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OBJECTIVE: The single-arm, phase II SORAYA trial (NCT04296890) of mirvetuximab soravtansine-gynx in folate receptor alpha (FRα)-high platinum-resistant ovarian cancer (n=105 (efficacy-evaluable)) met its primary endpoint with an objective response rate of 32.4% (95% CI, 23.6 to 42.2). Here we report final SORAYA trial results for overall survival and post hoc objective response rates in subgroups by sequence and number of prior therapies. METHODS: Eligible patients had high-grade serous platinum-resistant ovarian cancer with high FRα expression and one to three prior therapies (prior bevacizumab required). Enrolled participants received 6 mg/kg mirvetuximab soravtansine-gynx adjusted ideal body weight intravenously once every 3 weeks until progressive disease, unacceptable toxicity, withdrawal of consent, or death. Final overall survival and post hoc objective response rates were assessed in efficacy-evaluable participants. The safety population included all patients who received ≥1 dose of mirvetuximab soravtansine-gynx. RESULTS: At data cut-off (December 22, 2022; n=105), final median overall survival was 15.0 months (95% CI, 11.5 to 18.7). Median overall survival in participants with one to two prior therapy lines was 18.7 months (95% CI, 13.8 to not estimable (NE)) and 11.6 months (95% CI, 7.1 to 16.7) with three prior therapy lines. Median overall survival was 15.0 months (95% CI, 11.5 to NE) in participants with prior poly (ADP-ribose) polymerase inhibitor (PARPi) treatment versus 14.0 months (95% CI, 7.1 to NE) in those without. Objective response rate (data cut-off: November 17, 2021) differed among participants who received mirvetuximab soravtansine-gynx as their first treatment in the platinum-resistant setting (34.8%; 95% CI, 23.5 to 47.6) versus a different first treatment (28.2%; 95% CI, 15.0 to 44.9) or had received prior bevacizumab in a platinum-sensitive (34.0%; 95% CI, 24.6 to 44.5) versus platinum-resistant setting (17.6%; 95% CI, 3.8 to 43.4). No new safety signals were observed. CONCLUSION: These results support the clinically meaningful efficacy of mirvetuximab soravtansine-gynx in FRα-expressing platinum-resistant ovarian cancer, irrespective of prior treatment or sequence.
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Anticuerpos Monoclonales Humanizados , Resistencia a Antineoplásicos , Receptor 1 de Folato , Inmunoconjugados , Maitansina , Neoplasias Ováricas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Receptor 1 de Folato/metabolismo , Persona de Mediana Edad , Maitansina/análogos & derivados , Maitansina/uso terapéutico , Maitansina/administración & dosificación , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Adulto , Inmunoconjugados/administración & dosificación , Inmunoconjugados/efectos adversos , Inmunoconjugados/uso terapéutico , Anciano de 80 o más AñosRESUMEN
OPINION STATEMENT: Oral inhibitors of CDK4/6 have been shown to increase response rates and prolong disease control when combined with endocrine therapy in hormone-responsive (HR+) HER2-negative advanced breast cancer. Palbociclib, ribociclib and abemaciclib are all approved in combination with non-steroidal aromatase inhibitors in first-line therapy for post-menopausal women, with a 40-45% improvement in progression-free survival seen with the addition of any of these CDK4/6 inhibitors. Additional approved indications, including first- and second-line combination therapy for pre-menopausal women, combination with fulvestrant and use as monotherapy, vary with each agent and are reviewed fully in the subsequent texts. These agents also differ in their toxicity profiles and monitoring requirements, and prescribers should be aware of the individual requirements for each agent. Current clinical trials are investigating the expanded use of these agents in other breast cancer subtypes, such as HER2-positive and triple-negative breast cancer, as well as in the adjuvant and neoadjuvant treatments of early breast cancer. Resistance to CDK4/6 inhibition can occur through multiple mechanisms. Rational combinations with other therapies, such as PI3K inhibitors, HER2-directed therapies and immunotherapy, are being explored.
