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INTRODUCTION: Immune checkpoint blockers have revolutionized the first-line treatment of advanced non-small-cell lung cancer (NSCLC). Pembrolizumab, an anti-PD-1 monoclonal antibody, is a standard therapy either alone or in combination with chemotherapy (chemo-IO). The current study explores the efficacy and safety of pembrolizumab with carboplatin and weekly paclitaxel in a cohort of frail patients. METHODS: A monocentric retrospective study was conducted between 22 September 2020 and 19 January 2023 regarding patients with stage IV NSCLC treated with chemo-IO combination: carboplatin (AUC 5 mg/mL/min; Q4W), weekly paclitaxel (90 mg/m2 on days 1, 8, and 15), and pembrolizumab (200 mg Q4W). The primary objective was real-world progression-free survival (rwPFS). Secondary objectives were overall survival (OS), toxicity profile, and outcomes based on histological subtype. RESULTS: A total of 34 patients (20 squamous and 14 non-squamous NSCLC) benefited from the chemo-IO regimen for frail patients; 41.9% had an ECOG-PS = 2. The median age was 75.5 years. We observed an overall response rate (ORR) of 55.9%. Notably, squamous NSCLC exhibited a significantly higher ORR (80%) than non-squamous NSCLC (21.4%); p = 0.001. The median rw-PFS was 10.6 months (95% CI [6.0, NA]), with 6- and 12-month rw-PFS rates of 69% and 45.8%, respectively. The median OS was not reached, with 12- and 18-month OS rates of 75.6% and 61.4%, respectively. The median number of maintenance cycles of pembrolizumab was 5 (0; 27). Nine patients (26.5%) experienced a toxicity related to chemotherapy leading to a reduction of the dose administered and, in five patients (14.7%), to the permanent discontinuation of chemotherapy. Six patients (17.6%) had an immune-related adverse event leading to the discontinuation of immunotherapy. DISCUSSION: Pembrolizumab plus carboplatin and weekly paclitaxel demonstrates promising efficacy and safety in frail patients with metastatic NSCLC, especially for ORR in sq-NSCLC. Prospective studies focusing on frail populations are warranted in order to validate these findings and optimize therapeutic strategies in the first-line setting.
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BACKGROUND: Circulating tumour cells (CTCs), circulating tumour DNA (ctDNA), and extracellular vesicles (EVs) are minimally invasive liquid biopsy biomarkers. This study investigated whether they predict prognosis, alone or in combination, in heterogenous unbiased non-small cell lung cancer (NSCLC) patients. METHODS: Plasma samples of 54 advanced NSCLC patients from a prospective clinical trial. CtDNA mutations were identified using the UltraSEEK™ Lung Panel (MassARRAY® technology). PD-L1 expression was assessed in small EVs (sEVs) using an enzyme-linked immunosorbent assay. RESULTS: At least one ctDNA mutation was detected in 37% of patients. Mutations were not correlated with overall survival (OS) (HR = 1.1, 95% CI = 0.55; 1.83, P = 0.980) and progression-free survival (PFS) (HR = 1.00, 95% CI = 0.57-1.76, P = 0.991). High PD-L1+ sEV concentration was correlated with OS (HR = 1.14, 95% CI = 1.03-1.26, P = 0.016), but not with PFS (HR = 1.08, 95% CI = 0.99-1.18, P = 0.095). The interaction analysis suggested that PD-L1+ sEV correlation with PFS changed in function of CTC presence/absence (P interaction = 0.036). The combination analysis highlighted worse prognosis for patients with CTCs and high PD-L1+ sEV concentration (HR = 7.65, 95% CI = 3.11-18.83, P < 0.001). The mutational statuses of ctDNA and tumour tissue were significantly correlated (P = 0.0001). CONCLUSION: CTCs and high PD-L1+ sEV concentration correlated with PFS and OS, but not ctDNA mutations. Their combined analysis may help to identify patients with worse OS. TRIAL REGISTRATION: NCT02866149, Registered 01 June 2015, https://clinicaltrials.gov/ct2/show/study/NCT02866149 .
