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WHAT IS THIS SUMMARY ABOUT?: This is a summary of a paper published in a medical journal that describes the results of a study called CheckMate 274. This study looked at a new treatment for muscle-invasive urothelial cancer, a type of cancer found in the urinary tract that has spread from the inner lining of the urinary tract or bladder and into the surrounding muscle wall where it can then spread to other parts of the body. The standard treatment for muscle-invasive urothelial cancer is surgery to remove affected parts of the urinary tract. However, cancer returns in more than half of people after this surgery. Adjuvant therapy is given to people after surgery with muscle-invasive urothelial cancer with a goal to reduce the risk of the cancer coming back; however, at the time this study started, there was no standard adjuvant treatment. WHAT HAPPENED IN THE STUDY?: In the CheckMate 274 study, researchers compared nivolumab with a placebo as an adjuvant treatment for people with muscle-invasive urothelial cancer. The aim of the study was to understand how well nivolumab worked to reduce the chance of the cancer returning after surgery. The study also looked at what side effects (unwanted or unexpected results or conditions that are possibly related to the use of a medication) people had with treatment. WHAT DO THE RESULTS MEAN?: The results showed that people who received nivolumab versus placebo: Survived longer before the cancer was detected again, including people who had programmed death ligand-1 (shortened to PD-L1) on their cancer cells. Survived longer before a secondary cancer outside of the urinary tract was detected. Experienced no differences in health-related quality of life (the impact of the treatment on a person's mental and physical health). Had similar side effects to the people who received nivolumab in other studies. Clinical Trial Registration: NCT02632409 (ClinicalTrials.gov).
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Neoplasias de los Músculos , Neoplasias de la Vejiga Urinaria , Humanos , Nivolumab/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Calidad de Vida , Inmunoterapia/métodos , Músculos , Neoplasias de los Músculos/tratamiento farmacológicoRESUMEN
Increasing data suggests that an intact immune system is required for improvedoutcomes in patients with Human Epidermal Growth Factor Receptor 2 (HER2+) and Triple Negative Breast Cancer (TNBC) [...].
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INTRODUCTION: Triple negative breast cancer (TNBC) is an aggressive BC subtype, associated with higher rates of relapse and shorter overall survival upon metastatic relapse. The advent of antibody-drug conjugates (ADC), able to deliver selectively potent chemotherapeutic agents, has demonstrated promising clinical activity, with the first approval of an ADC, i.e. Sacituzumab Govitecan, in the metastatic setting. This paperprovides the most recent data indicating the promise of this novel class of drugs, as potential tools to improve clinical outcomes of patients diagnosed with TNBC. AREAS COVERED: Upon review of the main characteristics of TNBC, and those of ADCs, an overview of the data from clinical trials assessing ADCs in TNBC is provided, including those that led to the first approval of such a drug for patients with metastatic disease; furthermore, several other ADCs targeting different proteins (over)expressed by TNBC undergo clinical development. Combinations of ADCs with other targeted agents are discussed; the most pertinent considerations for improving the chances of successful clinical development of ADCs in TNBC are provided. EXPERT OPINION: ADCs could further improve clinical outcomes of patients with TNBC, and successful development depends upon: i) successful triaging of patients with the right ADC, ii) technical optimization of ADCs to maximize the efficacy, while reducing toxicity, and iii) assess rationally chosen combinations with synergistic antitumor activity and acceptable safety profile.
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Antineoplásicos , Inmunoconjugados , Neoplasias de la Mama Triple Negativas , Antineoplásicos/efectos adversos , Humanos , Inmunoconjugados/efectos adversos , Recurrencia Local de Neoplasia/inducido químicamente , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains ≥1% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive vs. negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs.
