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BACKGROUND: Bone-targeted agents (BTA), such as denosumab (DN) and zoledronic acid (ZA), have historically reduced the risk of skeletal related events in cancer patients with bone metastases (BM), with no improvement in survival outcomes. In the immunotherapy era, BM have been associated with poor prognosis upon immune-checkpoint inhibitors (ICI). Currently, the impact of bone tumor burden on survival upon BTAs in advanced non-small cell lung cancer (aNSCLC) patients treated with ICI remains unknown. METHODS: Data from ICI-treated aNSCLC patients with BM (4/2013-5/2022) in one institution were retrospectively collected. BTA-ICI concurrent treatment was defined as BTA administration at any time before or within 90 days from ICI start. High bone tumor burden (HBTB) was defined as ≥ 3 sites of BM. Median OS (mOS) was estimated with Kaplan-Meier. Aikaike's information criterion (AIC) was used to select the best model for data analysis adjusted for clinical variables. RESULTS: Of 134 patients included, 51 (38 %) received BTA. At a mFU of 39.6 months (m), BTA-ICIs concurrent treatment did not significantly impact on mOS [8.3 m (95% CI 3.9-12.8) versus (vs) 6.8 m (95% CI 4.0-9.6) p = 0.36]; these results were confirmed after adjustment for clinical variables selected by AIC. A multivariate model showed a significant interaction between BTA use and HBTB or radiation therapy to BM. In subgroup analyses, only HBTB confirmed to be associated with significantly longer mOS [8.3 m (95% CI 2.4-14.2) vs 3.5 m (95% CI 2.9-4.1), p = 0.003] and mPFS [3.0 m (95% CI 1.6-4.4) vs 1.8 m (95% CI 1.6-2.0) p = 0.001] upon BTA-ICI concurrent treatment, with the most pronounced OS benefit observed for DN-ICI concurrent regimen [15.2 m (95% CI 0.1-30.7) vs 3.5 m (95% CI 2.9-4.1) p = 0.002]. CONCLUSIONS: In the immunotherapy era, HBTB can identify patients experiencing survival benefit with BTA, especially with DN-ICI combination. HBTB should be included as a stratification factor in the upcoming trials assessing BTA and ICI combinations in patients with aNSCLC and BM.
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Antineoplásicos Inmunológicos , Antineoplásicos , Neoplasias Óseas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Carga Tumoral , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias Óseas/secundario , Antineoplásicos/uso terapéuticoRESUMEN
Background: Previous data, mostly from clinical trials, reported that HER2-low status is associated with low pathological complete response (pCR), and favourable prognosis. Since these findings suggest the existence of an additional breast cancer subtype, we questioned if the predictive/prognostic value of HER2-low was also relevant in the real world. Methods: Data from non-metastatic breast cancer patients treated with neoadjuvant chemotherapy and surgery (2009-2020) were retrieved from our institutional prospectively-maintained registry. Univariable and multivariable logistic models were implemented to study the association between pCR and baseline HER2 status. Univariable analysis of disease-free survival (DFS) was performed through Kaplan-Meier survival curves and log-rank tests. Results: Starting from a total of 790 consecutive cases, we identified 444 newly-diagnosed breast cancer patients featuring HER2 immunohistochemistry (IHC) 0 (HER2-0, n = 109), and 1 + or IHC 2+/in situ hybridization negative (HER2-low, n = 335) receiving anthracycline and taxane-based regimens in 88.9% of cases. Most of the patients were diagnosed with stage II (67.3%) and there was no difference of disease presentation according to HER2-status. pCR was attained by 71 (16.0%) patients and was significantly associated with increased DFS (p = 0.031). Compared to HER2-0, HER2-low cases were more likely hormone receptor-positive (81.2% vs. 43.1%, p < 0.001), well-differentiated (47.5% vs. 26.6%, p = 0.001), less proliferative (21.5% vs. 8.3%, p = 0.001) and less responsive to treatment (pCR 11.6% vs. 29.4%, p < 0.0001). There was no difference in DFS according to HER2 status, though hormone-receptor (HR) negative/HER2-low cases tended to have a worse prognosis compared to HR-negative/HER2-0. By pCR achievement, 3-years DFS was 87.5.% (75.1-100%) vs. 71.6% (65.9-77.8%) (p = 0.161) in HER2-low and 89.1% (75.8-100%) vs. 72.1% (59.7-87.0%) (p = 0.092) in HER2-0. Conclusion: Our real-world data show that HER2-low breast cancer patients represent roughly a half of the cases treated with neoadjuvant therapy, and have poor treatment response. In absence of pCR, HER2-low breast cancer patients have a dismal prognosis, especially when primary tumor hormone receptor status is negative. Studies are therefore needed to define the biology of these tumors for new therapeutic targets and to incorporate HER2-targeting agents in early-stage treatment.