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Carcinoma Pulmonar de Células não Pequenas , Vesículas Extracelulares , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Humanos , Carcinoma Pulmonar de Células não Pequenas/patologia , Prognóstico , Neoplasias Pulmonares/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Estudos Prospectivos , Vesículas Extracelulares/metabolismo , Biópsia Líquida , Biomarcadores Tumorais/genéticaRESUMO
Immune checkpoint inhibitors (ICIs) have been a major breakthrough in solid oncology over the past decade. The immune system and the gut microbiota are involved in their complex mechanisms of action. However, drug interactions have been suspected of disrupting the fine equilibrium necessary for optimal ICI efficacy. Thus, clinicians are facing a great deal of sometimes contradictory information on comedications with ICIs and must at times oppose conflicting objectives between oncological response and comorbidities or complications. We compiled in this review published data on the role of the microbiota in ICI efficacy and the impact of comedications. We found mostly concordant results on detrimental action of concurrent corticosteroids, antibiotics, and proton pump inhibitors. The timeframe seems to be an important variable each time to preserve an initial immune priming at ICIs initiation. Other molecules have been associated with improved or impaired ICIs outcomes in pre-clinical models with discordant conclusions in retrospective clinical studies. We gathered the results of the main studies concerning metformin, aspirin, and non-steroidal anti-inflammatory drugs, beta blockers, renin-angiotensin-aldosterone system inhibitors, opioids, and statins. In conclusion, one should always assess the necessity of concomitant treatment according to evidence-based recommendations and discuss the possibility of postponing ICI initiation or switching strategies to preserve the critical window.
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Palbociclib is a good candidate for therapeutic drug monitoring (TDM) due to its narrow therapeutic range and frequency of toxicities, particularly high-grade neutropenia. In this prospective, bicentric clinical trial, we evaluated the palbociclib exposure−toxicity relationship and determined the relevant sources of palbociclib pharmacokinetic variability, including drug−drug interactions (DDI). We followed 58 patients (mean age: 62.9 years) for 1 year. The geometric median of palbociclib plasma trough concentration (Ctrough) was 74.1 ng/mL. Neutropenia occurred in 70.7% of patients (high grade in 67.2% of patients). High-grade neutropenia occurrence during the first two palbociclib cycles was higher in patients with lower neutrophil count at initiation (p = 0.002). Palbociclib plasma Ctrough was correlated with high-grade neutropenia occurrence during the first two cycles (p = 0.024, OR 5.51). Co-treatment with agents that may interfere with palbociclib PK significantly influenced palbociclib Ctrough (p < 0.05). CYP3A4/P-glycoprotein inhibitors increased by 25% palbociclib Ctrough (p = 0.035), while antacids reduced it by 20% (p = 0.036). However, DDI did not have any significant effect on high-grade neutropenia occurrence (p > 0.05). This study confirms the major role of TDM to manage palbociclib safe use from the first week of treatment, particularly the significant incidence of hematological toxicity. Moreover, this first dedicated prospective study confirmed the importance of characterizing co-treatments to limit the DDI risk with oral-targeted therapies.