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BACKGROUND: The role of adjuvant treatment in high-risk muscle-invasive urothelial carcinoma after radical surgery is not clear. METHODS: In a phase 3, multicenter, double-blind, randomized, controlled trial, we assigned patients with muscle-invasive urothelial carcinoma who had undergone radical surgery to receive, in a 1:1 ratio, either nivolumab (240 mg intravenously) or placebo every 2 weeks for up to 1 year. Neoadjuvant cisplatin-based chemotherapy before trial entry was allowed. The primary end points were disease-free survival among all the patients (intention-to-treat population) and among patients with a tumor programmed death ligand 1 (PD-L1) expression level of 1% or more. Survival free from recurrence outside the urothelial tract was a secondary end point. RESULTS: A total of 353 patients were assigned to receive nivolumab and 356 to receive placebo. The median disease-free survival in the intention-to-treat population was 20.8 months (95% confidence interval [CI], 16.5 to 27.6) with nivolumab and 10.8 months (95% CI, 8.3 to 13.9) with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with nivolumab and 60.3% with placebo (hazard ratio for disease recurrence or death, 0.70; 98.22% CI, 0.55 to 0.90; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 74.5% and 55.7%, respectively (hazard ratio, 0.55; 98.72% CI, 0.35 to 0.85; P<0.001). The median survival free from recurrence outside the urothelial tract in the intention-to-treat population was 22.9 months (95% CI, 19.2 to 33.4) with nivolumab and 13.7 months (95% CI, 8.4 to 20.3) with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77.0% with nivolumab and 62.7% with placebo (hazard ratio for recurrence outside the urothelial tract or death, 0.72; 95% CI, 0.59 to 0.89). Among patients with a PD-L1 expression level of 1% or more, the percentage of patients was 75.3% and 56.7%, respectively (hazard ratio, 0.55; 95% CI, 0.39 to 0.79). Treatment-related adverse events of grade 3 or higher occurred in 17.9% of the nivolumab group and 7.2% of the placebo group. Two treatment-related deaths due to pneumonitis were noted in the nivolumab group. CONCLUSIONS: In this trial involving patients with high-risk muscle-invasive urothelial carcinoma who had undergone radical surgery, disease-free survival was longer with adjuvant nivolumab than with placebo in the intention-to-treat population and among patients with a PD-L1 expression level of 1% or more. (Funded by Bristol Myers Squibb and Ono Pharmaceutical; CheckMate 274 ClinicalTrials.gov number, NCT02632409.).
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Antineoplásicos Inmunológicos/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Nivolumab/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1/metabolismo , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/cirugía , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Humanos , Análisis de Intención de Tratar , Masculino , Persona de Mediana Edad , Invasividad Neoplásica , Estadificación de Neoplasias , Nivolumab/efectos adversos , Placebos/uso terapéutico , Calidad de Vida , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/cirugíaRESUMEN
BACKGROUND: The APHINITY (BIG 4-11) study showed that pertuzumab significantly improved the rates of invasive disease-free survival among patients with human epidermal growth factor receptor 2 (HER2)-positive, operable breast cancer when added to adjuvant trastuzumab and chemotherapy. Because diarrhea was a common adverse event that could compromise treatment administration, we evaluated the incidence and management of diarrhea in the APHINITY study. PATIENTS AND METHODS: The APHINITY trial is a prospective, randomized, multicenter, multinational, double-blind, placebo-controlled trial. The eligible patients were randomly assigned to receive standard adjuvant chemotherapy and 1 year of trastuzumab combined with pertuzumab or placebo. The diarrhea incidence, severity (National Cancer Institute common terminology criteria for adverse events, version 4.0), onset, and management were analyzed. RESULTS: A total of 4805 patients were randomized. Diarrhea of any grade was the most common adverse event and occurred in 71% of patients in the pertuzumab arm versus 45% in the placebo arm. Diarrhea grade 3 to 4 was observed in 10% and 4% in the pertuzumab and placebo arms, respectively. The greatest incidence of diarrhea was reported during the concomitant administration of HER2-targeted therapy and taxane (61% vs. 34% of patients experienced an event with pertuzumab vs. placebo, respectively). A marked decrease was observed on chemotherapy cessation. Antidiarrheal agents were commonly used, and diarrhea rarely caused treatment dose modifications or discontinuation. CONCLUSION: Diarrhea was a common adverse event in the APHINITY study. Most episodes were low grade and were generally manageable with common antidiarrheal agents. The incidence of diarrhea was greater with the combination of a taxane and HER2-targeted treatment and decreased once chemotherapy was stopped.