Spectrum of BRCA1/2 variants in 940 patients from Argentina including novel, deleterious and recurrent germline mutations: impact on healthcare and clinical practice.

BRCA1/2 mutations in Latin America are scarcely documented and in serious need of knowledge about the spectrum of BRCA pathogenic variants, information which may alter clinical practice and subsequently improve patient outcome. In addition, the search for data on testing policies in different regions constitutes a fundamental strength for the present study, which analyzes BRCA1/2 gene sequences and large rearrangements in 940 probands with familial and/or personal history of breast/ovary cancer (BOC). In non-mutated DNA samples, Multiplex Ligation-dependent Probe Amplification assays (MLPA) were used for the analysis of large rearrangements. Our studies detected 179 deleterious mutations out of 940 (19.04%) probands, including 5 large rearrangements and 22 novel mutations. The recurrent mutations accounted for 15.08% of the total and only 2.87% of the probands analyzed, very different from a Hispanic panel previously described. IN CONCLUSION: a) this first comprehensive description of the spectrum in BRCA1/2 sheds light on the low frequency of recurrent mutations; b) this information is key in clinical practice to select adequate sequencing studies in our population, subsequently improve patient outcome and prevent damage associated to false normal reports resulting from the use of invalid population panels; c) panels of mutations from other populations should be cautiously validated before imported, even those of apparently similar origin, a concept to be considered beyond significance in Argentina.

Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: a combined analysis of 3 pivotal, randomised, phase 3 trials.

BACKGROUND: Patients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies. METHODS: Patient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. FINDINGS: Denosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76-0.90]; P<0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P=0.13). CONCLUSION: Denosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.

Demoras en el proceso de atención de pacientes con cáncer de mama en dos hospitales públicos de la provincia de Santa Fe / Delays in the process of care of patients with breast cancer in two public hospitals in the province of Santa Fe

INTRODUCCIÓN: el retraso en el inicio de untratamiento efectivo del cáncer de mama reduce la tasa desupervivencia y está asociado a estadios más avanzados aldiagnóstico y a la necesidad de tratamientos más agresivos ycostosos. OBJETIVOS: Describir la trayectoria de la atención médicade mujeres con diagnóstico de cáncer de mama desde la apariciónde un signo o síntoma hasta la finalización del tratamiento.MÉTODOS: Se realizó un estudio descriptivo retrospectivo, quecombinó técnicas cuantitativas y cualitativas. Se estimaron lostiempos utilizados en cada etapa del proceso de atención de cáncerde mama en mujeres diagnosticadas y/o tratadas durante 2012 endos hospitales de la provincia de Santa Fe. RESULTADOS: Se incluyóa 62 pacientes en la muestra. El 20,3% obtuvo su diagnósticodentro del mes posterior a la mamografía y/o ecografía, y sólola mitad fue operada dentro del mes posterior al diagnóstico. El60% de las pacientes con necesidad de quimioterapia adyuvantey el 72,4% con necesidad de radioterapia tras la cirugía tuvierondemoras mayores a 60 días. Ninguna de las pacientes en estadio IVcomenzó el tratamiento antes de los 30 días. CONCLUSIONES: Si secompara con los parámetros establecidos en la guía del ProgramaNacional de Cáncer de Mama, hay demoras en todas las etapas. Esnecesario establecer estrategias que reduzcan los tiempos para laconfirmación diagnóstica en mujeres con sospecha, así como lostiempos de tratamiento en pacientes con cáncer confirmado.

INTRODUCTION: the delay to start an effectivetreatment for breast cancer reduces survival rate and is associatedto advanced stages at diagnosis and to the need for moreaggressive and costly treatments. OBJECTIVES: To describe thehealth care path of women with diagnosis of breast cancersince the first sign or symptom until the end of the treatment.METHODS: A retrospective descriptive study was performed,combining quantitative and qualitative techniques. It estimatedthe time used in each stage of the health care process amongwomen with breast cancer, diagnosed and/or treated during2012 in two hospitals of the province of Santa Fe, Argentina.RESULTS: A total of 62 patients were included in the sample.Of them, 20.3% received her diagnosis within 30 days of themammogram and/or ultrasound and 50% were operatedwithin one month of the diagnosis. There were delays of morethan 60 days in 60% and 72.4% of the patients who had toundergo adjuvant chemotherapy and radiotherapy, respectively.None of the patients with stage IV began the treatment withinthe first 30 days. CONCLUSIONS: Compared to the guidelinesof the National Program of Breast Cancer, there are delaysat all stages. It is necessary to develop strategies to shortenthe time for diagnosis confirmation in women with suspectedbreast cancer and for the access to treatment in patients withcancer confirmed.

Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study.

PURPOSE: This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. PATIENTS AND METHODS: Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS: Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39). CONCLUSION: Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.