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INTRODUCTION: Oral targeted therapies (OTTs) are widely used for cancer management. However, there is no consensus on OTT dose adaptation in older patients with cancer. METHODS: This noninterventional, retrospective study was a real-life assessment of dose adaptation for six OTTs (afatinib, everolimus, palbociclib, pazopanib, sorafenib and sunitinib), at baseline and during treatment, and the reasons for the changes, in ≥70-year-old patients treated between February 2016 and August 2019. Data were compared with univariate models fitted with all variables. RESULTS: Among the 986 patients treated with OTT, the group of ≥70-year-old patients (n = 122) received afatinib (15.6%), everolimus (14.8%), palbociclib (50.8%), pazopanib (9.8%), sorafenib (5.8%) or sunitinib (3.2%). At baseline, the prescribed OTT dose was adapted (reduction) in 29% of ≥70-year-old patients (35/122). These 35 patients were significantly older (mean age 80 vs 74 years, P < .001), and more frequently had a performance status score ≥2 (P < .01) than the other patients (n = 87). In the standard dose group, higher toxicity grades (P = .18) and subsequent dose reduction (41% of patients, 36/87) tended to be more frequent compared with the baseline adapted dose group (26%, 9/35, P = .1). At the study end, 53% of patients in the whole cohort (65/122) were taking a lower dose than the recommended one. CONCLUSION: At OTT initiation, dose was adapted in 29% of older adults with cancer, rarely after a formal oncogeriatric evaluation (6.5% of all patients). In the absence of recommendations, clinical studies are needed to evaluate the efficacy and safety of baseline OTT dose reduction in older adults with cancer.
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Antineoplásicos , Carcinoma de Células Renais , Neoplasias Renais , Administração Oral , Afatinib/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Humanos , Indóis , Neoplasias Renais/tratamento farmacológico , Pirróis , Estudos Retrospectivos , Sorafenibe/uso terapêutico , Sunitinibe/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: In non-small cell lung cancer (NSCLC), analysis of programmed cell death ligand 1 (PD-L1) expression in circulating tumor cells (CTCs) is a potential alternative to overcome the problems linked to the tumor biopsy spatiotemporal heterogeneity. However, the prognostic significance of PD-L1-positive [PD-L1(+)] CTCs remains controversial. METHODS: We prospectively evaluated the correlation with clinicopathological variables and prognostic value of PD-L1(+) CTCs, detected with the FDA-cleared CellSearch® system, in 54 patients with advanced NSCLC. RESULTS: We detected CTCs and PD-L1(+) CTCs in 43.4% and 9.4% of patients with NSCLC. PD-L1 expression concordance between tumor tissue and CTCs was low (54%). The presence of PD-L1(+) CTC correlated with the absence of gene alterations in tumor tissue and with poor prognosis-related biological variables (anemia, hyponatremia, increased lactate dehydrogenase). In univariate analysis, absence of gene alterations, number of metastatic sites, prior systemic therapies, and presence of CTCs and PD-L1(+) CTCs were associated with worse overall survival, whereas PD-L1 expression in tumor tissue was not. In multivariate analysis, squamous cell carcinoma histology, number of prior systemic treatments, and the presence of CTC were significantly associated with overall survival. Survival was worse in patients with PD-L1(+) CTCs than in patients with PD-L1-negative CTC or without any CTC. CONCLUSIONS: Our study suggests that the presence of PD-L1(+) CTCs is associated with poor prognosis in patients with advanced NSCLC. Studies with larger samples are needed to confirm our results and to determine how PD-L1(+) CTC detection could help to predict the response or resistance to anti-PD-1/PD-L1 therapies.Clinical trial registration NCT02866149.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Apoptose , Antígeno B7-H1/metabolismo , Biomarcadores , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Humanos , Ligantes , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Células Neoplásicas Circulantes/patologia , PrognósticoRESUMO
BACKGROUND: Changes in calcium metabolism and calcium urinary excretion during chemotherapy have not been thoroughly assessed in patients with early breast cancer (EBC), a population who frequently present vitamin D insufficiency. As hypercalciuria is a classical contra-indication to vitamin D (VD) supplementation, this study evaluated changes in VD and calcium metabolism parameters in patients with EBC undergoing adjuvant chemotherapy (CT). METHODS: In patients with EBC who received six cycles of adjuvant CT, VD and calcium parameters were monitored at inclusion, and then every 3 weeks, at each CT cycle initiation. The primary endpoint was the percentage of patients showing hypercalciuria during adjuvant CT (between Day 1, Cycle 1 [D1C1] and Day 1, Cycle 6 [D1C6]). RESULTS: The primary endpoint could be evaluated in 82 patients. Most patients (n = 66, 80.5%) had VD insufficiency (< 30 ng/mL) at baseline. Hypercalciuria was detected in 29 patients (35.4%; 95% CI: 25.6-46.5) between D1C1 and D1C6, but was not clinically significant in any of the affected patients. The percentage of hypercalciuria events was not different between patients with sufficient and insufficient baseline VD levels (34.8% vs. 37.5%), and between patients who received or not VD supplementation (37.5% vs. 34.5%,). CONCLUSIONS: This comprehensive study on VD and calcium parameter changes in patients with EBC during adjuvant chemotherapy shows that hypercalciuria is a frequent abnormality in this setting, although asymptomatic. Therefore, it should not be considered as a limitation for high dose VD supplementation in this population. TRIAL REGISTRATION: EudraCT:2014-A01454-43 . Registered 29 august 2016.
