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1.
Hematol Oncol Clin North Am ; 37(1): 103-115, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36435604

RESUMO

Systemic therapy for both early-stage and metastatic human epidermal growth factor receptor-2-positive (HER2+) breast cancer has seen significant evolution over the last 20 or more years. Innovative trials leveraging the prognostic and predictive information that neoadjuvant chemotherapy provides has led to preoperative systemic therapy becoming the overwhelmingly favored sequencing in the early-stage setting. However, deintensification of therapy is important to consider for patients with good-risk disease or significant comorbidities. Finally, with the abundance of newly approved agents, drug sequencing in the second-line setting has become an important and individualized decision for patients with metastatic disease.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Terapia Neoadjuvante , Quimioterapia Adjuvante , Prognóstico
2.
Target Oncol ; 17(6): 655-663, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36342619

RESUMO

BACKGROUND: DESTINY-Breast01 (NCT03248492) is a phase II single-arm trial evaluating trastuzumab deruxtecan (T-DXd) in adults with human epidermal growth factor receptor 2-positive (HER2+) unresectable or metastatic breast cancer (u/mBC) who have received two or more prior anti-HER2 therapies. OBJECTIVES: Objectives were to explore approaches for estimating long-term overall survival (OS) with T-DXd from immature data (June 2020 data-cut; median follow-up 20.5 months), and compare predicted long-term outcomes with UK-recommended non-targeted therapies eribulin, capecitabine, and vinorelbine. METHODS: Two methods were used to model T-DXd long-term OS: (1) applying a hazard ratio (HR) to the OS curve for another HER2 targeted therapy (third-line trastuzumab emtansine [T-DM1]) with longer trial follow-up; and (2) extrapolating T-DXd OS data directly. Comparator OS was based on direct extrapolation of published data (comparison with vinorelbine OS was not possible). Quality-adjusted life years (QALYs) were calculated using a previously published model of utility. RESULTS: Both extrapolation methods demonstrated longer mean/median OS with T-DXd versus eribulin, and capecitabine (44.7/32.9 months [applying an HR to the T-DM1 OS curve]; 47.7/29.9 months [using direct extrapolation]; vs 11.3/9.2, and 17.8/13.6 months, respectively), translating to 2.3, 2.3, 0.6, and 0.9 discounted QALYs. CONCLUSION: Alternative methods produced consistent results, showing T-DXd is associated with substantial gains in OS and QALYs versus eribulin, and capecitabine. Modelled median OS results were similar to a later data-cut (median of 29.1 months, March 2021 data-cut). The modelling approach in which an HR was applied to the T-DM1 OS curve informed a submission to the National Institute for Health and Care Excellence.


Assuntos
Neoplasias da Mama , Adulto , Humanos , Feminino , Neoplasias da Mama/metabolismo , Capecitabina/farmacologia , Capecitabina/uso terapêutico , Receptor ErbB-2/metabolismo , Vinorelbina/farmacologia , Vinorelbina/uso terapêutico , Anticorpos Monoclonais Humanizados , Ado-Trastuzumab Emtansina
3.
BMJ Open ; 12(11): e065299, 2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36379662

RESUMO

OBJECTIVE: Neratinib plus capecitabine (Ner+Cap) were proved to be clinically beneficial as a third-line treatment for women with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer (MBC). The objective of this study was to evaluate the cost-effectiveness of Ner+Cap from the Chinese healthcare perspective. DESIGN: A three-state Markov simulation model was performed based on the results of NALA trial. The utilities of health state and disutilities of adverse events were derived from the published literature. Direct costs of anticancer agents, drug administration, routine follow-up and serious adverse events management were calculated in the model. Uncertainty was evaluated through univariate and probability sensitivity analysis. PARTICIPANTS: Patients with confirmed HER2-positive MBC who previously received at least two HER2-targeted treatments and were aged ≥18 years with an Eastern Cooperative Oncology Group performance status 0 or 1. A total of 621 patients were enrolled in the NALA trial. INTERVENTIONS: Third-line treatment with Ner+Cap or lapatinib plus capecitabine (Lap+Cap). MAIN OUTCOME MEASURES: The primary health outcomes of the model were costs, expected life-years (LYs), quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs). RESULTS: When compared with Lap+Cap, Ner+Cap provided an additional 0.431 LYs and 0.339 QALYs, and increased the cost by $4299.2. The corresponding ICERs were 9970.1/LY and $12 670.2/QALY. Univariate sensitivity analyses suggested that the results were generally robust. Besides, Ner+Cap had a 100% probability of being cost-effective according to probabilistic sensitivity analysis. CONCLUSIONS: Ner+Cap was likely to be a cost-effective regimen as the third-line therapy for women with HER2-positive MBC at the willingness-to-pay threshold of $37 653.0/QALY in China.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Adolescente , Adulto , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Capecitabina/uso terapêutico , China , Análise Custo-Benefício , Lapatinib/uso terapêutico , Anos de Vida Ajustados por Qualidade de Vida , Receptor ErbB-2/metabolismo , Ensaios Clínicos como Assunto
4.
Breast Cancer Res ; 24(1): 80, 2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36401316

