Cyclin-Dependent Kinase 4/6 Inhibitor Outcomes in Patients With Advanced Breast Cancer Carrying Germline Pathogenic Variants in DNA Repair-Related Genes.

PURPOSE: In recent years, unprecedented benefits have been observed with the development of cyclin-dependent kinase (CDK) 4 and 6 inhibitors for the treatment of hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. However, there is scarce evidence of their value in specific populations, such as patients carrying germline pathogenic variants in DNA repair-related genes. PATIENTS AND METHODS: We retrospectively studied the efficacy of CDK 4/6 inhibitors plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer. Three cohorts were compared, including patients harboring germline pathogenic variants in DNA repair-related genes (gBRCA1/2-ATM-CHEK2 mutated), those tested without these mutations (wild type [WT]), and the nontested subgroup. Relevant prognostic factors including age, metastatic site (visceral v nonvisceral), Eastern Cooperative Oncology Group, and prior treatment with CDK 4/6 inhibitors were stratified by univariate and multivariate Cox regression models. RESULTS: Among the total population (n = 217), 15 (6.9%) patients carried gBRCA1/2 (n = 10)-ATM (n = 4)-CHEK2 (n = 1) pathogenic variants, 45 (20.7%) were WT, and 157 (72.4%) were nontested. Gene pathogenic variant carriers were younger (P < .001). Most patients (164, 75.6%) had not received prior endocrine therapy in the advanced setting. Median progression-free survival was shorter in patients with evaluated germline pathogenic variants (10.2 months [95% CI, 5.7 to 14.7]), compared with WT and nontested patients (15.6 months [95% CI, 7.8 to 23.4], and (17.6 months [95% CI, 12.9 to 22.2]; P = .002). Consistently, a worse median overall survival was observed in the subgroup with germline pathogenic variants than in the WT group (P = .006). Multivariable analysis showed that mutation status was an independent prognostic factor of progression-free survival (P = .020) and overall survival (P = .012). CONCLUSION: In this retrospective real-world study, gBRCA1/2-ATM-CHEK2 pathogenic variants were independently associated with poor outcomes in patients with advanced breast cancer treated with CDK4/6 inhibitors.

Valor de la ruptura capsular y extensión extranodal en el ganglio centinela como predictores del estado axilar en pacientes con cáncer de mama T1-T2 / Significance of extracapsular extension in sentinel lymph nodes as a predictor of axillary lymph node status in T1-T2 breast cancer patients

Introducción: Identificar aquellas pacientes con cáncer de mama en estadíos iniciales que no se benefician de la linfadenectomía (LA), a pesar de contar con ganglios centinela positivos, constituye un desafío. El ensayo ACOSOG-Z0011 modificó el paradigma de la cirugía axilar, pero aún no está claro qué efecto tiene la ruptura capsular (RC) y su extensión (EEC) en el compromiso axilar. Material y método: Se incluyeron 214 pacientes intervenidas quirúrgicamente entre 2009-2019 en el Centro mamario del Instituto Alexander Fleming, con cáncer de mama en T1-2, en las que la biopsia de ganglio centinela (BGC) resultó positiva, y se realizó LA. Se realizaron comparaciones entre aquellas pacientes con y sin RC. Las pacientes con RC fueron divididas en dos grupos, según la EEC fuera mayor o igual a 2 mm, o menor a 2 mm. Para los distintos grupos de pacientes, se analizaron variables clínicas y anatomo-patológicas, incluyendo edad, estado menopáusico, subtipo biológico, grado nuclear, tamaño tumoral, invasión linfovascular (ILV) y multicentricidad. Resultados: La RC se asoció a una mayor probabilidad de presentar ganglios no centinela positivos, y en particular a la presencia de 4 o más ganglios positivos. Este grupo de pacientes presentó con más frecuencia ILV. En cuanto a la EEC, no hallamos diferencias significativas de acuerdo a la extensión de la ruptura (EEC<2 mm y EEC≥2 mm), aunque en el análisis uni y multivariado evidenció un mayor riesgo de presentar ≥4 ganglios positivos en el grupo de pacientes con EEC≥2 mm. Discusión: En línea con la bibliografía actual, encontramos que la RC es un hallazgo frecuente y que se asocia a una mayor probabilidad de presentar metástasis ganglionar, en especial 4 o más ganglios positivos. Al separar a las pacientes de acuerdo a la EEC, no hallamos diferencias en cuanto a la proporción de pacientes con ganglios positivos en la LA. Estos resultados difieren de los obtenidos por otros centros, en donde se ha demostrado una mayor probabilidad de contar con ganglios no centinela positivos en el grupo de pacientes con EEC>2mm. Conclusiones: En la bibliografía actual existe consenso en relación al rol de la RC como factor de riesgo, y nuestros resultados apoyan esta hipótesis. Sin embargo, resulta menos claro el papel que juega la magnitud de la EEC. Esto podría deberse, por un lado, a la falta que bibliografía disponible, y por otro, a la falta de consenso para determinar la medición de la EEC En línea con publicaciones recientes que no hallan diferencias significativas en la recurrencia de la enfermedad a largo plazo según la magnitud de la EEC, será fundamental continuar con un futuro análisis que contemple estos aspectos en nuestra población. Al día de hoy, no contamos con evidencia que nos permita afirmar que las pacientes con EEC<2 mm puedan beneficiarse de la omisión de LA