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Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Cálcio/metabolismo , Vitamina D/metabolismo , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Adulto JovemRESUMO
WHAT IS KNOWN AND OBJECTIVE: Sunitinib pharmacokinetics can be influenced by the physio-pathological conditions of individual patients. Therapeutic drug monitoring (TDM) helps to optimize efficacy and reduce the risk of adverse effects. We report on the use of Bayesian analysis to optimize sunitinib blood levels. CASE SUMMARY: We describe two patients with risk of sunitinib pharmacokinetic variability due to gastrectomy and ongoing haemodialysis, respectively. TDM and Bayesian estimation allowed maintaining their sunitinib pharmacokinetic profiles within the usual limits. WHAT IS NEW AND CONCLUSION: Our analysis showed that Bayesian analysis can be successfully applied for real-time TDM to optimize sunitinib blood levels in patients with major comorbidities.
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Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Monitoramento de Medicamentos/métodos , Neoplasias Renais/tratamento farmacológico , Sunitinibe/farmacocinética , Sunitinibe/uso terapêutico , Fatores Etários , Idoso , Teorema de Bayes , Comorbidade , Feminino , Gastrectomia , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Diálise RenalRESUMO
BACKGROUND: Data regarding the prognostic value of programmed cell death ligand 1 (PD-L1) expression on circulating tumor cells (CTCs) are lacking. However, CTCs could represent an alternative approach to serial biopsies, allowing real-time monitoring of cancer phenotype. METHODS: We evaluated, in a dedicated prospective clinical trial, the clinicopathological correlations and prognostic value of PD-L1(+)-CTCs in 72 patients with metastatic breast cancer (MBC). RESULTS: Eighteen of 56 patients with available archival tissue presented at least one positive (≥1%) PD-L1 tumor sample. Baseline CTCs and PD-L1(+)-CTCs were detected in 57 (79.2%) and 26 (36.1%) patients. No significant correlation was found between PD-L1 tumors and CTC expression. In univariate analysis, triple negative (TN) phenotype, number of metastatic treatments, >2 metastatic sites, ≥5 CTCs and PD-L1(+)-CTCs were significantly associated with progression-free survival, while tissue PD-L1 expression was not. In multivariate analysis, TN phenotype, number of metastatic treatments and of metastatic sites were the only 3 variables independently associated with progression-free survival. Progesterone receptor negativity, TN phenotype, >2 metastatic sites and ≥5 CTCs were significantly associated with overall survival in univariate analysis. In multivariable analysis, TN phenotype and >2 metastatic sites were the only 2 independent variables. CONCLUSIONS: Unlike PD-L1(+)-tumor, PD-L1(+)-CTCs correlate to survival in MBC. Reappraisal of the role of PD-L1 expression by tumor tissue and by CTCs under anti-PD-1/PD-L1 treatment is necessary to evaluate its predictive value and potential role as a stratifying factor in strategies and trials for MBC patients with MBC. CLINICAL TRIAL REGISTRATION: NCT02866149.