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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 , Terapia Molecular Dirigida , Inhibidores de Proteínas Quinasas/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/etiología , Neoplasias de la Mama/mortalidad , Ensayos Clínicos como Asunto , Resistencia a Antineoplásicos , Femenino , Humanos , Pronóstico , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/farmacocinética , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/etiología , Neoplasias de la Mama Triple Negativas/mortalidadRESUMEN
AIMS AND OBJECTIVES: To measure cancer-related fatigue (CRF), self-care agency (SCA) and fatigue self-care strategies, and to explore the relationship between CRF and SCA. BACKGROUND: Cancer-related fatigue has been consistently rated as the most elusive, common and severe of symptoms that patients with cancer undergoing chemotherapy experience. Despite its frequency and severity, CRF is poorly managed. A renewed focus on supporting self-care among patients with cancer has been found to reduce symptom burden, empower patients and improve patient satisfaction. Understanding the link between self-care agency (i.e. capability and willingness to self-care) and CRF levels will help practitioners to better support individuals on the cancer journey. DESIGN: A descriptive, correlational survey design was employed. METHODS: Patients (n = 362) undergoing chemotherapy with a primary diagnosis of breast, colorectal, Hodgkin's and non-Hodgkin's lymphoma cancers were recruited from four oncology centres in one city in the South of Ireland. Participants completed the Piper Fatigue Scale-Revised, Appraisal of Self-care Agency Scale and a researcher-developed Fatigue Self-Care Survey. Multivariate logistic regression was used to examine the relationship between CRF and self-care agency using a dichotomous dependent variable score of four as the cut-off between those deemed to be fatigued (≥4) and those not fatigued (<4). As recommended by the EQUATOR Network, the STROBE checklist of items for cross-sectional studies is used to report the study. RESULTS: The incidence of CRF was high with 75% of participants scoring clinically relevant CRF. Higher SCA (OR = 0.96, 95% CI = 0.93-0.99, p = .011) was associated with decreased odds of developing CRF. Having non-Hodgkin's lymphoma (OR = 3.02, 95% CI = 1.29-7.07, p = .011) was associated with increased odds of developing CRF. CONCLUSIONS: Patient's undergoing chemotherapy experience significant fatigue. Higher capability for self-care is associated with lower fatigue. The promotion of SCA and self-care strategies can impact on CRF. RELEVANCE TO CLINICAL PRACTICE: Understanding the link between self-care abilities and fatigue can lead to more individualised and tailored approaches to CRF.
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Antineoplásicos/efectos adversos , Fatiga/etiología , Neoplasias/tratamiento farmacológico , Autocuidado/psicología , Adulto , Anciano , Estudios Transversales , Fatiga/psicología , Femenino , Humanos , Irlanda , Modelos Logísticos , Masculino , Persona de Mediana Edad , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Imbalance of the cyclin D and cyclin-dependent kinase (CDK) pathway in cancer cells may result in diversion away from a pathway to senescence and toward a more proliferative phenotype. Cancer cells may increase cyclin D-dependent activity through a variety of mechanisms. Therapeutic inhibition of CDKs in tumors to negate their evasion of growth suppressors has been identified as a key anticancer strategy. In this review, we outline the development of CDK inhibitory therapy in breast cancer, including the initial experience with the pan-CDK inhibitor flavopiridol and the next generation of oral highly selective CDK4 and CDK6 inhibitors PD0332991 (palbociclib), LEE011 (ribociclib), and LY2835219 (abemaciclib). Data from phase I and II studies in estrogen receptor-positive (ER+) breast cancer demonstrate promising efficacy with manageable toxic effects, chiefly neutropenia. We discuss these studies and the phase III studies that are accruing or nearing completion. We describe the application of such therapy to other breast cancer settings, including HER2-positive breast cancer and the adjuvant treatment of early breast cancer. We also discuss potential concerns surrounding the combination of CDK inhibitors with chemotherapy and their effects on repair of double-strand DNA breaks in cancer cells. Oral highly selective CDK inhibitors show great promise in improving the outcomes of patients with ER+ breast cancer, although caution must apply to their combination with other agents and in the early breast cancer setting.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Quinasa 4 Dependiente de la Ciclina/genética , Quinasa 6 Dependiente de la Ciclina/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Aminopiridinas/administración & dosificación , Neoplasias de la Mama/patología , Ciclo Celular/efectos de los fármacos , Ensayos Clínicos como Asunto , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Roturas del ADN de Doble Cadena/efectos de los fármacos , Receptor alfa de Estrógeno/genética , Femenino , Flavonoides/administración & dosificación , Humanos , Piperazinas/administración & dosificación , Piperidinas/administración & dosificación , Purinas/administración & dosificación , Piridinas/administración & dosificaciónRESUMEN
