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BACKGROUND: Immune-related adverse events (IRAE) pose a significant diagnostic and therapeutic challenge in patients treated with immune-oncology (IO) drugs. IRAEs have been suggested to correlate with better outcome, but studies are conflicting. Estimating the true incidence of IRAEs is particularly difficult in the early phase I/II trial setting. A key issue is the lack of IRAE diagnostic criteria, necessary to discriminate "pure" IRAEs from other treatment-related adverse events not sustained by an autoimmune process. METHODS: In patients treated with immune-oncology (IO) drugs in phases I-II trials at our institute, we identified high confidence (HC) or low confidence (LC) IRAEs by clinical consensus. We empirically developed an IRAE likelihood score (ILS) based on commonly available clinical data. Correlation with outcome was explored by multivariate Cox analysis. To mitigate immortal time-bias, analyses were conducted (1) at 2-month landmark and (2) modeling IRAEs as time-dependent covariate. RESULTS: Among 202 IO-treated patients, 29.2% developed >1 treatment-related adverse events (TRAE). Based on ILS >5, we classified patients in no IRAE (nâ =â 143), HC IRAE (nâ =â 24), or LC IRAE (nâ =â 35). hazard ratios (HR) for HC were significantly lower than LC patients (HR for PFS ranging 0.24-0.44, for OS 0.18-0.23, all Pâ <â .01). CONCLUSION: ILS provides a simple system to identify bona fide IRAEs, pruning for other treatment-related events likely due to different pathophysiology. Applying stringent criteria leads to lower and more reliable estimates of IRAE incidence and identifies events with significant impact on survival.
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BACKGROUND: Baseline tumor size (BTS) has been associated with outcomes in patients with cancer treated with immunotherapy. However, the prognostic impact of BTS on patients receiving targeted therapies (TTs) remains undetermined. METHODS: We reviewed data of patients with advanced solid tumors consecutively treated within early-phase clinical trials at our institution from 01/2014 to 04/2021. Treatments were categorized as immunotherapy-based or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST1.1 baseline target lesions. RESULTS: A total of 444 patients were eligible; the median BTS was 69 mm (IQR 40-100). OS was significantly longer for patients with BTS lower versus higher than the median (16.6 vs. 8.2 months, P < .001), including among those receiving immunotherapy (12 vs. 7.5 months, P = .005). Among patients receiving TT, lower BTS was associated with longer PFS (4.7 vs. 3.1 months, P = .002) and OS (20.5 vs. 9.9 months, P < .001) as compared to high BTS. However, such association was only significant among patients receiving biomarker-matched TT, with longer PFS (6.2 vs. 3.3 months, P < .001) and OS (21.2 vs. 6.7 months, P < .001) in the low-BTS subgroup, despite a similar ORR (28% vs. 22%, P = .57). BTS was not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs. 4.4 months, P = .30), OS (19.3 vs. 11.8 months, P = .20), and ORR (33% vs. 28%, P = .78) in the 2 BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (P = .03) and OS (P < .001) but not with ORR (P = .11). CONCLUSIONS: Higher BTS is associated with worse survival outcomes among patients receiving biomarker-matched, but not biomarker-unmatched TT.
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Neoplasias , Humanos , Pronóstico , Neoplasias/tratamiento farmacológico , Inmunoterapia , BiomarcadoresRESUMEN
PURPOSE OF REVIEW: Notch signaling is a highly evolutionarily conserved cell-to-cell communication system that is involved in a number of pivotal cellular processes, such as development, stem cell maintenance, cell fate specification, differentiation, proliferation, and death. Much progress has been made in understanding Notch signaling. This review will focus on the role of canonical Notch signaling pathway in breast cancer cause and progressing. RECENT FINDINGS: In this review, we will discuss the results of the studies using drugs, which target the Notch pathway. SUMMARY: Notch sustains a proliferative signaling and protects from apoptosis, favors the angiogenic switch, the chemoresistance and radioresistance, controls the cancer stemness, and induces a prometastatic phenotype. Therefore, Notch-signaling represented an interesting target in the strategy against cancer growth.