Introduction: The identification of those early breast cancer patients with no clear benefit from axillary lymph node dissection (ALND) in spite of the presence of positive sentinel lymph nodes (SLNs), remains controversial. Although the ACOSOG-Z001 trial has significantly altered management of the axilla, the role played by the extracapsular extension (ECE) is still a subject of debate. Materials and method: In the present study, we analysed 214 early breast cancer patients with positive SLN biopsy, who underwent ALND at Instituto Alexander Fleming between 2009 and 2019. Patients were divided into two categories based on the presence or absence of ECE; those patients with ECE were further divided based on the extent of ECE (ECE<2 mm and ECE≥2 mm). Analysis of clinical-pathological parameters was performed, including age, menopausal status, tumor subtype, nuclear grade, tumor size, lymphovascular invasion (LVI) and multicentricity. Results: ECE was associated with an increased probability of additional positive nodes in the ALND, and these patients were also more likely to have 24 positive nodes. LVI was increased in patients with ECE. Additionally, we found no significant differences regarding the number of positive nodes when comparing patients according to the extent of ECE (ECE<2 mm and ECE≥2 mm). Univariate and multivariate analyses of factors associated with involvement of ≥4 nodes at completion ALND resulted in an increased odds ratio for patients with ECE ≥2 mm. Discussion: In line with recent literature, we found ECE is frequently observed in breast cancer patients and is associated with an increased probability of lymph node metastases, and these patients are also more likely to have 24 positive nodes. We found no significant differences in terms of the proportion of patients with positive lymph nodes in ALND when comparing patients with and without ECE. Our results differ from other studies that showed a higher risk of non-sentinel lymph nodes metastases in patients with ECE>2mm. Conclussions: There is cumulative evidence on the role of ECE as a risk factor in breast cancer patients, and our findings further support this hypothesis. However, the extent of ECE is still a topic of heated debate, and its role in disease progression is less clear, given there are relatively few studies addressing this matter and there are discrepancies in the way the extent of ECE is measured. Considering recent publications where no significant differences were found in terms of longterm disease recurrence when stratifying patients according to the extent of ECE, our future endeavours should focus on the assessment of the course of the disease. To date, we have no evidence supporting the idea that patients with ECE<2mm could actually benefit from omis- sion of ALND.

Breast Cancer in Young Women Presents With More Aggressive Pathologic Characteristics: Retrospective Analysis From an Argentine National Database.

PURPOSE: Multiple studies have reported that breast cancer in young patients is associated with aggressive characteristics, and it is suggested that prognosis is worse independently of pathologic variables. PATIENTS AND METHODS: We performed a retrospective analysis of the Breast Cancer Registry of the Argentinian Society of Mastology, including public and private centers. Patients ≤ 40 years of age at diagnosis were classified as "young," and patients ≤ 35 years of age at diagnosis were classified as "very young." Univariate and multivariate analyses were performed to detect differences between groups. RESULTS: Patients ≤ 40 years of age comprised 10.40% (739/7,105) of the participants, with an average age of 35.61 ± 4.04 years. Multivariate analysis showed that human epidermal growth factor receptor 2 (HER2)-positive tumor phenotype (odds ratio [OR], 1.82), nodal involvement (OR, 1.69), histologic grade (grade 3 OR, 1.41), and tumor size (T2 OR, 1.37; T3-T4, 1.47) were independently associated with younger age at diagnosis. Patients ≤ 35 years of age (n = 286), compared with patients 36 to 40 years of age, had a higher proportion of HER2 tumors (24.58% v 16.94%; P = .021), absence of progesterone receptor expression (29.85% v 22.95%; P = .043), and stage 3 cancer (29.34% v 18.52%; P < .001). Fewer breast-conserving surgeries (75.37% v 62.89%; P < .001) and more adjuvant chemotherapy (59.04% v 36.66%; P < 0.001) were reported in patients ≤ 40 years of age. CONCLUSION: In the population studied, breast cancer in young women was associated with aggressive pathologic features and locally advanced disease at the time of diagnosis. Moreover, tumor characteristics in very young patients with breast cancer nested in the population ≤ 40 years of age showed differences in important prognostic factors. More high-quality evidence is needed to improve treatment strategies in these patients.

Quimioterapia neoadyuvante: indicaciones y resultados. Experiencia de 15 años en el Instituto Alexander Fleming / Neoadjuvant chemotherapy: indications and results. Fifteen years of experience at Instituto Alexander Fleming

Introducción Existe consenso sobre los subgrupos de pacientes con más probabilidades de beneficiarse del tratamiento neoadyuvante, pero su utilización en la práctica clínica es variable. Las pacientes con cáncer de mama en etapa temprana susceptibles de requerir quimioterapia adyuvante podrían considerarse para realizar quimioterapia neoadyuvante (qtna). Objetivos Evaluar las tasas de cirugía conservadora en pacientes con cáncer de mama que reciben qtna y describir las tendencias de respuestas clínica, imagenológica y patológica en la mama y la axila. Material y método Se realizó una evaluación retrospectiva de 125 pacientes con cáncer de mama invasor (Estadios IB-IIA/B-IIIA), operadas en el Instituto Alexander Fleming en el período 2002-2018. Resultados Las tasas más altas de respuesta patológica completa (pcr) se obtuvieron en los tumores her2, tn y Luminal B-her2, representando el 56%, 55% y 40% respectivamente. En la respuesta patológica completa ganglionar, las tasas más altas se obtuvieron en los Luminal B-her2 82%, los tn 80% y los her2 70%. Las tasas de cirugía conservadora fueron: para Luminal A 44%, para Luminal B 58%, para Luminal B-her2 54%, para her2 76% y para tn 59%. Conclusiones Concordante con trabajos publicados, se describen altas tasas de cirugía conservadora y altas tasas de pcr en tumores her2 y tn

