Management of early-stage triple-negative breast cancer: recommendations of a panel of experts from the Brazilian Society of Mastology.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogenous subtype involving different patterns of behavior and clinical course, demanding a complex, individualized sequence of treatment. The knowledge and attitudes of the affiliated members of the Brazilian Society of Mastology regarding TNBC were evaluated and a consensus regarding management and treatment was reached. METHODS: Affiliates completed a survey involving 44 objective questions. In addition, a specialist meeting was held with 27 experts and 3 ad hoc consultants. The panelists completed the survey before and after brainstorming. Answers achieving 70% of agreement were considered consensual. The chi-square test was used to compare answers between panelists and affiliates and the Kappa coefficient to calculate agreement. RESULTS: Consensus among the panelists increased from 26 (59.1%) to 32 questions (72.7%) following brainstorming (p = 0.17), including 7/10 questions on systemic treatment. Among the affiliates, consensus was achieved for 24 questions (54.5%), resulting in moderate agreement (κ = 0.445). Neoadjuvant chemotherapy should be indicated for almost all cases (except cT1a-b N0) and should include platinum agents. When indicated, immunotherapy is part of the standard of care. The panel reaffirmed the concept of no ink on tumor as indicative of adequate margins and the possibility of sentinel lymph node biopsy for cN1 patients who become cN0 following neoadjuvant therapy. Controversies remain on combining immunotherapy with capecitabine/olaparib in pertinent cases. CONCLUSION: Expert consensus was achieved for > 70% of the questions, with moderate agreement between panelists and affiliates. Educational interventions on systemic breast cancer treatment affected decision-making in 60% of the questions.

Trastuzumab Deruxtecan versus Trastuzumab Emtansine for Breast Cancer.

BACKGROUND: Trastuzumab emtansine is the current standard treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer whose disease progresses after treatment with a combination of anti-HER2 antibodies and a taxane. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial to compare the efficacy and safety of trastuzumab deruxtecan (a HER2 antibody-drug conjugate) with those of trastuzumab emtansine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane. The primary end point was progression-free survival (as determined by blinded independent central review); secondary end points included overall survival, objective response, and safety. RESULTS: Among 524 randomly assigned patients, the percentage of those who were alive without disease progression at 12 months was 75.8% (95% confidence interval [CI], 69.8 to 80.7) with trastuzumab deruxtecan and 34.1% (95% CI, 27.7 to 40.5) with trastuzumab emtansine (hazard ratio for progression or death from any cause, 0.28; 95% CI, 0.22 to 0.37; P<0.001). The percentage of patients who were alive at 12 months was 94.1% (95% CI, 90.3 to 96.4) with trastuzumab deruxtecan and 85.9% (95% CI, 80.9 to 89.7) with trastuzumab emtansine (hazard ratio for death, 0.55; 95% CI, 0.36 to 0.86; prespecified significance boundary not reached). An overall response (a complete or partial response) occurred in 79.7% (95% CI, 74.3 to 84.4) of the patients who received trastuzumab deruxtecan and in 34.2% (95% CI, 28.5 to 40.3) of those who received trastuzumab emtansine. The incidence of drug-related adverse events of any grade was 98.1% with trastuzumab deruxtecan and 86.6% with trastuzumab emtansine, and the incidence of drug-related adverse events of grade 3 or 4 was 45.1% and 39.8%, respectively. Adjudicated drug-related interstitial lung disease or pneumonitis occurred in 10.5% of the patients in the trastuzumab deruxtecan group and in 1.9% of those in the trastuzumab emtansine group; none of these events were of grade 4 or 5. CONCLUSIONS: Among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane, the risk of disease progression or death was lower among those who received trastuzumab deruxtecan than among those who received trastuzumab emtansine. Treatment with trastuzumab deruxtecan was associated with interstitial lung disease and pneumonitis. (Funded by Daiichi Sankyo and AstraZeneca; DESTINY-Breast03 ClinicalTrials.gov number, NCT03529110.).