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(1) Background: In advanced non-small cell lung cancer (aNSCLC), programmed death ligand 1 (PD-L1) remains the only biomarker for candidate patients to immunotherapy (IO). This study aimed at using artificial intelligence (AI) and machine learning (ML) tools to improve response and efficacy predictions in aNSCLC patients treated with IO. (2) Methods: Real world data and the blood microRNA signature classifier (MSC) were used. Patients were divided into responders (R) and non-responders (NR) to determine if the overall survival of the patients was likely to be shorter or longer than 24 months from baseline IO. (3) Results: One-hundred sixty-four out of 200 patients (i.e., only those ones with PD-L1 data available) were considered in the model, 73 (44.5%) were R and 91 (55.5%) NR. Overall, the best model was the linear regression (RL) and included 5 features. The model predicting R/NR of patients achieved accuracy ACC = 0.756, F1 score F1 = 0.722, and area under the ROC curve AUC = 0.82. LR was also the best-performing model in predicting patients with long survival (24 months OS), achieving ACC = 0.839, F1 = 0.908, and AUC = 0.87. (4) Conclusions: The results suggest that the integration of multifactorial data provided by ML techniques is a useful tool to select NSCLC patients as candidates for IO.
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Introduction: Artificial Intelligence (AI) methods are being increasingly investigated as a means to generate predictive models applicable in the clinical practice. In this study, we developed a model to predict the efficacy of immunotherapy (IO) in patients with advanced non-small cell lung cancer (NSCLC) using eXplainable AI (XAI) Machine Learning (ML) methods. Methods: We prospectively collected real-world data from patients with an advanced NSCLC condition receiving immune-checkpoint inhibitors (ICIs) either as a single agent or in combination with chemotherapy. With regards to six different outcomes - Disease Control Rate (DCR), Objective Response Rate (ORR), 6 and 24-month Overall Survival (OS6 and OS24), 3-months Progression-Free Survival (PFS3) and Time to Treatment Failure (TTF3) - we evaluated five different classification ML models: CatBoost (CB), Logistic Regression (LR), Neural Network (NN), Random Forest (RF) and Support Vector Machine (SVM). We used the Shapley Additive Explanation (SHAP) values to explain model predictions. Results: Of 480 patients included in the study 407 received immunotherapy and 73 chemo- and immunotherapy. From all the ML models, CB performed the best for OS6 and TTF3, (accuracy 0.83 and 0.81, respectively). CB and LR reached accuracy of 0.75 and 0.73 for the outcome DCR. SHAP for CB demonstrated that the feature that strongly influences models' prediction for all three outcomes was Neutrophil to Lymphocyte Ratio (NLR). Performance Status (ECOG-PS) was an important feature for the outcomes OS6 and TTF3, while PD-L1, Line of IO and chemo-immunotherapy appeared to be more important in predicting DCR. Conclusions: In this study we developed a ML algorithm based on real-world data, explained by SHAP techniques, and able to accurately predict the efficacy of immunotherapy in sets of NSCLC patients.