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Antineoplásicos/farmacología , Receptores Notch/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/uso terapéutico , Humanos , Terapia Molecular Dirigida , Receptores Notch/metabolismo , Transducción de Señal/efectos de los fármacos , Neoplasias de la Mama Triple Negativas/metabolismoRESUMEN
Immunotherapy for the treatment of breast cancer can be categorized as either (a) specific stimulation of the immune system by active immunization, with cancer vaccines, or (b) passive immunization, such as tumor-specific antibodies (including immune modulators) or adoptive cell therapy that inhibit the function of, or directly kill, tumor cells. We will present the current information and the future perspectives of immunotherapy in patients with breast cancer, including the prognostic role of tumor infiltrating lymphocytes, immune signatures, targeted therapies modulating the immune system, and tumor antigen cancer vaccines. Active immunotherapy in breast cancer and its implementation into clinical trials have been largely a frustrating experience in the last decades. The concept that the immune system regulates cancer development is experiencing a new era of interest. It is clear that the cancer immunosurveillance process indeed exists and potentially acts as an extrinsic tumor suppressor. Also, the immune system can facilitate tumor progression by sculpting the immunogenic phenotype of tumors as they develop. Cancer immunoediting represents a refinement of the cancer immunosurveillance hypothesis and resumes the complex interaction between tumor and immune system into three phases: elimination, equilibrium, and escape. Major topics in the field of immunology deserve a response: what do we know about tumor immunogenicity, and how might we therapeutically improve tumor immunogenicity? How can we modulate response of the immune system? Is there any gene signature predictive of response to immune modulators? The success of future immunotherapy strategies will depend on the identification of additional immunogenic antigens that can serve as the best tumor-rejection targets. Therapeutic success will depend on developing the best antigen delivery systems and on the elucidation of the entire network of immune signaling pathways that regulate immune responses in the tumor microenvironment.
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Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Inmunoterapia Adoptiva , Inmunoterapia/métodos , Anticuerpos Antineoplásicos/inmunología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/inmunología , Femenino , Humanos , Inmunoterapia/clasificaciónRESUMEN
Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue.
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Biopsia/métodos , Neoplasias de la Mama/patología , Mama/patología , Metástasis de la Neoplasia/diagnóstico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Biopsia/tendencias , Mama/efectos de los fármacos , Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Terapia Molecular Dirigida/métodos , Terapia Molecular Dirigida/tendencias , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Elderly patients are underrepresented in clinical trials, particularly in early-phase studies. Our study assessed the safety and efficacy of novel anti-cancer treatments investigated in early-phase clinical trials, comparing outcomes between younger and elderly patients. METHODS: This retrospective study analyzed data from patients enrolled in phase I/II trials at our center between January 2014 and April 2021. We evaluated clinicopathologic characteristics, toxicity, and clinical efficacy, categorizing patients into younger (≤ 65 years) and elderly (> 65 years) groups. RESULTS: 419 patients were included with a median age of 56 years. Among these, 107 (26 %) were older than 65 years. Predominant cancers included breast (48 %), lung (10 %), and melanoma (5 %). Patients were treated in 64 trials, predominantly receiving immunotherapy-based (47 %) or targeted therapy-based (45 %) treatment. Elderly presented with poorer ECOG performance status (P = 0.001) and had fewer prior therapy lines (P = 0.01) than younger patients. Grade ≥ 3 adverse events (AEs) were similar across age groups (31 % younger vs 33 % elderly; P = 0.7), including in combination therapy scenarios. However, elderly patients experienced more AEs with antibody-drug conjugates compared to younger counterparts (56 % vs 14 %, P = 0.036) and were more likely to discontinue treatment due to toxicity (15 % vs 7 %; P = 0.011). No significant age-related differences in response rates and survival outcomes were observed across treatment modalities, except for immunotherapy-based regimens for which elderly patients exhibited higher response rates, disease control rates, and prolonged progression-free survival. CONCLUSIONS: Our findings suggest that elderly exhibit comparable safety and efficacy outcomes to younger patients in early-phase clinical trials for new cancer drugs. This underscores the importance of including elderly patients in phase I/II trials to ensure the generalizability of study results and mitigate age-related disparities in cancer treatment access.