Introduction Even though there is evidence about better outcomes after neoadjuvant chemotherapy (nac) for breast cancer (bc), it is unclear who are the indicated patients and what are the correct indications for using it. Our hypothesis is that early stage bc patients, who are identified as susceptible for adjuvant chemotherapy, could be the most benefited of receiving nac. Objectives We aimed to study the number of patients who received nac and breast conserving surgery (bcs) assessing clinical, pathological and radiological response in both, breast and axilla. Materials and method We carried out a retrospective study of 125 patients newly diagnosed of bc (Stage IB-IIA-B and IIIA) who received nat and bcs in our institution, "Instituto Alexander Fleming", during the 2002-2018 period Results We obtained the higher rates of pathological complete response (pcr) in her2 being 56%; for tn was 55% and 40% for Luminal B-her2. The highest rates of complete pathological lymph node response were obtained in Luminal B-her2 82%, tn 80% and her2 70%. The rates for bcs where 44%, 58%, 54% and 76% for Luminal A, Luminal B, Luminal B-her2 and her2 respectively. Conclusions There is current data available supporting our findings, having similar results for bcs and pcr performing bcs after nat

Alertas de cardiotoxicidad en el tratamiento con trastuzumab en cáncer de mama, 4 años de seguimiento / Cardiotoxicity Alerts during Treatment with Trastuzumab in Breast Cancer at Four-year Follow-up

RESUMEN Introducción: El tratamiento adyuvante de cáncer de mama Her2+ incluye adriamicina y trastuzumab, un anticuerpo monoclonal con efecto cardiotóxico del que no se conoce el verdadero impacto epidemiológico de toxicidad cardíaca en poblaciones no seleccionadas en la Argentina. Objetivos: Conocer el impacto cardiotóxico del tratamiento con trastuzumab en adyuvancia en cáncer de mama en una población no seleccionada a más de 12 meses después de finalizado su tratamiento. Material y métodos: Sobre 888 pacientes prospectivos con cáncer de mama, 231 pacientes (38%) presentaban cáncer de mama Her2+, en tratamiento adyuvante con adriamicina + trastuzumab. Las pacientes fueron evaluadas mediante fracción de eyección ventricular izquierda, en pretratamiento, fin de adriamicina y cada 3 meses en el seguimiento. Se definió cardiotoxicidad a la caída de la fracción de eyección ventricular izquierda > 10% según el American College of Cardiology, se subanalizó con algoritmos del estudio B-31 y MD ANDERSON. Resultados: Presentaron caída de la fracción de eyección ventricular izquierda > 10%: 150/231 pacientes (65%) respecto del basal con un seguimiento medio de 48 ± 12 meses. En el análisis por grupo, las pacientes incluidas en el B-31 vs. MD Anderson vs. el American College of Cardiology presentaron mayor pérdida porcentual de la fracción de eyección ventricular izquierda durante el tratamiento: 20% vs. 20% vs. 16% con p < 0,04, finalizaron el seguimiento con fracción de eyección ventricular izquierda < 50%: 42% vs.41% vs. 33% con p = 0,01, respectivamente. Conclusiones: En la población con trastuzumab bajo control cardioncológico, se observó luego de un seguimiento medio de 48 ± 12 meses: 1 - Caída significativa de la fracción de eyección ventricular izquierda en más del 60% de la población. 2 - Las distintas guías muestran diferentes riesgos cardiotóxicos lo que requiere un monitoreo continuo cardioncológico.

ABSTRACT Background: Adjuvant treatment of HER2+ breast cancer includes adriamycin and trastuzumab, a monoclonal antibody that produces cardiotoxicity. The actual epidemiologic impact of trastuzumab-related cardiotoxicity in unselected populations in Argentina remains unknown. Objectives: The aim of this study was to evaluate the impact of trastuzumab-related cardiotoxicity during adjuvant treatment for breast cancer in an unselected population after >12 months of completing therapy. Methods: Among 888 patients prospectively evaluated for breast cancer, 231 (38%) were HER2+ and received adjuvant therapy with adriamycin and trastuzumab. Left ventricular ejection fraction was evaluated before treatment, after completing adriamycin and then every 3 months during follow-up. Cardiotoxicity was defined as a decline in left ventricular ejection fraction >10%, according to the definition of the American College of Cardiology and was compared with the definitions of the B-31 trial and the MD Anderson Cancer Center. Results: A decline in left ventricular ejection fraction >10% from baseline values occurred in 65% (n=150) of the patients during a mean follow-up of 48±12 months. In the per group analysis, patients included in the B-31and MD Anderson Cancer Center vs. the American College of Cardiology definitions presented greater percent fall in left ventricular ejection fraction during treatment: 20% vs. 20% vs. 16%, respectively (p<0.04) and ended treatment with left ventricular ejection fraction <50% in 42% vs. 41% vs. 33% of cases, respectively (p=0.01). Conclusions: In the population treated with trastuzumab under cardio-oncology surveillance during 48±12 months: 1 - Left ventricular ejection fraction was significantly decreased in more than 60% of patients. 2 - Different guidelines show different cardiotoxicity risks which demands continuous cardio-oncological monitoring.