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BACKGROUND: Immune-checkpoint inhibitors (ICIs) have significantly improved outcome of advanced non-small cell lung cancer (aNSCLC) patients. However, their efficacy remains uncertain in uncommon histologies (UH). MATERIALS AND METHODS: Data from ICI treated aNSCLC patients (April,2013-January,2021) in one Institution were retrospectively collected. Univariate and multivariate survival analyses were estimated by Kaplan-Meier and Cox proportional hazards regression model, respectively. Objective response rate (ORR) and disease control rate (DCR) were assessed. RESULTS: Of 375 patients, 79 (21.1%) had UH: 19 (24.1%) sarcomatoid carcinoma, 15 (19.0%) mucinous adenocarcinoma, 10 (12.6%) enteric adenocarcinoma, 8 (10.1%) adenocarcinoma not otherwise specified, 7 (8.9%) large-cell neuroendocrine carcinoma, 6 (7.6%) mixed histology non-adenosquamous, 5 (6.3%) adenosquamous carcinoma, 9 (11.4%) other UH. In UH group, programmed death-ligand 1 (PD-L1) <1%, 1-49%, ≥50% and unknown expression were reported in 27.8%, 22.8%, 31.7% and 17.7% patients respectively and ICI was the second/further-line in the majority of patients. After a median follow-up of 35.64 months (m), median progression-free survival (mPFS) was 2.5 m in UH [95% CI 2.2-2.9 m] versus (vs.) 2.7 m in CH [95% CI 2.3-3.2 m, P-value = .584]; median overall survival (mOS) was 8.8 m [95% CI 4.9-12.6 m] vs. 9.7 m [95% CI 8.0-11.3 m, P-value = .653]. At multivariate analyses only ECOG PS was a confirmed prognostic factor in UH. ORR and DCR were 25.3% and 40.5% in UH vs. 21.6% and 49.5% in CH [P-value = .493 and .155 respectively]. CONCLUSIONS: No significant differences were detected between UH and CH groups. Prospective trials are needed to understand ICIs role in UH population.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Análisis de SupervivenciaRESUMEN
BACKGROUND: Cabozantinib improves survival in metastatic renal cell carcinoma (mRCC) after prior antiangiogenics. The best treatment at disease progression (PD) is unknown. Being also a AXL/MET inhibitor, involved in acquired resistance, we hypothesized a prolonged tumor growth control in patients continuing cabozantinib despite PD. RESEARCH DESIGN AND METHODS: This retrospective multicenter study enrolled patients receiving cabozantinib after the first line between 2014 and 2020. We compared patients maintaining cabozantinib after first PD due to clinical benefit and good tolerability with those who changed therapy. The postprogression survival (PPS) of both was our primary endpoint. RESULTS: We analyzed 89 patients: 45 received cabozantinib beyond PD and 44 switched therapy. 40.4%, 31.5%, and 28.1% of patients received 1, 2, or >2 prior treatment, respectively. 84.3% were intermediate-poor International Metastatic Renal Cell Carcinoma Database risk. Patients continuing cabozantinib showed a higher response rate to cabozantinib before PD (46.7% vs 25%, p = 0.03) and were more heavily pretreated. Continuing cabozantinib showed a significantly longer PPS compared with switching therapy (median PPS 16.9 vs 13.2 months, HR 0.66, 95%CI 0.48-0.92, p = 0.011). CONCLUSIONS: We observed longer PPS in patients continuing cabozantinib beyond PD, suggesting that this could be an effective option.