Deregulation of the cyclin-dependent kinase (CDK) 4/6-retinoblastoma (RB) axis can occur through a number of mechanisms and contributes towards the unrestrained growth witnessed in a variety of cancers including breast cancers. Recent years have seen the development of selective CDK4/6 inhibitors, which have delivered promising preclinical and clinical results in breast cancer and other tumours. A number of trials assessing antitumour efficacy in various disease settings and combinations are ongoing. The cyclin D1-CDK-Rb axis and its role in the cell cycle of normal and cancer cells are delineated. The early pan-CDK inhibitor flavopiridol and subsequent preclinical and clinical development of selective CDK4/6 inhibitors are described. Ongoing studies in breast cancer with novel CDK4/6 inhibitors (palbociclib, abemaciclib and ribociclib) are explored. A literature search of these topics was performed through PubMed. Abstracts from major oncology meetings were also reviewed. Selective CDK4/6 inhibitors, as represented by the competing compounds currently in clinical development, comprise a novel, safe and, thus far, promisingly efficacious group of drugs. Considerable resources are being devoted towards exploring the efficacy of these drugs in combination with endocrine therapies, an approach that has yielded encouraging results and accelerated approval by the US Food and Drugs Administration for one of these agents (palbociclib). The results of confirmatory phase 3 trials are, however, awaited. We discuss further therapy combinations in development and highlight potential areas for caution including the potential for antagonistic interactions with cytotoxic chemotherapies.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinasa 4 Dependiente de la Ciclina/antagonistas & inhibidores , Quinasa 6 Dependiente de la Ciclina/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Animales , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Ensayos Clínicos como Asunto , Quinasa 4 Dependiente de la Ciclina/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , Femenino , Humanos , Inhibidores de Proteínas Quinasas/farmacologíaAsunto(s)
Detección Precoz del Cáncer/métodos , Necesidades y Demandas de Servicios de Salud , Melanoma/diagnóstico , Atención Secundaria de Salud/organización & administración , Neoplasias Cutáneas/diagnóstico , Adulto , Anciano , Concienciación , Femenino , Hospitales Universitarios , Humanos , Irlanda , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
BACKGROUND: Ireland has a mixed model of healthcare delivery with a public healthcare system funded by general taxation and a large private healthcare insurance system, covering 43% of the population in 2012 and 2016. We set out to examine disparities in outcomes among patients with breast cancer treated in a private hospital compared to national outcomes over a comparable period. METHODS: Medical records of patients diagnosed with early (Stage 1-3 as per AJCC version 5) breast cancer between 2010 and 2015 at Bon Secours Hospital, Cork, Ireland were reviewed. Staging was confirmed and 5-year disease specific survival (DSS) and overall survival (OS) were calculated. DSS was compared to 5-year net survival (NS) figures from the National Cancer Registry of Ireland (NCRI) for a comparable period (2010-2014). RESULTS: DSS (Bon Secours) and NS (NCRI) are summarized in Table 5 and Fig. 2. 5-year survival figures are numerically higher in the private hospital compared with national data for individual stage. Taking stages 1 to 3 combined, the 95% confidence intervals do not cross, indicating statistical significance. CONCLUSIONS: We found evidence of superior outcomes in patients with early breast cancer treated at a private hospital compared with national outcome figures. This was demonstrated in 'all comers' (stages 1-3 combined), and particularly in patients with stage 3 breast cancer. Potential reasons for this disparity include differences in socioeconomic status, health-seeking behaviours and/or underlying health status between the two populations included. Differences in extent or timeliness of access to therapies may also contribute.