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/terapia , Diarrea/epidemiología , Trastuzumab/efectos adversos , Adulto , Anciano , Antidiarreicos/uso terapéutico , Mama/patología , Mama/cirugía , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/efectos adversos , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Diarrea/inducido químicamente , Diarrea/diagnóstico , Diarrea/tratamiento farmacológico , Supervivencia sin Enfermedad , Femenino , Humanos , Incidencia , Mastectomía , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Supervivencia sin Progresión , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/metabolismo , Índice de Severidad de la Enfermedad , Taxoides/efectos adversosRESUMEN
BACKGROUND: Trastuzumab-associated cardiotoxicity remains an issue for patients with HER2-positive breast cancer. This pooled analysis of 3 adjuvant trials investigated the incidence, timing, impact on treatment completion, and risk factors for trastuzumab-associated cardiotoxicity. METHODS: This is an individual patient data level pooled analysis of HERA, NSBAP B-31, and NCCTG 9831 (Alliance Trials). Definitions of cardiac events were as per each individual study. RESULTS: A total of 7445 patients enrolled in the 3 trials were included in the analysis, of which 4017 were in the trastuzumab and 3428 in the control (observation) arms, respectively. Median follow-up exceeded 10 years (119.2-137.2 months). Nearly all patients (97.4%) in the trastuzumab arms received anthracycline-based chemotherapy. In total, 452 patients in the trastuzumab arms experienced a cardiac event (11.3%), with most being mildly symptomatic or asymptomatic left ventricular ejection fraction (LVEF) decrease (351 patients, 8.7%). Severe congestive heart failure was more common in the trastuzumab arm (2.3%) than in the control arm (0.8%). Most cardiac events occurred during trastuzumab treatment (78.1%) and cardiac events were the main cause of discontinuation across the sample (10.0%); nevertheless, a large majority of patients completed trastuzumab treatment (76.2%). Baseline risk factors that were significantly associated with the development of cardiac events were baseline LVEF < 60%, hypertension, body mass index > 25, age ≥ 60 and, non-Caucasian ethnicity. CONCLUSION: One year of trastuzumab increases the risk of cardiac events, though most consist of asymptomatic or mildly symptomatic LVEF drops. Adjuvant trastuzumab should be considered a safe treatment from a cardiac standpoint for most patients. Trastuzumab-associated cardiotoxicity is the main cause of discontinuation and further research is needed to individualize prevention and management.
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Antineoplásicos Inmunológicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Cardiopatías/epidemiología , Trastuzumab/administración & dosificación , Adulto , Anciano , Antineoplásicos Inmunológicos/efectos adversos , Estudios de Casos y Controles , Femenino , Cardiopatías/inducido químicamente , Humanos , Incidencia , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Endocrine therapy-based neoadjuvant treatment for luminal breast cancer allows efficient testing of new combinations before surgery. The activation of the phosphatidylinositol-3-kinase (PI3K) pathway is a known mechanism of resistance to endocrine therapy. Taselisib is an oral, selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. The LORELEI trial tested whether taselisib in combination with letrozole would result in an increased proportion of objective responses and pathological complete responses. METHODS: In this multicentre, randomised, double-blind, parallel-cohort, placebo-controlled phase 2, study, we enrolled postmenopausal women (aged ≥18 years) with histologically confirmed, oestrogen receptor (ER)-positive, HER2-negative, stage I-III, operable breast cancer, from 85 hospitals in 22 countries worldwide. To be eligible, patients had have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1, adequate organ function, and had to have evaluable tumour tissue for PIK3CA genotyping. Patients were randomly assigned (1:1) by means of a permuted block algorithm (block size of four) via an interactive voice or web-based response system, to receive letrozole (2·5 mg/day orally, continuously) with either 4 mg of oral taselisib or placebo (on a 5 days-on, 2 days-off schedule) for 16 weeks, followed by surgery. Randomisation was stratified by tumour size and nodal status. Site staff, patients, and the sponsor were masked to treatment assignment. Coprimary endpoints were the proportion of patients who achieved an objective response by centrally assessed breast MRI and a locally assessed pathological complete response in the breast and axilla (ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumours. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02273973, and is closed to accrual. FINDINGS: Between Nov 12, 2014, and Aug 12, 2016, 334 participants were enrolled and randomly assigned to receive letrozole and placebo (n=168) or letrozole and taselisib (n=166). Median follow-up was 4·9 months (IQR 4·7-5·1). The study met one of its primary endpoints: the addition of taselisib to letrozole was associated with a higher proportion of patients achieving an objective response in all randomly assigned patients (66 [39%] of 168 patients in the placebo group vs 83 [50%] of 166 in the taselisib group; odds ratio [OR] 1·55, 95% CI 1·00-2·38; p=0·049) and in the PIK3CA-mutant subset (30 [38%] of 79 vs 41 [56%] of 73; OR 2·03, 95% CI 1·06-3·88; p=0·033). No significant differences were observed in pathological complete response between the two groups, either in the overall population (three [2%] of 166 in the taselisib group vs one [1%] of 168 in the placebo group; OR 3·07 [95% CI 0·32-29·85], p=0·37) or in the PIK3CA-mutant cohort (one patient [1%) vs none [0%]; OR not estimable, p=0·48). The most common grade 3-4 adverse events in the taselisib group were gastrointestinal (13 [8%] of 167 patients), infections (eight [5%]), and skin-subcutaneous tissue disorders (eight [5%]). In the placebo group, four (2%) of 167 patients had grade 3 or worse vascular disorders, two (1%) had gastrointestinal disorders, and two (1%) patients had grade 3 or worse infections and infestations. There was no grade 4 hyperglycaemia and grade 3 cases were asymptomatic. Serious adverse events were more common in the taselisib group (eight [5%] patients with infections and seven [4%] with gastrointestinal effects) than in the placebo group (one [1%] patient each with grade 3 postoperative wound and haematoma infection, grade 4 hypertensive encephalopathy, grade 3 acute cardiac failure, and grade 3 breast pain). One death occurred in the taselisib group, which was not considered to be treatment-related. INTERPRETATION: The increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor-positive, HER2-negative, metastatic breast cancer. FUNDING: Genentech and F Hoffmann-La Roche.
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Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Imidazoles/administración & dosificación , Letrozol/administración & dosificación , Oxazepinas/administración & dosificación , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Método Doble Ciego , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Imidazoles/efectos adversos , Letrozol/efectos adversos , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Oxazepinas/efectos adversos , Posmenopausia , Receptor ErbB-2/genética , Resultado del TratamientoRESUMEN
BACKGROUND/AIM: This study sought to determine whether an autoimmune background could identify patients with HER2-positive early breast cancer (EBC) who derive differential benefit from primary adjuvant trastuzumab-based therapy. PATIENTS AND METHODS: HERA is an international randomized trial of 5,102 women with HER2-positive EBC, who were enrolled to either receive adjuvant trastuzumab or not. In this exploratory analysis, the interaction between autoimmune history and the magnitude of trastuzumab benefit was evaluated. RESULTS: A total of 5,099 patients were included in the current analysis. Among them, 325 patients (6.4%) had autoimmune disease history, 295 of whom had active disease. Patients were randomly assigned to trastuzumab or no-trastuzumab groups. Similar reductions in the risk of events in patients with and without autoimmune history were observed (interaction p=0.95 for disease-free survival, and p=0.62 for overall survival). CONCLUSION: No evidence of a differential benefit from trastuzumab in patients with a medical history of autoimmune disease was found.
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Antineoplásicos Inmunológicos/uso terapéutico , Enfermedades Autoinmunes/complicaciones , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Trastuzumab/uso terapéutico , Adulto , Anciano , Neoplasias de la Mama/complicaciones , Quimioterapia Adyuvante/efectos adversos , Supervivencia sin Enfermedad , Femenino , Humanos , Cooperación Internacional , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Riesgo , Resultado del TratamientoRESUMEN
The prognosis of patients with early stage breast cancer has greatly improved in the past three decades. Following the first adjuvant endocrine therapy and chemotherapy trials, continuous improvements of clinical outcomes have been achieved through intense therapeutic escalation, albeit with increased health-care costs and treatment-related toxicities. In contrast to the advances achieved in surgery or radiotherapy, the identification of the patient subgroups that will derive clinical benefit from therapeutic escalation has proved to be a daunting process hindered by a lack of collaboration between scientific groups and by the pace of drug development. In the past few decades, initiatives towards de-escalation of systemic adjuvant treatment have achieved success. Herein, we summarize attempts to escalate and de-escalate adjuvant systemic treatment for patients with breast cancer and argue that new, creative trial designs focused on patients' actual needs rather than on maximizing drug market size are needed. Ultimately, the adoption of effective treatments that do not needlessly expose patients and health-care systems to harm demands extensive international collaboration between academic groups, governments, and pharmaceutical companies.