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Carcinoma de Células Renales , Neoplasias Renales , Anilidas/farmacología , Anilidas/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Piridinas , Estudios RetrospectivosRESUMEN
BACKGROUND: Cabozantinib strongly inhibits osteoclast differentiation and bone resorption in vitro. We aimed to evaluate its effect on bone turnover markers (BTMs) in metastatic renal cell carcinoma. METHODS: This is a monocentric prospective study on patients with mRCC treated with cabozantinib between October 2016 and July 2018. We collected blood samples at baseline and after 3 and 6 months of treatment. We compared sets of data obtained from plasma samples in the whole population with unpaired 2-tailed Student t tests and data for a subset of patients for which all timepoints were available with paired 2-tailed Student t tests. We used the Kaplan-Meier method for survival analyses and the log-rank test to compare the curves. RESULTS: Our analysis included 39 patients. At month 3, the mean C-terminal cross-linked telopeptides of type I collagen (CTx) and the mean N-terminal propeptide of type 1 collagen (PINP) levels were significantly decreased in the whole population (p = 0.013 and p < 0.0001, respectively), as well as at paired analysis (p = 0.015 and p = 0.045, respectively). No differences were observed between baseline and 6 months (p = 0.053 and p = 0.087, respectively). After 3 months, the mean parathyroid hormone (PTH) levels significantly increased in the whole population (p = 0.004), as well as at paired analysis; the mean PTH levels increased significantly at 3 and 6 months, respectively (p = 0.019 and p = 0.041, respectively). Changes in BTM levels were not associated with outcome. CONCLUSIONS: Cabozantinib significantly reduced bone resorption as demonstrated by the decrease of CTx and showed a transient secondary increase of PTH.
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Anilidas/farmacología , Antineoplásicos/farmacología , Biomarcadores , Huesos/efectos de los fármacos , Huesos/metabolismo , Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Piridinas/farmacología , Anilidas/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Remodelación Ósea/efectos de los fármacos , Huesos/patología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Manejo de la Enfermedad , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Estudios Prospectivos , Piridinas/uso terapéuticoRESUMEN
Circulating microRNA (ct-miRNAs) are able to identify patients with differential response to HER2-targeted therapy. However, their dynamics are largely unknown. We assessed 752 miRNAs from 52 NeoALTTO patients with plasma pairs prior and two weeks after trastuzumab. Increased levels of ct-miR-148a-3p and ct-miR-374a-5p were significantly associated with pathological complete response (pCR) (p = 0.008 and 0.048, respectively). At a threshold ≥ the upper limit of the 95%CI of the mean difference, pCR resulted 45% (95%CI 24%-68%), and 44% (95%CI 22%-69%) for ct-miR-148a-3p and ct-miR-374a-5p, respectively. Notably, ct-miR-148a-3p retained its predictive value (OR 3.42, 95%CI 1.23-9.46, p = 0.018) in bivariate analysis along with estrogen receptor status. Combined information from ct-miR-148a-3p and ct-miR140-5p, which we previously reported to identify trastuzumab-responsive patients, resulted in greater predictive capability over each other, with pCR of 54% (95%CI 25%-81%) and 0% (95%CI 0%-31%) in ct-miR-148a/ct-miR-140-5p high/present and low/absent, respectively. GO and KEGG analyses showed common enriched terms between the targets of these ct-miRNAs, including cell metabolism regulation, AMPK and MAPK signaling, and HCC progression. In conclusion, early modulated ct-miR-148-3p may inform on the functional processes underlying treatment response, integrate the information from already available predictive biomarkers, and identify patients likely to respond to single agent trastuzumab-based neoadjuvant therapy.
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Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , MicroARN Circulante/sangre , Terapia Neoadyuvante , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/genética , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica , Redes Reguladoras de Genes , Humanos , Modelos Logísticos , Persona de Mediana Edad , Análisis MultivarianteRESUMEN
PURPOSE OF REVIEW: The aim of this review is to sum up the state of the art of urachal carcinoma (UC) in order to easily guide clinicians. RECENT FINDINGS: UC is a rare and aggressive disease with consequent few data about diagnosis and treatment. Dates are mainly based on retrospective trial and case reports with limited prospective trial. Clinical presentation is not specific, often with urinary symptoms. Diagnosis is mainly based on CT scan and MRI, useful to evaluate local invasion and nodal status and to detect the presence of distant metastases. Therefore, biopsy is needed to obtain histological confirmation. Surgery is the gold standard for localized disease, while different chemotherapy schemes have been used in metastatic setting. Novel findings based on mutational analysis of the tumor include the use of biological treatment, such as cetuximab, and immunotherapy, such as atezolizumab, with satisfactory responses, suggesting that personalized treatment could be the most suitable option for UC.
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Adenocarcinoma/diagnóstico , Adenocarcinoma/terapia , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/terapia , Adenocarcinoma/patología , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Quimioterapia Adyuvante , Cistectomía/métodos , Humanos , Inmunoterapia , Terapia Molecular Dirigida , Pronóstico , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
INTRODUCTION: Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)-ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. METHODS: In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. RESULTS: In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9-99.6) in the 450-mg cohort and 60% (95% CI: 26.2-87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7-84.3) in the 450-mg cohort and 25% (95% CI: 5.5-57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1-87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0-58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. CONCLUSION: Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Quinasa de Linfoma Anaplásico/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Nivolumab , Pirimidinas , SulfonasRESUMEN
BACKGROUND: In selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. OBJECTIVE: To assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. DESIGN, SETTING, AND PARTICIPANTS: The RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400â¯mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: RFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. RESULTS AND LIMITATIONS: At a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20-not available [NA]) in the observation arm versus 21 mo (95% CI 11-NA) in the sorafenib arm (log-rank test pâ¯=â¯0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3â¯AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. CONCLUSIONS: This prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. PATIENT SUMMARY: This article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.
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Antineoplásicos/uso terapéutico , Carcinoma de Células Renales/cirugía , Metastasectomía/métodos , Sorafenib/uso terapéutico , Adulto , Anciano , Antineoplásicos/farmacología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sorafenib/farmacologíaRESUMEN
BACKGROUND: Dual HER2-inhibition combined with neoadjuvant chemotherapy allows increased pathological complete response (pCR) rate. However, with the addition of new agents, there is a growing need to select patients to minimise overtreatment. Herein, we evaluated the 41-gene classifier TRAR to predict pCR to anti-HER2 therapies in the NeoALTTO trial. PATIENTS AND METHODS: Gene expression data were obtained using RNA from 226 pretreatment tumour biopsies. Logistic regression analysis and the area under the receiver operating characteristic (ROC) curve (AUC) were used to evaluate TRAR predictive and discriminatory capabilities. RESULTS: TRAR levels were associated with pCR (odds ratio, OR: 0.25, 95% confidence interval, CI: 0.15-0.42). The ROC analysis showed AUC values of 0.73 (95% CI: 0.67-0.80) overall; 0.70 (0.59-0.81) and 0.71 (0.62-0.80) for positive and negative oestrogen receptor cases and 0.74 (0.60-0.88), 0.76 (0.65-0.87) and 0.71 (0.59-0.83) for trastuzumab, lapatinib and combined treatment arms, respectively. TRAR provided reliable predictive information beyond established clinicopathological variables (OR: 0.26, 95% CI: 0.14-0.47). Furthermore, addition of TRAR to these variables provided greater predictive capability than the addition of PAM50: AUC 0.78 (0.72-0.84) versus 0.74 (0.67-0.81), p = 0.04. CONCLUSION: TRAR represents a promising tool to refine the ability to identify patients sensitive to anti-HER2 (including trastuzumab-only)-based therapy and eligible for de-escalated treatment strategies.