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Neoplasias de la Mama , Humanos , Femenino , Hospitales Privados , Atención a la Salud , Irlanda/epidemiología , Disparidades en Atención de SaludRESUMEN
PURPOSE: Single-agent chemotherapies have limited activity and considerable toxicity in patients with platinum-resistant epithelial ovarian cancer (PROC). Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate targeting folate receptor α (FRα). SORAYA is a single-arm, phase II study evaluating efficacy and safety of MIRV in patients with PROC. METHODS: SORAYA enrolled FRα-high patients with PROC who had received one to three prior therapies, including required bevacizumab. The primary end point was confirmed objective response rate (ORR) by investigator; duration of response was the key secondary end point. RESULTS: One hundred six patients were enrolled; 105 were evaluable for efficacy. All patients had received prior bevacizumab, 51% had three prior lines of therapy, and 48% received a prior poly ADP-ribose polymerase inhibitor. Median follow-up was 13.4 months. ORR was 32.4% (95% CI, 23.6 to 42.2), including five complete and 29 partial responses. The median duration of response was 6.9 months (95% CI, 5.6 to 9.7). In patients with one to two priors, the ORR by investigator was 35.3% (95% CI, 22.4 to 49.9) and in patients with three priors was 30.2% (95% CI, 18.3 to 44.3). The ORR by investigator was 38.0% (95% CI, 24.7 to 52.8) in patients with prior poly ADP-ribose polymerase inhibitor exposure and 27.5% (95% CI, 15.9 to 41.7) in those without. The most common treatment-related adverse events (all grade and grade 3-4) were blurred vision (41% and 6%), keratopathy (29% and 9%), and nausea (29% and 0%). Treatment-related adverse events led to dose delays, reductions, and discontinuations in 33%, 20%, and 9% of patients, respectively. CONCLUSION: MIRV demonstrated consistent clinically meaningful antitumor activity and favorable tolerability and safety in patients with FRα-high PROC who had received up to three prior therapies, including bevacizumab, representing an important advance for this biomarker-selected population.
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Antineoplásicos , Inmunoconjugados , Neoplasias Ováricas , Humanos , Femenino , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Bevacizumab/uso terapéutico , Neoplasias Ováricas/tratamiento farmacológico , Receptor 1 de Folato/uso terapéutico , Inmunoconjugados/efectos adversos , Antineoplásicos/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Adenosina Difosfato Ribosa/uso terapéuticoRESUMEN
BACKGROUND: Pregnancy-associated breast cancer (PABC) may be defined as breast cancer diagnosed during pregnancy or within 1 year of giving birth. Conflicting data exist regarding the impact of pregnancy on clinical features and prognosis of breast cancer. METHODS: A single-institution retrospective chart review was performed of 99 patients identified with PABC between 1992 and 2007. Non-PABC controls were matched 2:1 to PABC cases by year of diagnosis and age. The differences in clinical features were compared between cases and controls using chi-square tests. Univariate and multivariate analyses were performed to assess the effect of PABC on survival. RESULTS: Of the 99 PABC cases, breast cancer was diagnosed during pregnancy in 36 patients, and after delivery in 63. PABC cases were more likely than controls to be negative for estrogen receptor (59% vs 31%, P < .0001) and negative for progesterone receptor (72% vs 40%, P < .0001). Cases were also more likely to have advanced T class (P = .0271) and N class (P = .0104) and higher grade tumors (P = .0115). With a median follow-up of 6.3 years for cases and 4.7 years for controls, overall survival did not differ between cases and controls (P = .0787). On multivariate analysis, the independent prognostic factors for overall survival were estrogen receptor status (P = .0031) and N class (P = .0003). The diagnosis of PABC was not an independent prognostic factor (P = .1317). CONCLUSIONS: PABC is associated with more adverse tumor features than non-PABC matched for age and year of diagnosis. After correcting for pathologic features, the diagnosis of PABC is not in itself an adverse prognostic factor for survival.