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Antígeno B7-H1/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Mama/diagnóstico , Células Neoplásicas Circulantes/química , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Humanos , Biópsia Líquida , Pessoa de Meia-Idade , Células Neoplásicas Circulantes/patologia , Prognóstico , Intervalo Livre de Progressão , Estudos ProspectivosRESUMO
In oncology clinical research, the analysis and reporting of adverse events is of major interest. A consistent depiction of the safety profile of a new treatment is as crucial in establishing how to use it as its antitumor activity. The advent of new therapeutics has led to major changes in the management of patients and targeted therapies or immune checkpoint inhibitors are administered continuously for months or even years. However, the classical methods of adverse events analysis are no longer adequate to properly assess their safety profile. Indeed, the worst grade method and time-to-event analysis cannot capture the duration or the evolution of adverse events induced by extended treatment durations. Many authors have highlighted this issue and argue that the analysis of safety data from clinical trials should be modernized by considering the dimension of time and the recurrent nature of adverse events. This paper aims to illustrate the limitations of current methods and discusses the value of alternative approaches such as the prevalence function, Q-TWiST, the ToxT and the recurrent event approaches. The rationale and design of the MOTIVATE trial, which aims to model the evolution of toxicities over time using the prevalence function in patients treated by immunotherapy, is also presented ( ClinicalTrials.gov Identifier: NCT03447483; Date of registration: 27 February 2018).
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Antineoplásicos Imunológicos/efeitos adversos , Ensaios Clínicos como Assunto , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/efeitos adversos , Neoplasias/tratamento farmacológico , Humanos , OncologiaRESUMO
The decision to administer adjuvant chemotherapy in treatment of early invasive breast cancer (EBC) is often complex, particularly for hormone receptor-positive (HR+) diseases, and current guidelines often classify these patients in an intermediate-risk group. Several biomarkers are currently available in this indication, in order to obtain additional and more accurate prognostic information compared to classic clinicopathological characteristics and guide the indication of adjuvant chemotherapy, optimizing the efficacy/toxicity ratio. We conducted a systematic review to evaluate the clinical validity and clinical utility of five biomarkers (uPA/PAI-1, OncotypeDX®, MammaPrint®, PAM50, and EndoPredict®) in HR+/HER2- EBC, whatever the nodal status. A total of 89 studies met the inclusion criteria. Even though data currently available confirm the clinical validity of these biomarkers, there is a lack of data regarding clinical utility for most of them. Prospective studies in well-defined populations are needed to integrate these biomarkers in a decision strategy.
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Monoclonal antibodies are a therapeutic tool frequently used in oncology, as they allow the specific targeting of molecules expressed by cancer cells and, in most cases, induce minimal toxic effects on healthy tissues. Because monoclonal antibodies frequently lack significant toxicity and are not associated to a direct relationship between dose and effect, the methods of clinical development traditionally used for chemotherapy agents are scarcely useful for this class of drugs. In addition, no consensus exists on the definition of parameters different from toxicity that could assist the process of dose selection of monoclonal antibody in early clinical trials.
TITLE: Déterminer la dose à injecter lors des premières études cliniques menées avec un anticorps monoclonal - Pas si simple ! ABSTRACT: Les anticorps monoclonaux constituent une arme thérapeutique de plus en plus utilisée en oncologie car ils permettent de cibler très précisément les cellules cancéreuses tout en présentant l'avantage d'épargner les cellules saines des effets du traitement, avec, par conséquent, une réduction très importante de la toxicité. L'absence de toxicité significative et d'une relation directe entre dose et efficacité pour les anticorps rendent toutefois peu utiles les méthodes de sélection de la dose traditionnellement utilisées pour les médicaments de chimiothérapie. Il n'existe toutefois pas de consensus sur des paramètres alternatifs qui permettraient de sélectionner pendant les essais de phase précoce la meilleure dose de ces molécules pour le développement clinique ultérieur.