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Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Lapatinib/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Transcriptoma , Trastuzumab/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Toma de Decisiones Clínicas , Ensayos Clínicos Fase III como Asunto , Femenino , Humanos , Lapatinib/efectos adversos , Estudios Multicéntricos como Asunto , Terapia Neoadyuvante , Selección de Paciente , Medicina de Precisión , Valor Predictivo de las Pruebas , Inhibidores de Proteínas Quinasas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
PURPOSE: To investigate the potential of circulating-miRNAs (ct-miRNA) as noninvasive biomarkers to predict the efficacy of single/dual HER2-targeted therapy in the NeoALTTO study. EXPERIMENTAL DESIGN: Patients with plasma samples at baseline (T0) and/or after 2 weeks (T1) of treatment were randomized into training (n = 183) and testing (n = 246) sets. RT-PCR-based high-throughput miRNA profiling was employed in the training set. After normalization, ct-miRNAs associated with pathologic complete response (pCR) were identified by univariate analysis. Multivariate logistic regression models were implemented to generate treatment-specific signatures at T0 and T1, which were evaluated by RT-PCR in the testing set. Event-free survival (EFS) according to ct-miRNA signatures was estimated by Kaplan-Meier method and Cox regression model. RESULTS: In the training set, starting from 51 ct-miRNAs associated with pCR, six signatures with statistically significant predictive capability in terms of area under the ROC curve (AUC) were identified. Four signatures were confirmed in the testing set: lapatinib at T0 and T1 [AUC 0.86; 95% confidence interval (CI), 0.73-0.98 and 0.71 (0.55-0.86)], respectively; trastuzumab at T1 (0.81; 0.70-0.92); lapatinib + trastuzumab at T1 (0.67; 0.51-0.83). These signatures were confirmed predictive after adjusting for known variables, including estrogen receptor status. ct-miRNA signatures failed to correlate with EFS. However, the levels of ct-miR-140-5p, included in the trastuzumab signature, were associated with EFS (HR 0.43; 95% CI, 0.22-0.84). CONCLUSIONS: ct-miRNAs discriminate patients with and without pCR after neoadjuvant lapatinib- and/or trastuzumab-based therapy. ct-miRNAs at week two could be valuable to identify patients responsive to trastuzumab, to avoid unnecessary combination with other anti-HER2 agents, and finally to assist deescalating treatment strategies.
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Biomarcadores de Tumor , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , MicroARN Circulante , Receptor ErbB-2/genética , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Femenino , Perfilación de la Expresión Génica , Humanos , Persona de Mediana Edad , Terapia Molecular Dirigida , Terapia Neoadyuvante , Estadificación de Neoplasias , Pronóstico , Curva ROC , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversos , Trastuzumab/uso terapéutico , Resultado del Tratamiento , Carga TumoralRESUMEN
OBJECTIVES: Cancer Testis Antigens are immunogenic tumor-specific proteins. We investigated NY-ESO-1, MAGE-A3 and PRAME, in addition to WT1 expression in different Breast Cancer (BC) subtypes. We then evaluated the expression rate of NY-ESO-1 in early Triple Negative breast cancer (TNBC), and investigated whether its expression would be maintained or lost in the metastatic setting to explore possible immunotherapy indication. MATERIALS AND METHODS: Three subgroups of BC patients were selected by the expression of ER, PgR and Her2. Tissue microarray was performed on a total of 92 Invasive BC. Sections were stained for NY-ESO-1, MAGE-A3, PRAME and WT1. The second cohort was composed by 26 metastatic TNBC patients from whom both the primary and secondary lesion tissues were available. Sections were stained for NY-ESO-1. RESULTS: NY-ESO-1 was the only differentially expressed antigen and was absent in ER+ and ER-PgR + tumors, as for an exclusive expression of either NY-ESO-1 or at least one hormonal receptor (HR+). NY-ESO-1 was particularly represented in TNBC. No correlation has been found between MAGE-A3 and PRAME expression and subtype WT1 had low expression, except in the Her2+ group. In the second cohort, NY-ESO-1 was expressed in 12 and 24% of primary and metastatic lesions respectively. CONCLUSIONS: This study defines a distinction between HR+ and HR-tumors through NY-ESO-1 expression. TNBC subgroup has the highest frequency of NY-ESO-1+ cases, and it could be the candidate population for the development of anti-NY-ESO-1 vaccine, both in the adjuvant or metastatic setting, and for the selection of cases suitable for immunotherapy.