Los linfocitos estromales intratumorales (tils) como factor pronóstico en tumores primarios de mama Triple Negativos / Tumor infiltrating lymphocytes (tils) in Triple Negative breast cancer as a prognostic factor

Introducción Los tumores de mama se encuentran frecuentemente rodeados por células inflamatorias como signo de interacción entre el tumor y el huésped, siendo esta crítica para el desarrollo y progresión del cáncer. Algunas observaciones sugieren el valor pronóstico de los linfocitos estromales intratumorales (tils). Sin embargo, su evaluación no es rutinaria ya que su relevancia clínica aún no se encuentra consolidada. Objetivos Los objetivos de este trabajo son: • la evaluación de la concordancia interobservador de los linfocitos intratumorales (tils); • su relación con la sobrevida libre de enfermedad (sle); • su valoración como factor pronóstico en cáncer de mama Triple Negativo. Material y método Se seleccionaron retrospectivamente pacientes con tumores de mama Triple Negativos operados en el Instituto Alexander Fleming entre 2010-2016 sin tratamiento neoadyuvante, alcanzando una muestra de 65 pacientes. Resultados El porcentaje mediano de tils fue de 30% (12,5-50), y se consideraron como "Tumores ricos en linfocitos" (Lymphocyte Predominant Breast Cancerlpbc) a los de 19 pacientes (29,2%). Tanto la presencia de tils (p>0,01) como la definición del subtipo de lpbc (p=0,03) presentaron asociación estadísticamente significativa con la recurrencia de enfermedad. En el análisis multivariado, presentaron asociación la histología ductal y el valor de tils. Por cada 10% de aumento, disminuye 31% el riesgo de recaída. El valor de tils estratificado en 3 subgrupos (≤20; 30-40; ≥50%) presentó asociación estadísticamente significativa con la Sobrevida Libre de Enfermedad (Log Rank <0,01). Conclusiones En este trabajo se logró describir una característica tumoral y del huésped reproducible, cuya instrumentación podría generalizarle por el potencial valor pronóstico.

Introduction Breast tumors are frequently surrounded by inflammatory cells as a sign of interaction between the tumor and host, being this relationship critical for cancer development and progression. Present evidence suggests that tumor infiltrating lymphocytes (tils) may provide prognostic information. Nevertheless, tils description is not generalized as its clinical relevance is not consolidated. Objectives • evaluation of interobserver concordance of intratumoral lymphocytes (tils); • its relationship with Disease Free Survival; • its assessment as a prognostic factor in Triple Negative breast cancer. Materials end method Triple Negative breast cancer patients with surgery in Instituto Alexander Fleming, between 2010-2016, without neoadyuvant treatment, were selected retrospectively. 65 patients were selected. Results In the 65 patients selected, tils median percentage was 30% (12.5-50), and 19 (29.2%) were considered Lymphocyte Predominant Breast Cancer (lpbc). tils percentage (p>0.01) and lpbc subtype (p=0.03) presented significant association with disease recurrence. Multivariate analysis showed that ductal histology and tils percentage are associated with disease recurrence. For every 10% increment in tils, there was a 31% reduction of risk of recurrence. High tils value stratified in 3 subgroups (≤20; 30-40; ≥50%) was associated with better Disease Free Survival (Log Rank 0.01). Conclusions Due to its potential prognostic value and its technical reproducibility, we believe that this tumoral and host characteristic must be generalized.

Predictive Factors for Non-Sentinel Lymph Node Metastasis in Patients with ACOSOG Z0011 Criteria.

BACKGROUND: Nodal staging constitutes an element of great importance in the treatment planning for early breast cancer. The ACOSOG Z0011 trial demonstrated that sentinel lymph node (SLN) biopsy alone results in rates of local control, disease-free survival, and overall survival equivalent to those seen after axillary lymph node dissection. The purpose of this study was to determine the rate of patients that fulfill the ACOSOG Z0011 inclusion criteria and to define predictive factors for non-SLN positivity. METHODS: A retrospective analysis of the breast surgery database of the Argentinian Society of Mastology was carried out. Patients were selected if they fulfilled the ACOSOG Z0011 inclusion criteria. The association of clinical and pathological factors with non-SLN positivity was evaluated in univariate and multivariate analysis. RESULTS: Among 8,262 patients, 973 had positive SLN, and 348 satisfied the inclusion criteria. Histological grade (G3 vs. G1-2, odds ratio (OR) 1.81; p = 0.024), tumor size (T2 vs. T1, OR 2.39; p = 0.001), and age (>50 vs. <50 years, OR 1.95; p = 0.007) were associated with non-SLN positivity in multivariate analysis. CONCLUSION: Although the clinical relevance of our data is not established, older women with tumors bigger than 2 cm and/or high histological grade are at greater risk of having metastatic disease in the lymph nodes if axillary lymph node dissection is avoided. This subgroup of patients represents only 30% of the trial population.

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.

Eficacia de los inhibidores de ALK en dos casos con evaluación positiva por inmunohistoquímica y negativa por FISH / Efficacy of ALK inhibitors in two cases with positive evaluation by immunohistochemistry and negative by FISH

En el carcinoma de pulmón de células no pequeñas (CPCNP), la activación de ALK se produce por la formación de genes de fusión. El perfil clínico donde ocurre con más frecuencia corresponde a pacientes jóvenes, mayormente mujeres, no fumadores, histología de adenocarcinoma y ausencia de mutaciones de EGFR y KRAS. Su presencia se describe en el 3-10% de los CPCNP. La importancia de la determinación de ALK radica en que identifica un subgrupo de pacientes con un comportamiento biológico diferente, en los cuales el tratamiento con inhibidores específicos, como el crizotinib, ceritinib o alectinib, es más eficaz que los convencionales. Las alteraciones moleculares de ALK pueden identificarse por hibridación in situ (ISH), por inmunohistoquímica (IHQ) y por RT-PCR, aunque el FISH es el procedimiento diagnóstico de referencia a nivel clínico. Se examinaron 308 casos de CPCNP y se compararon los resultados por FISH e IHQ. De los 8 (3%) identificados con expresión positiva, sólo 6 presentaron el rearreglo de ALK. Se presentan dos casos clínicos con ALK positivo por IHC y FISH negativo, uno presentó respuesta al tratamiento dirigido y otro no. A pesar de que el FISH es el gold standard, se acepta el uso de IHQ ya sea para definir conducta como único test o para screening y ulterior confirmación por FISH en los casos positivos. Estos dos casos con distinta respuesta al tratamiento con IHQ positiva pero FISH negativo, indican la ausencia de pautas, requiriendo de más conocimiento en el futuro para optimizar las conductas médicas (AU)