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Antineoplásicos , Neoplasias , Humanos , Femenino , Masculino , Anciano , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias/tratamiento farmacológico , Factores de Edad , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversos , Adulto , Anciano de 80 o más Años , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , Adulto Joven , Resultado del TratamientoRESUMEN
Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6is) in combination with Endocrine Therapy (ET) represent the standard frontline therapy for patients with Hormone Receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic Breast Cancer (mBC). Clinical activity and efficacy of CDK4/6is-based therapies have been proven both in the endocrine sensitive and resistant settings. Therapy resistance eventually underpins clinical progression to any CDK4/6is-based therapies, yet there is a lack of validated molecular biomarkers predictive of either intrinsic or acquired resistance to CDK4/6is in clinical practice. As the "post-CDK4/6is" landscape for the management of HR-positive/HER2-negative mBC is rapidly evolving with the introduction of novel therapies, there is an urgent need for the definition of clinically relevant molecular biomarkers of intrinsic/acquired resistance mechanisms to CDK4/6is. This narrative review outlines the role of currently approved CDK4/6is-based therapies, describes the most relevant molecular biomarkers of CDK4/6is-resistance, and ultimately provides a perspective on the clinical and research scenario.
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Neoplasias de la Mama , Quinasa 6 Dependiente de la Ciclina , Humanos , Femenino , Quinasa 4 Dependiente de la Ciclina , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Breast cancer during pregnancy (BCP) is relatively rare and is associated with controversies about its biology and prognosis. Hence, we designed a case-control study to examine tumor features and outcome in a series of BCP patients diagnosed and treated in a single institution. MATERIAL AND METHODS: We identified 65 patients diagnosed with BCP and for each; we selected two non-pregnant breast cancer patients, who were matched for age, year of surgery, stage, and neoadjuvant chemotherapy. We then compared the differences in pathology, immunohistochemical features (ER, PR, HER2 and ki-67), disease-free (DFS) and overall survival (OS). RESULTS: We did not find any significant differences in tumor characteristics between the two groups. However, at a median follow-up of four years, BCP patients had an inferior DFS (HR 2.3; 95% CI 1.3-4.2), after adjustment for possible confounding covariates. No difference in OS was observed. However, upon restricting the analysis to patients who did not receive neoadjuvant chemotherapy, patients with BCP had inferior OS as well (HR 2.6; 95% CI 1.0-6.5). No association between induction of abortion and prognosis was observed. CONCLUSIONS: While we did not observe any differences in tumor features, BCP patients have poorer prognosis compared to age and stage-matched control. Further studies should try to elucidate reasons for such poor outcome.
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Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/mortalidad , Complicaciones Neoplásicas del Embarazo/diagnóstico , Complicaciones Neoplásicas del Embarazo/mortalidad , Adulto , Neoplasias de la Mama/terapia , Carcinoma Ductal de Mama/terapia , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Embarazo , Complicaciones Neoplásicas del Embarazo/terapia , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Pivotal trials of COVID-19 vaccines did not include cancer patients, with questions remaining about their safety and efficacy in this population. Patients enrolled in early-phase clinical trials receive novel treatments with unknown efficacy and safety profiles. Studies on the safety of COVID-19 vaccines in these patients are urgently required. This is a retrospective, real-world, cohort study of patients receiving anticancer treatments and COVID-19 vaccines between 1 February and 25 June 2021 at the Division of New Drugs Development for Innovative Therapies of the European Institute of Oncology. One hundred thirteen patients were enrolled, 40 in early-phase clinical trials, and 20 under novel immunotherapy agents. Nearly three-quarters of the patients experienced at least one adverse event (AE) after the first dose (1D) (74.3%) and second dose (2D) (72.6%). Most of the AEs were local (67.3% 1D and 61.9% after 2D), while 31.8% (1D) and 38.1% (2D) of the patients had systemic AEs. No AEs above grade 2 were observed. Therefore, COVID-19 vaccines appear to be safe in patients enrolled in early-phase clinical trials, including patients receiving novel immunotherapy compounds. All cancer patients should be prioritized for COVID-19 vaccination, regardless of ongoing treatments or enrollment in early-phase trials.