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Antígenos de Neoplasias/metabolismo , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Antígenos Específicos del Melanoma/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas WT1/metabolismo , Adulto , Neoplasias de la Mama/terapia , Estudios de Cohortes , Femenino , Humanos , Técnicas para Inmunoenzimas , Persona de Mediana Edad , Estadificación de NeoplasiasRESUMEN
INTRODUCTION: We hypothesized that activating KRAS mutations and inactivation of the liver kinase B1 (LKB1) oncosuppressor can cooperate to sustain NSCLC aggressiveness. We also hypothesized that the growth advantage of KRAS/LKB1 co-mutated tumors could be balanced by higher sensitivity to metabolic stress conditions, such as metformin treatment, thus revealing new strategies to target this aggressive NSCLC subtype. METHODS: We retrospectively determined the frequency and prognostic value of KRAS/LKB1 co-mutations in tissue specimens from NSCLC patients enrolled in the TAILOR trial. We generated stable LKB1 knockdown and LKB1-overexpressing isogenic H1299 and A549 cell variants, respectively, to test the in vitro efficacy of metformin. We also investigated the effect of metformin on cisplatin-resistant CD133+ cells in NSCLC patient-derived xenografts. RESULTS: We found a trend towards worse overall survival in patients with KRAS/LKB1 co-mutated tumors as compared to KRAS-mutated ones (hazard ratio: 2.02, 95% confidence interval: 0.94-4.35, p = 0.072). In preclinical experiments, metformin produced pro-apoptotic effects and enhanced cisplatin anticancer activity specifically in KRAS/LKB1 co-mutated patient-derived xenografts. Moreover, metformin prevented the development of acquired tumor resistance to 5 consecutive cycles of cisplatin treatment (75% response rate with metformin-cisplatin as compared to 0% response rate with cisplatin), while reducing CD133+ cells. CONCLUSIONS: LKB1 mutations, especially when combined with KRAS mutations, may define a specific and more aggressive NSCLC subtype. Metformin synergizes with cisplatin against KRAS/LKB1 co-mutated tumors, and may prevent or delay the onset of resistance to cisplatin by targeting CD133+ cancer stem cells. This study lays the foundations for combining metformin with standard platinum-based chemotherapy in the treatment of KRAS/LKB1 co-mutated NSCLC.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Cisplatino/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Metformina/farmacología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Quinasas de la Proteína-Quinasa Activada por el AMP , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Cisplatino/administración & dosificación , Sinergismo Farmacológico , Femenino , Humanos , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Metformina/administración & dosificación , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Entrectinib, a potent oral inhibitor of the tyrosine kinases TRKA/B/C, ROS1, and ALK, was evaluated in two phase I studies in patients with advanced or metastatic solid tumors, including patients with active central nervous system (CNS) disease. Here, we summarize the overall safety and report the antitumor activity of entrectinib in a cohort of patients with tumors harboring NTRK1/2/3, ROS1, or ALK gene fusions, naïve to prior TKI treatment targeting the specific gene, and who were treated at doses that achieved therapeutic exposures consistent with the recommended phase II dose. Entrectinib was well tolerated, with predominantly Grades 1/2 adverse events that were reversible with dose modification. Responses were observed in non-small cell lung cancer, colorectal cancer, mammary analogue secretory carcinoma, melanoma, and renal cell carcinoma, as early as 4 weeks after starting treatment and lasting as long as >2 years. Notably, a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.Significance: Gene fusions of NTRK1/2/3, ROS1, and ALK (encoding TRKA/B/C, ROS1, and ALK, respectively) lead to constitutive activation of oncogenic pathways. Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease. Cancer Discov; 7(4); 400-9. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 339.
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Benzamidas/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Indazoles/administración & dosificación , Carcinoma Secretor Análogo al Mamario/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Benzamidas/efectos adversos , Benzamidas/farmacocinética , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Crizotinib , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Indazoles/efectos adversos , Indazoles/farmacocinética , Masculino , Carcinoma Secretor Análogo al Mamario/genética , Melanoma/genética , Melanoma/patología , Glicoproteínas de Membrana/antagonistas & inhibidores , Glicoproteínas de Membrana/genética , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/genética , Receptor trkA/antagonistas & inhibidores , Receptor trkA/genética , Receptor trkB/antagonistas & inhibidores , Receptor trkB/genética , Receptor trkC/antagonistas & inhibidores , Receptor trkC/genética , Proteína Sequestosoma-1/genéticaRESUMEN
BACKGROUND: Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. METHODS: A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5%, H1 ≥ 20%, α = 10% and ß = 20%). Eligibility included failure of at least one platinum-based regimen. RESULTS: From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4%) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4%) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1%), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6% (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1%, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9% mucositis, 36.4% fatigue, 18.2% neutropenia (13.6% febrile neutropenia). There were 2 treatment-related deaths. CONCLUSIONS: The study did not meet the primary EP, yet sustained disease control was obtained in about 14% of patients. The incidence of AE and the issue of patient selection are two major concerns.