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/efectos adversos , Biomarcadores de Tumor/genética , Neoplasias de la Mama/economía , Neoplasias de la Mama/genética , Quimioterapia Adyuvante/economía , Ensayos Clínicos como Asunto , Relación Dosis-Respuesta a Droga , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Estadificación de Neoplasias , Pronóstico , Resultado del TratamientoRESUMEN
Purpose: To assess the prognostic and predictive value of selected biomarkers involved in cell-cycle regulation or proliferation in patients with HER2-positive early breast cancer.Experimental Design: Protein expression of TOP2A, Ki67, cyclin D1, and p27 was immunohistochemically determined in tissue microarrays of surgical specimens from 862 patients randomized to trastuzumab (1 or 2 years; N = 561) and observation (N = 301) arms of the HERA trial. The primary analysis endpoint was disease-free survival (DFS). Biomarkers were examined as continuous or categorical variables (predefined cutoffs). Interaction terms between biomarkers and treatment were assessed in multivariate Cox models adjusted for variables of clinical interest.Results: A significant interaction was detected between p27 and treatment (adjusted P = 0.0049). Trastuzumab effect was significant in the p27-low subgroup (≤70% p27-positive tumor cells; N = 318). HR Comb Trast vs. Obs 0.44, 95% CI, 0.29-0.65 (P < 0.001). No trastuzumab effect was observed in the p27-high subgroup N = 435; HR Comb Trast vs. Obs 0.97, 95% CI, 0.66-1.44, P = 0.89), indicating that these patients derived little or no benefit from trastuzumab treatment. A prognostic effect of p27 on DFS was observed, with p27-high patients experiencing half the hazard of a DFS event compared with low ones (HR p27 High vs. Low 0.49, 95% CI, 0.32-0.75). TOP2A, Ki67, and cyclin D1, as categorical variables were not predictive, whereas cyclin D1 as continuous variable was predictive of trastuzumab benefit.Conclusions: In TransHERA, patients with HER2-positive early breast cancer with low p27 expression in their tumors benefited from trastuzumab treatment, whereas patients with high p27 expression did not. Clin Cancer Res; 24(13); 3079-86. ©2018 AACR.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Ciclina D1/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Receptor ErbB-2/genética , Trastuzumab/uso terapéutico , Adulto , Anciano , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Quimioterapia Adyuvante , Ciclina D1/metabolismo , Inhibidor p27 de las Quinasas Dependientes de la Ciclina/metabolismo , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
Purpose Phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA) mutations are frequently observed in primary breast cancer. We evaluated their prognostic relevance by performing a pooled analysis of individual patient data. Patients and Methods Associations between PIK3CA status and clinicopathologic characteristics were tested by applying Cox regression models adjusted for age, tumor size, nodes, grade, estrogen receptor (ER) status, human epidermal growth factor receptor 2 (HER2) status, treatment, and study. Invasive disease-free survival (IDFS) was the primary end point; distant disease-free survival (DDFS) and overall survival (OS) were also assessed, overall and by breast cancer subtypes. Results Data from 10,319 patients from 19 studies were included (median OS follow-up, 6.9 years); 1,787 patients (17%) received chemotherapy, 4,036 (39%) received endocrine monotherapy, 3,583 (35%) received both, and 913 (9%) received none or their treatment was unknown. PIK3CA mutations occurred in 32% of patients, with significant associations with ER positivity, increasing age, lower grade, and smaller size (all P < .001). Prevalence of PIK3CA mutations was 18%, 22%, and 37% in the ER-negative/HER2-negative, HER2-positive, and ER-positive/HER2-negative subtypes, respectively. In univariable analysis, PIK3CA mutations were associated with better IDFS (HR, 0.77; 95% CI, 0.71 to 0.84; P < .001), with evidence for a stronger effect in the first years of follow-up (0 to 5 years: HR, 0.73; 95% CI, 0.66 to 0.81; P < .001; 5 to 10 years: HR, 0.82; 95% CI, 0.68 to 0.99; P = .037); > 10 years: (HR, 1.15; 95% CI, 0.84 to 1.58; P = .38; P heterogeneity = .02). In multivariable analysis, PIK3CA genotype remained significant for improved IDFS ( P = .043), but not for the DDFS and OS end points. Conclusion In this large pooled analysis, PIK3CA mutations were significantly associated with a better IDFS, DDFS, and OS, but had a lesser prognostic effect after adjustment for other prognostic factors.