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Neoplasias de la Mama/mortalidad , Complicaciones Neoplásicas del Embarazo/mortalidad , Embarazo , Adolescente , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Complicaciones Neoplásicas del Embarazo/metabolismo , Complicaciones Neoplásicas del Embarazo/patología , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Adulto JovenRESUMEN
The monoclonal antibody trastuzumab has improved the outcomes of patients with breast cancer that overexpresses the human epidermal growth factor receptor 2 (HER2). However, despite this advancement, many tumors develop resistance and novel approaches are needed. Recently, a greater understanding of cellular biology has translated into the development of novel anti-HER2 agents with varying mechanisms of action. The small molecule tyrosine kinase inhibitor lapatinib has demonstrated activity in HER2-positive metastatic breast cancer (MBC) and in the preoperative setting. Pertuzumab is a monoclonal antibody with a distinct binding site from trastuzumab, which inhibits receptor dimerization. In recent studies, the addition of pertuzumab to combination therapy has led to improvements in progression-free survival in patients with HER2-positive MBC and higher response rates in the preoperative setting. An alternative approach is the use of novel antibody-drug conjugates such as trastuzumab-emtansine, which recently demonstrated activity in MBC. Neratinib, a pan-HER tyrosine kinase inhibitor, which irreversibly inhibits HER1 and HER2, also has proven activity in MBC. A range of compounds is being developed to attempt to overcome trastuzumab resistance by targeting heat shock protein 90, a molecular chaperone required for the stabilization of cellular proteins. Furthermore, agents are being developed to inhibit the mammalian target of rapamycin, a downstream component of the PTEN/PI3K pathway, which has been implicated in trastuzumab resistance. Finally, there are emerging data indicating that combinations of anti-HER2 agents may circumvent resistance mechanisms and improve patient outcomes. In this review, recent data on these emerging agents and novel combinations for HER2-positive breast cancer are discussed.
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Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Receptor ErbB-2/metabolismo , Animales , Neoplasias de la Mama/patología , Diseño de Fármacos , Resistencia a Antineoplásicos , Femenino , Humanos , Terapia Molecular DirigidaRESUMEN
Patients with breast cancer, which lacks ER, PR, and HER2; "triple negative" (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20-91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0-8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4-7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.
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Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/secundario , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Anciano , Anciano de 80 o más Años , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Meníngeas/diagnóstico , Persona de Mediana Edad , Pronóstico , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Estudios Retrospectivos , Tasa de Supervivencia , Factores de Tiempo , Adulto JovenRESUMEN
The outlook for patients with HER2-positive breast cancer was revolutionized by the development of trastuzumab (Herceptin), a humanized murine monoclonal antibody. Use of this agent led to improved overall survival when it was added to chemotherapy for the treatment of metastatic breast cancer. Improved understanding of mechanisms of resistance to trastuzumab has facilitated the development of novel agents for HER2-positive breast cancer, and also resulted in superior outcomes when added to chemotherapy in the adjuvant setting. This review explores the use of several such agents, including lapatinib (Tykerb), HSP90 inhibitors, T-DM1, and other tyrosine kinase inhibitors. Emerging data from trials of these agents indicate that the HER2 pathway remains a valid therapeutic target following disease progression on trastuzumab, and suggest a promising role for combined HER2 blockade with two or more agents.
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Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales Humanizados , Antineoplásicos/administración & dosificación , Quimioterapia Adyuvante , Resistencia a Antineoplásicos , Femenino , Humanos , Lapatinib , Inhibidores de Proteínas Quinasas/administración & dosificación , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , TrastuzumabRESUMEN
Cancer clinical trials (CCTs) are critical to translation and development of better therapies to improve outcomes. CCTs require adequate patient involvement but accrual rates are low globally. Several known barriers impede participation and knowing how subpopulations differ in understanding of CCTs can foster targeted approaches to aid accrual and advance cancer treatments. We conducted the first nationwide survey of 1089 patients attending 14 Irish cancer centres, assessing understanding of fundamental concepts in CCT methodology and factors that influence participation, to help tailor patient support for accrual to CCTs. Two-thirds (66%) of patients reported never having been offered a CCT and only 5% of those not offered asked to participate. Misunderstanding of clinical equipoise was prevalent. There were differences in understanding of randomisation of treatment by age (p < 0.0001), ethnicity (p = 0.035) and marital status (p = 0.013), and 58% of patients and 61% previous CCT participants thought that their doctor would ensure better treatment in CCTs. Females were slightly more risk averse. Males indicated a greater willingness to participate in novel drug trials (p = 0.001, p = 0.003). The study identified disparities in several demographics; older, widowed, living in provincial small towns and fewer years-educated patients had generally poorer understanding of CCTs, highlighting requirements for targeted support in these groups.