In non-small cell lung cancer, ALK activation is produced by gene fusion. The clinical scenario where this type of tumor appears more frequently is in young, female patients, without smoking history, adenocarcinoma histology and with no EGFR or KRAS mutation. It is described as 3 to 10% of non- small cell lung cancer cases. The importance of ALK determinations lies in the identification of a subgroup of patients with a different biological behavior and sensible tumor to target therapy with ALK inhibitors. Molecular alterations of ALK can be determined by in situ hybridization, immunohistochemistry (IHC) and RT-PCR, FISH is the reference diagnostic procedure in clinical applications. Were evaluated 308 cases of non-small cell lung cancer, and FISH and IHC results were compared. Eight (3%) cases presented positive expression, but only 6 of them presented ALK rearrangements. These two clinical cases of patients with IHC positive but FISH negative for ALK are presented, observing good clinical response in only one of them. Although FISH is considered the gold standard technique, IHC use is accepted for treatment decisions as a lone procedure or as screening with FISH confirmation in positive cases. These two particular cases express the absence of guidelines in this infrequent scenario, needing more knowledge in the future in order to take better medical decisions (AU)

Cáncer renal. Descripción poblacional en una institución académica / Kidney cancer. Population description in an academic institution

El conocimiento en cáncer renal ha sido manifiesto en la última década, con adelantos que optimizan el abordaje diagnóstico, quirúrgico y terapéutico con agentes dirigidos contra blancos específicos. El objetivo del trabajo fue la evaluación retrospectiva de pacientes con cáncer de riñón, destacando los datos demográficos, patológicos, quirúrgicos, de recurrencia, así como las modalidades terapéuticas empleadas, y describir la evolución clínica a través de parámetros de eficacia y seguridad. Fueron incluidos 417 pacientes, analizándose los datos de 356. La edad mediana fue de 56 años y 68% eran hombres. El 14% presentó otro tumor primario no renal y 14 desarrollaron otro tumor renal. El diagnóstico fue incidental en el 28% de los casos, la histología más frecuente fue el carcinoma de células claras, el tamaño mediano fue 6.1 cm y en el 20% se observó infiltración capsular. De los 298 pacientes operados, 54% fueron a nefrectomía radical y 26% parcial. El 19% presentaba metástasis al diagnóstico. Recurrencia post-operatoria en 75 de los 298 operados. Los tratamientos más frecuentemente utilizados en primera línea fueron los inhibidores de tirosina-quinasa (55% de los casos) con remisiones del 43-50% y un tiempo a la progresión de 12.1 meses. La revisión retrospectiva de los datos en cáncer renal de una población académica que incorpora la metodología diagnóstica, quirúrgica y terapéutica en enfermedad localizada y avanzada, permite reproducir los datos que surgen de países centrales y de estudios clínicos aleatorizados (AU)

Improving knowledge in renal cancer has been successful in the last decade in terms of diagnosis, surgical and therapeutic approach with targeted agents. The objective of the study was the retrospective evaluation of patients with kidney cancer, emphasizing recurrence as well as therapeutic modalities, pathological and surgical, demographic data and to describe outcome through efficacy and safety parameters. There were included 417 patients. The median age was of 56 years and 68% were men. There was a 14% of patients with another non-renal primary tumor and 14 patients developed another kidney tumor. The diagnosis was incidental in 28% of cases. The most common histology was clear cell carcinoma, medium size was 6.1 cm and capsular infiltration was observed in 20%. Of the 298 patients operated, 54% were to radical nephrectomy and 26% partial. The 19% of the patients had metastases from diagnosis. Post-operative recurrence was developed in 75 of 298 surgical patients. The most frequent systemic first line therapy was tyrosine-kinase inhibitors (55% of cases) with remissions of 43-50% and time to progression was 12.1 months. The retrospective review in renal cancer of an academic population gives the rationale of data of the real world and to compare with those that arise from central countries and randomized clinical trials (AU)

TDM-1 en cáncer de mama metastásico HER2 positivo. Experiencia institucional / TDM-1 in HER2 positive metastatic breast cancer. Institutional experience

El cáncer de mama es una de las enfermedades más frecuentes en todo el mundo. La amplificación del proto-oncogén HER2 se presenta en 20-25% de los tumores de mama. TDM-1 es un conjugado anticuerpo-quimioterápico. Se realizó en forma retrospectiva, observacional y descriptiva un análisis de los datos de pacientes con diagnóstico de cáncer de mama metastásico HER2 positivo, que realizaban y/o habían realizado tratamiento con dicho fármaco. Se evaluaron 27 mujeres. La indicación de TDM-1 fue en 7.4% (2) en primera línea, 37% (10) en segunda línea, y 55.5% (15) en líneas posteriores, con un tiempo a la progresión de 7.44 meses (IC: 4.33-NC) para el global de pacientes, tasa de respuesta objetiva de 44% y se constataron 7 (26%) toxicidades G3-4 (AU)

Breast cancer is one of the most common diseases worldwide. HER2 proto-oncogene amplification occurs in 20-25% of breast tumors. TDM-1 is an antibody-chemotherapeutic conjugate. We performed a retrospective, observational and descriptive analysis of data from patients diagnosed with metastatic HER2 positive breast cancer who were and / or had been treated with this drug. Twenty-seven women were evaluated. The indication for TDM-1 was 7.4% (2) in the 1st line, 37% (10) in the 2nd line, and 55.5% (15) in later lines, with a time to progression of 7.44 months (CI:4.33-NC) for the global patient, objective response rate was 44% and 7 (26%) G3-4 toxicities were found (AU)

Análisis retrospectivo institucional de tratamiento quimio-radioterápico definitivo en cáncer de cuello uterino localmente avanzado / Institutional retrospective analysis of definitive chemo-radiotherapy treatment in locally advanced cervical cancer

El objetivo fue analizar retrospectivamente, en pacientes con cáncer de cuello uterino localmente avanzado tratados en nuestro centro, el perfil de toxicidad de la radioterapia concurrente con platinos mono droga o combinados con gemcitabine y su impacto en el tratamiento. Estudio descriptivo, retrospectivo y observacional de pacientes con cáncer de cuello uterino localmente avanzado (estadios IIa/IVa) desde marzo de 2011 a febrero de 2016. Se analizaron características patológicas, dosis de tratamiento radiante y quimioterápico, así como toxicidades graves (GIII/IV) y su impacto en el tratamiento, observado como reducción o suspensión de dosis y/o split de radioterapia (RT). Se evaluaron 60 pacientes, edad mediana 47 años (17-75), 93% PS0-1. Histología: escamoso (89%) y adenocarcinoma (8%). Estadio IIb 24 (40%) y IIIb 16 (27%). Dosis de RT utilizada 5040cGy; 35 (58%) realizaron boost y 47 (78%) braquiterapia posterior. Cuarenta y cinco realizaron tratamiento concurrente con PLA y 15 con platinos/gemcitabine (PLA/GEM). En el grupo que recibió PLA, uno requirió reducción de dosis de quimioterapia (QT), dos suspendieron algún ciclo por toxicidad y tres realizaron split de RT. El 100% completó el tratamiento de quimioradioterapia (QRT) concurrente. En el grupo que recibió PLA/GEM: 9 requirieron reducción de dosis de QT, 11 suspendieron algún ciclo y 4 no completaron el esquema por toxicidad; 4 hicieron split de RT, y 87% completó el tratamiento de RT. En este estudio, el esquema concurrente con quimioterapia combinada muestra mayor toxicidad que impacta en el cumplimiento del tratamiento, 15% no lo completó por toxicidades graves. No obstante, un correcto manejo institucional de toxicidades, permite utilizar la combinación de tratamiento para obtener potenciales beneficios (AU)

This is a retrospective analysis of profile toxicity and treatment impact of gemcitabine plus platinum radiotherapy in patients with locally advanced cervix cancer, treated at our Centre. Descriptive, retrospective and observational study of patients with locally advanced cervix cancer (Ila/IVa stages), since March 2011 until February 2016. The analysis included the pathological characteristics, chemo radiotherapy doses, as well as severs toxicity (GIII/V) and it impact in treatment observed as reduction or suspension of doses and/or radiotherapy (RT) split. There were evaluated 60 patients of 47 median age (17-75), 93-5 PS0-1. Histology: 89% of squamous cell carcinoma and 8% of adenocarcinoma. 40% of IIb 24 and 27% of IIIB 16 stages. RT doses used 5040cGy; 35 pts (58%) did boost and 47 pts (78%) followed with brachytherapy. 45pts took PLA concurrent treatment, 15pts gemcitabine plus platinum (PLA/GEM). Regarding PLA group, one required a doses reduction of chemotherapy (QT), 2pts suspended a cycle due to toxicity and 3pts did RT split. 100% pts completed chemo radiotherapy (QRT) concurrent treatment. Regarding PLA/GEM group: 9pts required QT doses reduction, 11pts suspended a cycle due to toxicity and 4 didn´t complete the cycle due to toxicity; 4 did RT split and 87% completed RT. The study shown that the scheme of concurrent combined chemotherapy presents higher toxicity that impacts in the fulfillment of treatment, 66 ONCOLOGÍA CLÍNICA - Vol. 21 Nº 3 - Diciembre 2016 15% couldn´t complete due to sever toxicity. However, a correct institutional manage of toxicities allows to use treatment combination to obtain potential benefits (AU)

Rol de la biopsia del ganglio centinela en el carcinoma ductal in situ y en el microinvasor: experiencia del Instituto de Oncología Alexander Fleming / Rol of Sentinel Node Biopsy in Ductal Carcinoma In Situ and Microinvasive Breast Cancer: Instituto Alexander Fleming Experience

Determinar la incidencia de ganglio centinela (GC) positivo en pacientes con Carcinoma ductal in situ (CDIS) y microinvasor (T1mic); y describir las características clinicopatológicas de los mismos en relación con el compromiso axilar. Material y método: Se realizó un estudio retrospectivo en 46 pacientes con diagnóstico de CDIS y en 88 pacientes con T1mic a las cuales se les realizó la biopsia del ganglio centinela (BGC), en el período comprendido entre marzo de 1999 y octubre de 2013. Para el análisis estadístico, se utilizó el programa SPSS 17.0. Resultados: Una paciente de 46 (2,1%) con CDIS presentó una micrometástasis en el estudio diferido. No se completó la linfadenectomía axilar (LA). En 4 de las 88 pacientes (4,5%) con T1mic, el GC fue positivo (2 micrometástasis y 2 macrometástasis). A este grupo se le efectuó linfadenetomía axilar (LA); A este grupo se le efectuó linfadenetomía axilar (LA); una paciente presentó un ganglio positivo (micrometástasis) en los ganglios no centinela (GNC). Cuatro pacientes (4,5%) con T1mic presentaron recidiva en la mama y una (1,1%) a distancia. No hubo recurrencias en la paciente con CDIS. En todos estos casos, el GC había sido negativo. Conclusiones: Nuestros resultados son coincidentes con los de la literatura mundial. Actualmente, en el CDIS, no indicamos la BGC, excepto en CDIS extensos, sospecha de invasión en biopsias con aguja gruesa o cuando la paciente debe ser sometida a una mastectomía. A pacientes con T1mic les realizamos la BGC...