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BACKGROUND: Baseline tumour burden is a prognostic factor for patients with melanoma and non-small-cell lung cancer treated with immunotherapy. However, no data are available on its role in other solid tumours, nor for treatment with next-generation immunoncology agents (NGIOs). METHODS: We reviewed data of patients with any solid tumour consecutively treated at our institution from August 2014 to March 2019, who received ≥1 dose of immune checkpoint inhibitor and/or NGIO within phase 1 trials. Baseline tumour burden was calculated as ∑i Response Evaluation Criteria in Solid Tumours 1.1 baseline target lesions (baseline tumour size [BTS]) or as sum of all measurable baseline lesions (total tumour burden [TTB]); the impact of both parameters on treatment outcomes was investigated. RESULTS: One hundred fifty patients were included in the analysis. Median BTS and TTB were 79 mm and 212 mm, respectively. Objective response rate was found significantly associated with BTS (p < 0.001) and TTB quartiles (p = 0.006), with response rates progressively increasing with decreasing tumour burden quartiles. Both progression-free survival (PFS) (p = 0.001) and overall survival (OS) (p < 0.001) were significantly associated with BTS quartiles, with 26% of the patients progression-free and 56% alive at 12 months in the lower BTS quartile, compared with 3% and 24%, respectively, in the upper quartile. TTB was also significantly associated with OS (P = 0.01) and borderline-significant for PFS (p = 0.07). Multivariate analysis confirmed that baseline burden, also considered as continuous variable, is independently associated with PFS and OS, when assessed with BTS (p = 0.001 and p < 0.001) and TTB (p = 0.007 and p < 0.001). CONCLUSIONS: Lower baseline tumour burden is associated with better outcomes in patients with cancer treated with novel immunotherapies.
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Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias/terapia , Carga Tumoral/efectos de los fármacos , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunoterapia/métodos , Masculino , Persona de Mediana Edad , Neoplasias/inmunología , Supervivencia sin Progresión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Resultado del TratamientoRESUMEN
BACKGROUND: GBC is a rare disease and chemotherapy in this setting lacks a standardized approach. PATIENTS AND METHODS: Patients 16-30 weeks pregnant with locally advanced/metastatic disease or with high risk of recurrence after surgery were evaluated. RESULTS: Twenty patients received weekly epirubicin 35 mg/m(2). Median maternal age was 37 years (23-42). Median gestational age at chemotherapy was 19 weeks. Thirteen patients were treated after surgery while 7 had locally advanced tumours of which one had liver metastases. Mean total epirubicin dose was 420 mg/m(2) with a median number of 12 administrations (4-16). No grade 3-4 toxicities were observed. No foetal adverse events were observed except 1 premature delivery at 28 weeks. Births were induced by caesarean section in 12 patients at a median gestational age of 35 weeks. No malformations were reported except 1 newborn with polycystic kidney. At a median age of 2 years, neurological, cardiological and immunological development was normal in all children as reported by their parents. In 7/20 patients with evaluable disease, five had an objective response. At a median follow-up of 38 months, 17 patients are alive; 14 are disease free. CONCLUSIONS: Weekly epirubicin appears safe and effective with low foetal toxicity and could be considered in GBC.