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Neoplasias de la Mama/genética , Fosfatidilinositol 3-Quinasa Clase I/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Supervivencia sin Enfermedad , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Mutación , Estadificación de Neoplasias , Pronóstico , Modelos de Riesgos Proporcionales , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Tasa de Supervivencia , Adulto JovenRESUMEN
BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel. RESULTS: 173 and 172 were tested at all three timepoints for NT-proBNP and TnT, respectively. The incidence of biomarker elevation was overall low at all timepoints for all the three treatment arms. A total of 13 CEs in 11 patients occurred. Biomarker elevations in patients with CEs were very rare; only one patient with subsequent CE had a NT-proBNP elevation at baseline and at week 2. CONCLUSION: These results suggest that TnT and proBNP may not be useful as early predictors of cardiac toxicity in anthracycline-naïve patients receiving trastuzumab and/or lapatinib.
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Biomarcadores/sangre , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Cardiotoxicidad/sangre , Anomalías Cardiovasculares/sangre , Anciano , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Cardiotoxicidad/patología , Anomalías Cardiovasculares/inducido químicamente , Anomalías Cardiovasculares/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Lapatinib/administración & dosificación , Lapatinib/efectos adversos , Persona de Mediana Edad , Péptido Natriurético Encefálico/sangre , Estadificación de Neoplasias , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Receptor ErbB-2/genética , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversos , Troponina T/sangreRESUMEN
INTRODUCTION: Dysregulated cellular proliferation, one of the hallmarks of cancer, is mediated by aberrant activation of the cell cycle machinery through the biological effects of cyclin-dependent kinases (CDKs). The clinical development of non-selective CDK inhibitors failed due to combined lack of efficacy and excessive toxicity reported by clinical trials across different cancer types. The clinical development of second generation, CDK4/6-selective inhibitors, namely palbociclib, abemaciclib and ribociclib, led to practice-changing results in the setting of breast cancer. Areas covered: This review illustrates how CDK4/6-selective inhibitors got approval for the treatment of patients with either newly diagnosed or pretreated advanced hormone receptor positive, HER2-negative breast cancer. Furthermore, data about potential predictive biomarkers, as well as preclinical and preliminary clinical evidence for potential antitumor activity of CDK4/6 inhibition in other breast cancer subtypes is provided. Expert opinion: Future clinical development of CDK4/6 inhibitors in breast cancer will focus on the following aspects: i) optimization of treatment sequencing for patients with advanced disease, ii) early-stage disease, iii) other subtypes of breast cancer in rationally chosen therapeutic combinations and iv) the identification of predictive biomarkers.
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Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Aminopiridinas/administración & dosificación , Aminopiridinas/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Bencimidazoles/administración & dosificación , Bencimidazoles/farmacología , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Proliferación Celular/efectos de los fármacos , Diseño de Fármacos , Femenino , Humanos , Estadificación de Neoplasias , Piperazinas/administración & dosificación , Piperazinas/farmacología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/farmacología , Purinas/administración & dosificación , Purinas/farmacología , Piridinas/administración & dosificación , Piridinas/farmacologíaRESUMEN
AIM: The Neoadjuvant PI3K inhibition in HER2 OverExpressing Breast cancEr (NeoPHOEBE) trial evaluated the efficacy and safety of buparlisib, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, plus trastuzumab and paclitaxel as neoadjuvant treatment for human epidermal growth factor receptor-2 positive (HER2+) breast cancer. METHODS: NeoPHOEBE was a neoadjuvant, phase II, randomised, double-blind study. Women with HER2+ breast cancer were randomised within two independent cohorts by PIK3CA mutation status and, in each cohort stratified by oestrogen receptor (ER) status to receive buparlisib or placebo plus trastuzumab (first 6 weeks) followed by buparlisib or placebo with trastuzumab and paclitaxel. Primary end-point was pathological complete response (pCR) rate; key secondary end-point was objective response rate (ORR) at 6 weeks. Exploratory end-points were evaluation of Ki67 levels and change in tumour infiltrating lymphocytes (TILs) in intermediate biopsies at day 15. RESULTS: Recruitment was suspended mainly due to liver toxicity after enrolment of 50 of the planned 256 patients. In each arm (buparlisib n = 25; placebo n = 25) 21 patients (84%) had wild type PIK3CA and 4 patients (16%) had mutant PIK3CA. Overall, pCR rate was similar between buparlisib and placebo arms (32.0% versus 40%; one-sided P = 0.811). A trend towards higher ORR (68.8% versus 33.3%; P = 0.053) and a significant decrease in Ki67 (75% versus 26.7%; P = 0.021) was observed in buparlisib versus placebo arm in the ER+ subgroup (Pinteraction = 0.03). CONCLUSIONS: Addition of the pan-PI3K inhibitor buparlisib to taxane-trastuzumab-based therapy in HER2+ early breast cancer was not feasible. However, the higher ORR and Ki67 reduction in the ER+, HER2+ subgroup indicates a potential role for PI3K-targeted therapy in this setting and may warrant further investigation with better-tolerated second-generation PI3K inhibitors. TRIAL REGISTRATION IDENTIFIER: NCT01816594.