PAGET'S DISEASE IN A MALE PATIENT: CASE REPORT / Doença de Paget do mamilo em paciente masculino: relato de caso

Paget's disease is a rare entity that accounts for 1 to 3% of breast tumors. Occurrence in male patients is even less common. Literature has reported only 24 cases in the last 20 years. We described the case of a 62-year-old male patient that sought medical care due to erosion and eczema on left nipple. After skin biopsy, the clinical suspicion of Paget's disease was confirmed by histological and immunohistochemical studies, which enabled the proper surgical and oncological treatment

A Doença de Paget do mamilo é uma entidade rara, representando 1 a 3% dos carcinomas de mama. Sua presença em pacientes masculinos é ainda menos comum, com apenas 24 casos na literatura nos últimos 20 anos. Em nosso relato de caso, descrevemos um paciente masculino de 62 anos que procurou atendimento por erosão e eczema no mamilo esquerdo. Após biópsia de pele, a histologia e o estudo imuno-histoquímico confirmaram a suspeita clínica de Doença de Paget do mamilo, possibilitando o tratamento cirúrgico-oncológico adequado.

A randomised phase II study of chemoradiotherapy with or without nimotuzumab in locally advanced oesophageal cancer: NICE trial.

PURPOSE: Chemoradiotherapy is the standard treatment for patients with inoperable locally advanced oesophageal cancer. We sought to assess the safety and efficacy of chemoradiation combined with nimotuzumab, a humanised antibody directed against epidermal growth factor receptor (EGFR). PATIENTS AND METHODS: Untreated patients with inoperable locally advanced oesophageal cancer and no distant metastases were randomised to chemoradiotherapy (cisplatin and fluorouracil combined with external beam radiation) alone or in combination with nimotuzumab. The primary end-point was the endoscopic complete response (eCR) rate, and secondary end-points comprised quality of life (QoL) and safety. The combined eCR and pathologic complete response (cEPCR) and overall survival (OS) were also evaluated. RESULTS: We enrolled 107 patients with a mean age of 59 years, and 93% had squamous cell carcinoma. Toxicity was manageable in both arms with no important differences in adverse events (AEs). We performed post-treatment endoscopies in 67 patients, including 60 who had a biopsy. In the intent-to-treat population, the eCR rates with and without nimotuzumab were 47.2% and 33.3% (P = 0.17), respectively, and the cEPCR rates were 62.3% and 37.0% (P = 0.02), respectively. With a median follow-up of 14.7 months, the hazard ratio (HR) for OS was 0.68 (95% confidence interval (CI): 0.44-1.07; P = 0.09) with a median OS of 15.9 months for the nimotuzumab arm and 11.5 months for the control arm. Regarding QoL, a significant difference was observed for the physical subscale score (P = 0.03) with lower values for the control arm. CONCLUSION: Combined chemoradiotherapy plus nimotuzumab is safe for patients with locally advanced oesophageal cancer, it appears to increase the cEPCR rate, and without compromising QoL. CLINICAL TRIALS: Identification number: EF024-201; Trial registry: NCT01249352.

Non-Hodgkin lymphoma in breast: case report / Linfoma não Hodgkin da mama: relato de caso

e primary breast lymphoma is a rare tumor, accounting for up to 0.5% of breast cancers. Most primary breast lymphoma is presented as non-Hodgkin lymphoma, the B-cells lymphoma is the most common, and Burkitt lymphoma is the most aggressive. We report the case of a 24-year-old female patient, with global, progressive and rapid increase of the right breast during 30 days with reaction to insect bite and progressive weight loss, fatigue, fever and nocturne sweating. An echo-guided core biopsy was held with injury and showed an atypical lymphoid proliferation, suggestive of high-grade non-Hodgkin lymphoma. Immunohistochemistry confirmed non-Hodgkin lymphoma, B immunophenotype, Burkitt type. Also, the diagnosis of HIV infec- tion was performed during hospitalization. Patient started with multidrug chemotherapy scheme and antiretroviral therapy. Burkitt lymphoma is an exceptionally aggressive subtype and can a ect the central nervous system and gastrointestinal tract, and treatment consists of chemothe- rapy with multiple agents as soon as possible. Radiotherapy has no function in the Burkitt type cases, even in case of only local disease.

