Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Mutação , Fulvestranto/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Receptores de Estrogênio/metabolismoRESUMO
BACKGROUND: Sacituzumab govitecan (SG) has been approved by FDA in April 2021 for pre-treated metastatic triple-negative breast cancer (mTNBC), following the ASCENT trial results. METHODS: We set up an ambispective bicentric cohort study to assess the real-world effectiveness and safety of SG in patients with mTNBC treated at Institut Curie Hospitals, with a focus on patients with brain metastases. RESULTS: This study included 99 patients treated through the French Early Access Program to SG from May 2021 to January 2023. Median age was 55 years [26-89], N = 8 patients (8%) had BRCA1/2 mutation, N = 12 (12%) de novo stage IV disease and N = 31 (31%) brain metastases. Patients had previously received a median of two [1-10] lines of treatment in advanced setting. After a median follow-up of 9.7 months, the median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95%CI[3.4-5.0]) and 8.6 months (95%CI[7.1-11.9]), respectively, while objective response rate was 29% (95%CI[21-39]). Among patients with brain metastases, median PFS and OS were 3.7 months (95%CI[2.6-6.2]) and 6.7 months (95%CI[6.3-NR]), respectively, with intracranial tumor responses. Dose reductions were required in N = 17 patients (17%) within a median of three [2-11] cycles, due to gastrointestinal toxicity (N = 6; 6%), hematological toxicity (N = 9; 9%) including febrile neutropenia (N = 2; 2%), liver enzyme elevation (N = 1; 1%), and physical deterioration (N = 1; 1%). There was no related death to SG. CONCLUSIONS: The observed response rate and safety of SG are consistent with the results of the ASCENT trial, with efficacy observed in patients with brain metastases, but observed PFS and OS are numerically shorter.
Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias Encefálicas , Camptotecina , Neoplasias de Mama Triplo Negativas , Humanos , Pessoa de Meia-Idade , Feminino , Adulto , Idoso , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Idoso de 80 Anos ou mais , Camptotecina/análogos & derivados , Camptotecina/uso terapêutico , Camptotecina/efeitos adversos , Camptotecina/administração & dosagem , França , Intervalo Livre de Progressão , Estudos Retrospectivos , ImunoconjugadosRESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, the STIC CTC trial established that, for choosing between endocrine therapy (ET) or chemotherapy, the use of circulating tumor cell (CTC) count is noninferior to the investigator's choice in terms of progression-free survival. Here, we report overall survival (OS) results, a secondary end point. Patients were randomly assigned in a 1:1 ratio to have their first-line treatment (ET or chemotherapy) determined by investigators or CTC count (chemotherapy if ≥ 5 CTCs/7.5 mL; ET if low CTC count; CellSearch). OS was assessed at the discontinuation of follow-up. After a median follow-up of 4.7 years, 382 deaths (50.6%) had occurred among 755 patients. Median OS was 51.3 months (95% CI, 46.8 to 55.1) in the CTC arm and 45.5 months (95% CI, 40.9 to 51.1) in the standard arm (hazard ratio [HR] for death, 0.85; 95% CI, 0.69 to 1.03; P = .11). Among 189 patients (25.0%) with ET recommended by clinicians and high CTC count, chemotherapy was superior to ET (HR for death, 0.53; 95% CI, 0.36 to 0.78; P = .001). In case of a discordant estimate, OS data demonstrate the clinical utility of CTC count.
Assuntos
Neoplasias da Mama , Células Neoplásicas Circulantes , Humanos , Feminino , Neoplasias da Mama/patologia , Células Neoplásicas Circulantes/metabolismo , Prognóstico , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The use of conventional methods (immunohistochemistry, pentaplex PCR) for detecting microsatellite instability (MSI), a predictive biomarker of immunotherapy efficacy, is debated for cancers with low MSI prevalence, such as breast cancer (BC). We developed two multiplex drop-off droplet digital PCR (ddPCR) assays targeting four microsatellites, initially identified from public BC whole-genome sequencing dataset. Performances of the assays were investigated and 352 tumor DNA and 28 circulating cell-free DNA from BC patients, with unknown MSI status were blindly screened. Cross-validation of ddPCR MSI status with other MSI detection methods was performed. We then monitored circulating tumor DNA (ctDNA) dynamics before and during pembrolizumab immunotherapy in one patient with MSI-high (MSI-H) metastatic BC. The assays showed high analytical specificity and sensitivity (limit of detection = 0.16%). Among N = 380 samples, seven (1.8%) were found as MSI-H by ddPCR with six of them confirmed by next-generation sequencing (NGS). Specificity was 100% in N = 133 microsatellite stable BC submitted to NGS. In the patient with MSI-H metastatic BC, ctDNA monitoring revealed an early decrease of microsatellite mutant allelic frequencies during immunotherapy. These results demonstrated MSI detection by ddPCR, a non-invasive, fast and cost-effective approach, allowing for large pre-screening of BC patients who may benefit from immunotherapy.