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Antibióticos Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Epirrubicina/uso terapéutico , Complicaciones Neoplásicas del Embarazo/tratamiento farmacológico , Adulto , Neoplasias de la Mama/complicaciones , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Estadificación de Neoplasias , Embarazo , Resultado del Embarazo , Pronóstico , Tasa de SupervivenciaRESUMEN
INTRODUCTION: Breast cancer (BC) remains the most frequently diagnosed cancer and the most common cause of cancer death among women of all races worldwide. Over 80% of BC cases are hormone receptor (HR)-positive, comprised of luminal A and luminal B per molecular subtypes, imposing an urgent need to fully understand the mechanisms behind progression. Ribociclib is a selective cycline-dependent kinase 4 and 6 inhibitor. A phase 1 and a phase 3 trial have established a definitive role of ribociclib as frontline in the treatment of endocrine-sensitive advanced BC. Areas covered: Herein, the authors provide an overview of the data on ribociclib covering all aspects of the drug from its pharmacokinetics to efficacy and safety. The authors also provide their perspectives for the future. Expert opinion: Ribociclib is offering an opportunity to explore a new compound at the crossroads of different molecular activity and cell targets, which focus on endocrine-resistance reversal in multiple settings including early BC. Moreover, its activity against different subtypes of BC is being studied as is its immune-modulating effect. One cautionary note is that, in a market of concomitant similar competitors, a financial discussion will be mandatory.
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Aminopiridinas/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/metabolismo , Purinas/uso terapéutico , Aminopiridinas/metabolismo , Aminopiridinas/farmacocinética , Neoplasias de la Mama/patología , Ensayos Clínicos como Asunto , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/metabolismo , Femenino , Semivida , Humanos , Estadificación de Neoplasias , Purinas/metabolismo , Purinas/farmacocinética , Receptor ErbB-2/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del TratamientoRESUMEN
Triple-negative breast cancer (TNBC) represents a heterogeneous breast cancer subtype with a poor prognosis. The optimal adjuvant chemotherapy regimen is still unknown. Although numerous large randomized trials have established the benefit of adjuvant anthracyclines and/or taxanes in TNBC, there is no preferred regimen for these patients. There is currently no guideline. Moreover, without knowing the optimal treatment backbone, it will not be possible to evaluate whether adding agents such as platinum or other novel therapies is beneficial for TNBC patients. Furthermore, the best duration of adjuvant treatment in TNBC is still unknown. This review will focus on results of clinical trials that analyzed the benefits of extending the duration of adjuvant treatment in TNBCs with maintenance treatments. We will further discuss promising results in favor of other new agents including capecitabine, metronomic treatment, and biological drugs.
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INTRODUCTION: Breast cancer accounts for 29% of malignant tumors. It is an heterogenous disease covering a spectrum of different molecular subtypes. Epigenetic aberrations may affect gene expression through DNA and histone proteins modifications thus promoting tumor progression and resistance to anti- tumor treatment. Area covered: This article explores the potential role of entinostat in the treatment of breast cancer. The clinical trials evaluating entinostat are discussed, highlighting preclinical data and early-phase clinical studies results. The emerging activity of entinostat in several clinical settings is evaluated by focusing on endocrine-resistant, HER2 positive and triple-negative breast cancer with promising activity in boosting the immune-system. Expert opinion: Entinostat, a synthetic benzamide derivative class I histone deacetylases (HDACs) inhibitor, inhibits cell proliferation and promotes apoptosis in breast cancer. Several results from clinical trials demonstrate that the addition of an epigenetic therapy to antiestrogen therapy may be an effective approach to targeting resistance pathways in breast cancer, particularly in hormone-positive disease. Agents such as entinostat may have a role in immunogenic modulation. Genetic and pharmacological inhibition studies identified HDAC as a key determinant in the reversal of carcinoma immune escape. This offers the rationale for combining HDAC inhibitors with immunotherapy, including therapeutic cancer vaccines.