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Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Ensaios Clínicos como Assunto/métodos , Cálculos da Dosagem de Medicamento , Anticorpos Monoclonais/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Relação Dose-Resposta Imunológica , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Humanos , Projetos de Pesquisa/normasRESUMO
BACKGROUND: Breast cancer (BC) is one of the solid tumors most commonly associated with leptomeningeal disease (LMD). LMD carries a devastating prognosis; however, disease presentation and prognostic factors are uncertain. SUBJECTS, MATERIALS, AND METHODS: In order to describe patient characteristics, treatment patterns, and factors associated with survival in a contemporary multicentric cohort, 153 consecutive BC patients diagnosed with LMD at two European institutions (2002-2017) were included. Time to LMD and overall survival (OS) after LMD diagnosis were evaluated using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Median age at LMD diagnosis was 58 years (25-84). Tumor phenotype distribution was as follows: hormone receptor (HR) positive (HR+)/human epidermal growth receptor 2 (HER2) negative 51.0%, triple-negative 15.0%, HR+/HER2 positive (HER2+) 13.1% and HR negative/HER2+ 7.2%. Most patients received active anticancer treatments (radiation therapy [RT] n = 42, systemic therapy n = 110, intrathecal treatment n = 103).Median OS was 3.9 months (95% confidence interval [CI] 2.4-5.5). Eastern Cooperative Oncology Group performance status (ECOG PS) >2, high white blood cells count, low glucose, and high protein in cerebrospinal fluid (CSF) were poor prognostic factors. Having received RT or systemic treatment was associated with better prognosis. In multivariate analysis, ECOG PS (hazard ratio 2.22, 95% CI 1.25-3.94), CSF glucose levels (hazard ratio 1.74, 95% CI 1.05-2.88), and having received systemic treatment (hazard ratio 0.17, 95% CI 0.09-0.32) were confirmed as independent prognostic factors. In HER2+ BC patients, having received systemic HER2-targeted therapy was the only factor maintaining independent prognostication (hazard ratio 0.12, 95% CI 0.02-0.67) in multivariate analysis. CONCLUSION: Despite being limited by their retrospective nature, these results highlight the need for clinical trials in BC LMD, stratified on tumor biology. IMPLICATIONS FOR PRACTICE: Leptomeningeal disease (LMD) is a devastating complication of breast cancer (BC), and its optimal therapy is still not defined. Here, patient characteristics, treatment patterns, and prognostic factors from a contemporary cohort of 153 BC-related LMD patients are reported. In multivariate analysis, Eastern Cooperative Oncology Group performance status, cerebrospinal fluid glucose levels, and having received systemic treatment were confirmed as independent prognostic factors in the overall population, whereas in human epidermal growth receptor 2 (HER2) positive BC patients, having received systemic HER2-targeted therapy was the only factor maintaining independent prognostication in multivariate analysis. These results highlight the need to consider stratification on tumor biology in the treatment of BC LMD.