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Aurora Quinasa A/antagonistas & inhibidores , Azepinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Urotelio/patología , Anciano , Aurora Quinasa A/metabolismo , Azepinas/efectos adversos , Azepinas/farmacología , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacología , Pirimidinas/efectos adversos , Pirimidinas/farmacología , Resultado del Tratamiento , Urotelio/efectos de los fármacosAsunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Carcinoma de Células Transicionales/genética , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Neoplasias de la Vejiga Urinaria/genética , Inhibidores de la Angiogénesis/farmacología , Carcinoma de Células Transicionales/tratamiento farmacológico , Variaciones en el Número de Copia de ADN , Análisis Mutacional de ADN , Resistencia a Antineoplásicos , Humanos , Indazoles , Mutación Missense , Pirimidinas/farmacología , Terapia Recuperativa , Sulfonamidas/farmacología , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
PURPOSE: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors. EXPERIMENTAL DESIGN: This open-label, multicenter study was based on a 3+3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg. RESULTS: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway. None of the deaths was deemed to be treatment-related. Three (6.8%) patients with advanced hepatocellular carcinoma, renal cell carcinoma, or non-small cell lung cancer achieved a partial response, and 12 (27.3%) patients had stable disease, across dose levels. Contrast-enhanced ultrasound analysis of tumor vascularity showed reduction in tumor perfusion in 2 patients with stable disease following treatment with PF-03446962. CONCLUSIONS: The clinical activity demonstrated in this study points to PF-03446962 as a novel approach to antiangiogenic therapy, with manageable safety profile and single-agent, antitumor activity in patients with advanced solid tumors. Clin Cancer Res; 22(9); 2146-54. ©2015 AACR.
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Receptores de Activinas Tipo II/inmunología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
BACKGROUND: The classic MVAC (methotrexate/vinblastine/doxorubicin/cisplatin) regimen was the first recognized option for untreated patients with locally advanced or metastatic urothelial cancer (UC). Modifying MVAC by reducing side effects may have the potential to improve efficacy. PATIENTS AND METHODS: Changes to classic MVAC were provided at the authors' institution: (1) deletion of day 22 and administration of 25 mg/m(2) cisplatin on days 2 to 5 (modified [m]MVAC); (2) deletion of day 22 only (simplified [s]MVAC1); and (3) deletion of days 15 and 22 in a 3-week schedule (sMVAC2). A total of 4 to 6 cycles were provided. Multivariate analysis was undertaken for recognized clinical variables. RESULTS: For the period from September 1986 to May 2012, 157 patients were identified (25 with mMVAC, 72 with sMVAC1, and 60 with sMVAC2). Overall, 43.9% had a Memorial Sloan-Kettering Cancer Center score of 1 or 2, with differences across series (P = .002). Altogether, 65.8% attained a complete (19.1%) or partial response (46.7%), and 24.3% a stable disease, with no difference across regimens. After a median follow-up of 87 months (interquartile range, 37-161), median progression-free survival was 10.2 months (95% CI, 8.4-10.8), and median overall survival (OS) was 19.5 months (95% CI, 16.3-24.1). Responses were mainly seen in nodal metastases or soft tissue relapse (odds ratio, 2.48; 95% CI, 1.12-5.54). Only visceral (hazard ratio [HR], 2.42; 95% CI, 1.37-4.30) and nodal metastases/local relapse (HR, 1.70; 95% CI, 1.07-2.69) were independently associated with OS. Grade 3 or 4 toxicities were similar across regimens and were 36% neutropenia, 14% thrombocytopenia, 12% anemia, 10% mucositis, and 4% renal toxicity. Two treatment-related deaths occurred. CONCLUSION: Simplifying MVAC may result in improved efficacy and reduced toxicity. The combined results of the original and modified MVAC regimens encourage a reappraisal of the frontline management of advanced UC.