O linfoma primário de mama é um tumor raro que corresponde a cerca de 0,5% de todos os cânceres de mama. A maioria dos linfomas primários de mama apresenta-se como linfoma não Hodgkin, sendo o mais comum o de células B e o mais agressivo o linfoma de Burkitt. Relatamos o caso de uma paciente feminina, 24 anos, com aumento global, progressivo e rápido da mama direita observado num período de 30 dias, acompanhado de progressiva perda de peso, fadiga, febre e sudorese noturna. Foi realizada biópsia guiada por agulhamento, que identi cou proliferação linfoide atípica, sugestiva de linfoma não Hodgkin de alto grau. A avaliação imuno-histoquímica con rmou o diagnóstico de linfoma não Hodgkin, imunofenótipo B, do tipo Burkitt. O diagnóstico de infecção pelo HIV também foi feito durante a hospitalização. Foi iniciado tratamento com esquema quimioterápico de múltiplas drogas e terapia antirretroviral. O linfoma de Burkitt é um subtipo bastante agressivo e pode afetar o sistema nervoso central e o trato gastrointestinal, e o tratamento consiste em quimioterapia com múltiplos agentes, devendo ser iniciado o mais brevemente possível. A radioterapia não tem papel no tratamento do linfoma de Burkitt, mesmo nos casos de doença localizada.

A phase III, randomized, non-inferiority study comparing the efficacy and safety of biosimilar filgrastim versus originator filgrastim for chemotherapy-induced neutropenia in breast cancer patients.

OBJECTIVES:: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non-inferiority of the test drug relative to the originator. METHODS:: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS:: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION:: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa's approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima¯).

A phase III, randomized, non-inferiority study comparing the efficacy and safety of biosimilar filgrastim versus originator filgrastim for chemotherapy-induced neutropenia in breast cancer patients

OBJECTIVES: To compare the efficacy and safety of two filgrastim formulations for controlling chemotherapy-induced neutropenia and to evaluate the non-inferiority of the test drug relative to the originator. METHODS: This phase III non-inferiority study had a randomized, multicenter, and open-label design. The patients were randomized at a ratio of 1:1 with a follow-up period of 6 weeks for each patient. In both study arms, filgrastim was administered subcutaneously at a daily dose of 5 mg/kg body weight. The primary endpoint was the rate of grade 4 neutropenia in the first treatment cycle. The secondary endpoints were the duration of grade 4 neutropenia, the generation of anti-filgrastim antibodies, and the rates of adverse events, laboratory abnormalities, febrile neutropenia, and neutropenia of any grade. RESULTS: The primary efficacy analysis demonstrated the non-inferiority of the test drug compared with the originator drug; the upper limit of the 90% confidence interval (CI) for the rate of neutropenia between the two groups (12.61%) was lower than the established margin of non-inferiority. The two treatments were similar with respect to the secondary endpoints and safety. CONCLUSION: The efficacy and safety profile of the test drug were similar to those of the originator product based on the rate of grade 4 neutropenia in the first treatment cycle. This study supports Anvisa’s approval of the first biosimilar drug manufactured by the Brazilian industry (Fiprima¯).

5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial.