IL-2- or IL-15-activated NK cells enhance Cetuximab-mediated activity against triple-negative breast cancer in xenografts and in breast cancer patients.

Triple-negative breast cancer (TNBC) patients do not benefit from target-specific treatments and is associated with a high relapse rate. Epidermal growth factor receptor is frequently expressed in TNBC and is a candidate for new therapies. In this work, we studied Cetuximab-mediated immune activity by NK cells. Thirteen activating/inhibitory receptors were examined on peripheral blood and tumor infiltrating NK cells. NK-cell functionality was evaluated using as effectors tumor-modulated NK cells and NK cells from patients. We evaluated the treatment with Cetuximab plus IL-2 or IL-15 in vivo in TNBC xenografts. Tumor NK-cells receptor profile showed upregulation of inhibitory receptors and downregulation of activating ones. Tumor-modulated NK cells were less cytotoxic. They could perform antibody-dependent cellular cytotoxicity (ADCC) triggered by Cetuximab, although impaired, it could still be restored by stimulation with IL-2 or IL-15. Patients with advanced disease displayed diminished levels of ADCC compared to healthy volunteers. ADCC was restored and potentiated with both cytokines, which were also effective in enhancing the therapeutic activity of Cetuximab in vivo. The combination of Cetuximab with IL-15 and IL-2 may be considered an attractive therapeutic approach to enhance the clinical efficacy of Cetuximab in TNBC.

BRCA1 And BRCA2 analysis of Argentinean breast/ovarian cancer patients selected for age and family history highlights a role for novel mutations of putative south-American origin.

BACKGROUND: The spectrum of BRCA1/2 genetic variation in breast-ovarian cancer patients has been scarcely investigated outside Europe and North America, with few reports for South America, where Amerindian founder effects and recent multiracial immigration are predicted to result in high genetic diversity. We describe here the results of BRCA1/BRCA2 germline analysis in an Argentinean series of breast/ovarian cancer patients selected for young age at diagnosis or breast/ovarian cancer family history. METHODS: The study series (134 patients) included 37 cases diagnosed within 40 years of age and no family history (any ethnicity, fully-sequenced), and 97 cases with at least 2 affected relatives (any age), of which 57 were non-Ashkenazi (fully-sequenced) and 40 Ashkenazi (tested only for the founder mutations c.66_67delAG and c.5263insC in BRCA1 and c.5946delT in BRCA2). DISCUSSION: We found 24 deleterious mutations (BRCA1:16; BRCA2: 8) in 38/134 (28.3%) patients, of which 6/37 (16.2%) within the young age group, 15/57 (26.3%) within the non-Ahkenazi positive for family history; and 17/40 (42.5%) within the Ashkenazi. Seven pathogenetic mutations were novel, five in BRCA1: c.1502_1505delAATT, c.2626_2627delAA c.2686delA, c.2728 C > T, c.3758_3759delCT, two in BRCA2: c.7105insA, c.793 + 1delG. We also detected 72 variants of which 54 previously reported and 17 novel, 33 detected in an individual patient. Four missense variants of unknown clinical significance, identified in 5 patients, are predicted to affect protein function. While global and European variants contributed near 45% of the detected BRCA1/2 variation, the significant fraction of new variants (25/96, 26%) suggests the presence of a South American genetic component. This study, the first conducted in Argentinean patients, highlights a significant impact of novel BRCA1/2 mutations and genetic variants, which may be regarded as putatively South American, and confirms the important role of founder BRCA1 and BRCA2 mutations in Argentinean Ashkenazi Jews.

Micrometástasis y células tumorales aisladas en ganglio centinela en pacientes con cáncer de mama: experiencia del Instituto Alexander Fleming / Micrometastases and isolated tumor cells in the centinela node in patients with breast cancer: experience of the Instituto Alexander Fleming

Introducción: el rol del vaciamiento axilar en pacientes con cáncer de mama (CM) con micrometástasis o células tumorales aisladas (CTA) en el ganglio centinella (GC) es controvertido. Objetivos: analizar retrospectivamente pacientes con CM y micrometástasis o CTA en el GC, en términos descriptivos histológicos, terapéuticos y evolución clínica. Métodos: mil veintidós (1.022) biopsias del GC en pacientes con CM (período 1998-2010) fueron evaluadas histológicamente y con inmunohistoquímica. Los tratamientos adyuvantes y los patrones de recurrencia fueron evaluados retrospectivamente de las historias clínicas. Resultados: doscientos treinta y ocho (238) pacientes (23.2%) presentaron GC+. Ciento cuarenta y tres (143) casos (60.0%) fueron macrometástasis, 58 casos (24.3%) micrometástasis y 37 casos (15.5%) CTA. De 58 pacientes con micrometástasis, 75.8% realizó VAG. Veintiocho (28) pacientes (75.6%) de 37 pacientes con CTA no completaron VAG. El porcentaje de GNC+ en las pacientes con micrometástasis y CTA fue 22.7% y 11.0%, respectivamente. Todas las pacientes recibieron tratamiento adyuvante. La mediana de seguimiento fue 54 meses. No hubo recurrencias axilares. El 5% de ambos grupos presentó recurrencias a distancia. La sobrevida libre de eventos es del 94% a 48 meses en ambos grupos. No hubo diferencias estadísticamente significativas para eventos y sobrevida global entre CTA y MIC (p=0.49). Conclusiones: en nuestro estudio las pacientes con micrometástasis y CTA no presentaron recurrencias axilares. No hubo diferencias entre ambos grupos con relación a sobrevida libre de eventos y sobrevida global...