RESUMO

PURPOSE: The vast majority of research studies that have described the links between DNA damage repair or homologous recombination deficiency (HRD) score, and tumor biology, have concerned either triple negative breast cancers or cancers with mutation of BRCA 1/2. We hypothesized that ER + /HER2- early breast tumors without BRCA 1/2 mutation could have high HRD score and aimed to describe their genomic, transcriptomic, and immune landscapes. PATIENTS AND METHODS: In this study, we reported BRCA 1/2 mutational status, HRD score, and mutational signature 3 (S3) expression, in all early breast cancer (eBC) subtypes from the TCGA database, with a particular focus in ER + /HER2-. In this subtype, bioinformatics analyses of tumor transcriptomic, immune profile, and mutational landscape were performed, according to HRD status. Overall survival (OS), progression free-interval (PFI), and variables associated with outcome were also evaluated. RESULTS: Among the 928 tumor samples analyzed, 46 harbored BRCA 1/2 mutations, and 606 were ER + /HER2- (of which 24 were BRCA 1/2 mutated). We found a subset of BRCA-proficient ER + /HER2- eBC, with high HRD score. These tumors displayed significantly different immune, mutational, and tumor molecular signatures landscapes, compared to BRCA-mutated and BRCA-proficient HRD-low tumors. Outcome did not significantly differ between these 3 groups, but biological factors associated with survival are not the same across the 3 entities. CONCLUSION: This study highlights possible novel biological differences among ER + /HER2- breast cancer related to HRD status. Our results could have important implications for translational research and/or the design of future clinical trials, but require prospective clinical evaluation.


Assuntos
Receptor ErbB-2 , Neoplasias de Mama Triplo Negativas , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Prospectivos , Genes BRCA2 , Genômica , Neoplasias de Mama Triplo Negativas/patologia
5.
Med Oncol ; 40(1): 16, 2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36352293

RESUMO

HER2 is an established prognostic and predictive marker for patients with invasive breast cancer. The clinical and biological significance of HER2 overexpression in patients with ductal carcinoma in situ (DCIS) remains poorly defined. DCIS is a heterogeneous disease and some patients with DCIS will not progress to invasive breast cancer. However, clinically significant recurrence rates have been reported after breast-conserving surgery for DCIS and approximately half of these cases will be life-threatening invasive recurrences. Since the incidence of DCIS is rising due to the widespread use of screening mammography, there is robust interest in selecting high-risk DCIS patients that may benefit from adjuvant therapies. Molecular prognostic and predictive models in early invasive breast cancer help clinicians identify patients that will benefit from chemotherapy. Molecular subtyping and profiling could also be useful in treating DCIS patients. According to current practice guidelines, HER2 testing is not recommended in DCIS patients. Nevertheless, evidence suggests that HER2-positive DCIS cases may be associated with adverse clinicopathological parameters and increased recurrence rates. This review summarizes the existing body of evidence linking HER2 expression and ipsilateral breast cancer recurrence in DCIS. HER2, as well as its correlation with other clinicopathological markers might be a useful prognostic and predictive marker, helping clinical decision-making in DCIS patients.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Humanos , Feminino , Carcinoma Intraductal não Infiltrante/genética , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Recidiva Local de Neoplasia/diagnóstico , Mamografia , Detecção Precoce de Câncer , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo
6.
Cancer J ; 28(6): 436-445, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36383906