BACKGROUND: In the primary analysis of the NeoSphere trial, patients given neoadjuvant pertuzumab, trastuzumab, and docetaxel showed a significantly improved pathological complete response compared with those given trastuzumab and docetaxel after surgery. Here, we report 5-year progression-free survival, disease-free survival, and safety. METHODS: In this multicentre, open-label, phase 2 randomised trial in hospitals and medical clinics, treatment-naive adults with locally advanced, inflammatory, or early-stage HER2-positive breast cancer were randomly assigned (1:1:1:1) to receive four neoadjuvant cycles of trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2) every 3 weeks, increasing to 100 mg/m(2) from cycle 2 if tolerated; group A), pertuzumab (840 mg loading dose, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B), pertuzumab and trastuzumab (group C), or pertuzumab and docetaxel (group D). After surgery, patients received three cycles of FEC (fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2), and cyclophosphamide 600 mg/m(2)) every 3 weeks (patients in group C received four cycles of docetaxel prior to FEC), and trastuzumab 6 mg/kg every 3 weeks to complete 1 year's treatment (17 cycles in total). Randomisation was done by a central centre using dynamic allocation, stratified by operable, locally advanced, and inflammatory breast cancer, and by oestrogen and/or progesterone receptor positivity. Safety analyses were done according to treatment received. The primary endpoint (pathological complete response) was previously reported; secondary endpoints reported here are 5-year progression-free survival (analysed in the intention-to-treat population) and disease-free survival (analysed in patients who had surgery). Secondary and exploratory analyses were not powered for formal statistical hypothesis testing, and therefore results are for descriptive purposes only. The study ended on Sept 22, 2014 (last patient, last visit). This study is registered with ClinicalTrials.gov, number NCT00545688. FINDINGS: Between Dec 17, 2007, and Dec 22, 2009, 417 eligible patients were randomly assigned to group A (107 patients), group B (107 patients), group C (107 patients), or group D (96 patients). One patient in group A withdrew before treatment. One patient assigned to group D received group A treatment, one patient assigned to group D received group B treatment, and one patient assigned to group B received group C treatment. At clinical cutoff, 87 patients had progressed or died. 5-year progression-free survival rates were 81% (95% CI 71-87) for group A, 86% (77-91) for group B, 73% (64-81) for group C, and 73% (63-81) for group D (hazard ratios 0·69 [95% CI 0·34-1·40] group B vs group A, 1·25 [0·68-2·30] group C vs group A, and 2·05 [1·07-3·93] group D vs group B). Disease-free survival results were consistent with progression-free survival results and were 81% (95% CI 72-88) for group A, 84% (72-91) for group B, 80% (70-86) for group C, and 75% (64-83) for group D. Patients who achieved total pathological complete response (all groups combined) had longer progression-free survival compared with patients who did not (85% [76-91] in patients who achieved total pathological response vs 76% [71-81] in patients who did not achieve total pathological response; hazard ratio 0·54 [95% CI 0·29-1·00]). There were no new or long-term safety concerns and tolerability was similar across groups (neoadjuvant and adjuvant treatment periods combined). The most common grade 3 or worse adverse events were neutropenia (group A: 71 [66%] of 107 patients; group B: 59 [55%] of 107; group C: 40 [37%] of 108; group D: 60 [64%] of 94), febrile neutropenia (group A: 10 [9%]; group B: 12 [11%]; group C: 5 [5%]; group D: 15 [16%]), and leucopenia (group A: 13 [12%]; group B: 6 [6%]; group C: 4 [4%]; group D: 8 [9%]). The number of patients with one or more serious adverse event was similar across groups (19-22 serious adverse events per group in 18-22% of patients). INTERPRETATION: Progression-free survival and disease-free survival at 5-year follow-up show large and overlapping CIs, but support the primary endpoint (pathological complete response) and suggest that neoadjuvant pertuzumab is beneficial when combined with trastuzumab and docetaxel. Additionally, they suggest that total pathological complete response could be an early indicator of long-term outcome in early-stage HER2-positive breast cancer. FUNDING: F Hoffmann-La Roche.

Uma nova plataforma terapêutica para o câncer de mama: a evoluçãodo tratamento sistêmico neoadjuvante / A new therapeutic platform for treating breast cancer: the evolution of systemic neoadjuvant treatment

O tratamento neoadjuvante do câncer de mama consiste no uso de diferentes modalidades terapêuticas prévias à remoção cirúrgica da doença. Tem sido aceito como uma opção para pacientes com doença não metastática, porque pode converter tumores inoperáveis em operáveis e aumentar os índices de cirurgias conservadoras, com os mesmos resultados oncológicos em longo prazo do tratamento adjuvante. A estratégia neoadjuvante está sendo cada vez mais aceita como uma plataforma de pesquisa, em que os efeitos biológicos dos agentes antitumorais podem ser avaliados, os biomarcadores preditivos e os prognósticos podem ser identificados e o desenvolvimento de terapias-alvo pode ser acelerado. Desfechos alternativos que podem predizer resultado clínico em longo prazo e estão disponíveis precocemente, como a resposta patológica completa, oferecem oportunidades únicas para a imediata avaliação dos agentes antitumorais. Além disso, esforços para determinar o perfil molecular da doença residual pós-tratamento neoadjuvante podem levar a uma terapia personalizada do câncer de mama em pacientes com doença de alto risco em estágio inicial.

Neoadjuvant therapy of breast cancer is related to the use of different treatment modalities prior to surgical removal of the disease. It has been accepted as an option for patients with nonmetastatic disease, because it renders inoperable tumors operable and increases the rates of breast-conserving surgery, while achieving the same long-term clinical outcomes as the adjuvant setting. The neoadjuvant strategy is being increasingly accepted as a research platform, where the biologic effects of anticancer agents can be evaluated, prognostic and predictive biomarkers can be identified, and the development of targeted agents can be accelerated. Surrogate endpoints that can predict long-term clinical outcome and are evaluable early on, such as the pathologic complete response, offer unique opportunities for prompt assessment of anticancer agents. Moreover, efforts for molecular profiling of the post-neoadjuvant residual disease may lead to a personalized therapy for breast cancer patients with early-stage high-risk disease.

Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial.

BACKGROUND: Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. METHODS: In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m(2), escalating, if tolerated, to 100 mg/m(2) every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. FINDINGS: Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). INTERPRETATION: Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. FUNDING: F Hoffmann-La Roche.

Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer.

BACKGROUND: The anti-human epidermal growth factor receptor 2 (HER2) humanized monoclonal antibody trastuzumab improves the outcome in patients with HER2-positive metastatic breast cancer. However, most cases of advanced disease eventually progress. Pertuzumab, an anti-HER2 humanized monoclonal antibody that inhibits receptor dimerization, has a mechanism of action that is complementary to that of trastuzumab, and combination therapy with the two antibodies has shown promising activity and an acceptable safety profile in phase 2 studies involving patients with HER2-positive breast cancer. METHODS: We randomly assigned 808 patients with HER2-positive metastatic breast cancer to receive placebo plus trastuzumab plus docetaxel (control group) or pertuzumab plus trastuzumab plus docetaxel (pertuzumab group) as first-line treatment until the time of disease progression or the development of toxic effects that could not be effectively managed. The primary end point was independently assessed progression-free survival. Secondary end points included overall survival, progression-free survival as assessed by the investigator, the objective response rate, and safety. RESULTS: The median progression-free survival was 12.4 months in the control group, as compared with 18.5 months in the pertuzumab group (hazard ratio for progression or death, 0.62; 95% confidence interval, 0.51 to 0.75; P<0.001). The interim analysis of overall survival showed a strong trend in favor of pertuzumab plus trastuzumab plus docetaxel. The safety profile was generally similar in the two groups, with no increase in left ventricular systolic dysfunction; the rates of febrile neutropenia and diarrhea of grade 3 or above were higher in the pertuzumab group than in the control group. CONCLUSIONS: The combination of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo plus trastuzumab plus docetaxel, when used as first-line treatment for HER2-positive metastatic breast cancer, significantly prolonged progression-free survival, with no increase in cardiac toxic effects. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT00567190.).

Recidiva locorregional: importância da margem cirúrgica livre e dos subtipos moleculares do câncer de mama / Locoregional recurrence: the importance of free surgical margins and molecular subtypes of breast cancer

Índices de sobrevida equivalentes observados entre a cirurgia conservadora de mama e a mastectomia tornaram a primeira o tratamento padrão para muitas mulheres com câncer de mama, sendo preferível à mastectomia pelo benefício estético da preservação da mama. A cirurgia conservadora complementada pela radioterapia apresenta altos níveis de controle local da doença. O tamanho da margem tumoral adequado é assunto de interesse em razão da tendência de menor radicalidade cirúrgica, com manutenção de segurança oncológica. É importante, também, em relação à mastectomia, devido à possibilidade de preservação da pele e do complexo aréolo-mandibular, o que pode significar menos margens livres. Diversos estudos sugerem que uma excisão adequada, com margens livres de tumor, é necessária para obter um controle local ótimo. Entretanto, o próprio conceito do que seja margem livre é controverso, além de ser altamente questionável se o aumento do tamanho dessa margem resulta na diminuição do risco de recidiva local. Ressecções mais amplas são associadas a menor recorrência local, mas os dados disponíveis sugerem que o aumento de milímetros da margem livre não resulta em uma diminuição proporcional no risco de recidiva. Atualmente, considera-se adequado o tratamento cirúrgico que obtenha margem cirúrgica negativa, independentemente de seu tamanho. Diversos fatores patológicos, clínicos e de diferentes tratamentos também têm sido associados a um aumento do risco de recorrência local, entre eles a dose de radioterapia, definição do que é margem positiva e negativa, a extensão do envolvimento da margem, a presença de componente intraductal extenso, o tempo de acompanhamento dos pacientes, a influência do tratamento sistêmico adjuvante e, com grande interesse atualmente, os subtipos moleculares genéticos do câncer de mama - luminal A, luminal B, Her-2 positivo e triplo-negativo. A identificação de fatores de risco para recorrência local entre pacientes com margens negativas é....

Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial.

BACKGROUND: Treatment with adjuvant trastuzumab for 1 year improves disease-free survival and overall survival in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer. We aimed to assess disease-free survival and overall survival after a median follow-up of 4 years for patients enrolled on the Herceptin Adjuvant (HERA) trial. METHODS: The HERA trial is an international, multicentre, randomised, open-label, phase 3 trial comparing treatment with trastuzumab for 1 and 2 years with observation after standard neoadjuvant, adjuvant chemotherapy, or both in patients with HER2-positive early breast cancer. The primary endpoint was disease-free survival. After a positive first interim analysis at a median follow-up of 1 year for the comparison of treatment with trastuzumab for 1 year with observation, event-free patients in the observation group were allowed to cross over to receive trastuzumab. We report trial outcomes for the 1-year trastuzumab and observation groups at a median follow-up of 48·4 months (IQR 42·0-56·5) and assess the effect of the extensive crossover to trastuzumab. Our analysis was by intention-to-treat. The HERA trial is registered with the European Clinical Trials Database, number 2005-002385-11. FINDINGS: The HERA trial population comprised 1698 patients randomly assigned to the observation group and 1703 to the 1-year trastuzumab group. Intention-to-treat analysis of disease-free survival showed a significant benefit in favour of patients in the 1-year trastuzumab group (4-year disease-free survival 78·6%) compared with the observation group (4-year disease-free survival 72·2%; hazard ratio [HR] 0·76; 95% CI 0·66-0·87; p<0·0001). Intention-to-treat analysis of overall survival showed no significant difference in the risk of death (4-year overall survival 89·3%vs 87·7%, respectively; HR 0·85; 95% CI 0·70-1·04; p=0·11). Overall, 885 patients (52%) of the 1698 patients in the observation group crossed over to receive trastuzumab, and began treatment at median 22·8 months (range 4·5-52·7) from randomisation. In a non-randomised comparison, patients in the selective-crossover cohort had fewer disease-free survival events than patients remaining in the observation group (adjusted HR 0·68; 95% CI 0·51-0·90; p=0·0077). Higher incidences of grade 3-4 and fatal adverse events were noted on 1-year trastuzumab than in the observation group. The most common grade 3 or 4 adverse events, each in less than 1% of patients, were congestive cardiac failure, hypertension, arthralgia, back pain, central-line infection, hot flush, headache, and diarrhoea. INTERPRETATION: Treatment with adjuvant trastuzumab for 1 year after chemotherapy is associated with significant clinical benefit at 4-year median follow-up. The substantial selective crossover of patients in the observation group to trastuzumab was associated with improved outcomes for this cohort. FUNDING: F Hoffmann-La Roche, Michelangelo Foundation.

The effect of neoadjuvant chemotherapy on hormone receptor status, HER2/neu and prolactin in breast cancer.

AIMS AND BACKGROUND: Histological and immunohistochemical findings may vary in cases of breast cancer. Possible changes in tumor markers between biopsies performed before and after neoadjuvant chemotherapy are controversial and pose a challenge when a clinical decision is needed. The objectives of the present study were: (i) to compare the immunohistochemical expression of estrogen, progesterone and prolactin receptors and HER-2/neu in breast cancer before and after neoadjuvant chemotherapy; and (ii) to correlate the expression of these tumor markers with partial tumor response to neoadjuvant chemotherapy. METHODS AND STUDY DESIGN: Immunohistochemical staining for breast tumor markers was performed in 90 cases of breast cancer. Statistical analysis was carried out using Fisher's exact test, McNemar's test, Spearman's correlation and the Kappa index with linear weighting (k). RESULTS: Agreement between markers before and after neoadjuvant chemotherapy was fair to moderate (k = 0.37-0.51). The immunohistochemical expression of HER-2/neu and prolactin receptors showed a significant, albeit weak correlation before and after neoadjuvant chemotherapy (HER-2/neu, rho = 0.34; P = 0.0009; k = 0.35 [95% CI, 0.19-0.51]). Prolactin status changed in 28/90 cases (P = 0.001; McNemar's test), whereas no changes were found in estrogen or progesterone receptors. No association was found between tumor marker expression and tumor response. CONCLUSIONS: It seems prudent to reevaluate immunohistochemical markers such as HER-2/neu after neoadjuvant chemotherapy, since the findings will guide the strategy for implementation of adjuvant systemic treatment. No correlation was found between the tumor markers analyzed in the present study and partial tumor response to neoadjuvant chemotherapy.

Neoadjuvância sistêmica / Systemic neoadjuvance

A neoadjuvância sistêmica é a aplicação de terapia antineoplásica como primeiro tratamento em pacientes sem evidência de metástases e com intenção plena de controle da doença. É tambem chamada de primária, pré-operatória, perioperatória, basal ou de indução. Cada vez mais pacientes estão sendo tratados com quimioterapia (QT), hormonioterapia (HT) e imunoterapia (IT) antes do tratamento cirúrgico e em estágios mais precoces da doença. A chamada Estratégia de Tratamento Multidisciplinar consiste no tratamento sistêmico primário ou adjuvante associada ao tratamento locorregional, através da cirurgia e radioterapia (RT). O tratamento do câncer de mama, em especial o localmente avançado, é baseado nesse planejamento, e a QT com antracíclicos e taxanos ocupa o papel central. Entretanto, a utilização de dados histológicos e marcadores imuno-histoquimicos relacionados a biologia molecular e a expressão genética tumoral conduzem a individualização do tratamento, que consiste na obtenção do máximo de informações disponíveis sobre o tumor para oferecer o tratamento mais adequado para cada paciente. Em relação à IT, ou terapia alvo, muitos ensaios clínicos tem mostrado bons índices de resposta em pacientes HER 2 positivo com esquemas quimioterapicos contendo Trastuzumab. Outras drogas anti-HER 2 também tem sido testadas. A HT neoadjuvante como tratamento único pode ser uma opção adequada em pós-menopáusicas com receptores hormonais (RH) positivo, e os inibidores da aromatase (IA) são a opção de escolha. As principais vantagens do tratamento sistêmico primario consistem na melhora das condições cirúrgicas, uma melhor avaliação do potencial de resposta tumoral a terapia sistêmica e uma possivel melhora da sobrevida.

Systemic neoadjuvant therapy is the first line treatment in patients without evidence of metastasis and with a good control of the disease. It is also named as primary, preoperative, perioperative, basal or induction. Chemotherapy (CT), hormone therapy (HT) and immunotherapy (IT) have been increasingly used before the surgical treatment and in early stages of the disease. The so-called Multidisciplinary Treatment Strategy consists in a primary or adjuvant systemic treatment associated to locoregional treatment through surgery and radiotherapy (RT). Breast cancer treatment, specially the locally advanced, is mainly based on this planning, and CT with anthracyclics and taxanes has the central role. Nevertheless, histologic data and tumor markers, related to molecular biology and tumor genetic expression, have been used to individualize the treatment for breast cancer, by obtaining the maximum available information about the tumor in order to offer the proper treatment for each patient. There are many clinical trials with IT, or target therapy, demonstrating good response rates in patients HER 2positive who used chemotherapy with Trastuzumab. Other anti-HER 2 drugs have been tested. The neoadjuvant HT as single agent can be used as an option in post-menopausal women with positive hormone receptor, and aromatase inhibitors are the drug of choice. The main advantages of primary systemic treatment are better surgical conditions, better evaluation of the potential of the tumor to respond to systemic therapy and, consequently, a better survival rate.

Are the pure in situ breast ductal carcinomas and those associated with invasive carcinoma the same?

It has been reported that pure ductal carcinoma in situ of the breast has morphologic differences from the in situ component of the invasive ductal carcinoma, as well estrogen and progesterone receptors expression according to their cytokeratin expression. However, there is no data comparing other tumor markers without using the cytokeratin expression. The objective of this study is to compare the expression of estrogen receptor (ER) and progesterone receptor (PR), HER-2/neu, p53, and Ki67 between pure ductal in situ carcinoma (pDCIS) and the in situ component of the invasive ductal carcinoma (DCIS + IDC) of the breast, and the in situ component to the invasive component of the same tumor (DCIS + IDC). The immunohistochemistry expression of the tumor markers was performed in 45 cases of pDCIS and DCIS + IDC, yielding a total of 90 cases. Statistical analysis was carried out using Fisher exact test, having a P < 0.05, and Kappa index (kappa) to assess intratumoral concordance. In DCIS + IDC, the in situ and invasive components did not show a significant difference and Kappa index (kappa) was high (0.7-1) for positive and negative expression. ER and PR were significantly different between the pDCIS and DCIS + IDC (ER: 86.7 vs. 66.7% P = 0.04; PR: 80% vs. 55.6% P = 0.02). These findings suggest that in situ component of DCIS + IDC and pDCIS are distinct conditions.