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Aminopiridinas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Neoplasias de la Mama/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/antagonistas & inhibidores , Morfolinas/administración & dosificación , Terapia Neoadyuvante , Paclitaxel/administración & dosificación , Inhibidores de Proteínas Quinasas/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Trastuzumab/administración & dosificación , Adulto , Anciano , Aminopiridinas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Australia , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Biopsia , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Quimioterapia Adyuvante , Fosfatidilinositol 3-Quinasa Clase I/genética , Fosfatidilinositol 3-Quinasa Clase I/metabolismo , Método Doble Ciego , Terminación Anticipada de los Ensayos Clínicos , Europa (Continente) , Femenino , Humanos , Antígeno Ki-67/metabolismo , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Persona de Mediana Edad , Morfolinas/efectos adversos , Mutación , Terapia Neoadyuvante/efectos adversos , Paclitaxel/efectos adversos , Inhibidores de Proteínas Quinasas/efectos adversos , Receptor ErbB-2/metabolismo , Factores de Tiempo , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
Cancer is one of the oldest diseases ever described, since ancient Egypt there have always been attempts to treat and cure this illness. The growing body of knowledge about breast cancer biology and improvements in surgical and medical treatments has been built over time with contributions from many talented and enthusiastic physicians and researchers. Medical advances have changed the approach from a previously incurable condition, into a surgical disease. Further improvements in cancer biology have allowed the development of systemic treatments, hormonal therapies, and targeted drugs. The description of the molecular intrinsic subtypes of breast cancer clarified the understanding of breast cancer as a group of heterogeneous diseases, associated with different clinical outcomes, and therapeutic opportunities. This paper reviews how breast cancer treatment has improved since the earliest descriptions, in ancient times, and how future approaches, such as gene signatures, molecular profiling, and liquid biopsies, aim to further develop individualised treatments and improve treatment outcomes.
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Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility. Sequencing results were obtained for 63% of the patients in real-time with variable turnaround time stemming from delays between patient consent and biopsy. At least one clinically actionable mutation was identified in 73% of patients. We used the Illumina sequencing technology for orthogonal validation and achieved an average of 66% concordance of substitution calls per patient. Additionally, copy number aberrations inferred from the Ion Torrent sequencing were compared to single nucleotide polymorphism arrays and found to be 59% concordant on average. Although this study demonstrates that powerful next generation genomic techniques are logistically ready for international molecular screening programs in routine clinical settings, technical challenges remain to be addressed in order to ensure the accuracy and clinical utility of the genomic data.