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AIM: To evaluate the clinical outcomes of patients with OMD from a CRC primary, who underwent SABR either as first treatment at diagnosis of metachronous oligometastatic disease to lung or at progression in lung after prior treatments for metastatic disease. METHODS: This is a retrospective review of 60 patients with 85 lung oligometastases treated by SABR at two institutions, between May 2009 and September 2014. Local control (LC), overall survival (OS), progression - free survival (PFS), and toxicity were evaluated. RESULTS: Median follow-up was 22.9±15.5 months (range: 2.6-68.6). For the entire cohort, LC was observed for 76.6% of the target lesions; the 2- year OS and PFS were 77% and 28 % respectively. After a median of 7.9 months from SABR, 39 patients presented a first progression. In univariate analysis, patients with multiple recurrences prior to SABR (p=0.001) and those who received chemotherapy for metastatic progression (p=0.014) had poorer PFS from time of SABR. Median PFS for patients with no prior treatment for L-OMD vs. prior chemotherapy +/- local treatment vs. local treatment only was: not reached vs. 8.83 (± 2) vs. 32.5 (±2.75) months. The main pattern of first progression was out of field progression: in-field progression alone occurred in 7 patients (12%) and with synchronous regional/distant progression in 10 patients (17%. In all patients, chemotherapy was withheld until progression post-SABR. Treatment was well tolerated; only one patient experienced grade 3 bronchial toxicity, three months after completion of SABR. CONCLUSIONS: SABR achieves high rates of local control with limited toxicities in patients with lung oligometastatic disease from a colorectal primary. This retrospective data indicates that patients with newly diagnosed lung oligometastatic disease may be safely treated with SABR as first treatment, with chemotherapy held in reserve. In heavily pretreated patients, SABR may allow patients a treatment break from systemic therapy, which may be beneficial both psychologically and physically. Future randomized SABR studies should evaluate sequencing of chemotherapy, the role of immunotherapies, and the quality of life of patients undergoing SABR.
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The majority of breast cancers may be considered hormone responsive due to expression of hormone receptors (HR+). Although endocrine therapy is always considered for advanced HR+ breast cancer, the emergence of resistance is inevitable over time and is present from the start in a proportion of patients. In this review, we explore the mechanisms underlying de novo and acquired resistance to endocrine therapy. We comprehensively review newly approved and emerging therapies that have been developed to counteract specific mechanisms of resistance. We discuss the challenges pertinent to this therapeutic arena including the potential relief of negative regulatory feedback inhibition with compensatory pathway activation and the evolution of molecular changes in HR+ breast cancers during treatment. We discuss strategies to address these challenges in order to develop rational therapy approaches for patients with advanced HR+ breast cancer.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Autofagia , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Ciclo Celular , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Mutación , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas/metabolismo , Receptores de Factores de Crecimiento/metabolismo , Transducción de SeñalRESUMEN
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer. Unlike HR-defective cells, HR-proficient cells manifest very low cytotoxicity when exposed to PARPi, although they mount a DNA damage response. However, the genotoxic effects on normal human cells when agents including PARPi disturb proficient cellular repair processes have not been substantially investigated. We quantified cytogenetic alterations of human cells, including primary lymphoid cells and non-tumorigenic and tumorigenic epithelial cell lines, exposed to PARPi at clinically relevant doses by both sister chromatid exchange (SCE) assays and chromosome spreading. As expected, both olaparib and veliparib effectively inhibited poly-ADP-ribosylation (PAR), and caused marked hypersensitivity in HR-deficient cells. Significant dose-dependent increases in SCEs were observed in normal and non-tumorigenic cells with minimal residual PAR activity. Clinically relevant doses of the FDA-approved olaparib led to a marked increase of SCEs (5-10-fold) and chromatid aberrations (2-6-fold). Furthermore, olaparib potentiated SCE induction by cisplatin in normal human cells. Our data have important implications for therapies with regard to sustained genotoxicity to normal cells. Genomic instability arising from PARPi warrants consideration, especially if these agents will be used in people with early stage cancers, in prevention strategies or for non-oncologic indications.