RESUMO

ABSTRACT: The therapeutic landscape of patients with breast cancer has changed significantly with the introduction of antibody-drug conjugates (ADCs). Although human epidermal growth factor receptor 2 (HER2) has been the centerpiece of ADC development, potentially any surface antigen with differential expression between tumor and normal cells may be suitable for targeting with ADCs. Exploration of new targets is critical to expand the fraction of patients who can benefit from ADCs. Sacituzumab govitecan, an anti-trophoblast cell surface antigen 2 ADC, is the only non-anti-HER2 ADC approved for breast cancer to date, with several novel ADCs directed against novel targets (e.g., HER3, LIV-1) at various stages of preclinical and clinical development. The aim of this review is to provide an overview of clinical trials investigating ADCs targeting novel antigens. We discuss the optimal characteristics of the target to be exploited in ADCs' design and potential future challenges in the evolving field of ADCs such as biomarker assessment, patient selection, and sequencing of ADCs.


Assuntos
Neoplasias da Mama , Imunoconjugados , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico
7.
Nat Commun ; 13(1): 7043, 2022 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-36396665

RESUMO

Current therapies for HER2-positive breast cancer have limited efficacy in patients with triple-positive breast cancer (TPBC). We conduct a multi-center single-arm phase 2 trial to test the efficacy and safety of an oral neoadjuvant therapy with pyrotinib, letrozole and dalpiciclib (a CDK4/6 inhibitor) in patients with treatment-naïve, stage II-III TPBC with a Karnofsky score of ≥70 (NCT04486911). The primary endpoint is the proportion of patients with pathological complete response (pCR) in the breast and axilla. The secondary endpoints include residual cancer burden (RCB)-0 or RCB-I, objective response rate (ORR), breast pCR (bpCR), safety and changes in molecular targets (Ki67) from baseline to surgery. Following 5 cycles of 4-week treatment, the results meet the primary endpoint with a pCR rate of 30.4% (24 of 79; 95% confidence interval (CI), 21.3-41.3). RCB-0/I is 55.7% (95% CI, 44.7-66.1). ORR is 87.4%, (95% CI, 78.1-93.2) and bpCR is 35.4% (95% CI, 25.8-46.5). The mean Ki67 expression reduces from 40.4% at baseline to 17.9% (P < 0.001) at time of surgery. The most frequent grade 3 or 4 adverse events are neutropenia, leukopenia, and diarrhoea. There is no serious adverse event- or treatment-related death. This fully oral, chemotherapy-free, triplet combined therapy has the potential to be an alternative neoadjuvant regimen for patients with TPBC.


Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Terapia Neoadjuvante/métodos , Letrozol/uso terapêutico , Neoplasias da Mama/patologia , Antígeno Ki-67 , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico
8.
Rom J Morphol Embryol ; 63(2): 421-429, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36374147

RESUMO

Breast cancer (BrCa) is the most frequent malignancy in female, and lymph node metastases (LNM) is an important prognostic and therapeutic parameter. The molecular classification is nowadays largely applied to characterize the primary tumors, but few studies focused on the comparison between the molecular profiles of the primary with corresponding LNM. In the current work, we investigated the expression of conventional markers used by molecular classification in both primary tumors and axillary LNM. A series of 156 patients with BrCa was investigated, and from these 80 cases showed LNM. After routine pathological investigation, including the histopathological form and grade, we performed additional step sections from the primary and lymph nodes for immunohistochemistry. All procedures for hormone receptors, human epidermal growth factor receptor 2 (HER2), Ki67, cytokeratin 5 (CK5), epidermal growth factor receptor (EGFR), p53, E-cadherin, and B-cell leukemia∕lymphoma-2 (Bcl-2) were performed using the standard automated procedures. We found significant differences between the primary tumors and corresponding LNM in luminal A, luminal B, and basal-like carcinoma. No phenotypical interconversions were noticed in HER2 and unclassified BrCa. Our data demonstrate that in almost 20% of the cases the molecular profile of the primary does not overlap with aspects found in the lymph nodes. Our results strongly suggest performing the molecular classification in both primary tumors and in LNM. Current data suggest that the application of this diagnostic procedure will significantly influence the therapeutic strategy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Metástase Linfática/patologia , Neoplasias da Mama/patologia , Biomarcadores Tumorais/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Imuno-Histoquímica , Linfonodos/patologia
9.
Int J Mol Sci ; 23(21)2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36362083

