to poor outcomes and drug resistance. Here, we show that fibroblasts counteract the cytotoxic effects of HER2 kinase-targeted therapy in a subset of HER2+ breast cancer cell lines and allow cancer cells to proliferate in the presence of the HER2 kinase inhibitor lapatinib. Fibroblasts from primary breast tumors, normal breast tissue, and lung tissue have similar protective effects on tumor cells via paracrine factors. This fibroblast-mediated reduction in drug sensitivity involves increased expression of antiapoptotic proteins and sustained activation of the PI3K/AKT/MTOR pathway, despite inhibition of the HER2 and the RAS-ERK pathways in tumor cells. HER2 therapy sensitivity is restored in the fibroblast cocultures by combination treatment with inhibitors of MTOR or the antiapoptotic proteins BCL-XL and MCL-1. Expression of activated AKT in tumor cells recapitulates the effects of fibroblasts resulting in sustained MTOR signaling and poor lapatinib response. Lapatinib sensitivity was not altered by fibroblasts in tumor cells that exhibited sustained MTOR signaling due to a strong gain-of-function PI3KCA mutation. These findings indicate that in addition to tumor cell-intrinsic mechanisms that cause constitutive PI3K/AKT/MTOR pathway activation, secreted factors from fibroblasts can maintain this pathway in the context of HER2 inhibition. Our integrated proteomic-phenotypic approach presents a strategy for the discovery of protective mechanisms in fibroblast-rich tumors and the design of rational combination therapies to restore drug sensitivity.


Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Fibroblastos/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Serina-Treonina Quinases TOR/metabolismo , Apoptose/efeitos dos fármacos , Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Linhagem Celular Tumoral , Feminino , Fibroblastos/citologia , Fibroblastos/enzimologia , Humanos , Lapatinib/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/genética
20.
Nat Commun ; 11(1): 3377, 2020 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-32632100

RESUMO

The mammary gland is a highly vascularized tissue capable of expansion and regression during development and disease. To enable mechanistic insight into the coordinated morphogenic crosstalk between the epithelium and vasculature, we introduce a 3D microfluidic platform that juxtaposes a human mammary duct in proximity to a perfused endothelial vessel. Both compartments recapitulate stable architectural features of native tissue and the ability to undergo distinct forms of branching morphogenesis. Modeling HER2/ERBB2 amplification or activating PIK3CA(H1047R) mutation each produces ductal changes observed in invasive progression, yet with striking morphogenic and behavioral differences. Interestingly, PI3KαH1047R ducts also elicit increased permeability and structural disorganization of the endothelium, and we identify the distinct secretion of IL-6 as the paracrine cause of PI3KαH1047R-associated vascular dysfunction. These results demonstrate the functionality of a model system that facilitates the dissection of 3D morphogenic behaviors and bidirectional signaling between mammary epithelium and endothelium during homeostasis and pathogenesis.


Assuntos
Glândulas Mamárias Humanas/metabolismo , Morfogênese/genética , Mutação , Comunicação Parácrina/genética , Biomimética/métodos , Linhagem Celular , Células Cultivadas , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Células HEK293 , Humanos , Glândulas Mamárias Humanas/irrigação sanguínea , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Fenótipo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
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