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Antineoplásicos/administración & dosificación , Benzamidas/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Piridinas/administración & dosificación , Animales , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Benzamidas/farmacología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Proliferación Celular/efectos de los fármacos , Epigénesis Genética , Femenino , Regulación Neoplásica de la Expresión Génica , Inhibidores de Histona Desacetilasas/administración & dosificación , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Inmunoterapia/métodos , Piridinas/farmacologíaRESUMEN
BACKGROUND: The NOTCH signaling pathway may be involved in the survival of stem cell-like tumor-initiating cells and contribute to tumor growth. In this phase Ib, open-label, multicenter study (NCT01876251), we evaluated PF-03084014, a selective gamma-secretase inhibitor in patients with advanced triple-negative breast cancer. METHODS: The dose-finding part was based on a 2×3 matrix design using the modified toxicity probability interval method. Oral PF-03084014 was administered twice daily continuously in combination with intravenous docetaxel given on day 1 of each 21-day cycle. Primary endpoint was first-cycle dose-limiting toxicity (DLT) for the dose-finding part and 6-month progression-free survival (PFS) for the expansion cohort treated at the maximum tolerated dose (MTD). Secondary endpoints included safety, objective response, and pharmacokinetics of the combination. RESULTS AND CONCLUSIONS: The MTD was estimated to be PF-03084014 100 mg twice daily / docetaxel 75 mg/m2. At this dose level, combination treatment was generally well tolerated (one DLT, grade 3 diarrhea, among eight DLT-evaluable patients). The most common all-grade, treatment-related adverse events reported in all patients (N = 29) were neutropenia (90%), fatigue (79%), nausea (72%), leukopenia (69%), diarrhea (59%), alopecia (55%), anemia (55%), and vomiting (48%). No effect was observed on the pharmacokinetics of docetaxel when administered in combination with PF-03084014. Four (16%) of 25 response-evaluable patients achieved a confirmed partial response; nine (36%) patients had stable disease, including five patients with unconfirmed partial response. In the expansion cohort, median PFS was 4.1 (95% CI 1.3-8.1) months (6-month PFS rate 17.1% [95% CI 0.8-52.6%]).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Taxoides/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Valina/análogos & derivados , Adulto , Anciano , Progresión de la Enfermedad , Docetaxel , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/inducido químicamente , Neutropenia/epidemiología , Taxoides/efectos adversos , Tetrahidronaftalenos/efectos adversos , Neoplasias de la Mama Triple Negativas/epidemiología , Neoplasias de la Mama Triple Negativas/patología , Valina/administración & dosificación , Valina/efectos adversos , Vómitos/inducido químicamente , Vómitos/epidemiologíaRESUMEN
In the era of personalized medicine detection of the molecular drivers of tumors and of specific DNA mutations predicting response or resistance to targeted agents has become routine practice in clinical oncology. The tumor biopsy depicts only a single timeframe from a single site, and might be inadequate to characterize a tumor because of intratumoral and intermetastatic heterogeneity. Circulating tumor DNA offers a "real time" tool for serially monitoring tumor genomes in a non-invasive manner providing accessible genetic biomarkers for cancer diagnosis, prognosis, and response to therapy. The liquid biopsy can be used for a variety of clinical and investigational applications. Future development will have to provide a cost effective analysis mainly identifying the genes known to be recurrently mutated in each tumor. Therefore, developing standardized methodologies for DNA analyses and validation in large prospective clinical studies is mandatory to implement the 'liquid biopsy' approach in the clinical management of cancer patients. In our review, we will focus on the clinical applications of liquid biopsies and on the recent findings in this field.