RESUMO

Treatment for the HER2+ breast cancer subtype is still unsatisfactory, despite breakthroughs in research. The discovery of various new molecular mechanisms of transcription factors may help to make treatment regimens more effective. The transcription factor SALL4 has been related to aggressiveness and resistance therapy in cancer. Its molecular mechanisms and involvement in various signaling pathways are unknown in the HER2+ breast cancer subtype. In this study, we have evaluated the implication of SALL4 in the HER2+ subtype through its expression in patients' samples and gain and loss of function in HER2+ cell lines. We found higher SALL4 expression in breast cancer tissues compared to healthy tissue. Interestingly, high SALL4 expression was associated with disease relapse and poor patient survival. In HER2+ cell lines, transient overexpression of SALL4 modulates PI3K/AKT signaling through regulating PTEN expression and BCL2, which increases cell survival and proliferation while reducing the efficacy of trastuzumab. SALL4 has also been observed to regulate the epithelial-mesenchymal transition and stemness features. SALL4 overexpression significantly reduced the epithelial markers E-cadherin, while it increased the mesenchymal markers ß-catenin, vimentin and fibronectin. Furthermore, it has been also observed an increased expression of MYC, an essential transcription factor for regulating epithelial-mesenchymal transition and/or cancer stem cells. Our study demonstrates, for the first time, the importance of SALL4 in the HER2+ subtype and partial regulation of trastuzumab sensitivity. It provides a viable molecular mechanism-driven therapeutic strategy for an important subset of HER2-overexpressing patients whose malignancies are mediated by SALL4 expression.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Linhagem Celular Tumoral , Trastuzumab/uso terapêutico , Transição Epitelial-Mesenquimal/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo
10.
Cancer Cell ; 40(11): 1341-1357.e13, 2022 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-36379207

RESUMO

The leukocyte Fcγ receptor (FcγR)-mediated response is important for the efficacy of therapeutic antibodies; however, little is known about the role of FcγRs in other cell types. Here we identify a subset of fibroblasts in human breast cancer that express CD16 (FcγRIII). An abundance of these cells in HER2+ breast cancer patients is associated with poor prognosis and response to trastuzumab. Functionally, upon trastuzumab stimulation, CD16+ fibroblasts reduce drug delivery by enhancing extracellular matrix stiffness. Interaction between trastuzumab and CD16 activates the intracellular SYK-VAV2-RhoA-ROCK-MLC2-MRTF-A pathway, leading to elevated contractile force and matrix production. Targeting of a Rho family guanine nucleotide exchange factor, VAV2, which is indispensable for the function of CD16 in fibroblasts rather than leukocytes, reverses desmoplasia provoked by CD16+ fibroblasts. Collectively, our study reveals a role for the fibroblast FcγR in drug resistance, and suggests that VAV2 is an attractive target to augment the effects of antibody treatments.


Assuntos
Neoplasias da Mama , Receptores de IgG , Humanos , Feminino , Trastuzumab/farmacologia , Receptores de IgG/metabolismo , Fibroblastos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Matriz Extracelular/metabolismo , Receptor ErbB-2/metabolismo , Microambiente Tumoral , Proteínas Proto-Oncogênicas c-vav/genética , Proteínas Proto-Oncogênicas c-vav/metabolismo
11.
J Med Chem ; 65(22): 15123-15139, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36351049

RESUMO

To enhance the affinity of the human epidermal growth receptor 2 (HER2) targeted peptide developed previously, bispecific fusion peptides P1GCGT1 and P1GCGCGT1 were designed using an in silico approach. Molecular dynamic simulation showed that both peptides strongly interacted with HER2 domains II and IV. Compared with peptides targeting each single domain, P1GCGT1 and P1GCGCGT1 could bind to HER2 more significantly and targeted HER2-positive cells specifically. Additionally, both peptides were used to generate peptide-drug conjugates with camptothecin (CPT), among which I-1 and I-4 were screened for enhanced cellular activity and selectivity. Biological evaluation demonstrated that I-1 and I-4 induced cell apoptosis, promoted cell cycle arrestin S-phase, and inhibited Topo I activity. The binding affinity assay and confocal analysis revealed that I-1 and I-4 were effective at targeting HER2. Moreover, I-1 and I-4 showed better stability than single targeting peptide and presented enhanced antitumor activity and safety than CPT in tumor-bearing mice.