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Bencimidazoles/efectos adversos , Aberraciones Cromosómicas/efectos de los fármacos , Inestabilidad Genómica/efectos de los fármacos , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Intercambio de Cromátides Hermanas/efectos de los fármacos , Cisplatino/farmacología , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Femenino , Expresión Génica , Recombinación Homóloga , Humanos , Cariotipificación , Poli(ADP-Ribosa) Polimerasas/genética , Poli(ADP-Ribosa) Polimerasas/metabolismoRESUMEN
We have previously reported that most patients with esophagogastric cancer (EGC) undergoing potentially curative resections have bone marrow micrometastases (BMM). We present 10-year outcome data of patients with EGC whose rib marrow was examined for micrometastases and correlate the findings with treatment and conventional pathologic tumor staging. A total of 88 patients with localized esophagogastric tumors had radical en-bloc esophagectomy, with 47 patients receiving neoadjuvant (5-fluorouracil/cisplatin based) chemoradiotherapy (CRT) and the remainder being treated with surgery alone. Rib marrow was examined for cytokeratin-18-positive cells. Standard demographic and pathologic features were recorded and patients were followed for a mean 10.04 years. Disease recurrences and all deaths in the follow-up period were recorded. No patients were lost to follow-up. 46 EGC-related and 10 non-EGC-related deaths occurred. Multivariate Cox analysis of interaction of neoadjuvant chemotherapy, nodal status, and BMM positivity showed that the contribution of BMM to disease-specific and overall survival is significant (P = 0.014). There is significant interaction with neoadjvant CRT (P < 0.005), and lymph node positivity (P < 0.001) but BMM positivity contributes to increase in risk of cancer-related death in patients treated with either CRT or surgery alone. Bone marrow micrometastases detected at the time of surgery for EGC is a long-term prognostic marker. Detection is a readily available, technically noncomplex test which offers a window on the metastatic process and a refinement of pathologic staging and is worthy of routine consideration.
Asunto(s)
Médula Ósea/patología , Neoplasias Esofágicas/mortalidad , Neoplasias Esofágicas/patología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Esofágicas/epidemiología , Neoplasias Esofágicas/terapia , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Micrometástasis de Neoplasia , Evaluación del Resultado de la Atención al PacienteRESUMEN
BACKGROUND: Breast cancer brain metastases (BCBM) are challenging complications that respond poorly to systemic therapy. The role of the blood-tumor barrier in limiting BCBM drug delivery and efficacy has been debated. Herein, we determined tissue and serum levels of capecitabine, its prodrug metabolites, and lapatinib in women with BCBM resected via medically indicated craniotomy. METHODS: Study patients with BCBM requiring surgical resection received either single-dose capecitabine (1250 mg/m(2)) 2-3 h before surgery or 2-5 doses of lapatinib (1250 mg) daily, the last dose 2-3 h before surgery. Serum samples were collected serially on the day of surgery. Drug concentrations were determined in serum and BCBM using liquid chromatography tandem mass spectrometry. RESULTS: Twelve patients were enrolled: 8 for capecitabine and 4 for lapatinib. Measurable drug levels of capecitabine and metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil, were detected in all BCBM. The ratio of BCBM to serum was higher for 5-fluorouracil than for capecitabine. As for lapatinib, the median BCBM concentrations ranged from 1.0 to 6.5 µM. A high variability (0.19-9.8) was noted for lapatinib BCBM-to-serum ratio. CONCLUSIONS: This is the first study to demonstrate that capecitabine and lapatinib penetrate to a significant though variable degree in human BCBM. Drug delivery to BCBM is variable and in many cases appears partially limiting. Elucidating mechanisms that limit drug concentration and innovative approaches to overcome limited drug uptake will be important to improve clinical efficacy of these agents in the central nervous system. Trial registration ID: NCT00795678.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Fluorouracilo/análogos & derivados , Quinazolinas/uso terapéutico , Adulto , Anciano , Antimetabolitos Antineoplásicos/farmacocinética , Antimetabolitos Antineoplásicos/uso terapéutico , Antineoplásicos/farmacocinética , Química Encefálica , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Neoplasias de la Mama/patología , Capecitabina , Desoxicitidina/sangre , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/sangre , Fluorouracilo/farmacocinética , Fluorouracilo/uso terapéutico , Humanos , Lapatinib , Persona de Mediana Edad , Estudios Prospectivos , Quinazolinas/sangre , Quinazolinas/farmacocinéticaRESUMEN
BACKGROUND: For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood-brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT. METHODS: This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m(2) once every 3 weeks until progression. Responses were scored according to the Macdonald criteria. RESULTS: Fifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events. CONCLUSIONS: Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer.