Benefits of a standardized protocol for axillary management after neoadjuvant chemotherapy in a single center

Introduction: The axillary lymph node status is one of the most important prognostic factors in breast cancer. For locally advanced tumors, neoadjuvant chemotherapy favors higher rates of breast lumpectomy and downstaging tumor burden of axilla. The aim of this study was to evaluate the use of a standardized image-guided protocol after neoadjuvant chemotherapy to enable sentinel node dissection in patients with axillary downstaging, avoiding axillary dissection. Methods: Retrospective cohort study of data collected from medical records of patients who underwent neoadjuvant chemotherapy in a single center, from January 2014 to December 2018. The protocol comprises the placement of a metal clip in positive axillary lymph node, in patients with up to two clinically abnormal lymph nodes presented on imaging. After neoadjuvant chemotherapy, and once a radiologic complete response was achieved, sentinel node dissection was performed using blue dye and radiotracer. Axillary dissection were avoided in patients whose clipped sentinel node were negative for metastasis and in patients with three identified and negative sentinel node dissection. Results: A total of 471 patients were analyzed for this study: 303 before and 165 after the implementation of the protocol; 3 cases were excluded. The rate of sentinel node dissection in clinical nodes positive patients was statistically higher in this group when compared to patients treated before the protocol implementation (22.8% vs. 40.8%; p=0.001). Patients with triple negative and HER2-positive tumors underwent sentinel node dissection more frequently when compared to luminal tumors (p=0.03). After multivariate analysis, the variables that were associated with a greater chance of performing sentinel node dissection were clinical staging, type of surgery performed and implementation of the axillary assessment protocol. Conclusions: The results showed that the use of an easily and accessible image-guided protocol can improve sentinel node dissection in selected patients, even if the lymph node was positive previously to neoadjuvant treatment.

Comparison of hormonal receptor expression and HER2 status between circulating tumor cells and breast cancer metastases

OBJECTIVES: Breast cancer (BC) is the most common neoplasm in women. Biopsy of metastatic lesions is recommended to confirm estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status as there are discrepancies in these patterns between primary tumors and metastases in up to 40% of the cases. Circulating tumor cells (CTCs) are related to BC outcomes and could potentially be an alternative to the invasive procedures of metastasis rebiopsy. ISET® technology is not currently employed to detect CTCs in patients with BC. Emerging data support that the characterization of CTC protein expression can refine its prognostic value. Transforming growth factor (TGF)-β plays a role in BC progression and invasiveness. Thus, in this study, we aimed to compare ER, PR, and HER2 expression in primary tumors, CTCs, and metastases and evaluate TGF-β type 1 receptor (TGF-β RI) expression in CTCs as prognostic factor for progression free survival (PFS) and overall survival (OS). METHODS: This prospective study was conducted at the A.C. Camargo Cancer Center, Brazil. Blood samples were processed in ISET® (Isolation by SizE of Tumors, Rarecells, France) before computed tomography-guided biopsy of suspected metastatic lesions. Protein expression levels in CTCs were compared to those in primary tumors/metastases (medical records). RESULTS: Of the 39 patients initially included, 27 underwent both biopsies of metastases and blood collection and were considered for analysis. The concordance rates for ER, PR, and HER2 expression between primary tumors and metastases were high. No loss of HER2 expression at any metastasis site and retention of the same pattern of protein expression in all triple-negative (TN) tumors (92.5%, 81.5% and 96.2% respectively) (p<0.0001) was observed. When metastases/CTCs were classified as TN/non-TN, CTCs showed high specificity (93%), accuracy (84.2%), and negative predictive value (88%). The median OS of patients without TGF-β RI expression in CTCs was 42.6 versus 20.8 months for TGF-β RI expression-positive ones (p>0.05). CONCLUSION: The role of CTCs detected by ISET has not yet been established in BC. Here, we suggest that this methodology may be useful to evaluate metastasis in non-TN cases as well as TGF-β RI expression in CTCs, which may impact patient survival. Due to sample limitations, future studies must focus on specific BC subtypes and an expansion of the cohort.

Comparação entre expressão de receptores hormonais e de HER-2 entre células tumorais circulantes e metástases de câncer de mama / Comparison of hormonal receptor expression and HER2 status in circulating tumor cells and breast cancer metastases

Introdução: O câncer de mama é a neoplasia mais comum em mulheres. A maioria deles é diagnosticada em estágios iniciais, quando o tratamento visa a cura. Mas apesar dos avanços no tratamento, metástases à distância podem ocorrer. A biópsia das lesões metastáticas é recomendada para confirmar o status do receptor de estrogênio (RE), receptor de progesterona (RP) e receptor do fator de crescimento epidérmico humano 2 (HER2), por ocorrerem discrepâncias nesses padrões entre tumores primários e metástases em até 40% dos casos. As células tumorais circulantes (CTCs) estão relacionadas às evoluções clínicas do câncer de mama e podem potencialmente desempenhar um papel substituto aos procedimentos invasivos de rebiópsia de metástase. A tecnologia ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, França) não é usualmente empregada para detectar CTCs em pacientes com câncer de mama, embora seja reconhecida como uma ferramenta útil em alguns outros tumores. Existem dados emergentes de que a caracterização da expressão proteica das CTC pode refinar seu valor prognóstico. Sabe-se que o fator de transformação de crescimento (TGF-ß) desempenha um papel na progressão e invasividade do câncer de mama. Objetivos: Comparar a expressão de RE, RP e HER2 em tumores primários, CTCs, metástases e avaliar a expressão do receptor TGF-ß tipo 1 (TGF-ß RI) em CTCs como fator prognóstico para sobrevida global. Metodologia: Estudo realizado no A.C.Camargo Cancer Center, Brasil. As amostras de sangue foram coletadas antes da biópsia guiada por tomografia computadorizada de lesões metastáticas suspeitas e processadas pela metodologia ISET®. Os níveis de expressão proteica das CTCs foram comparados aos de tumores primários e metástases e correlacionados aos resultados clínicos. Todos os dados clínicopatológicos foram obtidos dos prontuários médicos. Resultados: Dos 39 pacientes inicialmente incluídos, 27 tiveram tanto a biópsia de metástases quanto a coleta de sangue e foram considerados para análise. As taxas de concordância para a expressão de RE, RP e HER2 entre tumores primários e metástases foram altas. Não foi observada nenhuma perda de expressão de HER2 nas metástases e os tumores triplo negativos mantiveram o mesmo padrão em todas as metástases (p <0,0001). Quando as metástases e CTCs foram classificadas como triplo negativo (TN) ou não ­ TN, as CTCs determinaram alta especificidade (93%), acurácia (84,2%) e valor preditivo negativo (88%). A sobrevida global mediana de pacientes sem expressão de TGF-ß RI em CTCs foi de 42,6 x 20,8 meses para os positivos, clinicamente relevante, porém sem significância estatística (p> 0,05). Conclusões: No câncer de mama, o papel das CTCs detectadas pelo ISET® ainda não está estabelecido. Com este estudo, sugerimos que esta metodologia possa ser útil para avaliar metástases em casos de tumores não TN, assim como a expressão de TGF-ß RI em CTCs, o que pode impactar a sobrevida. Devido à limitação da amostra, estudos futuros devem se concentrar em subtipos específicos de câncer de mama, ampliando a coorte.

Introduction: Breast cancer (BC) is the most common neoplasm in women. Most of BC are diagnosed in early stages, when treatment aims cure. Despite advances in BC treatment, distant metastases may develop. Biopsy of metastatic lesions is recommended to confirm estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status, due to discrepancies in these patterns between primary tumors/metastasis in up to 40% of cases. Circulating Tumor Cells (CTCs) are related to breast cancer outcomes and could potentially play a role surrogating invasive procedures of metastasis rebiopsy. ISET® (Isolation by SizE of Tumor Cells, Rarecells-Diagnostics, Paris, France) technology is not currently employed to detect CTCs in breast cancer patients, although recognized as a useful tool in some other tumors. There are emerging data that characterization of CTC protein expression can refine its prognostic value. Transforming growth factor (TGF)-ß play a role in progression/invasiveness of BC. Objectives: To compare ER, PR and HER2 expression in primary tumors, CTCs, metastases and to evaluate TGF-ß type 1 receptor (TGF- ß RI) expression in CTCs as prognostic factor for overall survival. Methods: Study conducted at the A.C.Camargo Cancer Center, Brazil. Blood samples were processed in ISET® before computed tomography­guided biopsy of suspected metastatic lesions. Protein expression levels in CTCs were compared to those in primary tumors/metastases and correlated to clinical outcomes. All clinicopathological data were obtained from medical records. Results: From the 39 patients initially included, 27 had both biopsy of metastases and blood collection and were considered for analysis. Concordance rates for ER, PR and HER2 expression between primary tumors/metastases were high. No loss of HER2 expression at any metastasis site and retention of the same pattern in all triplenegative (TN) tumors (p <0.0001) were observed. When metastases/CTCs were classified as TN/non­TN, CTCs showed high specificity (93%), accuracy (84.2%) and negative predictive value (88%). The median overall survival of patients with no TGF-ß RI expression in CTCs was 42.6 x 20.8 months for positive ones, clinically relevant but not statistically significant (p>0.05). Conclusions: In BC, the role of CTCs detected by ISET® is not yet established. Here, we could suggest that this methodology may be useful to evaluate metastasis in non-TN cases as also TGF-ß RI expression in CTCs, which may impact survival. Due to sample limitation, future studies must focus on specific subtypes of BC, expanding the cohort.

BREAST CANCER SURVIVAL IN A BRAZILIAN CANCER CENTER: A COHORT STUDY OF 5, 095 PATIENTS / Sobrevida do câncer de mama em um centro de câncer brasileiro: um estudo de coorte de 5. 095 pacientes

Objectives: To describe the age group, clinical stage at diagnosis, treatment, and survival rates of breast cancer patients treated in a Brazilian specialized Cancer Center. Method: A hospital-based retrospective cohort study is presented herein, on women with breast cancer diagnosed between January 1, 2000 and December 31, 2012. Data were extracted from the Hospital Cancer Registry of the A.C.Camargo Cancer Center. Data on age group, histology of the tumor, TNM classification, clinical stage and treatments were described in absolute and relative frequencies for three periods. Survival curves were estimated with the Kaplan-Meier estimator. Hazard ratio (HR) and 95% confidence interval (95%CI) were calculated for all variables. Results: A total of 5,095 female breast cancer patients were identified, with most stages classified as I and II (60%). The overall survival was 82.7% for the period of 2000­2004, and 89.9% for 2010­2012 (p<0.001). Patients with invasive ductal carcinoma, who were treated with surgery and hormonal therapy, showed a reduction in the risk of death in the most recent period HRadj=0.42 (95%CI 0.34­0.53) (2010­2012). Conclusions: Early stage diagnosis and combined treatment (including HT) are predictive prognostic factors for high survival rates in patients with invasive breast cancer. Specialized cancer centers can provide valuable indications regarding cancer control policies, evaluating overall survival for breast cancer and its associated prognosis.

Objetivos: Descrever as faixas etárias, estadiamento clínico ao diagnóstico, tratamento e sobrevida global das pacientes com câncer de mama tratadas em um centro de câncer brasileiro. Método: Estudo de uma coorte retrospectiva de base hospitalar, com mulheres diagnosticadas de câncer de mama entre 1º de janeiro de 2000 e 31 de dezembro de 2012. Os dados foram extraídos do Registro Hospitalar de Câncer do A. C. Camargo Cancer Center. Faixa etária, tipo histológico, classificação TNM, estadiamento clínico e tratamento foram descritos em frequência absoluta e relativa estratificados em três períodos. As curvas de sobrevida global foram estimadas pelo método de Kaplan-Meier. A Hazard ratio (HR) com intervalo de confiança de 95% foram calculados para todas as variáveis. Resultados: O total de 5.095 pacientes mulheres com câncer de mama foi identificado, a maioria era estágio inicial 60% (I e II). A sobrevida global foi de 82,7% para o período de 2000­2004 e 89,9% para 2010­2012 (p<0,001). Pacientes com carcinoma ductal invasivo que foram tratadas com cirurgia e hormonioterapia, mostraram redução do risco de morte no período mais recente HRaj=0,42 (0,34­0,53 em 2010­2012). Conclusões: Diagnóstico precoce e tratamento combinado (incluindo hormonioterapia) são fatores prognósticos preditivos para altas taxas de sobrevida em pacientes com câncer de mama invasivo. Centros especializados em câncer podem prover informações valiosas sobre as políticas de controle do câncer, avaliando a sobrevida global do câncer de mama e fatores associados ao prognóstico.

Circulating tumor cells as a new and additional approach to follow-up patients with serous low-grade ovarian adenocarcinoma: a case report and review of the literature

Background: Current methods for follow-up of Ovarian Cancer (OC) are widespread, especially with CA125, which, however, is not a perfect biomarker and thus further investigation for new methods of evaluation are warranted. The feasibility of Circulating Tumor Cells (CTCs) in advanced OC was investigated in this case report. Case presentation: A 19-year-old woman with advanced low-grade serous papillary adenocarcinoma and relapsed disease did not have a CA125 correspondent with disease relapse. CTCs were evaluated, compared with CA125 and with image exams. Relapses were not correspondent to elevations of CA125. CTCs demonstrated usefulness, being proportional to major disease relapse, especially in the peritoneum. CTCs may be used as a complementary diagnosis tool when marginal/small increases in CA-125 levels are observed. Conclusions: In OC, CTCs can be an important tool to predict recurrence, response to treatment and improve the quality of decision-making, in order to offer the best treatment to a determined group of patients (AU)

Interação entre especialidades: miocardiopatia dilatada e neoplasia de mama HER2 positiva / Interaction between specialties: dilated cardiomyopathy and HER2-positive breast Cancer / Interacción entre especialidades: miocardiopatía dilatada y neoplasia de mama HER2 positiva

O progresso no conhecimento dos mecanismos da doença e suas potenciais possibilidades de tratamento, têm com o incremento da pesquisa básica, trazido a algumas situações inusitadas. Como quando algo observado em uma situação específica, definida na prática clínica, pode ser transportado para o laboratório, instigando a investigação de uma provável terapêutica em uma doença não relacionada e fazendo o caminho inverso da "bench-to-bedside". Nos últimos anos, o uso de um anticorpo monoclonal, o trastuzumabe, mostrou-se imprescindível no tratamento das neoplasias de mama com amplificação/superexpressão de HER2, com ganho de sobrevida significativo nos contextos adjuvante e terapêutico. A observação da ocorrência de cardiotoxicidade induzida pelo trastuzumabe, assim como a identificação dos mecanismos relacionados a esse efeito colateral, possibilitaram a pesquisa desses mesmos fatores na miocardiopatia dilatada, de uma forma muito interessante.

Basic research may result in unexpected benefit in terms of progress in the understanding of mechanisms responsible for different diseases and their potential treatment alternatives. This is seen, for instance, when a specific situation, defined in clinical practice, may be translated into laboratory findings which suggest a new therapy for an unrelated disease, representing the inverse of the more usual bench-to-bedside path. During the past few years, the use of the monoclonal antibody trastuzumab, in the adjuvant and therapeutic context, has become of fundamental importance in the treatment of breast cancer with amplification/overexpression of HER2, resulting in significant increase in survival rates. The observation that trastuzumab also induces cardiotoxicity, and the identification of mechanisms involved in this side effect, have allowed the investigation of these factors as a therapeutic alternative for dilated cardiomyopathy, in a highly interesting fashion.

El progreso en el conocimiento de los mecanismos de la enfermedad y sus potenciales posibilidades de tratamiento ocurre mediante el incremento de la investigación básica que se añade a algunas situaciones inusitadas. Así como cuando algo observado en una situación específica, definida en la práctica clínica, se puede trasladar al laboratorio, fomentando la investigación de una probable terapéutica en una enfermedad no relacionada, y haciendo el camino inverso de la "bench-to-bedside". En los últimos años, el uso de un anticuerpo monoclonal, el trastuzumabe, se halló imprescindible en el tratamiento de las neoplasias de mama con amplificación/superexpresión de HER2, con ganancia de sobrevida significativa en los contextos adyuvante y terapéutico. La observación de la ocurrencia de cardiotoxicidad inducida por el trastuzumabe, así como la identificación de los mecanismos relacionados a este efecto colateral, posibilitaran la investigación de estos mismos factores en la miocardiopatía dilatada, de una forma muy interesante.

Metástases ósseas: opçöes de tratamento sistêmico / Bone metastases: options of systemic treatment

As metástases ósseas podem ser um dos primeiros indicativos de doença disseminada nos pacientes com câncer, principalmente de mama, pulmäo e próstata. Embora a maior parte desses pacientes tenha sua sobrevida diminuída após o diagnóstico de doença metastática, uma proporçäo considerável sobreviverá por um período de tempo suficientemente grande para que a doença óssea provoque sintomas significativos, causando dor e afetando a qualidade de vida do indivíduo. Alternativas de tratamento vêm sendo pesquisadas para esses pacientes, em tentativas de interferência no processo fisiopatológico da doença óssea. Radioisótopos e agentes sem atividade citotóxica têm se destacado neste aspecto, e este artigo sobrepassa as diversas alternativas terapêuticas em investigaçäo clínica para esse grupo de pacientes.