Assuntos
Neoplasias da Mama , Animais , Humanos , Camundongos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Linhagem Celular Tumoral , Camundongos Nus , Peptídeos/farmacologia , Peptídeos/uso terapêutico
12.
J Med Chem ; 65(22): 15358-15373, 2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36368007

RESUMO

Because of their rapid tumor accumulation and normal tissue clearance, single-domain antibody fragments (sdAbs) are an attractive vehicle for developing radiotherapeutics labeled with the α-emitter 211At. Herein, we have evaluated iso-[211At]AGMB-PODS, a prosthetic agent that combines a functionality for residualizing radiohalogens with a phenyloxadiazolyl methylsulfone (PODS) moiety for site-specific sdAb conjugation. Iso-[211At]AGMB-PODS and its radioiodinated analogue were evaluated for thiol-selective conjugation to anti-HER2 5F7 sdAb bearing a C-terminus GGC tail. Both radiohalogenated PODS-5F7GGC conjugates were synthesized in good radiochemical yields and retained high binding affinity on HER2-positive BT474 breast carcinoma cells. Iso-[211At]AGMB-PODS-5F7GGC was considerably more stable in vitro than its maleimide analogue in the presence of cysteine and human serum albumin (HSA) and exhibited excellent tumor uptake and high in vivo stability. Superior tumor-to-kidney activity ratios were seen for both radiohalogenated PODS-5F7GGC conjugates compared with [177Lu]Lu-DOTA-PODS-5F7GGC. These results suggest that iso-[211At]AGMB-PODS-5F7GGC warrants further evaluation for the treatment of HER2-expressing malignancies.


Assuntos
Neoplasias da Mama , Anticorpos de Domínio Único , Humanos , Feminino , Receptor ErbB-2/metabolismo , Distribuição Tecidual , Compostos Radiofarmacêuticos/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral
13.
BMC Cancer ; 22(1): 1168, 2022 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-36371187

RESUMO

INTRODUCTION: Gastric cancer is the most fifth common tumor worldwide. Human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis and clinical characteristics in gastric cancer. Nevertheless, the biology of HER2-low expression has not reported in gastric cancer. MATERIALS AND METHODS: A total of 157 patients with early-stage gastric cancer were retrospectively analyzed. The associations between HER-2 low expression and clinical characteristics were analyzed by Chi-square test. And the prognostic value of HER-2 low expression and clinical characteristics in disease-free survival (DFS) and overall survival (OS) were analyzed by univariate and multivariate Cox regression analysis. RESULTS: Of 157 patients with early-stage gastric cancer, 31.8% had HER2-low tumors and 50.3% had HER2-negative tumors. HER2-low expression was associated with age, histological differentiation, tumor location and Ki-67 index. However, HER2-low expression was not associated with DFS or OS in early-stage gastric cancer. CONCLUSION: HER2-low expression might result in distinct biology, but it was not an independent prognostic factor of DFS or OS in early-stage gastric cancer.


Assuntos
Neoplasias Gástricas , Humanos , Prognóstico , Estudos Retrospectivos , Receptor ErbB-2/metabolismo , Intervalo Livre de Doença
14.
EBioMedicine ; 85: 104320, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36374768

RESUMO

BACKGROUND: HER2DX is a prognostic and predictive assay in early-stage HER2-positive breast cancer based on clinical features and the expression of 4 gene signatures (immune, proliferation, luminal differentiation and HER2 amplicon), including ERBB2 mRNA levels. Here, we evaluated the ability of HER2DX to predict efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HER2-positive/hormone receptor-positive breast cancer. METHODS: HER2DX was evaluated on pre-treatment tumour samples from the PerELISA phase II study focused on postmenopausal patients with operable HER2-positive/hormone receptor-positive breast cancer. Patients received 2-weeks of letrozole, and then underwent a re-biopsy for Ki67 evaluation. Patients with endocrine therapy sensitive disease (ESD) (i.e., >20.0% Ki67 relative reduction at week 2) continued letrozole and 5 cycles of trastuzumab and pertuzumab. Primary aim was to test the ability of HER2DX risk-score, HER2DX pCR score and HER2DX ERBB2 mRNA score (as continuous variables and group categories) to predict pathological complete response (pCR) in patients with ESD. Logistic regression and receiver...operator curve (ROC) analysis assessed associations of HER2DX scores with pCR and ESD. FINDINGS: HER2DX was evaluated in 55 patients (86.0%) enrolled in PerELISA and 40 patients (73.0%) had ESD. The pCR rate in patients with ESD was 22.5% (9/40). In this group, HER2DX pCR score and HER2DX ERBB2 mRNA score were significantly associated with pCR (p.ß=.ß0.008 and p.ß=.ß0.003, univariate logistic regression model; area under ROC [AUC].ß=.ß0.803 and 0.896). The pCR rate in low, medium, and high HER2DX pCR score groups was 7.7% (2/26), 46.2% (6/13) and 100.0% (1/1), respectively. The pCR rate in low, medium, and high HER2DX ERBB2 score groups was 0.0% (0/12), 7.7% (1/13) and 53.3% (8/15), respectively. HER2DX pCR score was also significantly associated with Ki-67 response following 2-weeks of letrozole (p.ß=.ß0.002, univariate logistic regression model; AUC.ß=.ß0.775). The rate of ESD in low, medium, and high HER2DX pCR score groups was 89.7% (26/29), 65.0% (13/20) and 16.7% (1/6), respectively. INTERPRETATION: HER2DX predicts response following neoadjuvant letrozole in combination with dual HER2 blockade with trastuzumab and pertuzumab in early-stage HER2-positive/hormone receptor-positive breast cancer. FUNDING: This study received funding from Reveal Genomics.


Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Trastuzumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Antígeno Ki-67/genética , Letrozol/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , RNA Mensageiro/uso terapêutico , Genômica , Resultado do Tratamento
15.
Med Oncol ; 39(12): 258, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224475

RESUMO

HER2-positive breast cancer is an aggressive subtype of breast cancer with five-year survival rates of 30% for the advanced stage. The development of anti-HER2 treatments has led to a paradigm shift in the management and clinical outcomes of advanced HER2-positive breast cancer patients. The standard first-line treatment consists of taxane-based chemotherapy plus dual anti-HER2 therapies with trastuzumab and pertuzumab. The antibody-drug conjugate (ADC) ado-trastuzumab emtansine (T-DM1) has been a second-line therapeutic standard, but the second-line treatment approach is rapidly evolving. Given a substantial advantage of another ADC, Fam-trastuzumab deruxtecan (T-DXd), compared to T-DM1 in a recent randomized trial in the second-line setting, T-DXd is currently the preferred second-line option. Optimal third-line treatment strategies are still not established, and multiple approaches have been used including combinations based on capecitabine, trastuzumab, or both with oral anti-HER2 tyrosine kinase inhibitors. Tucatinib plus capecitabine and trastuzumab, lapatinib plus trastuzumab, neratinib or lapatinib plus capecitabine are some of the FDA approved combinations. Another newer agent approved for third- or later-line therapy in the metastatic setting is margetuximab, an Fc-engineered anti-HER2 monoclonal antibody, in combination with chemotherapy. Other novel agents currently under clinical trials are the drugs that indirectly target HER2, including immune cell cycle inhibitors, PI3K/mTOR inhibitors, and immunotherapy agents.


Assuntos
Neoplasias da Mama , Imunoconjugados , Maitansina , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/metabolismo , Capecitabina/uso terapêutico , Feminino , Humanos , Imunoconjugados/uso terapêutico , Lapatinib/uso terapêutico , Maitansina/efeitos adversos , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/metabolismo , Taxoides , Trastuzumab/efeitos adversos
16.
Medicine (Baltimore) ; 101(40): e30892, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36221359

RESUMO

Clinical trials have shown that trastuzumab (H) and pertuzumab (P) combined with chemotherapy as neoadjuvant therapy increased pathological complete response (pCR) rate of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, date in China in the real world are currently limited. Clinical data from patients with HER2-positive breast cancer who received HP combined with chemotherapy as neoadjuvant therapy at 2 institutions from March 2019 to February 2022 were retrospectively analyzed. Adverse reactions were evaluated using CTCAE version 5.0. The primary endpoint was total pathologic complete response (tpCR; ypT0/isypN0), and the secondary endpoints were breast pathologic complete response (bpCR; ypT0/is) and axillary pathologic complete response (apCR; ypN0). Factors influencing tpCR were also analyzed. A total of 302 patients were included in the analysis, of which 145 were treated with H + P + taxane + carboplatin (TcbHP), 94 with H + P + taxane (THP) and 63 with sequential anthracycline and cyclophosphamide, followed by H + P + taxane (AC-THP). The overall tpCR rate was 64.9%, and those of TcbHP, THP, and AC-THP were 73.1%, 52.1%, and 65.1%, respectively. The tpCR rate of the hormone receptor (HR) negative group (80.3%) was higher than that of the HR positive group (52.1%). The overall bpCR rate was 73.5% and the apCR rate was 75.8%. In the univariate analysis, HR, HER2 status and treatment regimen were related factors that affected tpCR. In the multivariate analysis, HR, HER2 status and treatment regimen were independent predictors of tpCR (P < .001, P < .001 and P = .009). The levels 3 and 4 toxicities rates of TcbHP were slightly higher than those of THP and AC-THP. HP combined with chemotherapy has achieved a high pCR rate. The TcbHP regimen had the highest pCR. HR-negative tumors demonstrated a higher pCR. HR, HER2 status and treatment regimen were independent predictors of tpCR. The adverse reactions are controllable.


Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Antraciclinas/uso terapêutico , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes , Carboplatina/uso terapêutico , Ciclofosfamida , Feminino , Hormônios/uso terapêutico , Humanos , Terapia Neoadjuvante/efeitos adversos , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Taxoides/uso terapêutico , Trastuzumab
17.
World J Surg Oncol ; 20(1): 338, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224558

RESUMO

BACKGROUND: The purpose of this study was to explore a new estrogen receptor (ER) and/or progesterone receptor (PR)+ and human epidermal growth factor receptor 2 (HER2)- breast cancer prognostic model, called the extended Cox prognostic model, for determining the cutoff values for multiple continuous prognostic factors and their interaction via the new model concept and variable selection method. METHODS: A total of 335 patients with ER/PR+ and HER2- breast cancer were enrolled for the final analysis. The primary endpoint was breast cancer-specific mortality (BCSM). Prognostic factors (histological grade, histological type, stage, T, N, lymphovascular invasion (LVI), P53, Ki67, ER, PR, and age) were included in this study. The four continuous variables (Ki67, ER, PR, and age) were partitioned into a series of binary variables that were fitted in the multivariate Cox analysis. A smoothly clipped absolute deviation (SCAD) variable selection method was used. Model performance was expressed in discrimination and calibration. RESULTS: We developed an extended Cox model with a time threshold of 164-week (more than 3 years) postoperation and developed a user-friendly nomogram based on our extended Cox model to facilitate clinical application. We found that the cutoff values for PR, Ki67, and age were 20%, 60%, and 41-55 years, respectively. There was an interaction between age and PR for patients aged ≥ 41 years and PR ≥ 20% at 164-week postoperation: the older the patients with ER/PR+, HER2-, and PR ≥ 20% were, the lower the survival and more likely to recur and metastasize exceeding 164 weeks (more than 3 years) after surgery. CONCLUSIONS: Our study offers guidance on the prognosis of patients with ER/PR+ and HER2- breast cancer in China. The new concept can inform modeling and the determination of cutoff values of prognostic factors in the future.


Assuntos
Neoplasias da Mama , Receptores de Progesterona , Biomarcadores Tumorais , Neoplasias da Mama/patologia , Feminino , Humanos , Antígeno Ki-67/metabolismo , Recidiva Local de Neoplasia , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Proteína Supressora de Tumor p53
18.
BMC Cancer ; 22(1): 1040, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-36195836