Assuntos
Neoplasias da Mama , DNA Tumoral Circulante , Neoplasias Colorretais , Humanos , Feminino , Instabilidade de Microssatélites , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , DNA Tumoral Circulante/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reação em Cadeia da Polimerase , Neoplasias Colorretais/genéticaRESUMO
BACKGROUND: CirCe01 trial aimed to assess the clinical utility of circulating tumour cell (CTC)-based monitoring in metastatic breast cancer (MBC) patients beyond the third line of chemotherapy (LC). METHODS: CirCe01 was a prospective, multicentre, randomised trial (NCT01349842) that included patients with MBC after two systemic LC. Patients with ≥5 CTC/7.5 mL (CellSearch®) were randomised between the CTC-driven and the standard arm. In the CTC arm, changes in CTC count were assessed at the first cycle of each LC; patients in whom CTC levels predicted early tumour progression had to switch to a subsequent LC. RESULTS: Greater than or equal to 5 CTC/7.5 mL were observed in N = 101/204 patients. In the CTC arm (N = 51), 43 (83%) and 18 (44%) patients completed CTC monitoring in the third and fourth lines, respectively, and 18 (42%) and 11 (61%) of these patients, respectively, had no CTC response. Thirteen (72%) and 5 (46%) of these patients underwent early switch to the next LC. Overall survival was not different between the two arms (hazard ratio = 0.95, 95% confidence interval = [0.6;1.4], p = 0.8). In subgroup analyses, patients with no CTC response who switched chemotherapy experienced longer survival than patients who did not. CONCLUSIONS: Due to the limited accrual and compliance, this trial failed to demonstrate the clinical utility of CTC monitoring. CLINICAL TRIAL REGISTRATION: NCT, NCT01349842, https://clinicaltrials.gov/ct2/show/NCT01349842 , registered 9 May 2011.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Lobular/secundário , Células Neoplásicas Circulantes/patologia , Idoso , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Carcinoma Lobular/sangue , Carcinoma Lobular/tratamento farmacológico , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
The prognostic role of circulating tumor cells (CTCs) has been clearly demonstrated in many types of cancer. However, their roles in diagnostic and treatment strategies remain to be defined. In this review, we present an overview of the current clinical validity of CTCs in nonmetastatic and metastatic cancer, and the main studies or concepts investigating the clinical utility of CTCs. In particular, we focus on breast, lung, colorectal, and prostate cancer. Two major topics concerning the clinical utility of CTC are discussed: treatment based on CTC count or CTC variations, and treatment based on the molecular characteristics of CTCs. Although some of these studies are inconclusive, many are still ongoing, and their results could help to define the role of CTCs in the management of cancers. A summary of published or ongoing phase II-III trials is also presented.