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Resistencia a Antineoplásicos , Neoplasias/patología , Antineoplásicos/uso terapéutico , Biopsia , ADN de Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Células Neoplásicas CirculantesRESUMEN
Is breast cancer (BC) immunogenic? Many data suggest that it is. Many observations demonstrated the prognostic role of tumor-infiltrating lymphocytes (TILs) in triple negative (TN) and human epidermal growth factor receptor 2 (HER-2)-positive BC. TNBCs are poorly differentiated tumors with high genetic instability and very high heterogeneity. This heterogeneity enhances the 'danger signals' and select clone variants that could be more antigenic or, in other words, that could more strongly stimulate a host immune antitumor response. The response to chemotherapy is at least partly dependent on an immunological reaction against those tumor cells that are dying during the chemotherapy. One of the mechanisms whereby chemotherapy can stimulate the immune system to recognize and destroy malignant cells is commonly known as immunogenic cell death (ICD). ICD elicits an adaptive immune response. Which are the clinical implications of all 'immunome' data produced in the last years? First, validate prognostic or predictive role of TILs. Second, validate immune genomic signatures that may be predictive and prognostic in patients with TN disease. Third, incorporate an 'immunoscore' into traditional classification of BC, thus providing an essential prognostic and potentially predictive tool in the pathology report. Fourth, implement clinical trials for BC in the metastatic setting with drugs that target immune-cell-intrinsic checkpoints. Blockade of one of these checkpoints, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) or the programmed cell death 1 (PD-1) receptor may provide proof of concepts for the activity of an immune-modulation approach in the treatment of a BC.
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In anticancer drug development, there has been increasing consideration for the potential of a compound to cause adverse electrocardiographic changes, especially QT interval prolongation, which can be associated with risk of torsades de pointes and sudden death. Irrespective of overt clinical toxicities, QTc assessment can influence decision making during the conduct of clinical studies, including eligibility for protocol therapy, dose delivery or discontinuation, and analyses of optimal dose for subsequent development. Efforts are needed to refine strategies for risk management, avoiding unintended consequences that negatively affect patient access and clinical development of promising new cancer treatments. In this comprehensive review, we will analyze potential effects on QTc prolongations of targeted agents approved by regulatory agencies and under investigation. A thoughtful risk management plan was generated by an organized collaboration between oncologists, cardiologists, and regulatory agencies to support a development program essential for oncology agents with cardiac safety concerns.
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Antineoplásicos/efectos adversos , Arritmias Cardíacas/inducido químicamente , Sistema de Conducción Cardíaco/anomalías , Corazón/efectos de los fármacos , Terapia Molecular Dirigida/efectos adversos , Síndrome de Brugada , Trastorno del Sistema de Conducción Cardíaco , Humanos , Gestión de RiesgosRESUMEN
OBJECTIVES: To assess efficacy of bevacizumab in combination with oral chemotherapy in patients with breast cancer with lymphangitic spread to the chest wall (LBC). To identify surrogate biomarkers of response to bevacizumab. PATIENTS AND METHODS: We randomly assigned patients to receive bevacizumab plus either sequential or concurrent oral vinorelbine and capecitabine every 3 weeks. The primary endpoint was time to ultimate progression (TTP); the response rate and overall survival (OS) were secondary endpoints. We performed gene expression profiling on baseline tissue samples collected from triple negative LBC. We assessed circulating endothelial cells (CEC), circulating endothelial progenitors (CEP) and circulating pericyte progenitors (CPP). RESULTS: A total of 66 patients were enrolled. There was no difference in TTP (median TTP 5.3 vs. 4.8 months, p = 0.21) and in OS (median OS 15.8 vs 11.9 months; p = 0.25) when comparing concurrent vs sequential treatment, respectively. Response rate was 25% vs 28% in the concurrent vs sequential arm (p = 1.00), respectively. A set of 16 genes predictive of response to bevacizumab was identified. The counts of CEPs and viable CECs below the median value were associated with an improved overall survival: 26.6 vs 9.5 months for CEPs and 22.6 vs 11.0 months for viable CECs, respectively (p = 0.02). CONCLUSIONS: Oral chemotherapy and bevacizumab (BEVIX) is an active regimen in patients with LBC. We support the importance of using LBC as a biological model for investigating angiogenesis inhibitors. CECs and CEPs biomarkers have been identified as predictive markers of outcome and warrant further investigation.