RESUMO

BACKGROUND: Overexpression of the EVI1 (ecotropic viral integration site 1) oncogene has recently been implicated as a prognostic factor in breast cancer (BC), particularly in triple-negative BC (TNBC). In this study we aimed to investigate frequency and clinical relevance of EVI1 expression in newly diagnosed BC treated with neoadjuvant chemotherapy. METHODS: EVI1 expression was determined by immunohistochemistry using H-score as a cumulative measurement of protein expression in pretherapeutic biopsies of BC patients treated with anthracycline/taxane based neoadjuvant chemotherapy within the GeparTrio trial. EVI1 was analyzed as a continuous variable and dichotomized into low or high based on median expression. Endpoints were pathological complete response (pCR), disease-free survival (DFS) and overall survival (OS). RESULTS: Of the 993 tumors analyzed, 882 had available subtype information: 50.8% were HR + /HER2-, 15% HR + /HER2 + , 9.8% HR-/HER2 + , and 24.5% TNBC. Median EVI1 H-score was 112.16 (range 0.5-291.4). High EVI1 expression was significantly associated with smaller tumor size (p = 0.002) but not with BC subtype. Elevated EVI1 levels were not significantly associated with therapy response and survival in the entire cohort or within BC subtypes. However, TNBC patients with high EVI1 showed a trend towards increased pCR rates compared to low group (37.7% vs 27.5%, p = 0.114; odds ratio 1.60 (95%CI 0.90-2.85, p = 0.110) and numerically better DFS (HR = 0.77 [95%CI 0.48-1.23], log-rank p = 0.271) and OS (HR = 0.76 [95% 0.44-1.31], log-rank p = 0.314) without reaching statistical significance. CONCLUSION: EVI1 was not associated with response to neoadjuvant therapy or patient survival in the overall cohort. Further analyses are needed to verify our findings especially in the pathological work-up of early-stage HER2-negative BC patients. TRIAL REGISTRATION: NCT00544765.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Feminino , Humanos , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/metabolismo , Taxoides , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
19.
Anticancer Res ; 42(10): 4879-4886, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36191996

RESUMO

BACKGROUND/AIM: This study describes a rare cell sorter (RCS) method to detect circulating tumor cells (CTCs) and CTC clusters in whole blood without pretreatment. PATIENTS AND METHODS: We collected samples from breast cancer patients at the University of Tsukuba Hospital. A total of 15 whole-blood specimens from patients with breast cancer were collected and analyzed via a microfluidics chip, fluorescence-conjugated antibody staining, and fluorescence microscopy. Of 15 total cases, eight were analyzed by RCS ver3 and seven were analyzed by RCS ver3.5 to reveal potential clinical differences in scanning methods. We then examined the HER2 status on 4 of the 15 patients using our RCS system. RESULTS: RCS efficiently detected all subtypes of CTCs and CTC clusters from the peripheral blood of cancer patients. The concordance rate of HER2 status between tissue and CTCs in 4 tested clinical samples was 100%. CONCLUSION: RCS is a non-invasive method that allows for simultaneous detection of CTCs, cluster presence, and surface marker (e.g., HER2) status. Frequent sampling is, thus, possible and the large amount of data obtained will be clinically useful to predict response to therapy as well as plan adjunct support therapies in cancer patients.


Assuntos
Neoplasias da Mama , Células Neoplásicas Circulantes , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Contagem de Células , Feminino , Citometria de Fluxo , Humanos , Células Neoplásicas Circulantes/patologia , Receptor ErbB-2/metabolismo
20.
Nat Commun ; 13(1): 6002, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36224176

RESUMO

In this multi-center phase II trial, we evaluated the efficacy and safety of a quadruplet regimen (pembrolizumab, trastuzumab, and doublet chemotherapy) as first-line therapy for unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer (AGC) (NCT02901301). The primary endpoints were recommended phase 2 dose (RP2D) for phase Ib and objective response rate (ORR) for phase II. The secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response, time to response and safety. Without dose-limiting or unexpected toxicities, the starting dose in the phase Ib trial was selected as RP2D. In 43 patients, the primary endpoint was achieved: the objective response rate was 76.7% (95% confidence interval [CI]: 61.4-88.2), with complete and partial responses in 14% and 62.8% of patients, respectively. The median progression-free survival, overall survival, and duration of response were 8.6 months, 19.3 months, and 10.8 months, respectively. No patients discontinued pembrolizumab because of immune-related adverse events. Programmed death ligand-1 status was not related to survival. Post hoc analyses of pretreatment tumor specimens via targeted sequencing indicated that ERBB2 amplification, RTK/RAS pathway alterations, and high neoantigen load corrected by HLA-B were positively related to survival. The current quadruplet regimen shows durable efficacy and safety for patients with HER2-positive AGC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Gástricas , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Trastuzumab/uso terapêutico
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