Triple-negative breast cancer.

Perou's molecular classification defines tumors that neither express hormone receptors nor overexpress HER2 as triple-negative (TN) tumors. These tumors account for approximately 15% of breast cancers. The so-called basaloid tumors are not always synonymous with TN tumors; they differ in the fact that they express different molecular markers, have a higher histologic grade, and have a worse prognosis. Clinically they occur in younger women as interval cancer, and the risk of recurrence is higher within the first 3 years. Distant recurrences in the brain and visceral metastases are more common than in hormone receptor-positive tumors. Therapeutically, despite being highly chemosensitive, their progression-free time is generally short. In terms of chemotherapeutic treatment, anthracyclines and taxanes are useful drugs, and high response rates have been described for the combination of ixabepilone-capecitabine and platinums. The combination with antiangiogenic drugs has also proven useful. A group of new drugs, poly-(ADP-ribose)-polymerase inhibitors, showed favorable results in TN tumors with BRCA mutation. There are currently several ongoing studies with new drugs including epidermal growth factor receptor inhibitors, c-kit inhibitors, Raf/Mek/Map kinase inhibitors and mTOR inhibitors.

Efecto de las drogas antracíclicas sobre la función ventricular izquierda en pacientes con cáncer de mama / Effect of antracíclicas drugs on the left ventricular function in patients with breast cancer

Objetivo: analizar la fracción de eyección ventricular izquierda (FEVI) en pacientes (ptes.) mujeres tratadas por cáncer de mama (Ca.ma) con drogas antracíclicas y con criterio de curación bajo seguimiento clínico oncológico y comparar la FEVI con un grupo de ptes. testigo con diagnóstico de Ca.ma que no hayan comenzado su tratamiento quimioterápico con antraciclinas. Materiales y métodos: sobre un total de 160 ptes. mujeres con Ca.ma se evaluó la FEVI por método de Simpson´s por ecocardiografia (utilizando un ecógrafó digital GE vivid five), de las cuales 92 ptes. presentaron criterio de curación y tratamiento previo con antraciclinas denominado grupo tratamiento (grupo T-1). Se comparó su función ventricular por el mismo método con mujeres con diagnóstico de Ca.ma antes del tratamiento adyuvante con antraciclinas como grupo contro denominado grupo tratamiento (grupo T-2). Los resultados fueron expresados en medias y medianas según correspondan y el análisis estadístico para medias de Kruskal-Wallis y Chi-cuadrado. Resultados: número de ptes.: grupo T-1 92p, grupo T-2 68p. No se encontraron diferencias significativas en la edad entre los grupos T-1: 50± 10,7 años, T-2: 53±10 años ni en la cantidad de factores de riesgo coronarios mayores grupo T-1: 2,3% y grupo T-2: 2,1%. El tiempo de exposición a la droga en el seguimiento antes de ser evaluadas las ptes. en el grupo T-1 fue de 37 (±31) meses. La FEVI presentó una diferencia significativa entre ambos grupo T-1: 57,8% (±9,1) y grupo T-2: 65,6% (±6,7) con valor de p<0,00005. La dosis media acumulada de antraciclinas en el grupo T-1 fue de 449,6 (±108) mg/m2. Conclusiones: el tratamiento con drogas antracíclicas en esta población de bajo riesgo de enfermedad cardiovascular demostró predisponer al deterioro de la FEVI la cual demuestra que la función ventriclar debe ser evaluada en forma rutinaria en todo pte. expuesto a este tipo de droga con beneficio demostrado en mayor tasa de curación del...

A phase I study of an allogeneic cell vaccine (VACCIMEL) with GM-CSF in melanoma patients.

We investigated whether recombinant human granulocyte-monocyte-colony-stimulating factor (rhGM-CSF) increased the immunogenicity of VACCIMEL, a vaccine consisting of 3 irradiated allogeneic melanoma cell lines. A phase I clinical trial was performed on 20 melanoma patients in stages IIB (n=2), III (n=10), and IV (n=8), who were disease free after surgery (n=16) or had minimal disease (n=4). Cohorts of 4 patients were vaccinated 4 times with VACCIMEL and bacillus Calmette Guerin (BCG) as adjuvant. Besides, the patients received placebo (group 1) or GM-CSF: 150 microg (group 2), 300 microg (group 3), 400 microg (group 4), and 600 microg (group 5) per vaccine. The combination of VACCIMEL and GM-CSF had low toxicity. Only in group 5, grade 2 thoracic pain (3/4 patients) and abdominal cramps (2/4 patients) were observed. Delayed-type hypersensitivity increased after vaccination and it was highest in group 4. Phytohemagglutinin stimulation of peripheral blood lymphocytes was analyzed in 9 patients: 4/9 had normal stimulation; 3/9 had low basal stimulation, which recovered after vaccination; and 2/9 were not stimulated. Antimelanoma antibodies preexisted in 9/19 patients; in 3/19 patients, antibodies anti-33 kd, 90 kd, and 100 kd antigens were induced by vaccination. IgG2 but not IgG1 antibodies were detected. Anti-BCG antibodies, mostly IgG2, reached the highest post/prevaccination ratio in group 4. Median serum interleukin-12 was lower in progressing patients (61.6 pg/mL) than in those without evident disease (89 pg/mL). Thus, its low toxicity and the induction of a predominantly cellular immune response suggest that the addition of 300 to 400 microg GM-CSF to VACCIMEL is useful in increasing the immune response.