Assuntos
Células Neoplásicas Circulantes/patologia , Pesquisa Biomédica , Detecção Precoce de Câncer , Humanos , Células Neoplásicas Circulantes/metabolismo , Reprodutibilidade dos Testes , Células Tumorais CultivadasRESUMO
IMPORTANCE: The choice between chemotherapy and endocrine therapy as first-line treatment for hormone receptor-positive, ERBB2 (also known as HER2)-negative metastatic breast cancer is usually based on the presence of clinical features associated with a poor prognosis. In this setting, a high circulating tumor cell (CTC) count (≥5 CTCs/7.5 mL) is a strong adverse prognostic factor for overall survival and progression-free survival (PFS). OBJECTIVE: To compare the efficacy of a clinician-driven treatment choice vs a CTC-driven choice for first-line treatment. INTERVENTIONS: In the CTC arm, patients received chemotherapy or endocrine therapy according to the CTC count (chemotherapy if ≥5 CTCs/7.5 mL; endocrine therapy if <5 CTCs/7.5 mL), whereas in the control arm, the choice was left to the investigator. DESIGN, SETTING, AND PARTICIPANTS: In the STIC CTC randomized, open-label, noninferiority phase 3 trial, participants were randomized to a clinician-driven choice of first-line treatment or a CTC count-driven first-line treatment choice. Eligible participants were premenopausal and postmenopausal women 18 years or older diagnosed with hormone receptor-positive, ERBB2-negative metastatic breast cancer. Data were collected at 17 French cancer centers from February 1, 2012, to July 28, 2016, and analyzed June 2019 to October 2019. MAIN OUTCOME AND MEASURES: The primary end point was the investigator-assessed PFS in the per-protocol population, with a noninferiority margin of 1.25 for the 90% CI of the hazard ratio. RESULTS: Among the 755 women in the per-protocol population, the median (range) age was 63 (30-88) years [64 (30-88) years for the 377 patients allocated to the CTC arm and 63 (31-87) years for the 378 patients allocated to the standard arm]; 138 (37%) and 103 (27%) received chemotherapy, respectively. Median PFS was 15.5 months (95% CI, 12.7-17.3) in the CTC arm and 13.9 months (95% CI, 12.2-16.3) in the standard arm. The primary end point was met, with a hazard ratio of 0.94 (90% CI, 0.81-1.09). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that the CTC count may be a reliable biomarker method for guiding the choice between chemotherapy and endocrine therapy as the first-line treatment in hormone receptor-positive, ERBB2-negative metastatic breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01710605.
Assuntos
Neoplasias da Mama , Células Neoplásicas Circulantes , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Células Neoplásicas Circulantes/patologia , Prognóstico , Intervalo Livre de Progressão , Receptor ErbB-2 , Receptores de EstrogênioRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a current pandemic worldwide. This virus can reach all organs and disturbs the immune system, leading to a cytokine storm in severe forms. We aimed to report cutaneous features among coronavirus disease 2019 (COVID-19) hospitalized patients. METHODS: We performed a cross-sectional study on 1 given day among all patients hospitalized in acute care for COVID-19 and included all patients with cutaneous features. Follow-up 48 hours later was obtained. RESULTS: Among 59 adult patients hospitalized on the day of the study in an infectious diseases ward for SARS-CoV-2 infection who were confirmed by molecular assay and/or radiological findings (computed tomography scan), 40 were included. Several cutaneous manifestations were found: macular exanthema (80%), face edema (32%), livedo (13%), urticarial rash (8%), purpura (5%), oral lichenoid lesions (33%), and conjunctivitis (18%). Cutaneous biopsy was performed in 17 patients. Histological findings showed mast cell hyperplasia (100%), superficial perivascular infiltrate of lymphocytes (94%), and superficial edema (47%) consistent with capillary leak. CONCLUSIONS: Various dermatological signs can be encountered during COVID-19. A macular rash was the most frequent. All cutaneous features could be related to a vascular leak process.
RESUMO
PURPOSE: Previous cohort studies have reported plasma TK1 activity (pTKa) as a potential prognostic biomarker in estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer (MBC). In this prospective study, we report here the prognostic impact of pTKa in ER+/HER2- MBC patients treated with endocrine therapy and CDK4/6 inhibitor. EXPERIMENTAL DESIGN: Patients were included into the prospective, ethics committee-approved ALCINA study (NCT02866149). Eligibility criteria were patients with ER+/HER2- MBC treated at Institut Curie with endocrine therapy and palbociclib. Plasma samples were obtained at baseline and after 4 weeks of treatment. pTKa was quantified by the DiviTum® assay (Biovica, Sweden). RESULTS: From May 2016 to August 2018, 103 patients treated with endocrine therapy and palbociclib were included. Patients had received a median of two prior systemic therapies for MBC (range 0-14). Median follow-up was 13.8 months (range 6-31), with median PFS and OS of 9.6 months (95%CI [7.0-11.3]) and 28 months (95%CI [23-not reached]), respectively. Median baseline pTKa was 292 Du/L (range 20-27,312 Du/L, IQR [89-853]). After adjusting for other prognostic factors, baseline pTKa remained an independent prognostic factor for both PFS (HR = 1.3 95%CI [1.1-1.4], p = 0.0005) and OS (HR = 1.3 95%CI [1.2-1.6], p < 0.0001), and 4-week pTKa was associated with OS (HR = 1.6 95%CI [1.3-2], p < 0.0001). That survival prediction was significantly improved by the addition of baseline pTKa to clinicopathological characteristics. Adding pTKa changes at 4 weeks to baseline pTKa did not further increase survival prediction. CONCLUSION: This study demonstrates the clinical validity of pTKa as a new circulating prognostic marker in ER+/HER2- MBC patients treated with endocrine therapy and palbociclib.