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Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/complicações , Carcinomatose Meníngea/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Humanos , Carcinomatose Meníngea/patologia , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: There has been interest in the potential benefit of vitamin D (VD) to improve breast cancer outcomes. Pre-clinical studies suggest VD enhances chemotherapy-induced cell death. Vitamin D deficiency was associated with not attaining a pathologic complete response (pCR) following neoadjuvant chemotherapy (NAC) for operable breast cancer. We report the impact of VD on pCR and survival in an expanded cohort. METHODS: Patients from Iowa and Montpellier registries who had serum VD level measured before or during NAC were included. Vitamin D deficiency was defined as < 20 ng/mL. Pathological complete response was defined as no residual invasive disease in the breast and lymph nodes. Survival was defined from the date of diagnosis to the date of relapse (PFS) or date of death (OS). RESULTS: The study included 327 women. Vitamin D deficiency was associated with the odds of not attaining pCR (p = 0.04). Fifty-four patients relapsed and 52 patients died. In multivariate analysis, stage III disease, triple-negative (TN) subtype and the inability to achieve pCR were independently associated with inferior survival. Vitamin D deficiency was not significantly associated with survival in the overall sample; however a trend was seen in the TN (5-years PFS 60.4% vs. 72.3%, p = 0.3), and in the hormone receptor positive /human epidermal growth factor receptor 2 negative (HER2-) subgroups (5-years PFS 89% vs 78%, p = 0.056). CONCLUSION: Vitamin D deficiency is associated with the inability to reach pCR in breast cancer patients undergoing NAC.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Terapia Neoadjuvante/estatística & dados numéricos , Vitamina D/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva , Estudos RetrospectivosRESUMO
BACKGROUND: Our previous survey on first-in-human trials (FIHT) of monoclonal antibodies (mAbs) showed that, due to their limited toxicity, the recommended phase II dose (RP2D) was only tentatively defined. METHODS: We identified, by MEDLINE search, articles on single-agent trials of mAbs with an FIHT included in our previous survey. For each mAb, we examined tested dose(s) and dose selection rationale in non-FIHTs (NFIHTs). We also assessed the correlation between doses tested in the registration trials (RTs) of all FDA-approved mAbs and the corresponding FIHT results. RESULTS: In the 37 dose-escalation NFIHTs, the RP2D indication was still poorly defined. In phase II-III NFIHTs (n=103 on 37 mAbs), the FIHT RP2D was the only dose tested for five mAbs. For 16 mAbs, only doses different from the FIHT RP2D or the maximum administered dose (MAD) were tested and the dose selection rationale infrequently indicated. In the 60 RTs on 27 FDA-approved mAbs with available FIHT, the FIHT RP2D was tested only for two mAbs, and RT doses were much lower than the FIHT MAD. CONCLUSIONS: The rationale beyond dose selection in phase II and III trials of mAbs is often unclear in published articles and not based on FIHT data.
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Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Tomada de Decisão Clínica , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Relação Dose-Resposta a Droga , Humanos , Projetos de PesquisaRESUMO
INTRODUCTION: There has been increasing interest in the potential benefit of vitamin D in improving breast cancer outcome. Preclinical studies suggest that vitamin D enhances chemotherapy-induced cell death. We investigated the impact of serum vitamin D levels during neoadjuvant chemotherapy (NAC) on the rates of achieving pathologic complete response (pCR) after breast cancer NAC. PATIENTS AND METHODS: Patients from 1 of 2 Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled onto a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. A Firth penalized logistic regression multivariable model was used. RESULTS: The study included 144 women. There was no difference between the French and Iowan cohorts with regard to age at diagnosis (P = .20), clinical stage (P = .22), receptor status (P = .32), and pCR rate (P = .34). French women had lower body mass index (mean 24.8 vs. 28.8, P < .01) and lower vitamin D levels (mean 21.5 vs. 27.5, P < .01) compared to Iowan patients. In multivariable analysis, after adjusting for the effects of cohort, clinical stage, and receptor status, vitamin D deficiency increased the odds of not attaining pCR by 2.68 times (95% confidence interval, 1.12-6.41, P = .03). CONCLUSION: Low serum vitamin D levels were associated with not attaining a pCR. Prospective trials could elucidate if maintaining vitamin D levels during NAC, a highly modifiable variable, may be utilized to improve cancer outcomes.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/terapia , Deficiência de Vitamina D/epidemiologia , Vitamina D/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/sangue , Neoplasias da Mama/patologia , Feminino , França , Humanos , Iowa , Linfonodos/patologia , Mastectomia , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Estudos Retrospectivos , Resultado do Tratamento , Deficiência de Vitamina D/sangueRESUMO
PURPOSE: Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision proves to be difficult. Clinical and pathological criteria are sometimes insufficient to determine the best therapeutic options, and validated biomarkers such as uPA/PAI-1, are needed to contribute to the decision-making. The objective of this study was to evaluate the clinical outcome of an unselected ER+/HER2- pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination. METHOD: This monocentric retrospective study included 520 patients who underwent curative surgery in our institute between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinical-pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels using fresh, extemporaneously sampled tissue. We evaluated the correlation between uPA/PAI-1 levels, clinical-pathological variables, and the patient's outcome (relapse-free survival, RFS, and overall survival, OS). RESULT: Median follow-up was 5.4 years. The 5- and 10-year RFS rates were ,respectively, 95 and 89%, and the five-year OS rate was 96.3%. Forty percent of tumors had low uPA/PAI-1 levels. Seventy-five percent of patients with low uPA/PAI-1 levels did not receive chemotherapy, when 25% did. Sixty percent of patients with high uPA and/or PAI-1 levels received chemotherapy, while 40% did not. No statistical significant correlation was found between the uPA/PAI-1 levels and RFS or OS. CONCLUSION: The personalization of the patients' treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly supports the use of this biomarker in clinical practice.