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BACKGROUND: Pertuzumab increases the rate of pathological complete response in the preoperative context and increases overall survival among patients with metastatic disease when it is added to trastuzumab and chemotherapy for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In this trial, we investigated whether pertuzumab, when added to adjuvant trastuzumab and chemotherapy, improves outcomes among patients with HER2-positive early breast cancer. METHODS: We randomly assigned patients with node-positive or high-risk node-negative HER2-positive, operable breast cancer to receive either pertuzumab or placebo added to standard adjuvant chemotherapy plus 1 year of treatment with trastuzumab. We assumed a 3-year invasive-disease-free survival rate of 91.8% with pertuzumab and 89.2% with placebo. RESULTS: In the trial population, 63% of the patients who were randomly assigned to receive pertuzumab (2400 patients) or placebo (2405 patients) had node-positive disease and 36% had hormone-receptor-negative disease. Disease recurrence occurred in 171 patients (7.1%) in the pertuzumab group and 210 patients (8.7%) in the placebo group (hazard ratio, 0.81; 95% confidence interval [CI], 0.66 to 1.00; P=0.045). The estimates of the 3-year rates of invasive-disease-free survival were 94.1% in the pertuzumab group and 93.2% in the placebo group. In the cohort of patients with node-positive disease, the 3-year rate of invasive-disease-free survival was 92.0% in the pertuzumab group, as compared with 90.2% in the placebo group (hazard ratio for an invasive-disease event, 0.77; 95% CI, 0.62 to 0.96; P=0.02). In the cohort of patients with node-negative disease, the 3-year rate of invasive-disease-free survival was 97.5% in the pertuzumab group and 98.4% in the placebo group (hazard ratio for an invasive-disease event, 1.13; 95% CI, 0.68 to 1.86; P=0.64). Heart failure, cardiac death, and cardiac dysfunction were infrequent in both treatment groups. Diarrhea of grade 3 or higher occurred almost exclusively during chemotherapy and was more frequent with pertuzumab than with placebo (9.8% vs. 3.7%). CONCLUSIONS: Pertuzumab significantly improved the rates of invasive-disease-free survival among patients with HER2-positive, operable breast cancer when it was added to trastuzumab and chemotherapy. Diarrhea was more common with pertuzumab than with placebo. (Funded by F. Hoffmann-La Roche/Genentech; APHINITY ClinicalTrials.gov number, NCT01358877 .).
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Trastuzumab/uso terapéutico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Diarrea/inducido químicamente , Supervivencia sin Enfermedad , Método Doble Ciego , Femenino , Insuficiencia Cardíaca/inducido químicamente , Humanos , Persona de Mediana Edad , Receptor ErbB-2/análisis , Tasa de Supervivencia , Trastuzumab/efectos adversosRESUMEN
Estrogen receptor positive (ER+) and HER2-negative (HER2-) breast cancer (BC) is the most common BC subtype, defined by expression of the ER and absence of HER2 amplification. Endocrine treatment (ET), aiming at therapeutic blockade of ER signaling, represents the therapeutic mainstay for patients with both early and advanced disease. Despite its wide therapeutic efficacy, ET fails for a proportion of ER+, HER2- BC patients with early disease who develop endocrine resistance, resulting in disease recurrence. Endocrine resistance occurs almost invariably in patients with metastatic disease. Recently, increasing understanding of the molecular mediators of endocrine resistance has been achieved. This review focuses on the molecular mechanisms mediating endocrine resistance, on molecularly targeted agents to overcome or delay it, and potential predictive biomarkers for accurate patient stratification.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Metilación de ADN , Resistencia a Antineoplásicos/genética , Receptor alfa de Estrógeno/genética , Femenino , Inhibidores de Histona Desacetilasas , Humanos , Mutación , Inhibidores de las Quinasa Fosfoinosítidos-3 , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
BACKGROUND: The development of trastuzumab is considered to be one of the greatest improvements in breast cancer treatment in recent years. This study aims to evaluate changes in the uptake of trastuzumab over the last 12 years and to determine whether its use is proportional to patient needs in the European Union and the USA. METHODS: Using national registry data, the number of new cases of HER2-positive breast cancer patients per year was estimated. The number of likely trastuzumab treatments per year was estimated using trastuzumab procurement data for each country. RESULTS: Western Europe and the USA show increasing procurement level of trastuzumab over the years studied, reaching proportional of use of trastuzumab few years after its marketing authorization in the early 2000's. After the approval in the adjuvant setting, in the year 2006, it was observed underuse of trastuzumab given the increase of the number of patients in need of treatment. Proportional use was shortly met after a couple of years. Few countries in Eastern Europe acquired the needed quantity of trastuzumab, with procurement levels starting to increase only after approval in the adjuvant setting in 2006. CONCLUSION: Significant differences in trastuzumab procurement are observed between Western Europe, the USA and Eastern Europe, with the latter geographic region acquiring insufficient amounts of the drug required to treat all patients in need.