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Timidina Quinase/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Receptor alfa de Estrogênio/metabolismo , Feminino , Fulvestranto/administração & dosagem , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Metástase Neoplásica , Piperazinas/administração & dosagem , Prognóstico , Estudos Prospectivos , Piridinas/administração & dosagem , Receptor ErbB-2/metabolismo , Taxa de Sobrevida , Tamoxifeno/administração & dosagemRESUMO
HER3, a member of the EGFR family of receptor tyrosine kinases coded by the ERBB3 gene, plays an important role in cancer, despite its lack of intrinsic kinase activity. As with genes coding for potential heterodimeric partners of HER3, EGFR, and HER2, oncogenic mutations of ERBB3 have been explored by several studies. In this review, we discuss the evidence presenting ERBB3 somatic mutations as potential tumoral drivers. We then show that ERBB3 mutations are not uncommon in many cancer types. Finally, we present the recent results of several studies evaluating different therapeutic approaches for treating patients with oncogenic ERBB3 mutations.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinogênese/genética , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Receptor ErbB-3/genética , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinogênese/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Humanos , Camundongos , Terapia de Alvo Molecular/métodos , Mutação , Neoplasias/genética , Neoplasias/mortalidade , Neoplasias/patologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Multimerização Proteica/efeitos dos fármacos , Multimerização Proteica/genética , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/antagonistas & inibidores , Receptor ErbB-3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Resultado do Tratamento , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The management of patients with colorectal cancer (CRC) and potentially resectable liver metastases (LM) requires quick assessment of mutational status and of response to pre-operative systemic therapy. In a prospective phase II trial (NCT01442935), we investigated the clinical validity of circulating tumor cell (CTC) and circulating tumor DNA (ctDNA) detection. CRC patients with potentially resectable LM were treated with first-line triplet or doublet chemotherapy combined with targeted therapy. CTC (Cellsearch®) and Kirsten RAt Sarcoma (KRAS) ctDNA (droplet digital polymerase chain reaction (PCR)) levels were assessed at inclusion, after 4 weeks of therapy and before LM surgery. 153 patients were enrolled. The proportion of patients with high CTC counts (≥3 CTC/7.5mL) decreased during therapy: 19% (25/132) at baseline, 3% (3/108) at week 4 and 0/57 before surgery. ctDNA detection sensitivity at baseline was 91% (N=42/46) and also decreased during treatment. Interestingly, persistently detectable KRAS ctDNA (p=0.01) at 4 weeks was associated with a lower R0/R1 LM resection rate. Among patients who had a R0/R1 LM resection, those with detectable ctDNA levels before liver surgery had a shorter overall survival (p<0.001). In CRC patients with limited metastatic spread, ctDNA could be used as liquid biopsy tool. Therefore, ctDNA detection could help to select patients eligible for LM resection.
Assuntos
DNA Tumoral Circulante/sangue , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Células Neoplásicas Circulantes/patologia , Adulto , Idoso , Neoplasias Colorretais/cirurgia , Humanos , Estimativa de Kaplan-Meier , Biópsia Líquida , Pessoa de Meia-Idade , Mutação/genética , Metástase Neoplásica , Estudos Prospectivos , Proteínas Proto-Oncogênicas p21(ras)/genética , Resultado do TratamentoRESUMO
Desmoplastic small round cell tumor (DSRCT) is a rare and aggressive malignancy that occurs with unpredictable chemosensitivity and limited treatment options in the advanced setting. Prognosis is poor, and exploring new treatment options for such diseases is difficult because of its rarity. Clinical activity of trabectedin for advanced DSRCT was scarcely reported in the literature. Here, we report a series of six patients treated with trabectedin for an unresectable DSRCT. After receiving trabectedin, two patients had stable disease with a time to progression of 3 and 3.5 months; four patients experienced disease progression after one cycle, two of them could receive one and two patients another line regiment. Four patients experienced grade 3-4 adverse events, two grade 3 thrombocytopenia, and one neutropenic fever. Prognosis was poor with a median overall survival of 4 (range: 2-14) months. In our experience, trabectedin had limited activity in advanced DSRCT. Further studies are warranted to find effective treatments.