Assuntos
Neoplasias da Mama/sangue , Neoplasias da Mama/mortalidade , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tipo Uroquinase/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Tomada de Decisão Clínica , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Recidiva , Análise de Sobrevida , Resultado do TratamentoRESUMO
Activating EGFR mutations discovery and efficacy of 1st generation tyrosine kinase inhibitors (TKI), such as erlotinib or gefitinib, inaugurated the beginning of personalized medicine in the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). However, all patients showed a tumor progression of 10 to 16 months after the onset of TKI therapy related to molecular resistance mechanisms as T790M mutation. Till now, patients suffering from EGFR-mutated NSCLC with acquired resistance have conventional treatment options. Two new 3rd generations' TKI, AZD9291 and rociletinib, are currently being studied in phases 1-3 studies. Preliminary results show relevant therapeutic properties in patients with T790M mutated-EGFR NSCLC. This review aims to highlight these new molecules, their effectiveness and their clinical toxicities in the treatment of advanced stages of NSCLC expressing the T790M mutation.
Assuntos
Acrilamidas/uso terapêutico , Compostos de Anilina/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores ErbB/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , Progressão da Doença , Humanos , Neoplasias Pulmonares/genéticaRESUMO
The identification of the EML4-ALK rearrangement in 5% of NSCLC enhanced the development of 1st generation ALK inhibitors such as crizotinib. Two phase III trials demonstrated crizotinib efficacy in second line metastatic (PROFILE 1007) and more recently first line metastatic (PROFILE 1014) NSCLC in terms of progression-free survival and also objective response. However, within 12 to 16 months, patients will progress due to the emergence of acquired resistance mechanisms such as mutation (L1196M) or amplification of the ALK gene, as well as activation of alternative signaling pathways (EGFR, KRAS). Second generation ALK inhibitors have been developed such as ceritinib, alectinib, and AP26113. This review will present those new drugs, summarize the results of their ongoing trials, and discuss the best way to treat ALK+ NSCLC patients.
Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores de Proteínas Quinases , Receptores Proteína Tirosina Quinases , Humanos , Quinase do Linfoma Anaplásico , Carbazóis/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Ensaios Clínicos Fase III como Assunto , Crizotinibe , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Proteínas de Fusão Oncogênica/análise , Compostos Organofosforados/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Receptores Proteína Tirosina Quinases/genética , Sulfonas/uso terapêuticoRESUMO
Numerous studies have demonstrated that a significant change in weight during chemotherapy treatment was a factor of poor prognosis in early breast cancer women. However, the causes and mechanisms involved in this phenomenon are not fully known. This review summarizes current knowledge about the causes of energy imbalance during chemotherapy treatment and the mechanisms that have been proposed as responsible for the increased risk of relapse and death in this population. Current preventive strategies focus on physical activity programs but also on the use of metformin during and after chemotherapy.