Censo de recursos humanos y recursos moleculares para diagnóstico y evaluación de cáncer hereditario en Argentina / Survey of Human and Molecular resources for diagnosis and evaluation of hereditary cancer in Argentina

INTRODUCCION: El Instituto Nacional del Cáncer ha realizado un Censo de Recursos Humanos y Moleculares en Cáncer Hereditario. OBJETIVOS: Identificar y categorizar consultorios deasesoramiento genético oncológico y laboratorios que realizan estudiosmoleculares en Argentina para elaborar estrategias tendientes a mejorar la detección y manejo de los tumores de alto riesgo más frecuentes, como cáncer de mama y cáncer colorrectal hereditarios. METODOS: Se relevaron 187 instituciones públicas y privadas detodo el país y como recurso para el relevamiento se consultaron basesde datos nacionales. RESULTADOS: Se identificaron 44 consultorios de asesoramiento genético y 25 laboratorios. Dos tercios de las entidades incluidas fueron privadas y un tercio, públicas. Todas las prestaciones se concentraban en 9 de las 24 jurisdicciones. El 94% de las instituciones públicas ofrecían asesoramiento mediante profesionales especializados, mientras que el 43% de las instituciones privadas no tenían profesionales especializados a cargo dela consulta. En los laboratorios relevados se realizan determinacionespara 15 síndromes, 25 genes y 2 entidades no sindrómicas.CONCLUSIONES: Los recursos humanos y moleculares relevados son heterogéneos en su distribución geográfica y muestran una amplia variabilidad en las prestaciones proporcionadas.

INTRODUCTION: The National Cancer Institute of Argentina has developed a national Survey of Human and Molecular Hereditary Cancer Resources. OBJECTIVES: To identify and categorize cancer genetic counseling clinics andlaboratories performing molecular studies as the basis for public health strategies to improve detection and management of the most frequent hereditary cancers, like breast andcolorectal ones. METHODS: A total of 187 public and private institutions around the country were surveyed and as a resource for mapping national databases were consulted. RESULTS: A total of 44 genetic counseling clinics and 25 laboratories were identified. Two-thirds of the institutions are private and one-third, public. All services are concentrated in 9 of the 24 jurisdictions. While 94% of the public institutionsoffer counseling by specialized professionals, 43% of the private institutions do not have specialized professionals in charge of that area. Determinations for 15 syndromes,25 different genes and 2 non-syndromic entities are made. CONCLUSIONS: The surveyed human and molecular resources are heterogeneous in their distribution and show a wide variability in the services provided.

Cáncer de mama en Argentina: organización, cobertura y calidad de las acciones de prevención y control

La finalidad del presente estudio es llevar a cabo un diagnóstico de base de las acciones de prevención y control de cáncer de mama, desarrolladas a nivel nacional y en las 24 jurisdicciones del país, e identificar los elementos que deben ser modificados o fortalecidos.

La biopsia del ganglio centinela en el cáncer de la mama, resultados de un estudio de 106 pacientes / Sentinel node biopsy in breast cancer. Results of a study of 106 patients

Introducción: La linfadenectomía axilar es parte fundamental del tratamiento quirúrgico del cáncer de mama (CM).Ultimamente su aplicación rutinaria es cuestionada debido a su morbilidad, al hecho que la mayoría de los pacientes tienen axila negativa y a que las terapias adyuvantes se basan cada vez máa en las características del tumor primario. La biopsia del ganglio centinela (BGC), un test mínimamente invasor, ha sido propuesta en su reemplazo en pacientes con axila negativa. Recientes estudios han demostrado que el ganglio centinela (GC) predice en forma confiable el estado del resto de los ganglios axilares (RGA). Objetivos: comprobar la factibilidad de identificar el GC y si suestado refleja el del RGA. Pacientes: pacientes con CM temprano que iban a recibir tratamiento qirúrgico primario. Métodos: El GC fue identificado a través de un colorante vital, patent blue, en 106 pacientes combinado con un radioisótopo, cloide sulfúrico de Tc99, en 46 pacientes. Luego de la BGC se efectuó vaciamiento axilar completo en todas las pacientes. Resultados: Se realizaron 107 BGC (106 pacientes, 1 bilateral). Identificamos el GC en 94/107 biopsias (88 por ciento). Hubo 61/94 GC negativos; en 59/61 coincidió con el estado del RGA (valor de predicción negativo: 97 por ciento); en 2 (3 por ciento), no hubo coincidencia (2 falsos negativos). 33/94GC fueron positivos; en 24 (73 por ciento) coincidieron con el estado de RGA;, 9(27 por ciento) fueron únicos positivos. Conclusión: nuestro estudio confirma la factibilidad técnica de la BGC en pacientes con CM. Su resultado negativo permite predecir con alto grado de confiabilidad el estado del RGA...